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Recent Articles in BMC Cancer

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Margolin S, Eiberg H, Lindblom A, Bisgaard ML
CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer.
BMC Cancer. 2007;7163.
BACKGROUND: A truncating variant, 1100delC, in check point-kinase CHEK2, has been identified as a risk factor for familial and sporadic breast cancer. The prevalence in healthy non-breast cancer cases is low and varies between populations. METHODS: We analyzed the prevalence of CHEK2 1100delC in 763 breast cancer patients with a defined family history and 760 controls from the Stockholm region. The breast cancer patients originated from; a population-based cohort (n = 452) and from a familial cancer clinic (n = 311), the detailed family history was known in both groups. RESULTS: The variant was found in 2.9% of the familial cases from the population-based cohort and in 1.9% from the familial cancer clinic. In total 2.2% of the patients with a family history of breast cancer carried the variant compared to 0.7% of the controls (p = 0.03). There was no increased prevalence in sporadic patients (0.3%). The variant was most frequent in young familial patients (5.1% of cases <or=45 years, p = 0.003). The mean age at diagnosis of variant carriers was 12 years lower than in non-carriers (p = 0.001). CONCLUSION: In conclusion, CHEK2 1100delC exists in the Swedish population. The prevalence is increased in familial breast cancer and the variant seems to influence age at onset. [Abstract/Link to Full Text]

López-Cima MF, González-Arriaga P, García-Castro L, Pascual T, Marrón MG, Puente XS, Tardón A
Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain.
BMC Cancer. 2007;7162.
BACKGROUND: Polymorphisms in DNA repair genes have been associated to repair DNA lesions, and might contribute to the individual susceptibility to develop different types of cancer. Nucleotide excision repair (NER), base excision repair (BER), and double-strand break repair (DSBR) are the main DNA repair pathways. We investigated the relationship between polymorphisms in two NER genes, XPC (poly (AT) insertion/deletion: PAT-/+) and XPD (Asp312Asn and Lys751Gln), the BER gene XRCC1 (Arg399Gln), and the DSBR gene XRCC3 (Thr241Met) and the risk of developing lung cancer. METHODS: A hospital-based case-control study was designed with 516 lung cancer patients and 533 control subjects, matched on ethnicity, age, and gender. Genotypes were determined by PCR-RFLP and the results were analysed using multivariate unconditional logistic regression, adjusting for age, gender and pack-years. RESULTS: Borderline association was found for XPC and XPD NER genes polymorphisms, while no association was observed for polymorphisms in BER and DSBR genes. XPC PAT+/+ genotype was associated with no statistically significant increased risk among ever smokers (OR = 1.40; 95%CI = 0.94-2.08), squamous cell carcinoma (OR = 1.44; 95%CI = 0.85-2.44), and adenocarcinoma (OR = 1.72; 95%CI = 0.97-3.04). XPD variant genotypes (312Asn/Asn and 751Gln/Gln) presented a not statistically significant risk of developing lung cancer (OR = 1.52; 95%CI = 0.91-2.51; OR = 1.38; 95%CI = 0.85-2.25, respectively), especially among ever smokers (OR = 1.58; 95%CI = 0.96-2.60), heavy smokers (OR = 2.07; 95%CI = 0.74-5.75), and adenocarcinoma (OR = 1.88; 95%CI = 0.97-3.63). On the other hand, individuals homozygous for the XRCC1 399Gln allele presented no risk of developing lung cancer (OR = 0.87; 95%CI = 0.57-1.31) except for individuals carriers of 399Gln/Gln genotype and without family history of cancer (OR = 0.57; 95%CI = 0.33-0.98) and no association was found between XRCC3 Thr241Met polymorphism and lung cancer risk (OR = 0.92; 95%CI = 0.56-1.50), except for the 241Met/Met genotype and squamous cell carcinoma risk (OR = 0.47; 95%CI = 0.23-1.00). CONCLUSION: In conclusion, we analysed the association between XPC, XPD, XRCC1, and XRCC3 polymorphisms and the individual susceptibility to develop lung cancer in the Spanish population, specifically with a highly tobacco exposed population. We attempt to contribute to the discovery of which biomarkers of DNA repair capacity are useful for screening this high-risk population for primary preventing and early detection of lung cancer. [Abstract/Link to Full Text]

Esteva M, Ramos M, Cabeza E, Llobera J, Ruiz A, Pita S, Segura JM, Cortes JM, Gonzalez-Lujan L
Factors influencing delay in the diagnosis of colorectal cancer: a study protocol.
BMC Cancer. 2007;786.
BACKGROUND: Colorectal cancer (CRC) is the second most frequent tumor in developed countries. Since survival from CRC depends mostly on disease stage at the time of diagnosis, individuals with symptoms or signs suspicious of CRC should be examined without delay. Many factors, however, intervene between symptom onset and diagnosis. This study was designed to: 1) Describe the diagnostic process of CRC from the onset of first symptoms to diagnosis and treatment. 2) Establish the time interval from initial symptoms to diagnosis and treatment, globally and considering patient's and doctors' delay, with the latter due to family physician and/or hospital services. 3) Identify the factors related to defined types of delay. 4) Assess the concordance between information included in primary health care and hospital clinical records regarding onset of first symptoms. METHODS: Descriptive study, coordinated, with 5 participant groups of 5 different Spanish regions (Balearic Islands, Galicia, Catalunya, Aragon and Valencia Health Districts), with a total of 8 acute public hospitals and 140 primary care centers. Incident cases of CRC during the study period, as identified from pathology services at the involved hospitals. A sample size of 896 subjects has been estimated, 150 subjects for each participant group. Information will be collected through patient interviews and primary health care and hospital clinical records. Patient variables will include sociodemographic variables, family history of cancer, symptom perception, and confidence in the family physician; tumor variables will include tumor site, histological type, grade and stage; symptom variables will include date of onset, type and number of symptoms; health system variables will include number of patient contacts with family physician, type and content of the referral, hospital services attending the patient, diagnostic modalities and results; and delay intervals, including global delays and delays attributed to the patient, family physician and hospital. DISCUSSION: To obtain a nonrestricted sample of patients with CRC we have minimized selection risk by identifying the patients from pathology services. A greater constraint may be associated with information sources based on clinical records. Due to inherent features of coordinated studies, it is important to standardize the collection of information. [Abstract/Link to Full Text]

Davoodpour P, Landström M, Welsh M
Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein.
BMC Cancer. 2007;7161.
BACKGROUND: Induction of apoptosis is one strategy for treatment of prostate cancer. The Shb adapter protein has been found to regulate apoptosis in various cell types and consequently human prostate cancer 3 (PC3) cells were transfected to obtain cells overexpressing Shb in order to increase our understanding of the mechanisms regulating PC3 cell apoptosis. METHODS: Human prostate cancer cells (PC3) were transfected with control vector or a vector containing the Shb cDNA. Clones overexpressing Shb were studied with respect to apoptosis (Dapi, M30) and c-Abl activation (Western blot for pY-245-Abl). The cells were exposed to the anti-tumor agent 2-methoxyestradiol (2-ME) and the p38 MAPK and c-Abl inhibitors SB203580 and STI-571, respectively, after which cell death was determined. In vivo tumor growth and tumor cell proliferation (Ki-67 staining) or apoptosis (active caspase 3 staining) were also determined in nude mice. RESULTS: PC3 cells overexpressing Shb exhibited increased rates of apoptosis in the presence of the anti-tumor agent 2-ME. The Shb cells displayed increased activity of the pro-apoptotic kinase c-Abl. Pre-treatment with p38 MAPK (SB203580) or c-Abl (STI-571) inhibitors completely blocked 2-ME-induced apoptosis, implicating these two pathways in the response. The PC3-Shb cells displayed reduced tumor growth in vivo, an effect occurring as a consequence of increased apoptosis and reduced DNA synthesis. CONCLUSION: It is concluded that Shb promotes 2-ME-induced PC3 cell apoptosis by increased pro-apoptotic signaling via the c-Abl pathway and that this causes reduced tumor growth in vivo. [Abstract/Link to Full Text]

Eccles D, Gerty S, Simmonds P, Hammond V, Ennis S, Altman DG
Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol.
BMC Cancer. 2007;7160.
BACKGROUND: Young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors. METHODS/DESIGN: The study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period. DISCUSSION: Power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforward. [Abstract/Link to Full Text]

Kamai T, Yanai Y, Arai K, Abe H, Yamanishi T, Kurimoto M, Yoshida K
Increased interferon alpha receptor 2 mRNA levels is associated with renal cell carcinoma metastasis.
BMC Cancer. 2007;7159.
BACKGROUND: Interferon-alpha (IFN-alpha) is one of the central agents in immunotherapy for renal cell carcinoma (RCC) and binds to the IFN-alpha receptor (IFNAR). We investigated the role of IFNAR in RCC. METHODS: We quantified IFNAR mRNA expression in paired tumor and non-tumor samples from the surgical specimens of 103 consecutive patients with RCC using a real-time reverse transcription polymerase chain reaction (RT-PCR), and IFNAR2 protein using Western blotting. RESULTS: The absolute level of IFNAR1 and IFNAR2 mRNAs in tumor and non-tumor tissues did not correlate with the malignant and metastatic profiles. The relative yields of the PCR product from the tumor tissue to that from the corresponding non-tumor tissue (T/N) for the expression of IFNAR mRNAs were calculated. While the T/N ratio of IFNAR1 did not correlate with any factor, a high T/N ratio of IFNAR2 correlated with poor differentiation (P < 0.05), local invasion (P < 0.001), and metastasis (P < 0.0001). By multivariate analysis, a high T/N ratio of IFNAR2 predicted a shortened overall survival in all cases (P < 0.05) and a shorter disease-free survival in those without metastasis (M0; 68 cases, P < 0.05). Impressively, patients with a poorer response to IFN-alpha treatment had a higher IFNAR2 T/N ratio than those who had a good response (P < 0.05). IFNAR2c protein expression was higher in the primary tumors in patients with metastases (M1; 35 cases) compared to those without ( P < 0.0001). CONCLUSION: IFNAR2 is associated with the progression of RCC. [Abstract/Link to Full Text]

García-Tuńón I, Ricote M, Ruiz A A, Fraile B, Paniagua R, Royuela M
Influence of IFN-gamma and its receptors in human breast cancer.
BMC Cancer. 2007;7158.
BACKGROUND: Interferons are a group of proteins that trigger multiple responses including prevention of viral replication, inhibition of cell growth, and modulation of cell differentiation. In different mammary carcinoma cell lines IFNgamma induces growth arrest at mid-G1. At the present there are no in vivo studies in human breast. The aim of this study was to investigate the expression patterns of IFNgamma and its two receptors (IFNgamma-Ralpha and IFNgamma-Rbeta) by Western blot and immunohistochemistry, in order to elucidate its role in the different types of human breast cancer (in situ and infiltrative). METHODS: Immunohistochemical and semiquantitative study of IFNgamma, its receptors types (IFNgamma-Ralpha and IFNgamma-Rbeta), cell proliferation (proliferating cell nuclear antigen, also named PCNA), and apoptosis (TUNEL method) was carried between the three breast groups (fibrocystic lesions, in situ tumors and infiltrating tumors). RESULTS: In the three groups of patients, IFNgamma and IFNgamma-Ralpha immunoreactions appeared in the cytoplasm while IFNgamma-Rbeta also was found in the nucleus. The optical density to IFNgamma was higher in in situ carcinoma than in benign and infiltrating tumors. When we observed IFNgamma-Ralpha, the optical density was lower in infiltrating carcinoma than in benign and in situ tumors (the higher density). To IFNgamma-Rbeta, the optical density was similar in the three group samples. In tumor samples PCNA and TUNEL index was significantly higher; than in benign diseases. PCNA index increased with the malignance. No significant differences were found between cancer types to TUNEL. IFNgamma could be a potential therapeutic tool in breast cancer. However, tumor cells are able to escape from the control of this cytokine in the early tumor stages; this is probably due to a decreased expression of IFNgamma, or also to an alteration of either its receptors or some transduction elements. CONCLUSION: We conclude that the decrease in the % positive samples that expressed IFNgamma and IFNgamma-Ralpha together with the nuclear localization of IFNgamma-Rbeta, could be a tumoral cell response, although perhaps insufficient to inhibit the uncontrolled cell proliferation. Perhaps, IFNgamma might be unable to activate p21 to stop the cell cycle, suggesting a possible participation in breast cancer development. [Abstract/Link to Full Text]

Abdul-Hussein A, Morris PA, Markova T
An unusual presentation of adenoid cystic carcinoma of the minor salivary glands with cranial nerve palsy: a case study.
BMC Cancer. 2007;7157.
BACKGROUND: Adenoid Cystic Carcinoma (ACC) is a rare tumor entity and comprises about 1% of all malignant tumor of the oral and maxillofacial region. It is slow growing but a highly invasive cancer with a high recurrence rate. Intracranial ACC is even more infrequent and could be primary or secondary occurring either by direct invasion, hematogenous spread, or perineural spread. We report the first case of the 5th and 6th nerve palsy due to cavernous sinus invasion by adenoid cystic carcinoma. CASE PRESENTATION: A 49-year-old African American female presented to the emergency room complaining of severe right-sided headache, photophobia, dizziness and nausea, with diplopia. The patient had a 14 year history migraine headaches, hypertension, and mild intermittent asthma. Physical examination revealed right lateral rectus muscle palsy with esotropia. There was numbness in all three divisions of the right trigeminal nerve. Motor and sensory examination of extremities was normal. An MRI of the brain/brain stem was obtained which showed a large mass in the clivus extending to involve the nasopharynx, pterygoid plate, sphenoid and right cavernous sinuses. Biopsy showed an ACC tumor with a cribriform pattern of the minor salivary glands. The patient underwent total gross surgical resection and radiation therapy. CONCLUSION: This is a case of ACC of the minor salivary glands with intracranial invasion. The patient had long history of headaches which changed in character during the past year, and symptoms of acute 5th and 6th cranial nerve involvement. Our unique case demonstrates direct invasion of cavernous sinus and could explain the 5th and 6th cranial nerve involvement as histopathology revealed no perineural invasion. [Abstract/Link to Full Text]

Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A
TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study.
BMC Cancer. 2007;7156.
BACKGROUND: Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited. METHODS: Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed. RESULTS: High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival. CONCLUSION: Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms. [Abstract/Link to Full Text]

Melichar B, Hyspler R, Dragounová E, Dvorák J, Kalábová H, Tichá A
Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum.
BMC Cancer. 2007;7155.
BACKGROUND: Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum. METHODS: Intestinal permeability was assessed in 36 breast and ovarian cancer patients treated with paclitaxel/platinum combination by measuring, using capillary gas chromatography, urinary sucrose, lactulose, xylose and mannitol after oral challenge. The significance of differences during the therapy compared to pre-treatment values was studied by Wilcoxon paired test. The differences between groups of patient were studied by Mann-Whitney U test. Fisher exact test was used to compare the frequency in different subgroups. RESULTS: After administration of the first dose, a significant (p < 0.05) decrease in xylose absorption and increased lactulose/mannitol, sucrose/mannitol, lactulose/xylose and sucrose/xylose ratios were observed, but these parameters returned subsequently to pre-treatment levels. Patients who experienced serious (grade 3 or 4) toxicity had at baseline significantly lower percentages of xylose, mannitol and sucrose, and higher lactulose/mannitol ratio. Nine of 13 (69%) patients with baseline lactulose/mannitol ratio 0.070 or above experienced serious toxicity compared to 4 out of 23 patients (17%) with the ratio below 0.070 (p = 0.002). Post-treatment lactulose, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were significantly increased in patients with serious toxicity. CONCLUSION: A transient significant increase in lactulose/monosaccharide and sucrose/monosaccharide ratios was observed in ovarian and breast cancer patients treated with paclitaxel and platinum. Increased lactulose absorption, lactulose/mannitol, sucrose/mannitol and lactulose/xylose ratios were evident in patients with grade 3 or 4 toxicity, and increased baseline lactulose/mannitol ratio predicted serious toxicity. [Abstract/Link to Full Text]

Spence RR, Heesch KC, Eakin EG, Brown WJ
Randomised controlled trial of a supervised exercise rehabilitation program for colorectal cancer survivors immediately after chemotherapy: study protocol.
BMC Cancer. 2007;7154.
BACKGROUND: Colorectal cancer (CRC) diagnosis and the ensuing treatments can have a substantial impact on the physical and psychological health of survivors. As the number of CRC survivors increases, so too does the need to develop viable rehabilitation programs to help these survivors return to good health as quickly as possible. Exercise has the potential to address many of the adverse effects of CRC treatment; however, to date, the role of exercise in the rehabilitation of cancer patients immediately after the completion of treatment has received limited research attention. This paper presents the design of a randomised controlled trial which will evaluate the feasibility and efficacy of a 12-week supervised aerobic exercise program (ImPACT Program) on the physiological and psychological markers of rehabilitation, in addition to biomarkers of standard haematological outcomes and the IGF axis. METHODS/DESIGN: Forty CRC patients will be recruited through oncology clinics and randomised to an exercise group or a usual care control group. Baseline assessment will take place within 4 weeks of the patient completing adjuvant chemotherapy treatment. The exercise program for patients in the intervention group will commence a week after the baseline assessment. The program consists of three supervised moderate-intensity aerobic exercise sessions per week for 12 weeks. All participants will have assessments at baseline (0 wks), mid-intervention (6 wks), post-intervention (12 wks) and at a 6-week follow-up (18 wks). Outcome measures include cardio-respiratory fitness, biomarkers associated with health and survival, and indices of fatigue and quality of life. Process measures are participants' acceptability of, adherence to, and compliance with the exercise program, in addition to the safety of the program. DISCUSSION: The results of this study will provide valuable insight into the role of supervised exercise in improving life after CRC. Additionally, process analyses will inform the feasibility of implementing the program in a population of CRC patients immediately after completing chemotherapy. TRIAL REGISTRATION: ACTRN012606000395538. [Abstract/Link to Full Text]

Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV
Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials.
BMC Cancer. 2007;7153.
BACKGROUND: Breast cancer is the most common cancer in women in the U.S. and Western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastático HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. Here, we performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting. Survival, recurrence, brain metastases, cardiotoxicity and directions for future research are discussed. METHODS: A meta-analysis of randomized controlled trials (RCT) was performed comparing adjuvant trastuzumab treatment for HER2-positive early breast cancer (EBC) to observation. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, and abstracts published in the annual proceedings were systematically searched for evidence. Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria. RESULTS: Pooled results from that five randomized trials of adjuvant Trastuzumab showed a significant reduction of mortality (p < 0.00001), recurrence (p < 0.00001), metastases rates (p < 0.00001) and second tumors other than breast cancer (p = 0.007) as compared to no adjuvant Trastuzumab patients. There were more grade III or IV cardiac toxicity after trastuzumab (203/4555 = 4.5%) versus no trastuzumab (86/4562 = 1.8%). The likelihood of cardiac toxicity was 2.45-fold higher (95% CI 1.89 - 3.16) in trastuzumab arms, however that result was associated with heterogeneity. The likelihood of brain metastases was 1.82-fold higher (95% CI 1.16 - 2.85) in patients who received trastuzumab. CONCLUSION: The results from this meta-analysis are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk: benefit ratio demonstrated in these studies. Adequate assessment of HER-2/neu status is critical, and careful cardiac monitoring is warranted because of cardiac toxicity. Clinical trials should be designed to answer unsolved questions. [Abstract/Link to Full Text]

Friedenson B
The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers.
BMC Cancer. 2007;7152.
BACKGROUND: The present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias. METHODS: Literature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products. RESULTS: Deleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers. CONCLUSION: An important function of the BRCA pathway is to prevent a subgroup of human leukemias and lymphomas that may involve non-random, characteristic gene rearrangements. Here, the genetic defect in BRCA pathway deficiencies is a chromosomal misrepair syndrome that may facilitate this subgroup of somatic cancers. Inactivation of a single gene within the pathway can increase risks for multiple cancers and inactivation of a different gene in the same pathway may have similar effects. The results presented here may have clinical implications for surveillance and therapy. [Abstract/Link to Full Text]

Baker SG, Kramer BS
Paradoxes in carcinogenesis: new opportunities for research directions.
BMC Cancer. 2007;7151.
BACKGROUND: The prevailing paradigm in cancer research is the somatic mutation theory that posits that cancer begins with a single mutation in a somatic cell followed by successive mutations. Much cancer research involves refining the somatic mutation theory with an ever increasing catalog of genetic changes. The problem is that such research may miss paradoxical aspects of carcinogenesis for which there is no likely explanation under the somatic mutation theory. These paradoxical aspects offer opportunities for new research directions that should not be ignored. DISCUSSION: Various paradoxes related to the somatic mutation theory of carcinogenesis are discussed: (1) the presence of large numbers of spatially distinct precancerous lesions at the onset of promotion, (2) the large number of genetic instabilities found in hyperplastic polyps not considered cancer, (3) spontaneous regression, (4) higher incidence of cancer in patients with xeroderma pigmentosa but not in patients with other comparable defects in DNA repair, (5) lower incidence of many cancers except leukemia and testicular cancer in patients with Down's syndrome, (6) cancer developing after normal tissue is transplanted to other parts of the body or next to stroma previously exposed to carcinogens, (7) the lack of tumors when epithelial cells exposed to a carcinogen were transplanted next to normal stroma, (8) the development of cancers when Millipore filters of various pore sizes were was inserted under the skin of rats, but only if the holes were sufficiently small. For the latter paradox, a microarray experiment is proposed to try to better understand the phenomena. SUMMARY: The famous physicist Niels Bohr said "How wonderful that we have met with a paradox. Now we have some hope of making progress." The same viewpoint should apply to cancer research. It is easy to ignore this piece of wisdom about the means to advance knowledge, but we do so at our peril. [Abstract/Link to Full Text]

Makris D, Scherpereel A, Copin MC, Colin G, Brun L, Lafitte JJ, Marquette CH
Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer.
BMC Cancer. 2007;7150.
BACKGROUND: Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor which is used for non-small-cell lung cancer treatment. Despite that erlotinib is considered to have a favorable safety profile, adverse events such as interstitial lung disease (ILD) were reported in pivotal studies. The authors report the first histologically confirmed case of fatal ILD associated with erlotinib therapy. CASE PRESENTATION: The medical record of a patient who developed fatal ILD after receiving erlotinib treatment was reviewed to identify the cause of death and other factors potentially contributive to this adverse outcome. A 55-year-old smoker with no evidence of pre-existing interstitial disease developed bilateral ILD and respiratory failure which could be explained only as a toxicity of erlotinib. He had a history of stage IV left upper lobe squamous-cell carcinoma for which he had received three successive regimens of chemotherapy (ifosfamide plus gemcitabine, docetaxel, mitomycin plus navelbine), followed five months later by erlotinib. At initiation of erlotinib treatment there were no radiological signs suggestive of ILD disease or apparent clinical signs of respiratory distress. While the patient completed two months with erlotinib therapy he developed bilateral interstitial infiltrates; despite discontinuation of erlotinib he was admitted with respiratory failure two weeks later. Diagnostic work up for other causes of pneumonitis including infectious diseases, congestive cardiac failure and pulmonary infraction was negative. Empiric treatment with oxygene, corticosteroids and later with cyclophosphamide was ineffective and the patient progressively deteriorated and died. The clinical and post-mortem examination findings are presented and the possible association relationship between erlotinib induced ILD and previous chemotherapy is discussed. CONCLUSION: Physicians should be alert to the fact that erlotinib related ILD, although infrequent, is potential fatal. The association between selective EGFR-inhibitors and ILD should be further investigated. [Abstract/Link to Full Text]

Zhang X, Zhang J, Wang L, Wei H, Tian Z
Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice.
BMC Cancer. 2007;7149.
BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is usually constitutively activated in a variety of malignancies. Therefore, STAT3 may be a promising target for treatment of tumor cells. To explore the possibility of a double-stranded decoy oligodeoxynucleotide (ODN) targeted blocking STAT3 over-activated tumor cells, we, here, evaluate the efficacy of STAT3 decoy ODN on human lung cancer cells in vitro and in vivo. METHODS: A STAT3 decoy ODN was transfected into A549 lung cancer cell line in vitro by using lipofectamine. The flow cytometry and fluorescent microscopy were used to detect the transfection efficiency and the sub-cellular localization of STAT3 decoy ODN in A549 cells. Cell proliferation was determined by counting cell numbers and [3H]-thymidine uptake. Cell apoptosis was examined with Annexin V and propidum iodide by flow cytometry. The expression levels of STAT3 target genes were identified by RT-PCR and immunoblot. For in vivo experiment, A549 lung carcinoma-nude mice xenograft was used as a model to examine the effect of the STAT3 decoy by intratumoral injection. At the end of treatment, TUNEL and immunohistochemistry were used to examine the apoptosis and the expression levels of bcl-xl and cyclin D1 in tumor tissues. RESULTS: STAT3 decoy ODN was effectively transfected into A549 lung cancer cells and mainly located in nucleus. STAT3-decoy ODN significantly induced apoptosis and reduced [3H]-thymidine incorporation of A549 cells as well as down-regulated STAT3-target genes in vitro. STAT3 decoy ODN also dramatically inhibited the lung tumor growth in xenografted nude mice and decreased gene expression of bcl-xl and cyclin D1. CONCLUSION: STAT3 decoy ODN significantly suppressed lung cancer cells in vitro and in vivo, indicating that STAT3 decoy ODN may be a potential therapeutic approach for treatment of lung cancer. [Abstract/Link to Full Text]

Morrissey C, Kostenuik PL, Brown LG, Vessella RL, Corey E
Host-derived RANKL is responsible for osteolysis in a C4-2 human prostate cancer xenograft model of experimental bone metastases.
BMC Cancer. 2007;7148.
BACKGROUND: C4-2 prostate cancer (CaP) cells grown in mouse tibiae cause a mixed osteoblastic/osteolytic response with increases in osteoclast numbers and bone resorption. Administration of osteoprotegerin (OPG) blocks these increases, indicating the critical role of RANKL in osteolysis in this model. The objective of our study was to investigate whether RANKL expressed by tumor cells (human origin) directly stimulates osteolysis associated with the growth of these cells in bone or whether the increased osteolysis is caused by RANKL expressed by the host environment cells (murine origin). The relative contribution of tumor-vs. host-derived RANKL has been difficult to establish, even with human xenografts, because murine and human RANKL are both capable of stimulating osteolysis in mice, and the RANKL inhibitors used to date (OPG and RANK-Fc) inhibit human and murine RANKL. METHODS: To address this question we used a neutralizing, antibody (huRANKL MAb), which specifically neutralizes the biological activities of human RANKL and thereby the contribution of C4-2 derived RANKL in this tibial injection model of experimental bone metastases. RESULTS: Administration of huRANKL MAb did not inhibit the osteolytic response of the bone to these cells, or affect the establishment and growth of the C4-2 tumors in this environment. CONCLUSION: In conclusion, our results suggest that in this model, murine RANKL and not the tumor-derived human RANKL is the mediator of the osteolytic reaction associated with C4-2 growth in bone. We hypothesize that C4-2 cells express other factor/s inducing host production of RANKL, thereby driving tumor-associated osteolysis. [Abstract/Link to Full Text]

Wang J, Cook G, Frank J, Dina R, Livni N, Lynn J, Fleming W, Seckl MJ
Case report: PET/CT, a cautionary tale.
BMC Cancer. 2007;7147.
BACKGROUND: The use of combined positron emission tomography/computerised tomography (PET/CT) scanners in oncology has been shown to improve the staging of tumours and the detection of relapses. However, mis-registration errors are increasingly recognised to be a common pitfall of PET/CT studies. CASE PRESENTATION: We report a patient with a germ cell tumour of the testis, who underwent a PET/CT scan to detect the site of relapse with a view to surgical removal. However, the PET/CT scan mislocalised the tumour site to be within the T2 vertebral body. A subsequent endoscopic ultrasound scan however showed the tumour to be anterior to the vertebral body, which was confirmed at surgery. CONCLUSION: In this report, we highlight the artefactual mislocalisation errors which may occur with PET/CT imaging, and the need to review and verify these scans. [Abstract/Link to Full Text]

Otis JS, Lees SJ, Williams JH
Functional overload attenuates plantaris atrophy in tumor-bearing rats.
BMC Cancer. 2007;7146.
BACKGROUND: Late stage cancer malignancies may result in severe skeletal muscle wasting, fatigue and reduced quality of life. Resistance training may attenuate these derangements in cancer patients, but how this hypertrophic response relates to normal muscle adaptations in healthy subjects is unknown. Here, we determined the effect of resistance training on muscle mass and myosin heavy chain (MHC) isoform composition in plantaris muscles from tumor-bearing (TB) rats. METHODS: Age- and gender-matched Buffalo rats were used for all studies (n = 6/group). Suspensions of Morris Hepatoma MH7777 cells or normal saline were injected subcutaneously into the dorsum. Six weeks after cell implantation, muscles from TB rats were harvested, weighed and processed for ATP-independent proteasome activity assays. Once tumor-induced atrophy had been established, subgroups of TB rats underwent unilateral, functional overload (FO). Healthy, sham-operated rats served as controls. After six weeks, the extent of plantaris hypertrophy was calculated and MHC isoform compositions were determined by gel electrophoresis. RESULTS: Six weeks of tumor growth reduced body mass and the relative masses of gastrocnemius, plantaris, tibialis anterior, extensor digitorum longus, and diaphragm muscles (p < or = 0.05). Percent reductions in body mass had a strong, negative correlation to final tumor size (r = -0.78). ATP-independent proteasome activity was increased in plantaris muscles from TB rats (p < or = 0.05). In healthy rats, functional overload (FO) increased plantaris mass ~44% compared to the contralateral control muscle, and increased the relative percentage of MHC type I and decreased the relative percentage of MHC type IIb compared to the sham-operated controls (p < or = 0.05). Importantly, plantaris mass was increased ~24% in TB-FO rats and adaptations to MHC isoform composition were consistent with normal, resistance-trained muscles. CONCLUSION: Despite significant skeletal muscle derangements due to cancer, muscle retains the capacity to respond normally to hypertrophic stimuli. Specifically, when challenged with functional overload, plantaris muscles from TB rats displayed greater relative mass, increased percentages of MHC type I and decreased percentages of MHC type IIb. Therefore, resistance training paradigms should provide relative morphological and functional benefits to cancer patients suffering from muscle wasting. [Abstract/Link to Full Text]

Zhang Y, Pu X, Shi M, Chen L, Song Y, Qian L, Yuan G, Zhang H, Yu M, Hu M, Shen B, Guo N
Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model.
BMC Cancer. 2007;7145.
BACKGROUND: c-Jun/AP-1 has been linked to invasive properties of aggressive breast cancer. Recently, it has been reported that overexpression of c-Jun in breast cancer cell line MCF-7 resulted in increased AP-1 activity, motility and invasiveness of the cells in vitro and tumor formation in nude mice. However, the role of c-Jun in metastasis of human breast cancer in vivo is currently unknown. METHODS: To further investigate the direct involvement of c-Jun in tumorigenesis and metastasis, in the present study, the effects of c-Jun overexpression were studied in both in vitro and in nude mice. RESULTS: Ectopic overexpression of c-Jun promoted the growth of MCF-7 cells and resulted in a significant increase in the percentage of cells in S phase and increased motility and invasiveness. Introduction of c-Jun gene alone into weakly invasive MCF-7 cells resulted in the transfected cells capable of metastasizing to the nude mouse liver following tail vein injection. CONCLUSION: The present study confirms that overexpression of c-Jun contributes to a more invasive phenotype in MCF-7 cells. It indicates an interesting relationship between c-Jun expression and increased property of adhesion, migration and in vivo liver metastasis of MCF-7/c-Jun cells. The results provide further evidence that c-Jun is involved in the metastasis of breast cancer. The finding also opens an opportunity for development of anti-c-Jun strategies in breast cancer therapy. [Abstract/Link to Full Text]

Mohanty SK, Piccoli AL, Devine LJ, Patel AA, William GC, Winters SB, Becich MJ, Parwani AV
Synoptic tool for reporting of hematological and lymphoid neoplasms based on World Health Organization classification and College of American Pathologists checklist.
BMC Cancer. 2007;7144.
BACKGROUND: Synoptic reporting, either as part of the pathology report or replacing some free text component incorporates standardized data elements in the form of checklists for pathology reporting. This ensures the pathologists make note of these findings in their reports, thereby improving the quality and uniformity of information in the pathology reports. METHODS: The purpose of this project is to develop the entire set of elements in the synoptic templates or "worksheets" for hematologic and lymphoid neoplasms using the World Health Organization (WHO) Classification and the College of American Pathologists (CAP) Cancer Checklists. The CAP checklists' content was supplemented with the most updated classification scheme (WHO classification), specimen details, staging as well as information on various ancillary techniques such as cytochemical studies, immunophenotyping, cytogenetics including Fluorescent In-situ Hybridization (FISH) studies and genotyping. We have used a digital synoptic reporting system as part of an existing laboratory information system (LIS), CoPathPlus, from Cerner DHT, Inc. The synoptic elements are presented as discrete data points, so that a data element such as tumor type is assigned from the synoptic value dictionary under the value of tumor type, allowing the user to search for just those cases that have that value point populated. RESULTS: These synoptic worksheets are implemented for use in our LIS. The data is stored as discrete data elements appear as an accession summary within the final pathology report. In addition, the synoptic data can be exported to research databases for linking pathological details on banked tissues. CONCLUSION: Synoptic reporting provides a structured method for entering the diagnostic as well as prognostic information for a particular pathology specimen or sample, thereby reducing transcription services and reducing specimen turnaround time. Furthermore, it provides accurate and consistent diagnostic information dictated by pathologists as a basis for appropriate therapeutic modalities. Using synoptic reports, consistent data elements with minimized typographical and transcription errors can be generated and placed in the LIS relational database, enabling quicker access to desired information and improved communication for appropriate cancer management. The templates will also eventually serve as a conduit for capturing and storing data in the virtual biorepository for translational research. Such uniformity of data lends itself to subsequent ease of data viewing and extraction, as demonstrated by rapid production of standardized, high-quality data from the hemopoietic and lymphoid neoplasm specimens. [Abstract/Link to Full Text]

Schilling D, Bayer C, Geurts-Moespot A, Sweep FC, Pruschy M, Mengele K, Sprague LD, Molls M
Induction of plasminogen activator inhibitor type-1 (PAI-1) by hypoxia and irradiation in human head and neck carcinoma cell lines.
BMC Cancer. 2007;7143.
BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) often contain highly radioresistant hypoxic regions, nonetheless, radiotherapy is a common treatment modality for these tumours. Reoxygenation during fractionated radiotherapy is desired to render these hypoxic tumour regions more radiosensitive. Hypoxia additionally leads to up-regulation of PAI-1, a protein involved in tumour progression and an established prognostic marker for poor outcome. However, the impact of reoxygenation and radiation on PAI-1 levels is not yet clear. Therefore, we investigated the kinetics of PAI-1 expression and secretion after hypoxia and reoxygenation, and determined the influence of ionizing radiation on PAI-1 levels in the two human SCCHN cell lines, BHY and FaDu. METHODS: HIF-1alpha immunoblot was used to visualize the degree of hypoxia in the two cell lines. Cellular PAI-1 expression was investigated by immunofluorescence microscopy. ELISA was used to quantify relative changes in PAI-1 expression (cell lysates) and secretion (cell culture supernatants) in response to various lengths (2-4 h) of hypoxic exposure (< 0.66% O2), reoxygenation (24 h, 20% O2), and radiation (0, 2, 5 and 10 Gy). RESULTS: HIF-1alpha expression was induced between 2 and 24 h of hypoxic exposure. Intracellular PAI-1 expression was significantly increased in BHY and FaDu cells as early as 4 h after hypoxic exposure. A significant induction in secreted PAI-1 was seen after 12 to 24 h (BHY) and 8 to 24 h (FaDu) hypoxia, as compared to the normoxic control. A 24 h reoxygenation period caused significantly less PAI-1 secretion than a 24 h hypoxia period in FaDu cells. Irradiation led to an up-regulation of PAI-1 expression and secretion in both, BHY and FaDu cells. CONCLUSION: Our data suggest that both, short-term (approximately 4-8 h) and long-term (approximately 20-24 h) hypoxic exposure could increase PAI-1 levels in SCCHN in vivo. Importantly, radiation itself could lead to PAI-1 up-regulation in head and neck tumours, whereas reoxygenation of hypoxic tumour cells during fractionated radiotherapy could counteract the increased PAI-1 levels. [Abstract/Link to Full Text]

Gross M, Higano C, Pantuck A, Castellanos O, Green E, Nguyen K, Agus DB
A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer.
BMC Cancer. 2007;7142.
BACKGROUND: Docetaxel is the standard first-line agent for the treatment of androgen-independent prostate cancer (AIPC). The combination of docetaxel with molecularly targeted therapies may offer the potential to increase the efficacy and decrease the toxicity of cytotoxic chemotherapy for prostate cancer. Previous studies demonstrate activation of the human epidermal growth factor receptor (EGFR) in prostate cancer. Erlotinib is a specific inhibitor of the tyrosine-kinase activity of EGFR. The goal of this study is to determine the anti-cancer activity docetaxel combined with erlotinib for the treatment of elderly subjects with AIPC. METHODS: This is a multi-institutional Phase II study in patients with histologically confirmed adenocarcinoma of the prostate and age > or = 65 years. Patients were requred to have progressive disease despite androgen-deprivation therapy as determined by: (1) measurable lesions on cross-sectional imaging; (2) metastatic disease by radionucleotide bone imaging; or (3) elevated prostate specific antigen (PSA). Treatment cycles consisted of docetaxel 60 mg/m2 IV on day 1 and erlotinib 150 mg PO days 1-21. Patients with responding or stable disease after 9 cycles were eligible to continue on erlotinib alone as maintenance therapy. RESULTS: Characteristics of 22 patients enrolled included: median age 73.5 years (range, 65-80); median Karnofsky Performance Status 90 (range 70-100); median hemoglobin 12.1 g/dl (range, 10.0-14.3); median PSA 218.3 ng/ml (range, 9-5754). A median of 6 treatment cycles were delivered per patient (range 1-17). No objective responses were observed in 8 patients with measurable lesions (0%, 95% CI 0-31%). Bone scan improvement and PSA decline was seen in 1 patient (5%, 95% CI 0.1-25%). Five of 22 patients experienced > or = 50 % decline in PSA (23%, 95% CI 8-45%). Hematologic toxicity included grade 3 neutropenia in 9 patients and neutropenic fever in 2 patients. Common non-hematologic toxicities (> or = grade 3) included fatigue, anorexia, and diarrhea. CONCLUSION: Docetaxel/erlotinib can be delivered safely in elderly patients with AIPC. Anti-cancer disease activity appears generally comparable to docetaxel when used as monotherapy. Hematologic and non-hematologic toxicity may be increased over docetaxel monotherapy. Prospective randomized studies would be required to determine if the toxicity of docetaxel and erlotinib justifies its use in this setting. [Abstract/Link to Full Text]

Sjřbakk TE, Johansen R, Bathen TF, Sonnewald U, Kvistad KA, Lundgren S, Gribbestad IS
Metabolic profiling of human brain metastases using in vivo proton MR spectroscopy at 3T.
BMC Cancer. 2007;7141.
BACKGROUND: Metastases to the central nervous system from different primary cancers are an oncologic challenge as the overall prognosis for these patients is generally poor. The incidence of brain metastases varies with type of primary cancer and is probably increasing due to improved therapies of extracranial metastases prolonging patient's overall survival and thereby time for brain metastases to develop. In addition, the greater access to improved neuroimaging techniques can provide earlier diagnosis. The aim of this study was to investigate the feasibility of using proton magnetic resonance spectroscopy (MRS) and multivariate analyses to characterize brain metastases originating from different primary cancers, to assess changes in spectra during radiation treatment and to correlate the spectra to clinical outcome after treatment. METHODS: Patients (n = 26) with brain metastases were examined using single voxel MRS at a 3T clinical MR system. Five patients were excluded due to poor spectral quality. The spectra were obtained before start (n = 21 patients), immediately after (n = 6 patients) and two months after end of treatment (n = 4 patients). Principal component analysis (PCA) and partial least square regression analysis (PLS) were applied in order to identify clustering of spectra due to origin of metastases and to relate clinical outcome (survival) of the patients to spectral data from the first MR examination. RESULTS: The PCA results indicated that brain metastases from primary lung and breast cancer were separated into two clusters, while the metastases from malignant melanomas showed no uniformity. The PLS analysis showed a significant correlation between MR spectral data and survival five months after MRS before start of treatment. CONCLUSION: MRS determined metabolic profiles analysed by PCA and PLS might give valuable clinical information when planning and evaluating the treatment of brain metastases, and also when deciding to terminate further therapies. [Abstract/Link to Full Text]

Terauchi M, Kajiyama H, Shibata K, Ino K, Nawa A, Mizutani S, Kikkawa F
Inhibition of APN/CD13 leads to suppressed progressive potential in ovarian carcinoma cells.
BMC Cancer. 2007;7140.
BACKGROUND: Aminopeptidase N (APN/CD13), a 150-kDa metalloprotease, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression of several human malignancies. In the current study, we investigated the role of APN/CD13 in ovarian carcinoma (OVCA) progression. METHODS: We first examined the expression of APN/CD13 at the protein level in a variety of OVCA cell lines and tissues. We subsequently investigated whether there was a correlation between APN/CD13 expression and invasive potential of various OVCA cell lines. Moreover, we investigated the function of APN/CD13 in OVCA cells using bestatin, an APN/CD13 inhibitor, or transfection of siRNA for APN/CD13. RESULTS: We confirmed that APN/CD13 was expressed in OVCA tissues and cell lines to various extents. There was a positive correlation between APN/CD13 expression and migratory potential in various OVCA cell lines with accordingly enhanced secretion of endogenous MMP-2. Subsequently, we found a significant decrease in the proliferative and migratory abilities of OVCA cells after the addition of bestatin or the inhibition of APN/CD13 expression by siRNA. Furthermore, in an animal model, daily intraperitoneal administration of bestatin after inoculation of OVCA cells resulted in a decrease of peritoneal dissemination and in prolonged survival of nude mice. CONCLUSION: The current data indicate the possible involvement of APN/CD13 in the development of OVCA, and suggest that clinical use of bestatin may contribute to better prognosis for ovarian carcinoma patients. [Abstract/Link to Full Text]

Favier J, Lapointe S, Maliba R, Sirois MG
HIF2 alpha reduces growth rate but promotes angiogenesis in a mouse model of neuroblastoma.
BMC Cancer. 2007;7139.
BACKGROUND: HIF2alpha/EPAS1 is a hypoxia-inducible transcription factor involved in catecholamine homeostasis, vascular remodelling, physiological angiogenesis and adipogenesis. It is overexpressed in many cancerous tissues, but its exact role in tumour progression remains to be clarified. METHODS: In order to better establish its function in tumourigenesis and tumour angiogenesis, we have stably transfected mouse neuroblastoma N1E-115 cells with the native form of HIF2alpha or with its dominant negative mutant, HIF2alpha (1-485) and studied their phenotype in vitro and in vivo. RESULTS: In vitro studies reveal that HIF2alpha induces neuroblastoma cells hypertrophy and decreases their proliferation rate, while its inactivation by the HIF2alpha (1-485) mutant leads to a reduced cell size, associated with an accelerated proliferation. However, our in vivo experiments show that subcutaneous injection of cells overexpressing HIF2alpha into syngenic mice, leads to the formation of tumour nodules that grow slower than controls, but that are well structured and highly vascularized. In contrast, HIF2alpha (1-485)-expressing neuroblastomas grow fast, but are poorly vascularized and quickly tend to extended necrosis. CONCLUSION: Together, our data reveal an unexpected combination between an antiproliferative and a pro-angiogenic function of HIF2alpha that actually seems to be favourable to the establishment of neuroblastomas in vivo. [Abstract/Link to Full Text]

Hammamieh R, Sumaida D, Zhang X, Das R, Jett M
Control of the growth of human breast cancer cells in culture by manipulation of arachidonate metabolism.
BMC Cancer. 2007;7138.
BACKGROUND: Arachidonate metabolites are important regulators of human breast cancer cells. Production of bioactive lipids are frequently initiated by the enzyme phospholipase A2 which releases arachidonic acid (AA) that is rapidly metabolized by cyclooxygenases (COX) or lipoxygenases (LO) to other highly potent lipids. METHODS: In this study we screened a number of inhibitors which blocked specific pathways of AA metabolism for their antiproliferative activity on MCF-7 wild type and MCF-7 ADR drug resistant breast cancer cells. The toxicity of these inhibitors was further tested on human bone marrow cell proliferation. RESULTS: Inhibitors of LO pathways (specifically the 5-LO pathway) were most effective in blocking proliferation. Inhibitors of platelet activating factor, a byproduct of arachidonate release, were also effective antiproliferative agents. Curcumin, an inhibitor of both COX and LO pathways of eicosanoid metabolism, was 12-fold more effective in blocking proliferation of the MCF-7 ADRs cells compared to MCF-7 wild type (WT) cells. These inhibitors that effectively blocked the proliferation of breast cancer cells showed varying degrees of toxicity to cultures of human bone marrow cells. We observed greater toxicity to bone marrow cells with inhibitors that interfere with the utilization of AA in contrast to those which block utilization of its downstream metabolites. MK-591, MK-886, PCA-4248, and AA-861 blocked proliferation of breast cancer cells but showed no toxicity to bone marrow cells. CONCLUSION: These inhibitors were effective in blocking the proliferation of breast cancer cells and may be potentially useful in human breast cancer therapy. [Abstract/Link to Full Text]

Knostman KA, McCubrey JA, Morrison CD, Zhang Z, Capen CC, Jhiang SM
PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer.
BMC Cancer. 2007;7137.
BACKGROUND: The sodium/iodide symporter (NIS) is a membrane glycoprotein mediating active iodide uptake in the thyroid gland and is the molecular basis for radioiodide imaging and therapeutic ablation of thyroid carcinomas. NIS is expressed in the lactating mammary gland and in many human breast tumors, raising interest in similar use for diagnosis and treatment. However, few human breast tumors have clinically evident iodide uptake ability. We previously identified PI3K signaling as important in NIS upregulation in transgenic mouse models of breast cancer, and the PI3K pathway is commonly activated in human breast cancer. METHODS: NIS expression, subcellular localization, and function were analyzed in MCF-7 human breast cancer cells and MCF-7 cells stably or transiently expressing PI3K p110alpha subunit using Western blot of whole cell lysate, cell surface biotinylation Western blot and immunofluorescence, and radioiodide uptake assay, respectively. NIS localization was determined in a human breast cancer tissue microarray using immunohistochemical staining (IHC) and was correlated with pre-existing pAkt IHC data. Statistical analysis consisted of Student's t-test (in vitro studies) or Fisher's Exact Test (in vivo correlational studies). RESULTS: In this study, we demonstrate that PI3K activation in MCF-7 human mammary carcinoma cells leads to expression of underglycosylated NIS lacking cell surface trafficking necessary for iodide uptake ability. PI3K activation also appears to interfere with cell surface trafficking of exogenous NIS as well as all-trans retinoic acid-induced endogenous NIS. A correlation between NIS expression and upregulation of PI3K signaling was found in a human breast cancer tissue microarray. CONCLUSION: Thus, the PI3K pathway likely plays a major role in the discordance between NIS expression and iodide uptake in breast cancer patients. Further study is warranted to realize the application of NIS-mediated radioiodide ablation in breast cancer. [Abstract/Link to Full Text]

Haffner MC, Petridou B, Peyrat JP, Révillion F, Müller-Holzner E, Daxenbichler G, Marth C, Doppler W
Favorable prognostic value of SOCS2 and IGF-I in breast cancer.
BMC Cancer. 2007;7136.
BACKGROUND: Suppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer. METHODS: We determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry. RESULTS: SOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 - 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 - 0.388, P = 0.002). CONCLUSION: This is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors. [Abstract/Link to Full Text]

Taylor JA, Kuchel GA, Hegde P, Voznesensky OS, Claffey K, Tsimikas J, Leng L, Bucala R, Pilbeam C
Null mutation for macrophage migration inhibitory factor (MIF) is associated with less aggressive bladder cancer in mice.
BMC Cancer. 2007;7135.
BACKGROUND: Inflammatory cytokines may promote tumorigenesis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We studied the development of bladder cancer in wild type (WT) and MIF knockout (KO) mice given N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression. METHODS: 5-month old male C57Bl/6 MIF WT and KO mice were treated with and without BBN. Animals were sacrificed at intervals up to 23 weeks of treatment. Bladder tumor stage and grade were evaluated by H&E. Immunohistochemical (IHC) analysis was performed for MIF and platelet/endothelial cell adhesion molecule 1 (PECAM-1), a measure of vascularization. MIF mRNA was analyzed by quantitative real-time polymerase chain reaction. RESULTS: Poorly differentiated carcinoma developed in all BBN treated mice by week 20. MIF WT animals developed T2 disease, while KO animals developed only T1 disease. MIF IHC revealed predominantly urothelial cytoplasmic staining in the WT control animals and a shift toward nuclear staining in WT BBN treated animals. MIF mRNA levels were 3-fold higher in BBN treated animals relative to controls when invasive cancer was present. PECAM-1 staining revealed significantly more stromal vessels in the tumors in WT animals when compared to KOs. CONCLUSION: Muscle invasive bladder cancer with increased stromal vascularity was associated with increased MIF mRNA levels and nuclear redistribution. Consistently lower stage tumors were seen in MIF KO compared to WT mice. These data suggest that MIF may play a role in the progression to invasive bladder cancer. [Abstract/Link to Full Text]

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Recent Articles in Molecular Cancer

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Ulazzi L, Sabbioni S, Miotto E, Veronese A, Angusti A, Gafŕ R, Manfredini S, Farinati F, Sasaki T, Lanza G, Negrini M
Nidogen 1 and 2 gene promoters are aberrantly methylated in human gastrointestinal cancer.
Mol Cancer. 2007;617.
BACKGROUND: Nidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals. RESULTS: We show that CpG islands of both NID1 and NID2 genes are aberrantly methylated in human cancer samples and cancer cell lines. For both genes, methylation was correlated with loss of gene transcription in human cell lines. Furthermore, demethylation of the NID1 and NID2 promoters restored gene transcription, demonstrating that methylation was responsible for silencing nidogen genes. In primary tumors, we detected NID1 promoter methylation in 67% of colon cancer samples and in 90% of gastric cancers. NID2 promoter was methylated in 29% of colon and 95% of gastric cancers. Immuno-staining for nidogen-2 confirmed the correlation between aberrant methylation and loss of nidogen expression also in primary tumors, implying that aberrant methylation was a mechanism for inhibiting nidogens expression in human gastrointestinal tumors. CONCLUSION: These results suggest that loss of nidogens expression has a potential pathogenetic role in colon and stomach tumorigenesis. Nidogens are believed to connect laminin and collagen IV networks, hence stabilizing the basement membrane structure. Nidogens are also important for cell adhesion, as they establish contacts with various cellular integrins. Loss of nidogen expression may favor invasion and metastasis of cancer cells by loosening cell interaction with basal membrane and by weakening the strength of the basement membrane itself, first barrier from the connective vascularized matrix. [Abstract/Link to Full Text]

Lin PY, Fosmire SP, Park SH, Park JY, Baksh S, Modiano JF, Weiss RH
Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance.
Mol Cancer. 2007;616.
BACKGROUND: The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (approximately 90% in metastatic cases), and these tumors frequently contain PTEN abnormalities. RESULTS: Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. CONCLUSION: Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories. [Abstract/Link to Full Text]

Ahmed FE, Vos PW, Holbert D
Modeling survival in colon cancer: a methodological review.
Mol Cancer. 2007;615.
The Cox proportional hazards model is the most widely used model for survival analysis because of its simplicity. The fundamental assumption in this model is the proportionality of the hazard function. When this condition is not met, other modifications or other models must be used for analysis of survival data. We illustrate in this review several methodological approaches to deal with the violation of the proportionality assumption, using survival in colon cancer as an illustrative example. [Abstract/Link to Full Text]

Schulz WA, Alexa A, Jung V, Hader C, Hoffmann MJ, Yamanaka M, Fritzsche S, Wlazlinski A, Müller M, Lengauer T, Engers R, Florl AR, Wullich B, Rahnenführer J
Factor interaction analysis for chromosome 8 and DNA methylation alterations highlights innate immune response suppression and cytoskeletal changes in prostate cancer.
Mol Cancer. 2007;614.
BACKGROUND: Alterations of chromosome 8 and hypomethylation of LINE-1 retrotransposons are common alterations in advanced prostate carcinoma. In a former study including many metastatic cases, they strongly correlated with each other. To elucidate a possible interaction between the two alterations, we investigated their relationship in less advanced prostate cancers. RESULTS: In 50 primary tumor tissues, no correlation was observed between chromosome 8 alterations determined by comparative genomic hybridization and LINE-1 hypomethylation measured by Southern blot hybridization. The discrepancy towards the former study, which had been dominated by advanced stage cases, suggests that both alterations converge and interact during prostate cancer progression. Therefore, interaction analysis was performed on microarray-based expression profiles of cancers harboring both alterations, only one, or none. Application of a novel bioinformatic method identified Gene Ontology (GO) groups related to innate immunity, cytoskeletal organization and cell adhesion as common targets of both alterations. Many genes targeted by their interaction were involved in type I and II interferon signaling and several were functionally related to hereditary prostate cancer genes. In addition, the interaction appeared to influence a switch in the expression pattern of EPB41L genes encoding 4.1 cytoskeleton proteins. Real-time RT-PCR revealed GADD45A, MX1, EPB41L3/DAL1, and FBLN1 as generally downregulated in prostate cancer, whereas HOXB13 and EPB41L4B were upregulated. TLR3 was downregulated in a subset of the cases and associated with recurrence. Downregulation of EPB41L3, but not of GADD45A, was associated with promoter hypermethylation, which was detected in 79% of carcinoma samples. CONCLUSION: Alterations of chromosome 8 and DNA hypomethylation in prostate cancer probably do not cause each other, but converge during progression. The present analysis implicates their interaction in innate immune response suppression and cytoskeletal changes during prostate cancer progression. The study thus highlights novel mechanisms in prostate cancer progression and identifies novel candidate genes for diagnostic and therapeutic purposes. In particular, TLR3 expression might be useful for prostate cancer prognosis and EPB41L3 hypermethylation for its detection. [Abstract/Link to Full Text]

Hernández P, Solé X, Valls J, Moreno V, Capellá G, Urruticoechea A, Pujana MA
Integrative analysis of a cancer somatic mutome.
Mol Cancer. 2007;613.
BACKGROUND: The consecutive acquisition of genetic alterations characterizes neoplastic processes. As a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. The recent identification of the collection of somatically mutated genes in breast tumors (breast cancer somatic "mutome") allows the comprehensive study of its function and organization in complex networks. RESULTS: We analyzed functional genomic data (loss of heterozygosity, copy number variation and gene expression in breast tumors) and protein binary interactions from public repositories to identify potential novel components of neoplastic processes, the functional relationships between them, and to examine their coordinated function in breast cancer pathogenesis. This analysis identified candidate tumor suppressors and oncogenes, and new genes whose expression level predicts survival rate in breast cancer patients. Mutome network modeling using different types of pathological and healthy functional relationships unveils functional modules significantly enriched in genes or proteins (genes/proteins) with related biological process Gene Ontology terms and containing known breast cancer-related genes/proteins. CONCLUSION: This study presents a comprehensive analysis of the breast somatic mutome, highlighting those genes with a higher probability of playing a determinant role in tumorigenesis and better defining molecular interactions related to the neoplastic process. [Abstract/Link to Full Text]

Hoei-Hansen CE, Kraggerud SM, Abeler VM, Kaern J, Rajpert-De Meyts E, Lothe RA
Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers.
Mol Cancer. 2007;612.
BACKGROUND: Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. RESULTS: We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2gamma) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13-40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. CONCLUSION: This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females. [Abstract/Link to Full Text]

Gopalan B, Shanker M, Chada S, Ramesh R
MDA-7/IL-24 suppresses human ovarian carcinoma growth in vitro and in vivo.
Mol Cancer. 2007;611.
BACKGROUND: Previous studies showed that the human melanoma differentiation-associated gene-7 (mda-7), also known as interleukin-24 (IL-24), has potent antitumor activity against human and murine cancer cells. However, the majority of these studies were limited to in vitro testing. In the present study, we investigated the antitumor activity of mda-7/IL-24 against human ovarian cancer cells both in vitro and in vivo. RESULTS: In vitro, treatment of ovarian cancer cells with an adenoviral vector carrying the mda-7 gene (Ad-mda7) resulted in inhibition of cell proliferation and induction of cell cycle arrest, leading to apoptosis. We did not observe inhibitory activity in Ad-mda7-treated normal cells. In vivo, treatment of subcutaneous tumor xenografts with Ad-mda7 resulted in significant tumor growth inhibition when compared with that in control groups (p < 0.001). Molecular analysis of ovarian tumor tissue lysates treated with Ad-mda7 showed that MDA-7 protein expression was associated with activation of the caspase cascade. CONCLUSION: Our results show that treatment of ovarian cancer cells with mda-7/IL-24 results in growth suppression both in vitro and in vivo. [Abstract/Link to Full Text]

Menendez L, Walker D, Matyunina LV, Dickerson EB, Bowen NJ, Polavarapu N, Benigno BB, McDonald JF
Identification of candidate methylation-responsive genes in ovarian cancer.
Mol Cancer. 2007;610.
BACKGROUND: Aberrant methylation of gene promoter regions has been linked to changes in gene expression in cancer development and progression. Genes associated with CpG islands (CGIs) are especially prone to methylation, but not all CGI-associated genes display changes in methylation patterns in cancers. RESULTS: In order to identify genes subject to regulation by methylation, we conducted gene expression profile analyses of an ovarian cancer cell line (OVCAR-3) before and after treatment with the demethylating agent 5-aza-deoxycytidine (5-aza-dC). An overlapping subset of these genes was found to display significant differences in gene expression between normal ovarian surface epithelial cells and malignant cells isolated from ovarian carcinomas. While 40% of all human genes are associated with CGIs, > 94% of the overlapping subset of genes is associated with CGIs. The predicted change in methylation status of genes randomly selected from the overlapping subset was experimentally verified. CONCLUSION: We conclude that correlating genes that are upregulated in response to 5-aza-dC treatment of cancer cell lines with genes that are down-regulated in cancer cells may be a useful method to identify genes experiencing epigenetic-mediated changes in expression over cancer development. [Abstract/Link to Full Text]

Wang Z, Lecane PS, Thiemann P, Fan Q, Cortez C, Ma X, Tonev D, Miles D, Naumovski L, Miller RA, Magda D, Cho DG, Sessler JL, Pike BL, Yeligar SM, Karaman MW, Hacia JG
Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression.
Mol Cancer. 2007;69.
BACKGROUND: Sapphyrin analogues and related porphyrin-like species have attracted attention as anticancer agents due to their selective localization in various cancers, including hematologic malignancies, relative to surrounding tissues. Sapphyrins are electron affinic compounds that generate high yields of singlet oxygen formation. Although initially explored in the context of photodynamic therapy, sapphyrins have intrinsic anticancer activity that is independent of their photosensitizing properties. However, the mechanisms for their anticancer activity have not been fully elucidated. RESULTS: We have prepared a series of hydrophilic sapphyrins and evaluated their effect on proliferation, uptake, and cell death in adherent human lung (A549) and prostate (PC3) cancer cell lines and in an A549 xenograft tumor model. PCI-2050, the sapphyrin derivative with the highest in vitro growth inhibitory activity, significantly lowered 5-bromo-2'-deoxyuridine incorporation in S-phase A549 cells by 60% within eight hours and increased levels of reactive oxygen species within four hours. The growth inhibition pattern of PCI-2050 in the National Cancer Institute 60 cell line screen correlated most closely using the COMPARE algorithm with known transcriptional or translational inhibitors. Gene expression analyses conducted on A549 plateau phase cultures treated with PCI-2050 uncovered wide-spread decreases in mRNA levels, which especially affected short-lived transcripts. Intriguingly, PCI-2050 increased the levels of transcripts involved in RNA processing and trafficking, transcriptional regulation, and chromatin remodeling. We propose that these changes reflect the activation of cellular processes aimed at countering the observed wide-spread reductions in transcript levels. In our A549 xenograft model, the two lead compounds, PCI-2050 and PCI-2022, showed similar tumor distributions despite differences in plasma and kidney level profiles. This provides a possible explanation for the better tolerance of PCI-2022 relative to PCI-2050. CONCLUSION: Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression. [Abstract/Link to Full Text]

Pisano M, Pagnan G, Loi M, Mura ME, Tilocca MG, Palmieri G, Fabbri D, Dettori MA, Delogu G, Ponzoni M, Rozzo C
Antiproliferative and pro-apoptotic activity of eugenol-related biphenyls on malignant melanoma cells.
Mol Cancer. 2007;68.
BACKGROUND: Malignant melanoma is one of the most aggressive skin cancer and chemotherapeutic agents currently in use are still unsatisfactory. Prevention and early diagnosis are the only effective tools against this tumour whose incidence and mortality rates are highly increased during the last decades in fair skin populations. Therefore the search for novel therapeutic approaches is warranted. Aim of this work was to identify and test new compounds with antiproliferative and cytotoxic activity on melanoma cells. We tested eugenol together with six natural and synthetic eugenol-related compounds for their capability to inhibit cell growth on primary melanoma cell lines established from patients' tissue samples. RESULTS: Eugenol and isoeugenol monomers and their respective O-methylated forms did not show to inhibit melanoma cells proliferation. Conversely, the dimeric forms (biphenyls) showed some antiproliferative activity which was mild for dehydrodieugenol, higher for its O,O'-methylated form (O,O'-dimethyl-dehydrodieugenol), and markedly pronounced for the racemic mixture of the brominated biphenyl (6,6'-dibromo-dehydrodieugenol) (S7), being its enantiomeric form (S) the most effective compared to the other compounds. Such activity resulted to be selective against tumour cells, without affecting cultured normal human skin fibroblasts. Dose and time dependence curves have been obtained for the enantiomeric form S7-(S). Then IC50 and minimal effective doses and times have been established for the melanoma cell lines tested. TUNEL and phosphatidylserine exposure assays demonstrated the occurrence of apoptotic events associated with the antiproliferative activity of S7-(S). Cytotoxic activity and apoptosis induced by treating melanoma cells with eugenol-related biphenyls was partially dependent by caspase activation. CONCLUSION: Our findings demonstrate that the eugenol related biphenyl (S)-6,6'-dibromo-dehydrodieugenol elicits specific antiproliferative activity on neuroectodermal tumour cells partially triggering apoptosis and its activity should be further investigated on in vivo melanoma models in order to evaluate the real anticancer effectiveness on such tumour. [Abstract/Link to Full Text]

Li Y, Pan J, Li JL, Lee JH, Tunkey C, Saraf K, Garbe JC, Whitley MZ, Jelinsky SA, Stampfer MR, Haney SA
Transcriptional changes associated with breast cancer occur as normal human mammary epithelial cells overcome senescence barriers and become immortalized.
Mol Cancer. 2007;67.
BACKGROUND: Human mammary epithelial cells (HMEC) overcome two well-characterized genetic and epigenetic barriers as they progress from primary cells to fully immortalized cell lines in vitro. Finite lifespan HMEC overcome an Rb-mediated stress-associated senescence barrier (stasis), and a stringent, telomere-length dependent, barrier (agonescence or crisis, depending on p53 status). HMEC that have overcome the second senescence barrier are immortalized. METHODS: We have characterized pre-stasis, post-selection (post-stasis, with p16 silenced), and fully immortalized HMEC by transcription profiling and RT-PCR. Four pre-stasis and seven post-selection HMEC samples, along with 10 representatives of fully immortalized breast epithelial cell lines, were profiled using Affymetrix U133A/B chips and compared using both supervised and unsupervised clustering. Datasets were validated by RT-PCR for a select set of genes. Quantitative immunofluorescence was used to assess changes in transcriptional regulators associated with the gene expression changes. RESULTS: The most dramatic and uniform changes we observed were in a set of about 30 genes that are characterized as a "cancer proliferation cluster," which includes genes expressed during mitosis (CDC2, CDC25, MCM2, PLK1) and following DNA damage. The increased expression of these genes was particularly concordant in the fully immortalized lines. Additional changes were observed in IFN-regulated genes in some post-selection and fully immortalized cultures. Nuclear localization was observed for several transcriptional regulators associated with expression of these genes in post-selection and immortalized HMEC, including Rb, Myc, BRCA1, HDAC3 and SP1. CONCLUSION: Gene expression profiles and cytological changes in related transcriptional regulators indicate that immortalized HMEC resemble non-invasive breast cancers, such as ductal and lobular carcinomas in situ, and are strikingly distinct from finite-lifespan HMEC, particularly with regard to genes involved in proliferation, cell cycle regulation, chromosome structure and the DNA damage response. The comparison of HMEC profiles with lines harboring oncogenic changes (e.g. overexpression of Her-2neu, loss of p53 expression) identifies genes involved in tissue remodeling as well as proinflamatory cytokines and S100 proteins. Studies on carcinogenesis using immortalized cell lines as starting points or "normal" controls need to account for the significant pre-existing genetic and epigenetic changes inherent in such lines before results can be broadly interpreted. [Abstract/Link to Full Text]

Samant RS, Clark DW, Fillmore RA, Cicek M, Metge BJ, Chandramouli KH, Chambers AF, Casey G, Welch DR, Shevde LA
Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-kappaB activation.
Mol Cancer. 2007;66.
BACKGROUND: Osteopontin (OPN), a secreted phosphoglycoprotein, has been strongly associated with tumor progression and aggressive cancers. MDA-MB-435 cells secrete very high levels of OPN. However metastasis-suppressed MDA-MB-435 cells, which were transfected with breast cancer metastasis suppressor 1 (BRMS1), expressed significantly less OPN. BRMS1 is a member of mSin3-HDAC transcription co-repressor complex and has been shown to suppress the metastasis of breast cancer and melanoma cells in animal models. Hence we hypothesized that BRMS1 regulates OPN expression. RESULTS: The search for a BRMS1-regulated site on the OPN promoter, using luciferase reporter assays of the promoter deletions, identified a novel NF-kappaB site (OPN/NF-kappaB). Electrophoretic mobility shift assays and chromatin immunoprecipitations (ChIP) confirmed this site to be an NF-kappaB-binding site. We also show a role of HDAC3 in suppression of OPN via OPN/NF-kappaB. CONCLUSION: Our results show that BRMS1 regulates OPN transcription by abrogating NF-kappaB activation. Thus, we identify OPN, a tumor-metastasis activator, as a crucial downstream target of BRMS1. Suppression of OPN may be one of the possible underlying mechanisms of BRMS1-dependent suppression of tumor metastasis. [Abstract/Link to Full Text]

Hebert C, Norris K, Scheper MA, Nikitakis N, Sauk JJ
High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma.
Mol Cancer. 2007;65.
BACKGROUND: HMGA2 expression has been shown to be associated with enhanced selective chemosensitivity towards the topoisomerase (topo) II inhibitor, doxorubicin, in cancer cells. Although the roles of signaling cascades and proteins as regulatory factors in development, neoplasia and adaptation to the environment are becoming well established, evidence for the involvement of regulatory small RNA molecules, such as microRNAs (miRNAs) as important regulators of both transcriptional and posttranscriptional gene silencing is presently mounting. RESULTS: Here we report that HMGA2 expression in head and neck squamous cell carcinoma (HNSCC) cells is regulated in part by miRNA-98 (miR-98). Albeit HMGA2 is associated with enhanced selective chemosensitivity towards topoisomerase (topo) II inhibitor, doxorubicin in HNSCC, the expression of HMGA2 is thwarted by hypoxia. This is accompanied by enhanced expression of miRNA-98 and other miRNAs, which predictably target HMGA2. Moreover, we show that transfection of pre-miR-98trade mark during normoxia diminishes HMGA2 and potentiates resistance to doxorubicin and cisplatin. These findings implicate the role of a miRNA as a key element in modulating tumors in variable microenvironments. CONCLUSION: These studies validate the observation that HMGA2 plays a prominent role in governing genotoxic responses. However, this may only represent cells growing under normal oxygen tensions. The demonstration that miRNA profiles are altered during hypoxia and repress a genotoxic response indicates that changes in microenvironment in eukaryotes mimic those of lower species and plants, where, for example, abiotic stresses regulate the expression of thousands of genes in plants at both transcriptional and posttranscriptional levels through a number of miRNAs and other small regulatory RNAs. [Abstract/Link to Full Text]

Cristina C, Díaz-Torga GS, Goya RG, Kakar SS, Perez-Millán MI, Passos VQ, Giannella-Neto D, Bronstein MD, Becu-Villalobos D
PTTG expression in different experimental and human prolactinomas in relation to dopaminergic control of lactotropes.
Mol Cancer. 2007;64.
BACKGROUND: Pituitary tumor transforming gene (pttg) is a novel oncogene that is expressed at higher level in most of the tumors analyzed to date compared to normal tissues. Nevertheless, its expression in prolactinomas and its relation with the pituitary dopamine receptor 2 (D2R) are not well defined. We sought to determine the pituitary level of pttg in three different experimental models of prolactinomas with altered dopaminergic control of the pituitary: the dopaminergic D2R knockout female mouse, the estrogen-treated rat, and the senescent female rat. These three models shared the characteristics of increased pituitary weight, hyperprolactinemia, lactotrope hyperplasia and reduced or absent dopaminergic action at the pituitary level. We also studied samples from human macroprolactinomas, which were characterized as responsive or resistant to dopamine agonist therapy. RESULTS: When compared to female wild-type mice, pituitaries from female D2R knockout mice had decreased PTTG concentration, while no difference in pttg mRNA level was found. In senescent rats no difference in pituitary PTTG protein expression was found when compared to young rats. But, in young female rats treated with a synthetic estrogen (Diethylstylbestrol, 20 mg) PTTG protein expression was enhanced (P = 0.029). Therefore, in the three experimental models of prolactinomas, pituitary size was increased and there was hyperprolactinemia, but PTTG levels followed different patterns.Patients with macroprolactinomas were divided in those in which dopaminergic therapy normalized or failed to normalize prolactin levels (responsive and resistant, respectively). When pituitary pttg mRNA level was analyzed in these macroprolactinomas, no differences were found.We next analyzed estrogen action at the pituitary by measuring pituitary estrogen receptor alpha levels. The D2R knockout female mice have low estrogen levels and in accordance, pituitary estrogen receptors were increased (P = 0.047). On the other hand, in senescent rats estrogen levels were slightly though not significantly higher, and estrogen receptors were similar between groups. The estrogen-treated rats had high pharmacological levels of the synthetic estrogen, and estrogen receptors were markedly lower than in controls (P < 0.0001). Finally, in patients with dopamine resistant or responsive prolactinomas no significant differences in estrogen receptor alpha levels were found. Therefore, pituitary PTTG was increased only if estrogen action was increased, which correlated with a decrease in pituitary estrogen receptor level. CONCLUSION: We conclude that PTTG does not correlate with prolactin levels or tumor size in animal models of prolactinoma, and its pituitary content is not related to a decrease in dopaminergic control of the lactotrope, but may be influenced by estrogen action at the pituitary level. Therefore it is increased only in prolactinomas generated by estrogen treatment, and not in prolactinomas arising from deficient dopamine control, or in dopamine resistant compared with dopamine responsive human prolactinomas. These results are important in the search for reliable prognostic indicators for patients with pituitary adenomas which will make tumor-specific therapy possible, and help to elucidate the poorly understood phenomenon of pituitary tumorigenesis. [Abstract/Link to Full Text]

Rao SP, Rechsteiner MP, Berger C, Sigrist JA, Nadal D, Bernasconi M
Zebularine reactivates silenced E-cadherin but unlike 5-Azacytidine does not induce switching from latent to lytic Epstein-Barr virus infection in Burkitt's lymphoma Akata cells.
Mol Cancer. 2007;63.
Epigenetic silencing of regulatory genes by aberrant methylation contributes to tumorigenesis. DNA methyltransferase inhibitors (DNMTI) represent promising new drugs for anti-cancer therapies. The DNMTI 5-Azacytidine is effective against myelodysplastic syndrome, but induces switching of latent to lytic Epstein-Barr virus (EBV) in vitro and results in EBV DNA demethylation with the potential of induction of lytic EBV in vivo. This is of considerable concern given that recurrent lytic EBV has been linked with an increased incidence of EBV-associated lymphomas. Based on the distinct properties of action we hypothesized that the newer DNMTI Zebularine might differ from 5-Azacytidine in its potential to induce switching from latent to lytic EBV. Here we show that both 5-Azacytidine and Zebularine are able to induce expression of E-cadherin, a cellular gene frequently silenced by hypermethylation in cancers, and thus demonstrate that both DNMTI are active in our experimental setting consisting of EBV-harboring Burkitt's lymphoma Akata cells. Quantification of mRNA expression of EBV genes revealed that 5-Azacytidine induces switching from latent to lytic EBV and, in addition, that the immediate-early lytic infection progresses to early and late lytic infection. Furthermore, 5-Azacytidine induced upregulation of the latent EBV genes LMP2A, LMP2B, and EBNA2 in a similar fashion as observed following switching of latent to lytic EBV upon cross-linking of the B-cell receptor. In striking contrast, Zebularine did not exhibit any effect neither on lytic nor on latent EBV gene expression. Thus, Zebularine might be safer than 5-Azacytidine for the treatment of cancers in EBV carriers and could also be applied against EBV-harboring tumors, since it does not induce switching from latent to lytic EBV which may result in secondary EBV-associated malignancies. [Abstract/Link to Full Text]

Kleivi K, Lind GE, Diep CB, Meling GI, Brandal LT, Nesland JM, Myklebost O, Rognum TO, Giercksky KE, Skotheim RI, Lothe RA
Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses.
Mol Cancer. 2007;62.
BACKGROUND: Despite the fact that metastases are the leading cause of colorectal cancer deaths, little is known about the underlying molecular changes in these advanced disease stages. Few have studied the overall gene expression levels in metastases from colorectal carcinomas, and so far, none has investigated the peritoneal carcinomatoses by use of DNA microarrays. Therefore, the aim of the present study is to investigate and compare the gene expression patterns of primary carcinomas (n = 18), liver metastases (n = 4), and carcinomatoses (n = 4), relative to normal samples from the large bowel. RESULTS: Transcriptome profiles of colorectal cancer metastases independent of tumor site, as well as separate profiles associated with primary carcinomas, liver metastases, or peritoneal carcinomatoses, were assessed by use of Bayesian statistics. Gains of chromosome arm 5p are common in peritoneal carcinomatoses and several candidate genes (including PTGER4, SKP2, and ZNF622) mapping to this region were overexpressed in the tumors. Expression signatures stratified on TP53 mutation status were identified across all tumors regardless of stage. Furthermore, the gene expression levels for the in vivo tumors were compared with an in vitro model consisting of cell lines representing all three tumor stages established from one patient. CONCLUSION: By statistical analysis of gene expression data from primary colorectal carcinomas, liver metastases, and carcinomatoses, we are able to identify genetic patterns associated with the different stages of tumorigenesis. [Abstract/Link to Full Text]

Cho WC
Nasopharyngeal carcinoma: molecular biomarker discovery and progress.
Mol Cancer. 2007;61.
Nasopharyngeal carcinoma (NPC) is a rare malignancy in most part of the world and it is one of the most confusing, commonly misdiagnosed and poorly understood diseases. The cancer is an Epstein-Barr virus-associated malignancy with a remarkable racial and geographical distribution. It is highly prevalent in southern Asia where the disease occurs at a prevalence about a 100-fold higher compared with other populations not at risk. The etiology of NPC is thought to be associated with a complex interaction of genetic, viral, environmental and dietary factors. Thanks to the advancements in genomics, proteomics and bioinformatics in recent decades, more understanding of the disease etiology, carcinogenesis and progression has been gained. Research into these components may unravel the pathways in NPC development and potentially decipher the molecular characteristics of the malignancy. In the era of molecular medicine, specific treatment to the potential target using technologies such as immunotherapy and RNAi becomes formulating from bench to bedside application and thus makes molecular biomarker discovery more meaningful for NPC management. In this article, the latest molecular biomarker discovery and progress in NPC is reviewed with respect to the diagnosis, monitoring, treatment and prognostication of the disease. [Abstract/Link to Full Text]

Ujiki MB, Ding XZ, Salabat MR, Bentrem DJ, Golkar L, Milam B, Talamonti MS, Bell RH, Iwamura T, Adrian TE
Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest.
Mol Cancer. 2006;576.
BACKGROUND: Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro. RESULTS: Apigenin caused both time- and concentration-dependent inhibition of DNA synthesis and cell proliferation in four pancreatic cancer cell lines. Apigenin induced G2/M phase cell cycle arrest. Apigenin reduced levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25, which are all proteins required for G2/M transition. CONCLUSION: Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer. [Abstract/Link to Full Text]

Yoshihara T, Kadota Y, Yoshimura Y, Tatano Y, Takeuchi N, Okitsu H, Umemoto A, Yamauchi T, Itoh K
Proteomic alteration in gastic adenocarcinomas from Japanese patients.
Mol Cancer. 2006;575.
BACKGROUND: Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from Japanese patients was carried out by means of two-dimensional gel electrophoresis (2D-EP) and liquid chromatography-electrospray ionic tandem mass spectrometry (LC-ESI-MS) to establish gastric cancer-specific proteins as putative clinical biomarkers and molecular targets for chemotherapy. RESULTS: Relatively common alterations in protein expression were revealed in the tumor tissues. Increases in manganese dismutase and nonhistone chromosomal protein HMG-1 (HMG-1) were observed, while decreases in carbonic anhydrases I and II, glutatione-S-transferase and foveolin precursor (gastrokine-1) (FOV), an 18-kDa stomach-specific protein with putative tumor suppressor activity, were detected. RT-PCR analysis also revealed significant down-regulation of FOV mRNA expression in tumor tissues. CONCLUSION: A possible pathological role for down-regulation of FOV in gastric carcinogenesis was demonstrated. Evaluation of the specific decreases in gene and protein expression of FOV in patients may be utilized as clinical biomarkers for effective diagnosis and assessment of gastric cancer. [Abstract/Link to Full Text]

O'Driscoll L, McMorrow J, Doolan P, McKiernan E, Mehta JP, Ryan E, Gammell P, Joyce H, O'Donovan N, Walsh N, Clynes M
Investigation of the molecular profile of basal cell carcinoma using whole genome microarrays.
Mol Cancer. 2006;574.
BACKGROUND: Skin cancer accounts for 1/3 of all newly diagnosed cancer. Although seldom fatal, basal cell carcinoma (BCC) is associated with severe disfigurement and morbidity. BCC has a unique interest for researchers, as although it is often locally invasive, it rarely metastasises. This paper, reporting the first whole genome expression microarray analysis of skin cancer, aimed to investigate the molecular profile of BCC in comparison to non-cancerous skin biopsies. RNA from BCC and normal skin specimens was analysed using Affymetrix whole genome microarrays. A Welch t-test was applied to data normalised using dCHIP to identify significant differentially-expressed genes between BCC and normal specimens. Principal component analysis and support vector machine analysis were performed on resulting genelists, Genmapp was used to identify pathways affected, and GOstat aided identification of areas of gene ontology more highly represented on these lists than would be expected by chance. RESULTS: Following normalisation, specimens clustered into groups of BCC specimens and of normal skin specimens. Of the 54,675 gene transcripts/variants analysed, 3,921 were differentially expressed between BCC and normal skin specimens. Of these, 2,108 were significantly up-regulated and 1,813 were statistically significantly down-regulated in BCCs. CONCLUSION: Functional gene sets differentially expressed include those involved in transcription, proliferation, cell motility, apoptosis and metabolism. As expected, members of the Wnt and hedgehog pathways were found to be significantly different between BCC and normal specimens, as were many previously undescribed changes in gene expression between normal and BCC specimens, including basonuclin2 and mrp9. Quantitative-PCR analysis confirmed our microarray results, identifying novel potential biomarkers for BCC. [Abstract/Link to Full Text]

Sui G, Zhou S, Wang J, Canto M, Lee EE, Eshleman JR, Montgomery EA, Sidransky D, Califano JA, Maitra A
Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: a biomarker for the early detection of cancer.
Mol Cancer. 2006;573.
BACKGROUND: Somatic mutations of mitochondrial DNA (mtDNA) are common in many human cancers. We have described an oligonucleotide microarray ("MitoChip") for rapid sequencing of the entire mitochondrial genome (Zhou et al, J Mol Diagn 2006), facilitating the analysis of mtDNA mutations in preneoplastic lesions. We examined 14 precancerous lesions, including seven Barrett esophagus biopsies, with or without associated dysplasia; four colorectal adenomas; and three inflammatory colitis-associated dysplasia specimens. In all cases, matched normal tissues from the corresponding site were obtained as germline control. MitoChip analysis was performed on DNA obtained from cryostat-embedded specimens. RESULTS: A total of 513,639 bases of mtDNA were sequenced in the 14 samples, with 490,224 bases (95.4%) bases assigned by the automated genotyping software. All preneoplastic lesions examined demonstrated at least one somatic mtDNA sequence alteration. Of the 100 somatic mtDNA alterations observed in the 14 cases, 27 were non-synonymous coding region mutations (i.e., resulting in an amino acid change), 36 were synonymous, and 37 involved non-coding mtDNA. Overall, somatic alterations most commonly involved the COI, ND4 and ND5 genes. Notably, somatic mtDNA alterations were observed in preneoplastic lesions of the gastrointestinal tract even in the absence of histopathologic evidence of dysplasia, suggesting that the mitochondrial genome is susceptible at the earliest stages of multistep cancer progression. CONCLUSION: Our findings further substantiate the rationale for exploring the mitochondrial genome as a biomarker for the early diagnosis of cancer, and confirm the utility of a high-throughput array-based platform for this purpose from a clinical applicability standpoint. [Abstract/Link to Full Text]

Cobrinik D, Francis RO, Abramson DH, Lee TC
Rb induces a proliferative arrest and curtails Brn-2 expression in retinoblastoma cells.
Mol Cancer. 2006;572.
BACKGROUND: Retinoblastoma is caused by loss of the Rb protein in early retinal cells. Although numerous Rb functions have been identified, Rb effects that specifically relate to the suppression of retinoblastoma have not been defined. RESULTS: In this study, we examined the effects of restoring Rb to Y79 retinoblastoma cells, using novel retroviral and lentiviral vectors that co-express green fluorescent protein (GFP). The lentiviral vector permitted transduction with sufficient efficiency to perform biochemical analyses. Wild type Rb (RbWT) and to a lesser extent the low penetrance mutant Rb661W induced a G0/G1 arrest associated with induction of p27KIP1 and repression of cyclin E1 and cyclin E2. Microarray analyses revealed that in addition to down-regulating E2F-responsive genes, Rb repressed expression of Brn-2 (POU3F2), which is implicated as an important transcriptional regulator in retinal progenitor cells and other neuroendocrine cell types. The repression of Brn-2 was a specific Rb effect, as ectopic p27 induced a G0/G1 block, but enhanced, rather than repressed, Brn-2 expression. CONCLUSION: In addition to Rb effects that occur in many cell types, Rb regulates a gene that selectively governs the behavior of late retinal progenitors and related cells. [Abstract/Link to Full Text]

Chen J, Ghazawi FM, Bakkar W, Li Q
Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B.
Mol Cancer. 2006;571.
BACKGROUND: In eukaryotic cells, the genomic DNA is packed with histones to form the nucleosome and chromatin structure. Reversible acetylation of the histone tails plays an important role in the control of specific gene expression. Mounting evidence has established that histone deacetylase inhibitors selectively induce cellular differentiation, growth arrest and apoptosis in variety of cancer cells, making them a promising class of anticancer drugs. However, the molecular mechanisms of the anti-cancer effects of these inhibitors have yet to be understood. RESULTS: Here, we report that a key determinant for the susceptibility of cancer cells to histone deacetylase inhibitors is their ability to maintain cellular Akt activity in response to the treatment. Also known as protein kinase B, Akt is an essential pro-survival factor in cell proliferation and is often deregulated during tumorigenesis. We show that histone deacetylase inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2 expression, which leads to Akt deactivation and apoptotic cell death. In addition, valproic acid and butyrate induce apoptosis through the caspase-dependent pathway. The activity of caspase-9 is robustly activated upon valproic acid or butyrate treatment. Constitutively active Akt is able to block the caspase activation and rescues cells from butyrate-induced apoptotic cell death. CONCLUSION: Our study demonstrates that although the primary target of histone deacetylase inhibitors is transcription, it is the capacity of cells to maintain cellular survival networks that determines their fate of survival. [Abstract/Link to Full Text]

Cahill S, Smyth P, Finn SP, Denning K, Flavin R, O'Regan EM, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ, Sheils O
Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.
Mol Cancer. 2006;570.
BACKGROUND: microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nt in length that have been found to control cell growth, differentiation and apoptosis. miRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. ret/PTC 1 is an oncogene with constitutive kinase activity implicated in the development of papillary thyroid carcinoma (PTC). This rearrangement leads to aberrant MAPK activation that is implicated in PTC tumourigenesis. AIM: The aim of this study was to identify the effect that ret/PTC 1 has on transcription and post-transcriptional regulation in PTC by using DNA microarray and microRNA analysis. RESULTS: DNA microarray analysis revealed a group of genes differentially expressed between normal thyroid cell lines and those harbouring a ret/PTC 1 rearrangement.Furthermore, a unique miRNA expression signature differentiated between PTC cell lines with ret/PTC 1 and a normal thyroid cell line. 21 miRNAs showed significant overexpression and 14 miRNAs showed underexpression in these cell lines when compared to normal thyroid. Several of these up/down regulated miRNAs may be involved in PTC pathogenesis. [Abstract/Link to Full Text]

Fisher KE, Pop A, Koh W, Anthis NJ, Saunders WB, Davis GE
Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling.
Mol Cancer. 2006;569.
BACKGROUND: Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive lipid signaling molecules implicated in tumor dissemination. Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-tethered collagenase thought to be involved in tumor invasion via extracellular matrix degradation. In this study, we investigated the molecular requirements for LPA- and S1P-regulated tumor cell migration in two dimensions (2D) and invasion of three-dimensional (3D) collagen matrices and, in particular, evaluated the role of MT1-MMP in this process. RESULTS: LPA stimulated while S1P inhibited migration of most tumor lines in Boyden chamber assays. Conversely, HT1080 fibrosarcoma cells migrated in response to both lipids. HT1080 cells also markedly invaded 3D collagen matrices (approximatly 700 microm over 48 hours) in response to either lipid. siRNA targeting of LPA1 and Rac1, or S1P1, Rac1, and Cdc42 specifically inhibited LPA- or S1P-induced HT1080 invasion, respectively. Analysis of LPA-induced HT1080 motility on 2D substrates vs. 3D matrices revealed that synthetic MMP inhibitors markedly reduced the distance (approximately 125 microm vs. approximately 45 microm) and velocity of invasion (approximately 0.09 microm/min vs. approximately 0.03 microm/min) only when cells navigated 3D matrices signifying a role for MMPs exclusively in invasion. Additionally, tissue inhibitors of metalloproteinases (TIMPs)-2, -3, and -4, but not TIMP-1, blocked lipid agonist-induced invasion indicating a role for membrane-type (MT)-MMPs. Furthermore, MT1-MMP expression in several tumor lines directly correlated with LPA-induced invasion. HEK293s, which neither express MT1-MMP nor invade in the presence of LPA, were transfected with MT1-MMP cDNA, and subsequently invaded in response to LPA. When HT1080 cells were seeded on top of or within collagen matrices, siRNA targeting of MT1-MMP, but not other MMPs, inhibited lipid agonist-induced invasion establishing a requisite role for MT1-MMP in this process. CONCLUSION: LPA is a fundamental regulator of MT1-MMP-dependent tumor cell invasion of 3D collagen matrices. In contrast, S1P appears to act as an inhibitory stimulus in most cases, while stimulating only select tumor lines. MT1-MMP is required only when tumor cells navigate 3D barriers and not when cells migrate on 2D substrata. We demonstrate that tumor cells require coordinate regulation of LPA/S1P receptors and Rho GTPases to migrate, and additionally, require MT1-MMP in order to invade collagen matrices during neoplastic progression. [Abstract/Link to Full Text]

Zhang L, Nie L, Maki CG
P53 and p73 differ in their ability to inhibit glucocorticoid receptor (GR) transcriptional activity.
Mol Cancer. 2006;568.
BACKGROUND: p53 is a tumor suppressor and potent inhibitor of cell growth. P73 is highly similar to p53 at both the amino acid sequence and structural levels. Given their similarities, it is important to determine whether p53 and p73 function in similar or distinct pathways. There is abundant evidence for negative cross-talk between glucocorticoid receptor (GR) and p53. Neither physical nor functional interactions between GR and p73 have been reported. In this study, we examined the ability of p53 and p73 to interact with and inhibit GR transcriptional activity. RESULTS: We show that both p53 and p73 can bind GR, and that p53 and p73-mediated transcriptional activity is inhibited by GR co-expression. Wild-type p53 efficiently inhibited GR transcriptional activity in cells expressing both proteins. Surprisingly, however, p73 was either unable to efficiently inhibit GR, or increased GR activity slightly. To examine the basis for this difference, a series of p53:p73 chimeric proteins were generated in which corresponding regions of either protein have been swapped. Replacing N- and C-terminal sequences in p53 with the corresponding sequences from p73 prevented it from inhibiting GR. In contrast, replacing p73 N- and C-terminal sequences with the corresponding sequences from p53 allowed it to efficiently inhibit GR. Differences in GR inhibition were not related to differences in transcriptional activity of the p53:p73 chimeras or their ability to bind GR. CONCLUSION: Our results indicate that both N- and C-terminal regions of p53 and p73 contribute to their regulation of GR. The differential ability of p53 and p73 to inhibit GR is due, in part, to differences in their N-terminal and C-terminal sequences. [Abstract/Link to Full Text]

Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS
Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma.
Mol Cancer. 2006;567.
BACKGROUND: Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. RESULTS: In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. CONCLUSION: Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients. [Abstract/Link to Full Text]

Petrella BL, Brinckerhoff CE
Tumor cell invasion of von Hippel Lindau renal cell carcinoma cells is mediated by membrane type-1 matrix metalloproteinase.
Mol Cancer. 2006;566.
BACKGROUND: Metastatic renal cell carcinoma (RCC) remains the leading cause of mortality in patients with clear cell RCC arising from mutations in the von Hippel Lindau (VHL) tumor suppressor. Successful RCC tumor suppression by VHL requires the negative regulation of hypoxia inducible factor alpha (HIF alpha) protein and its downstream targets. Thus, identification of HIF target genes responsible for RCC tumor progression will aid in the development of therapies for this disease. We previously identified membrane type-1 matrix metalloproteinase (MT1-MMP) as a transcriptional target of HIF-2alpha in RCC cells null for VHL and showed that MT1-MMP is overexpressed in these cells. MT1-MMP is a key regulator of tumor progression through its functions as a matrix-degrading enzyme, as well as its ability to cleave factors, such as adhesion molecules and other MMPs. The aim of this study was to investigate the contribution of MT1-MMP to the invasive potential of RCC cells using in vitro type I collagen degradation and invasion assays. RESULTS: We evaluated RCC cells wild-type (WT8) and null (pRc-9) for VHL for invasive characteristics and showed that the pRc-9 cells demonstrated a greater propensity for both invasion and degradation of a type I collagen matrix. Furthermore, overexpression of either HIF-2alpha or MT1-MMP in the poorly invasive cell line, WT8, promoted collagen degradation and invasion of these cells. Finally, using RNAi, we show that inhibition of MT1-MMP suppresses tumor cell invasion of RCC cells. CONCLUSION: Our results suggest that MT1-MMP is a major mediator of tumor cell invasiveness and type I collagen degradation by VHL RCC cells that express either MT1-MMP or HIF-2alpha. As such, MT1-MMP may represent a novel target for anti-invasion therapy for this disease. [Abstract/Link to Full Text]

Revankar CM, Advani SH, Naik NR
Altered Ca2+ homeostasis in polymorphonuclear leukocytes from chronic myeloid leukaemia patients.
Mol Cancer. 2006;565.
BACKGROUND: In polymorphonuclear leukocytes (PMNL), mobilization of calcium ions is one of the early events triggered by binding of chemoattractant to its receptors. Besides chemotaxis, a variety of other functional responses are dependent on calcium ion mobilization. PMNL from chronic myeloid leukaemia (CML) patients that were morphologically indistinguishable from normal PMNL were found to be defective in various functions stimulated by a chemoattractant - fMLP. To study the mechanism underlying defective functions in CML PMNL, we studied calcium mobilization in CML PMNL in response to two different classical chemoattractants, fMLP and C5a. RESULTS: Release of calcium estimated by flow cytometry and spectrofluorimetry using fluo-3 as an indicator showed that the [Ca2+]i levels were lower in CML PMNL as compared to those in normal PMNL. But, both normal and CML PMNL showed maximum [Ca2+]i in response to fMLP and C5a at 10 sec and 30 sec, respectively. Spectrofluorimetric analysis of the total calcium release in chemoattractant treated PMNL indicated more and faster efflux of [Ca2+]i in CML PMNL as compared to normal PMNL. CONCLUSION: Fine-tuning of Ca2+ homeostasis was altered in CML PMNL. The altered Ca2+ homeostasis may contribute to the defective functions of CML PMNL. [Abstract/Link to Full Text]

Perroud B, Lee J, Valkova N, Dhirapong A, Lin PY, Fiehn O, Kültz D, Weiss RH
Pathway analysis of kidney cancer using proteomics and metabolic profiling.
Mol Cancer. 2006;564.
BACKGROUND: Renal cell carcinoma (RCC) is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC). We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease. RESULTS: Using 2-dimensional electrophoresis and mass spectrometric analysis, we identified 31 proteins which were differentially expressed with a high degree of significance in ccRCC as compared to adjacent non-malignant tissue, and we confirmed some of these by immunoblotting, immunohistochemistry, and comparison to published transcriptomic data. When evaluated by several pathway and biological process analysis programs, these proteins are demonstrated to be involved with a high degree of confidence (p values < 2.0 E-05) in glycolysis, propanoate metabolism, pyruvate metabolism, urea cycle and arginine/proline metabolism, as well as in the non-metabolic p53 and FAS pathways. In a pilot study using random urine samples from both ccRCC and control patients, we performed metabolic profiling and found that only sorbitol, a component of an alternative glycolysis pathway, is significantly elevated at 5.4-fold in RCC patients as compared to controls. CONCLUSION: Extensive pathway and network analysis allowed for the discovery of highly significant pathways from a set of clear cell RCC samples. Knowledge of activation of these processes will lead to novel assays identifying their proteomic and/or metabolomic signatures in biofluids of patient at high risk for this disease; we provide pilot data for such a urinary bioassay. Furthermore, we demonstrate how the knowledge of networks, processes, and pathways altered in kidney cancer may be used to influence the choice of optimal therapy. [Abstract/Link to Full Text]

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Recent Articles in Cancer Cell International

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Ponce de León V, Barrera-Rodríguez R
Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids.
Cancer Cell Int. 2005 Jul 7;5(1):20.
BACKGROUND: Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to multidrug resistance in tumours. However, the physiological role of P-gp in tumours growing as multicellular spheroids is not well understood. Recent evidence suggests that P-gp activity may be modulated by cellular components such as membrane proteins, membrane-anchoring proteins or membrane-lipid composition. Since, multicellular spheroids studies have evidenced alterations in numerous cellular components, including those related to the plasma membrane function, result plausible that some of these changes might modulate P-gp function and be responsible for the acquisition of multicellular drug resistance. In the present study, we asked if a human lung cancer cell line (INER-51) grown as multicellular spheroids can modify the P-gp activity to decrease the levels of doxorubicin (DXR) retained and increase their drug resistance. RESULTS: Our results showed that INER-51 spheroids retain 3-folds lower doxorubicin than the same cells as monolayers however; differences in retention were not observed when the P-gp substrate Rho-123 was used. Interestingly, neither the use of the P-gp-modulating agent cyclosporin-A (Cs-A) nor a decrease in ATP-pools were able to increase DXR retention in the multicellular spheroids. Only the lack of P-gp expression throughout the pharmacological selection of a P-gp negative (P-gpneg) mutant clone (PSC-1) derived from INER-51 cells, allow increase of DXR retention in spheroids. CONCLUSION: Thus, multicellular arrangement appears to alter the P-gp activity to maintain lower levels of DXR. However, the non expression of P-gp by cells forming multicellular spheroids has only a minor impact in the resistance to chemotherapeutic agents. [Abstract/Link to Full Text]

Ifon ET, Pang AL, Johnson W, Cashman K, Zimmerman S, Muralidhar S, Chan WY, Casey J, Rosenthal LJ
U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3.
Cancer Cell Int. 2005 Jun 22;519.
BACKGROUND: Insensitivity of advanced-stage prostate cancer to androgen ablation therapy is a serious problem in clinical practice because it is associated with aggressive progression and poor prognosis. Targeted therapeutic drug discovery efforts are thwarted by lack of adequate knowledge of gene(s) associated with prostate tumorigenesis. Therefore there is the need for studies to provide leads to targeted intervention measures. Here we propose that stable expression of U94, a tumor suppressor gene encoded by human herpesvirus 6A (HHV-6A), could alter gene expression and thereby inhibit the tumorigenicity of PC3 cell line. Microarray gene expression profiling on U94 recombinant PC3 cell line could reveal genes that would elucidate prostate cancer biology, and hopefully identify potential therapeutic targets. RESULTS: We have shown that stable expression of U94 gene in PC3 cell line inhibited its focus formation in culture, and tumorigenesis in nude mice. Moreover gene expression profiling revealed dramatic upregulation of FN 1 (fibronectin, 91 +/- 16-fold), and profound downregulation of ANGPTL 4 (angiopoietin-like-4, 20 +/- 4-fold) in U94 recombinant PC3 cell line. Quantitative real-time polymerase chain reaction (QRT-PCR) analysis showed that the pattern of expression of FN 1 and ANGPTL 4 mRNA were consistent with the microarray data. Based on previous reports, the findings in this study implicate upregulation of FN 1 and downregulation of ANGPTL 4 in the anti tumor activity of U94. Genes with cancer inhibitory activities that were also upregulated include SERPINE 2 (serine/cysteine protease inhibitor 2, 7 +/- 1-fold increase) and ADAMTS 1 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, 7 +/- 2-fold increase). Additionally, SPUVE 23 (serine protease 23) that is pro-tumorigenic was significantly downregulated (10 +/- 1-fold). CONCLUSION: The dramatic upregulation of FN 1 and downregulation of ANGPTL 4 genes in PC3 cell line stably expressing U94 implicate up-regulation of FN 1 and downregulation of ANGPTL 4 in anti tumor activity of U94. Further studies are necessary to determine functional roles of differentially expressed genes in U94 recombinant PC3 cell line, and hopefully provide leads to potential therapeutic targets in prostate cancer. [Abstract/Link to Full Text]

Boccadoro M, Morgan G, Cavenagh J
Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy.
Cancer Cell Int. 2005 Jun 1;5(1):18.
Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor kappaB-alpha, which prevents activation of nuclear factor kappaB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors. [Abstract/Link to Full Text]

Chattopadhyay MB, Mukherjee S, Kulkarni I, Vijayan V, Doloi M, Kanjilal N, Chatterjee M
Proton-Induced X-ray Emission (PIXE) Analysis and DNA-chain Break study in rat hepatocarcinogenesis: A possible chemopreventive role by combined supplementation of vanadium and beta-carotene.
Cancer Cell Int. 2005 May 26;5(1):16.
Combined effect of vanadium and beta-carotene on rat liver DNA-chain break and Proton induced X-ray emission (PIXE) analysis was studied during a necrogenic dose (200 mg/kg of body weight) of Diethyl Nitrosamine (DENA) induced rat liver carcinogenesis. Morphological and histopathological changes were observed as an end point biomarker. Supplementation of vanadium (0.5 ppm ad libitum) in drinking water and beta-carotene in the basal diet (120 mg/Kg of body weight) were performed four weeks before DENA treatment and continued till the end of the experiment (16 weeks). PIXE analysis revealed the restoration of near normal value of zinc, copper, and iron, which were substantially altered when compared to carcinogen treated groups. Supplementation of both vanadium and beta-carotene four weeks before DENA injection was found to offer significant (64.73%, P < 0.001) protection against generation of single-strand breaks when compared with the carcinogen control counter parts. A significant stabilization of hepatic architecture of the cells was observed as compared to carcinogen control in vanadium plus beta-carotene treated group. This study thus suggests that vanadium, a prooxidant but potential therapeutic agent yield safe and effective pharmacological formulation with beta-carotene, an antioxidant, in the inhibition of experimental rat hepatocarcinogenesis. [Abstract/Link to Full Text]

Cameron IL, Short N, Sun L, Hardman WE
Endothelial cell pseudopods and angiogenesis of breast cancer tumors.
Cancer Cell Int. 2005 May 26;5(1):17.
BACKGROUND: A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sections of tumors greater than 35 mm3 were stained with PAS, with CD-31 antibody (an endothelial cell maker), or with hypoxia inducible factor 1alpha antibody (HIF). The extent of blood vessel and endothelial cell pseudopod volume density was measured by ocular grid intercept counting in the PAS stained slides. RESULTS: The tumor area within 100-150 mum of the well-vascularized capsule had few blood vessels and only occasional endothelial cell pseudopods, whereas the area greater than 150 mum from the capsule had more blood vessels, capillaries, and a three-fold increase in volume density of pseudopods sprouting from the capillary endothelial cells. This subcortical region, rich in pseudopods, some of which were observed to have vacuoles/lumens, was strongly positive for presence of HIF. In some larger tumors, pseudopods were observed to insinuate for mm distances through hypoxic regions of the tumor. CONCLUSION: The positive correlation between presence of HIF and the increased extent of pseudopods suggests volume density measure of the latter as a quantifiable marker of tumor hypoxia. Apparently, hypoxic regions of the tumor produce HIF leading to production of vascular endothelial growth factors that stimulate sprouting of capillary endothelial cells and formation of endothelial cell pseudopods. [Abstract/Link to Full Text]

Stromskaya TP, Rybalkina EY, Zabotina TN, Shishkin AA, Stavrovskaya AA
Influence of RARalpha gene on MDR1 expression and P-glycoprotein function in human leukemic cells.
Cancer Cell Int. 2005 May 24;515.
BACKGROUND: Multidrug resistance (MDR) phenotype of malignant cells is the major problem in the chemotherapy of neoplasia. The treatment of leukemia with retinoids is aimed on the induction of leukemic cells differentiation. However the interconnections between retinoid regulated differentiation of leukemic cells and regulation of MDR remains unclear. METHODS: Four lines of cultured leukemic cells of diverse types of differentiation were infected with RARalpha gene and stable transfectants were isolated. We investigated the differentiation of these cells as well as the expression of RARalpha and MDR1 genes and P-glycoprotein (Pgp, MDR protein) functional activity in these cells. RESULTS: All RARalpha transfected sublines demonstrated the increase in the quantity of RARalpha mRNA. All these sublines became more differentiated. Intrinsic activity of MDR1 gene (but not Pgp functional activity) was increased in one of the transfectants. All-trans-retinoic acid (ATRA) induced Pgp activity in two of three infectants to a larger extent than in parental cells. CONCLUSION: The data show that RARalpha regulates MDR1/ Pgp activity in human leukemic cells, in the first place, Pgp activity induced by ATRA. These results show that RARalpha overexpression in leukemic cells could result in MDR. [Abstract/Link to Full Text]

Ervin H, Cox JL
Late stage inhibition of hematogenous melanoma metastasis by cystatin C over-expression.
Cancer Cell Int. 2005 May 17;5(1):14.
BACKGROUND: Tumor metastasis is a frequent cause of treatment failure for cancer patients. A key feature of metastatic cancer cells is their invasive ability. Cysteine proteases contribute to invasive properties of many cancer cell types. To analyze the contribution of cysteine proteases to metastasis we have over-expressed in B16 melanoma cells the natural cysteine protease inhibitor, cystatin C. We measured in vitro invasion of cystatin over-expression clones with Boyden chamber type assays. Tail-vein injections of cells were used to compare lung tumor colonization. Subcutaneous tumor growth and tumor cell metastasis from primary tumors were also analyzed. Apoptosis of tumor cells was measured in lung tissues following melanoma cell injection. RESULTS: Results show the in vitro invasion of cystatin C over-expressing cells was dramatically inhibited. Lung tumor colonization was also reduced. Increased tumor cell apoptosis was found to be an important factor and may be related to the reduced tumor burden noted in this system of melanoma metastasis. CONCLUSION: Cysteine proteases therefore, may be a target for future anti-metastatic therapies. [Abstract/Link to Full Text]

Machado CM, Schenka A, Vassallo J, Tamashiro WM, Gonçalves EM, Genari SC, Verinaud L
Morphological characterization of a human glioma cell l ine.
Cancer Cell Int. 2005 May 10;5(1):13.
A human malignant continuous cell line, named NG97, was recently established in our laboratory. This cell line has been serially subcultured over 100 times in standard culture media presenting no sign of cell senescence. The NG97 cell line has a doubling time of about 24 h. Immunocytochemical analysis of glial markers demonstrated that cells are positive for glial fibrillary acidic protein (GFAP) and S-100 protein, and negative for vimentin. Under phase-contrast microscope, cultures of NG97 showed cells with variable morphological features, such as small rounded cells, fusiform cells (fibroblastic-like cells), and dendritic-like cells. However, at confluence just small rounded and fusiform cells can be observed. At scanning electron microscopy (SEM) small rounded cells showed heterogeneous microextentions, including blebs and filopodia. Dendritic-like cells were flat and presented extensive prolongations, making several contacts with small rounded cells, while fusiform cells presented their surfaces dominated by microvilli.We believe that the knowledge about NG97 cell line may be useful for a deeper understanding of biological and immunological characteristics of gliomas. [Abstract/Link to Full Text]

Hardman WE, Sun L, Short N, Cameron IL
Dietary omega-3 fatty acids and ionizing irradiation on human breast cancer xenograft growth and angiogenesis.
Cancer Cell Int. 2005 Apr 28;5(1):12.
BACKGROUND: The effects of an omega-3 (n-3) fatty acid enriched diet alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA-MB231 breast cancer xenograft were tested. The cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into two diet groups: 1) mice with 10% corn oil (rich in omega 6 fatty acids) in their food, 2) mice consuming a 10% fat diet that was enriched in n-3 fatty acids. After two weeks on the diet, treatment with 200 cGy of IR every second day for four treatments (total 800 cGy) was initiated on half of the mice from each diet group. Some mice in each of the 4 groups were euthanized 24 hours after the end of IR while the remaining mice were followed for 3 additional weeks. Tumor sections were stained for endothelial cells with CD31 and PAS and for hypoxia inducible factor 1alpha (HIF-alpha). RESULTS: The tumor cortex within 100 microns of the well-vascularized capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at areas greater than 100 microns from the capsule (subcortex). Mice on the corn oil diet and treated with IR 24 hours previously or non-irradiated mice fed the n-3 diet had tumors with fewer blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic (HIF- alpha positive) areas than did mice from the non-irradiated corn oil fed group. The tumor growth rate of mice that received IR or that were fed the n-3 fatty acid enriched diet was significantly slower than in the mice fed the 10% corn oil diet. Harmful side effects were found only in the IR treated mice. CONCLUSION: The omega-3 fatty acid enriched diet proved to be a safe means for retarding tumor growth and vascularization. [Abstract/Link to Full Text]

Shehata MF
Rel/Nuclear factor-kappa B apoptosis pathways in human cervical cancer cells.
Cancer Cell Int. 2005 Apr 27;5(1):10.
Cervical cancer is considered a common yet preventable cause of death in women. It has been estimated that about 420 women out of the 1400 women diagnosed with cervical cancer will die during 5 years from diagnosis. This review addresses the pathogenesis of cervical cancer in humans with a special emphasis on the human papilloma virus as a predominant cause of cervical cancer in humans. The current understanding of apoptosis and regulators of apoptosis as well as their implication in carcinogenesis will follow. A special focus will be given to the role of Rel/NF-kappaB family of genes in the growth and chemotherapeutic treatment of the malignant HeLa cervical cells emphasizing on Xrel3, a cRel homologue. [Abstract/Link to Full Text]

Hoffmeyer MR, Wall KM, Dharmawardhane SF
In vitro analysis of the invasive phenotype of SUM 149, an inflammatory breast cancer cell line.
Cancer Cell Int. 2005 Apr 27;5(1):11.
BACKGROUND: Inflammatory breast cancer (IBC) is the most lethal form of locally invasive breast cancer known. However, very little information is available on the cellular mechanisms responsible for manifestation of the IBC phenotype. To understand the unique phenotype of IBC, we compared the motile and adhesive interactions of an IBC cell line, SUM 149, to the non-IBC cell line SUM 102. RESULTS: Our results demonstrate that both IBC and non-IBC cell lines exhibit similar adhesive properties to basal lamina, but SUM 149 showed a marked increase in adhesion to collagen I. In vitro haptotaxis assays demonstrate that SUM 149 was less invasive, while wound healing assays show a less in vitro migratory phenotype for SUM 149 cells relative to SUM 102 cells. We also demonstrate a role for Rho and E-cadherin in the unique invasive phenotype of IBC. Immunoblotting reveals higher E-cadherin and RhoA expression in the IBC cell line but similar RhoC expression. Rhodamine phalloidin staining demonstrates increased formation of actin stress fibers and larger focal adhesions in SUM 149 relative to the SUM 102 cell line. CONCLUSION: The observed unique actin and cellular architecture as well as the invasive and adhesive responses to the extracellular matrix of SUM 149 IBC cells suggest that the preference of IBC cells for connective tissue, possibly a mediator important for the vasculogenic mimicry via tubulogenesis seen in IBC pathological specimens. Overexpression of E-cadherin and RhoA may contribute to passive dissemination of IBC by promoting cell-cell adhesion and actin cytoskeletal structures that maintain tissue integrity. Therefore, we believe that these findings indicate a passive metastatic mechanism by which IBC cells invade the circulatory system as tumor emboli rather than by active migratory mechanisms. [Abstract/Link to Full Text]

Prehn RT
The role of mutation in the new cancer paradigm.
Cancer Cell Int. 2005 Apr 26;5(1):9.
The almost universal belief that cancer is caused by mutation may gradually be giving way to the belief that cancer begins as a cellular adaptation that involves the local epigenetic silencing of various genes. In my own interpretation of the new epigenetic paradigm, the genes epigenetically suppressed are genes that normally serve in post-embryonic life to suppress and keep suppressed those other genes upon which embryonic development depends. Those other genes, if not silenced or suppressed in the post-embryonic animal, become, I suggest, the oncogenes that are the basis of neoplasia.Mutations that occur in silenced genes supposedly go unrepaired and are, therefore, postulated to accumulate, but such mutations probably play little or no causative role in neoplasia because they occur in already epigenetically silenced genes. These mutations probably often serve to make the silencing, and therefore the cancer, epigenetically irreversible. [Abstract/Link to Full Text]

Yang Q, Fung KM, Day WV, Kropp BP, Lin HK
Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival.
Cancer Cell Int. 2005 Apr 6;5(1):8.
BACKGROUND: Androgens and androgen receptors (AR) regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA). This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. RESULTS: The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. CONCLUSION: We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression. [Abstract/Link to Full Text]

Padma S, Sowjanya AP, Poli UR, Jain M, Rao B, Ramakrishna G
Downregulation of calcineurin activity in cervical carcinoma.
Cancer Cell Int. 2005 Apr 1;5(1):7.
BACKGROUND: Calcineurin (CaN) is an important serine-threonine phosphatase (PP2B), which plays a crucial role in calcium-calmodulin mediated signal transduction events. Calcineurin has been implicated in pathogenesis of various diseases cardiac hypertrophy, diabetic neuropathy and Alzheimer's, however its role in neoplasia remains unclear. RESULTS: In view of this we evaluated the calcineurin activity in serum and biopsy samples collected from women diagnosed with invasive squamous cell carcinoma of cervix. A significant reduction was observed in the calcineurin activity in cancer cervix patients compared to the control group. However the calcineurin activity remained unaltered in the cervical scrapes obtained from patients diagnosed with low-grade squamous intra epithelial lesions (LSIL). Interestingly the downregulation of calcineurin activity in squamous cell carcinomas was not accompanied by any significant change in DNA-binding affinity of the transcriptional factor NFAT (Nuclear Factor of Activated T-cells). All the squamous cell carcinoma samples used in the present study were positive for high-risk human papillomavirus (HPV) types. CONCLUSION: The present study demonstrates the downregulation of calcineurin activity in squamous cell carcinoma of cervix with high risk HPV infection. We conclude that perturbations in calcineurin-mediated pathway may be involved in development of cervical neoplasia. [Abstract/Link to Full Text]

Zhang J, Tu Y, Smith-Schneider S
Activation of p53, inhibition of telomerase activity and induction of estrogen receptor beta are associated with the anti-growth effects of combination of ovarian hormones and retinoids in immortalized human mammary epithelial cells.
Cancer Cell Int. 2005 Mar 8;5(1):6.
BACKGROUND: A full-term pregnancy has been associated with reduced risk for developing breast cancer. In rodent models, the protective effect of pregnancy can be mimicked with a defined regimen of estrogen and progesterone combination (E/P). However, the effects of pregnancy levels of E/P in humans and their underlying mechanisms are not fully understood. In this report, we investigated the growth inhibitory effects of pregnancy levels of E/P and both natural and synthetic retinoids in an immortalized human mammary epithelial cell line, 76N TERT cell line. RESULTS: We observed that cell growth was modestly inhibited by E/P, 9-cis-retinoic acid (9-cis RA) or all-trans-retinoic acid (ATRA), and strongly inhibited by N-(4-hydroxyphenyl) retinamide (HPR). The growth inhibitory effects of retinoids were further increased in the presence of E/P, suggesting their effects are additive. In addition, our results showed that both E/P and retinoid treatments resulted in increased RARE and p53 gene activity. We further demonstrated that p53 and p21 protein expression were induced following the E/P and retinoid treatments. Furthermore, we demonstrated that while the telomerase activity was moderately inhibited by E/P, 9-cis RA and ATRA, it was almost completely abolished by HPR treatment. These inhibitions on telomerase activity by retinoids were potentiated by co-treatment with E/P, and correlated well with their observed growth inhibitory effects. Finally, this study provides the first evidence that estrogen receptor beta is up-regulated in response to E/P and retinoid treatments. CONCLUSION: Taken together, our studies show that part of the anti-growth effects of E/P and retinoids is p53 dependent, and involve activation of p53 and subsequent induction of p21 expression. Inhibition of telomerase activity and up-regulation of estrogen receptor beta are also associated with the E/P- and retinoid-mediated growth inhibition. Our studies also demonstrate that the potency of retinoids on cell growth inhibition may be increased through combination of estrogen and progesterone treatment. [Abstract/Link to Full Text]

Lichtenstein AV
On evolutionary origin of cancer.
Cancer Cell Int. 2005 Mar 2;5(1):5.
BACKGROUND: The necessary and sufficient capabilities of cancer cell have been identified. Strikingly, this list does not include one that would seem to be a key property, namely the ability of cancer cells to kill their "host". This is believed to be a self-evident consequence of the other capabilities (e.g., metastasis), although the available evidence suggests a distinct killer function. Taking into account this unlisted property can significantly affect the current paradigm of carcinogenesis. PRESENTATION OF THE HYPOTHESIS: On the assumption that killer function is a key capability of the cancer cell, it is suggested that cancer has evolved as a mechanism of negative selection of mutant alleles of vitally important genes present in population. Similarly to apoptosis, which is an altruistic suicidal act of a damaged cell, cancer is an altruistic suicidal act of an individual who carries dangerous alleles and presents a hazard for genetic stability of the population. From this point of view, apoptosis is not a protection means against cancer as generally believed, but rather they are the first and second lines of defense against genome instability, respectively. TESTING THE HYPOTHESIS: The modern DNA array technology is capable of revealing gene expression profiles responsible for killer function of cancer cell as well as those specific targets in the body that are most strongly affected by the tumor growth. IMPLICATIONS OF THE HYPOTHESIS: This hypothesis suggests new avenues of cancer research as well as principally new therapeutic strategies. [Abstract/Link to Full Text]

Kalejs M, Erenpreisa J
Cancer/testis antigens and gametogenesis: a review and "brain-storming" session.
Cancer Cell Int. 2005 Feb 16;5(1):4.
Genes expressed both in normal testis and in malignancies (Cancer/ Testis associated genes - CTA) have become the most extensively studied antigen group in the field of tumour immunology. Despite this, many fundamentally important questions remain unanswered: what is the connection between germ-cell specific genes and tumours? Is the expression of these genes yet another proof for the importance of genome destabilisation in the process of tumorigenesis?, or maybe activation of these genes is not quite random but instead related to some programme giving tumours a survival advantage?This review collates most of the recent information available about CTAs expression, function, and regulation. The data suggests a programme related to ontogenesis, mostly to gametogenesis. In the "brain-storming" part, facts in conflict with the hypothesis of random CTA gene activation are discussed. We propose a programme borrowed from organisms phylogenetically much older than humans, which existed before the differentiation of sexes. It is a programme that has served as a life cycle with prominent ploidy changes, and from which, as we know, the germ-cell ploidy cycle - meiosis - has evolved. Further work may show whether this hypothesis can lead to a novel anti-tumour strategy. [Abstract/Link to Full Text]

El Fitori J, Kleeff J, Giese NA, Guweidhi A, Bosserhoff AK, Büchler MW, Friess H
Melanoma Inhibitory Activity (MIA) increases the invasiveness of pancreatic cancer cells.
Cancer Cell Int. 2005 Feb 14;5(1):3.
BACKGROUND: Melanoma inhibitory activity (MIA) is a small secreted protein that interacts with extracellular matrix proteins. Its over-expression promotes the metastatic behavior of malignant melanoma, thus making it a potential prognostic marker in this disease. In the present study, the expression and functional role of MIA was analyzed in pancreatic cancer by quantitative real-time PCR (QRT-PCR), immunohistochemistry, immunoblot analysis and ELISA. To determine the effects of MIA on tumor cell growth and invasion, MTT cell growth assays and modified Boyden chamber invasion assays were used. RESULTS: The mRNA expression of MIA was 42-fold increased in pancreatic cancers in comparison to normal pancreatic tissues (p < 0.01). In contrast, MIA serum levels were not significantly different between healthy donors and pancreatic cancer patients. In pancreatic tissues, MIA was predominantly localized in malignant cells and in tubular complexes of cancer specimens, whereas normal ductal cells, acinar cells and islets were devoid of MIA immunoreactivity. MIA significantly promoted the invasiveness of cultured pancreatic cancer cells without influencing cell proliferation. CONCLUSION: MIA is over-expressed in pancreatic cancer and has the potential of promoting the invasiveness of pancreatic cancer cells. [Abstract/Link to Full Text]

Mannechez A, Reungpatthanaphong P, de Certaines JD, Leray G, Le Moyec L
Proton NMR visible mobile lipid signals in sensitive and multidrug-resistant K562 cells are modulated by rafts.
Cancer Cell Int. 2005 Feb 9;5(1):2.
BACKGROUND: Most cancer cells are characterized by mobile lipids visible on proton NMR (1H-NMR), these being comprised mainly of methyl and methylene signals from lipid acyl chains. Erythroleukemia K562 cells show narrow signals at 1.3 and 0.9 ppm, corresponding to mobile lipids (methylene and methyl, respectively), which are reduced when K562 cells are multidrug resistant (MDR). While the significance of the mobile lipids is unknown, their subcellular localization is still a matter of debate and may lie in the membrane or the cytoplasm. In this study, we investigate the role of cholesterol in the generation of mobile lipid signals. RESULTS: The proportion of esterified cholesterol was found to be higher in K562-sensitive cells than in resistant cells, while the total cholesterol content was identical in both cell lines. Cholesterol extraction in the K562 wild type (K562wt) cell line and its MDR counterpart (K562adr), using methyl-beta-cyclodextrin, was accompanied by a rise of mobile lipids in K562wt cells only. The absence of caveolae was checked by searching for the caveolin-1 protein in K562wt and K562adr cells. However, cholesterol was enriched in another membrane microdomain designated as "detergent-insoluble glycosphingomyelin complexes" or rafts. These microdomains were studied after extraction with triton X-100, a mild non-ionic detergent, revealing mobile lipid signals preserved only in the K562wt spectra. Moreover, following perturbation/disruption of these microdomains using sphingomyelinase, mobile lipids increased only in K562wt cells. CONCLUSION: These results suggest that cholesterol and sphingomyelin are involved in mobile lipid generation via microdomains of detergent-insoluble glycosphingomyelin complexes such as rafts. Increasing our knowledge of membrane microdomains in sensitive and resistant cell lines may open up new possibilities in resistance reversion. [Abstract/Link to Full Text]

Morgan H, Hill PA
Human breast cancer cell-mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activity.
Cancer Cell Int. 2005 Feb 8;5(1):1.
BACKGROUND: Breast cancer cells frequently metastasize to the skeleton and induce extensive bone destruction. Cancer cells produce proteinases, including matrix metalloproteinases (MMPs) and the plasminogen activator system (PAS) which promote invasion of extracellular matrices, but whether these proteinases degrade bone matrix is unclear. To characterize the role that breast cancer cell proteinases play in bone degradation we compared the effects of three human breast cancer cell lines, MDA-MB-231, ZR-75-1 and MCF-7 with those of a normal breast epithelial cell line, HME. The cell lines were cultured atop radiolabelled matrices of either mineralized or non-mineralized bone or type I collagen, the principal organic constituent of bone. RESULTS: The 3 breast cancer cell lines all produced significant degradation of the 3 collagenous extracellular matrices (ECMs) whilst the normal breast cell line was without effect. Breast cancer cells displayed an absolute requirement for serum to dissolve collagen. Degradation of collagen was abolished in plasminogen-depleted serum and could be restored by the addition of exogenous plasminogen. Localization of plasmin activity to the cell surface was critical for the degradation process as aprotinin, but not alpha2 antiplasmin, prevented collagen dissolution. During ECM degradation breast cancer cell lines expressed urokinase-type plasminogen activator (u-PA) and uPA receptor, and MMPs-1, -3, -9,-13, and -14. The normal breast epithelial cell line expressed low levels of MMPs-1, and -3, uPA and uPA receptor. Inhibitors of both the PAS (aprotinin and PA inhibitor-1) and MMPs (CT1166 and tisue inhibitor of metalloproteinase) blocked collagen degradation, demonstrating the requirement of both plasminogen activation and MMP activity for degradation. The activation of MMP-13 in human breast cancer cells was prevented by plasminogen activator inhibitor-1 but not by tissue inhibitor of metalloproteinase-1, suggesting that plasmin activates MMP-13 directly. CONCLUSIONS: These data demonstrate that breast cancer cells dissolve type I collagen and that there is an absolute requirement for plasminogen activation and MMP activity in the degradation process. [Abstract/Link to Full Text]

Zelvyte I, Stevens T, Westin U, Janciauskiene S
alpha1-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro.
Cancer Cell Int. 2004 Nov 21;4(1):7.
BACKGROUND: Tumor microenvironment, which is largely affected by inflammatory cells, is a crucial participant in the neoplastic process through promotion of cell proliferation, survival and migration. We measured the effects of polymorphonuclear neutrophil (PMN) conditioned medium alone, and supplemented with serine proteinase inhibitor alpha-1 antitrypsin (AAT) or its C-terminal fragment (C-36 peptide), on cultured lung cancer cells. METHODS: Lung cancer HCC cells were grown in a regular medium or in a PMN-conditioned medium in the presence or absence of AAT (0.5 mg/ml) or its C-36 peptide (0.06 mg/ml) for 24 h. Cell proliferation, invasiveness and release of IL-8 and VEGF were analyzed by [3H]-thymidine incorporation, Matrigel invasion and ELISA methods, respectively. RESULTS: Cells exposed to PMN-conditioned medium show decreased proliferation and IL-8 release by 3.9-fold, p < 0.001 and 1.3-fold, p < 0.05, respectively, and increased invasiveness by 2-fold (p < 0.001) compared to non-treated controls. In the presence of AAT, PMN-conditioned medium loses its effects on cell proliferation, invasiveness and IL-8 release, whereas VEGF is up-regulated by 3.7-fold (p < 0.001) compared to controls. Similarly, C-36 peptide abolishes the effects of PMN-conditioned medium on cell invasiveness, but does not alter its effects on cell proliferation, IL-8 and VEGF release. Direct HCC cell exposure to AAT enhances VEGF, but inhibits IL-8 release by 1.7-fold (p < 0.001) and 1.4-fold (p < 0.01) respectively, and reduces proliferation 2.5-fold (p < 0.01). In contrast, C-36 peptide alone did not affect these parameters, but inhibited cell invasiveness by 51.4% (p < 0.001), when compared with non-treated controls. CONCLUSIONS: Our data provide evidence that neutrophil derived factors decrease lung cancer HCC cell proliferation and IL-8 release, but increase cell invasiveness. These effects were found to be modulated by exogenously present serine proteinase inhibitor, AAT, and its C-terminal fragment, which points to a complexity of the relationships between tumor cell biological activities and local microenvironment. [Abstract/Link to Full Text]

Choi CH, Cha YJ, An CS, Kim KJ, Kim KC, Moon SP, Lee ZH, Min YD
Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein.
Cancer Cell Int. 2004 10 19;4(1):6.
BACKGROUND: Heptaplatin is a new platinum derivative with anticancer activity against various cancer cell lines, including cisplatin-resistant cancer cell lines (Cancer Chemother Pharmacol 1995; 35: 441). METHODS: Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines has been investigated in connection with metallothionein (MT). Cytotoxicity was determined by an MTT assay. MT mRNA, was determined by RT-PCR assay. Transfection study was carried out to examine the function of MT. RESULTS: Of various gastric cancer cell lines, SNU-638 and SNU-601 showed the highest and lowest levels of MT mRNA, respectively, showing 80-fold difference. The IC50 values of SNU-638 to cisplatin, carboplatin and heptaplatin were 11.2-fold, 5.1-fold and 2.0-fold greater than those of SNU-601, respectively. Heptaplatin was more effective against cisplatin-resistant and MT-transfected gastric cancer sublines than cisplatin or carboplatin was. In addition, heptaplatin attenuated cadmium, but not zinc, induction of MT. CONCLUSION: These results indicate that molecular mechanisms of heptaplatin effective against cisplatin-resistant gastric cancer sublines is at least in part due to the less involvement of MT in heptaplatin resistance as well as its attenuation of MT induction. [Abstract/Link to Full Text]

Kumi-Diaka J, Saddler-Shawnette S, Aller A, Brown J
Potential mechanism of phytochemical-induced apoptosis in human prostate adenocarcinoma cells: Therapeutic synergy in genistein and beta-lapachone combination treatment.
Cancer Cell Int. 2004 Aug 17;4(1):5.
BACKGROUND: Prostate cancer is the second leading cause of male death in the United States. The incidence increases most rapidly with age, and multiple genetic and epigenetic factors have been implicated in the initiation, progression, and metastasis of the cancer. Nevertheless, scientific knowledge of the molecular mechanisms underlying the disease is still limited; and hence treatment has only been partially successful. The objective of the current studies was to examine the role of caspase 3 (CPP32) and NAD(P)H:quinone oxidoreductase (NQO1) in the signaling of genistein-and beta-lapachone (bLap)-induced apoptosis in human prostate carcinoma cells PC3. RESULTS: Both genistein and bLap produced dose-dependent growth inhibition and treatment-induced apoptosis in PC3. Treatment with caspase 3 inhibitor, DEVD-fmk before exposure to genistein, significantly inhibited caspase 3 expression and treatment-induced apoptosis; implicating CPP32 as the main target in genistein-induced apoptosis in PC3. Contrary to this observation, inhibition of CPP32 did not significantly influence bLap-induced apoptosis; implying that the major target of bLap-induced apoptosis may not be the caspase. Treatment with NQO1 inhibitor, dicoumarol (50 microM), prior to exposure of PC3 to bLap led to significant decrease in bLap toxicity concurrent with significant decrease in treatment-induced apoptosis; thus implicating NQO1 as the major target in beta-lapachone-induced apoptosis in PC3. In addition, the data demonstrated that NQO1 is the major target in bLap-genistein (combination)-induced apoptosis. On the contrary, blocking NQO1 activity did not significantly affect genistein-induced apoptosis; implying that NQO1 pathway may not be the main target for genistein-induced apoptosis in PC3 cells. Furthermore, blocking NQO1 and CPP32 did not confer 100% protection against genistein-induced or bLap-induced apoptosis. CONCLUSION: The data thus demonstrate that both genistein-and bLap-induced apoptosis are mostly but not completely dependent on CPP32 and NQO1 respectively. Other minor alternate death pathways may be involved. This suggests that some death receptor signals do not utilize the caspase CPP32 and/or the NQO1 death pathways in PC3. The demonstrated synergism between genistein and bLap justifies consideration of these phytochemicals in chemotherapeutic strategic planning. [Abstract/Link to Full Text]


Association for Immunotherapy of Cancer: Cancer Immunotherapy - 2nd Annual Meeting. Mainz, Germany, 6-7 May 2004. Abstracts.
Cancer Cell Int. 2004 Jul 1;4 Suppl 1S1-S59. [Abstract/Link to Full Text]

Frahm S, Kurtz A, Kluwe L, Farassati F, Friedrich RE, Mautner VF
Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients.
Cancer Cell Int. 2004 May 17;4(1):4.
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone (Exisulind) are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients. RESULTS: Exisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 microM and 63 microM, respectively. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 microM Exisulind and 125 microM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1/2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen. CONCLUSIONS: Our results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST. [Abstract/Link to Full Text]

Sharma R, Kline R
Chemosensitivity assay in mice prostate tumor: Preliminary report of flow cytometry, DNA fragmentation, ion ratiometric methods of anti-neoplastic drug monitoring.
Cancer Cell Int. 2004 Mar 19;4(1):3.
Flow cytometry, DNA fragmentation, ion ratiomateric analysis and NMR peaks characterized drug chemosensitivity of antineoplastic drugs. Hypotheses were: 1. The chemosensitive effect of different cancer cell lines is characteristic; 2. DNA fragmentation, ion ratiometric analysis suggest apoptosis status of tumor cells. METHODS: PC-3 cell lines were compared with DU-145, LNCaP cell lines in culture for the [Na]i and [Ca]i ion sensing dyes, cell death, NMR peaks and apoptosis staining for chemotherapeutic action of different drugs. RESULTS: DNA fragmentation, ratiometric ions and fluorescence endlabelling plots were characteristic for cell lines and drug response. 31P-23Na NMR spectra showed characteristic high phospho-choline and sodium peaks. CONCLUSION: Flow cytometry, DNA fragmentation, ion ratiometric methods and NMR peaks indicated apoptosis and offered in vivo drug monitoring method. [Abstract/Link to Full Text]

Evdonin AL, Guzhova IV, Margulis BA, Medvedeva ND
Phospholipse c inhibitor, u73122, stimulates release of hsp-70 stress protein from A431 human carcinoma cells.
Cancer Cell Int. 2004 Feb 27;4(1):2.
BACKGROUND: Accumulating evidences suggest that Hsp 70, the inducible component of Hsp70 family, might release from a living cell. Here we show that a pharmacological inhibitor of phospholipase C activity U73122 caused a 2-4 fold reduction of an intracellular level of Hsp70 in A431 human carcinoma cells. RESULTS: A depletion of Hsp70 under U73122 was a result of the protein release since it was detected in cell culture medium, as was established by immunoprecipitation and precipitation with ATP-agarose. The reduction of Hsp70 level was specifically attributed to the inhibition of PLC, since the non-active inhibitor, U73343, had no effect on Hsp70 level. The PLC-dependent decrease of Hsp70 intracellular level was accompanied by the enhanced sensitivity of A431 cells to the apoptogenic effect of hydrogen peroxide. Here for the first time we demonstrated one of the possibilities for a cell to export Hsp70 in PLC-dependent manner. CONCLUSION: From our data we suggest that phospholipase C inhibition is one of the possible mechanisms of Hsp70 release from cells. [Abstract/Link to Full Text]

Calogero A, Lombari V, De Gregorio G, Porcellini A, Ucci S, Arcella A, Caruso R, Gagliardi FM, Gulino A, Lanzetta G, Frati L, Mercola D, Ragona G
Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma.
Cancer Cell Int. 2004 Jan 7;4(1):1.
BACKGROUND: The aim of this work was to investigate in vitro the putative role of EGR-1 in the growth of glioma cells. EGR-1 expression was examined during the early passages in vitro of 17 primary cell lines grown from 3 grade III and from 14 grade IV malignant astrocytoma explants. The explanted tumors were genetically characterized at the p53, MDM2 and INK4a/ARF loci, and fibronectin expression and growth characteristics were examined. A recombinant adenovirus overexpressing EGR-1 was tested in the primary cell lines. RESULTS: Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1-2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus. CONCLUSIONS: Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene. [Abstract/Link to Full Text]

Pe?ina-Slaus N
Tumor suppressor gene E-cadherin and its role in normal and malignant cells.
Cancer Cell Int. 2003 Oct 14;3(1):17.
E-cadherin tumor suppressor genes are particularly active area of research in development and tumorigenesis. The calcium-dependent interactions among E-cadherin molecules are critical for the formation and maintenance of adherent junctions in areas of epithelial cell-cell contact. Loss of E-cadherin-mediated-adhesion characterises the transition from benign lesions to invasive, metastatic cancer. Nevertheless, there is evidence that E-cadherins may also play a role in the wnt signal transduction pathway, together with other key molecules involved in it, such as beta-catenins and adenomatous poliposis coli gene products.The structure and function of E-cadherin, gene and protein, in normal as well as in tumor cells are reviewed in this paper. [Abstract/Link to Full Text]

Lee AT, Azimahtol HL, Tan AN
Styrylpyrone Derivative (SPD) induces apoptosis in a caspase-7-dependent manner in the human breast cancer cell line MCF-7.
Cancer Cell Int. 2003 Oct 4;3(1):16.
BACKGROUND: Styrylpyrone derivative (SPD) is a plant-derived pharmacologically active compound extracted from Goniothalamus sp. Previously, we have reported that SPD inhibited the proliferation of MCF-7 human breast cancer cells by inducing apoptotic cell death, while having minimal effects on non-malignant cells. Here, we attempt to further elucidate the mode of action of SPD. RESULTS: We found that the intrinsic apoptotic pathway was invoked, with the accumulation of cytosolic cytochrome c and processing of the initiator caspase-9. Cleaved products of procaspase-8 were not detected. Next, the executioner caspase-7 was cleaved and activated in response to SPD treatment. To confirm that apoptosis was induced following caspase-7 activation, the caspase inhibitor Ac-DEVD-CHO was used. Pre-incubation of cells with this inhibitor reversed apoptosis levels and caspase-7 activity in SPD-treated cells to untreated levels. CONCLUSIONS: Taken together, these results suggest SPD as a potent antiproliferative agent on MCF-7 cells by inducing apoptosis in a caspase-7-dependent manner. [Abstract/Link to Full Text]

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Recent Articles in Breast Cancer Research

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Finak G, Sadekova S, Pepin F, Hallett M, Meterissian S, Halwani F, Khetani K, Souleimanova M, Zabolotny B, Omeroglu A, Park M
Gene expression signatures of morphologically normal breast tissue identify basal-like tumors.
Breast Cancer Res. 2006;8(5):R58.
INTRODUCTION: The role of the cellular microenvironment in breast tumorigenesis has become an important research area. However, little is known about gene expression in histologically normal tissue adjacent to breast tumor, if this is influenced by the tumor, and how this compares with non-tumor-bearing breast tissue. METHODS: To address this, we have generated gene expression profiles of morphologically normal epithelial and stromal tissue, isolated using laser capture microdissection, from patients with breast cancer or undergoing breast reduction mammoplasty (n = 44). RESULTS: Based on this data, we determined that morphologically normal epithelium and stroma exhibited distinct expression profiles, but molecular signatures that distinguished breast reduction tissue from tumor-adjacent normal tissue were absent. Stroma isolated from morphologically normal ducts adjacent to tumor tissue contained two distinct expression profiles that correlated with stromal cellularity, and shared similarities with soft tissue tumors with favorable outcome. Adjacent normal epithelium and stroma from breast cancer patients showed no significant association between expression profiles and standard clinical characteristics, but did cluster ER/PR/HER2-negative breast cancers with basal-like subtype expression profiles with poor prognosis. CONCLUSION: Our data reveal that morphologically normal tissue adjacent to breast carcinomas has not undergone significant gene expression changes when compared to breast reduction tissue, and provide an important gene expression dataset for comparative studies of tumor expression profiles. [Abstract/Link to Full Text]

Mylona E, Magkou C, Giannopoulou I, Agrogiannis G, Markaki S, Keramopoulos A, Nakopoulou L
Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: relation to tumor phenotype and clinical outcome.
Breast Cancer Res. 2006;8(5):R57.
INTRODUCTION: Our aim was to study the expression pattern of tissue inhibitor of metalloproteinases (TIMP)-3 protein in invasive breast carcinoma, and its clinicopathological and prognostic value as well as its relation to markers indicative of the tumor phenotype. METHODS: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 173 invasive breast carcinomas to detect the proteins TIMP-3, estrogen receptor (ER), progesterone receptor, p53, c-erbB-2, topoisomerase IIalpha and Bcl-2. RESULTS: TIMP-3 protein was immunodetected in the cytoplasm of the malignant cells and the peritumoral stroma, as well as in in situ carcinoma and normal epithelium. Reduced expression of TIMP-3 protein within cancer cells was correlated with carcinomas of high nuclear and histological grade (p = 0.032 and p = 0.015, respectively), and low ER expression (p = 0.053). Moreover, TIMP-3 immunopositivity was inversely correlated with the expression of p53 and topoIIalpha proteins (p = 0.002 and p = 0.008, respectively), whereas it was positively associated with Bcl-2 expression (p = 0.020). Reduced expression of TIMP-3 protein within cancer cells was found to have an unfavorable impact on disease-free survival (p = 0.052) in the entirety of the patient population, as well as in both subgroups of lymph-node-positive and mutant-p53-negative patients (p = 0.007 and p = 0.037, respectively). Stromal localization of TIMP-3 protein was found to have no clinicopathological or prognostic value. CONCLUSION: This is the first immunohistochemical study to show that TIMP-3 protein within cancer cells is associated with tumor phenotype. Reduced expression of TIMP-3 protein within cancer cells was found to correlate with an aggressive tumor phenotype, negatively affecting the disease-free survival of both subgroups of lymph node-positive and mutant-p53-negative patients. [Abstract/Link to Full Text]

Grigoriadis A, Mackay A, Reis-Filho JS, Steele D, Iseli C, Stevenson BJ, Jongeneel CV, Valgeirsson H, Fenwick K, Iravani M, Leao M, Simpson AJ, Strausberg RL, Jat PS, Ashworth A, Neville AM, O'Hare MJ
Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data.
Breast Cancer Res. 2006;8(5):R56.
INTRODUCTION: Diverse microarray and sequencing technologies have been widely used to characterise the molecular changes in malignant epithelial cells in breast cancers. Such gene expression studies to identify markers and targets in tumour cells are, however, compromised by the cellular heterogeneity of solid breast tumours and by the lack of appropriate counterparts representing normal breast epithelial cells. METHODS: Malignant neoplastic epithelial cells from primary breast cancers and luminal and myoepithelial cells isolated from normal human breast tissue were isolated by immunomagnetic separation methods. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using massively parallel signature sequencing (MPSS) and four different genome wide microarray platforms. Functional related transcripts of the differential tumour epithelial transcriptome were used for gene set enrichment analysis to identify enrichment of luminal and myoepithelial type genes. Clinical pathological validation of a small number of genes was performed on tissue microarrays. RESULTS: MPSS identified 6,553 differentially expressed genes between the pool of normal luminal cells and that of primary tumours substantially enriched for epithelial cells, of which 98% were represented and 60% were confirmed by microarray profiling. Significant expression level changes between these two samples detected only by microarray technology were shown by 4,149 transcripts, resulting in a combined differential tumour epithelial transcriptome of 8,051 genes. Microarray gene signatures identified a comprehensive list of 907 and 955 transcripts whose expression differed between luminal epithelial cells and myoepithelial cells, respectively. Functional annotation and gene set enrichment analysis highlighted a group of genes related to skeletal development that were associated with the myoepithelial/basal cells and upregulated in the tumour sample. One of the most highly overexpressed genes in this category, that encoding periostin, was analysed immunohistochemically on breast cancer tissue microarrays and its expression in neoplastic cells correlated with poor outcome in a cohort of poor prognosis estrogen receptor-positive tumours. CONCLUSION: Using highly enriched cell populations in combination with multiplatform gene expression profiling studies, a comprehensive analysis of molecular changes between the normal and malignant breast tissue was established. This study provides a basis for the identification of novel and potentially important targets for diagnosis, prognosis and therapy in breast cancer. [Abstract/Link to Full Text]

Stuedal A, Ursin G, Veierřd MB, Bremnes Y, Reseland JE, Drevon CA, Gram IT
Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study.
Breast Cancer Res. 2006;8(5):R55.
INTRODUCTION: Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk. METHODS: We included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Tromsř, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area. RESULTS: After adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (P(trend) = 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (P(trend) = 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content (P(trend) = 0.003, P for interaction = 0.05). CONCLUSION: We found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast. [Abstract/Link to Full Text]

Cox DG, Blanché H, Pearce CL, Calle EE, Colditz GA, Pike MC, Albanes D, Allen NE, Amiano P, Berglund G, Boeing H, Buring J, Burtt N, Canzian F, Chanock S, Clavel-Chapelon F, Feigelson HS, Freedman M, Haiman CA, Hankinson SE, Henderson BE, Hoover R, Hunter DJ, Kaaks R, Kolonel L, Kraft P, LeMarchand L, Lund E, Palli D, Peeters PH, Riboli E, Stram DO, Thun M, Tjonneland A, Trichopoulos D, Yeager M
A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).
Breast Cancer Res. 2006;8(5):R54.
INTRODUCTION: Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). METHODS: The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls). RESULTS: We found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. CONCLUSION: Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer. [Abstract/Link to Full Text]

Preda L, Villa G, Rizzo S, Bazzi L, Origgi D, Cassano E, Bellomi M
Magnetic resonance mammography in the evaluation of recurrence at the prior lumpectomy site after conservative surgery and radiotherapy.
Breast Cancer Res. 2006;8(5):R53.
INTRODUCTION: The aim was to assess the value of magnetic resonance mammography (MRM) in the detection of recurrent breast cancer on the prior lumpectomy site in patients with previous conservative surgery and radiotherapy. METHODS: Between April 1999 and July 2003, 93 consecutive patients with breast cancer treated with conservative surgery and radiotherapy underwent MRM, when a malignant lesion on the site of lumpectomy was suspected by ultrasound and/or mammography. MRM scans were evaluated by morphological and dynamic characteristics. MRM diagnosis was compared with histology or with a 36-month imaging follow-up. Enhancing areas independent of the prior lumpectomy site, incidentally detected during the MRM, were also evaluated. RESULTS: MRM findings were compared with histology in 29 patients and with a 36-month follow-up in 64 patients. MRM showed 90% sensitivity, 91.6% specificity, 56.3% positive predictive value and 98.7% negative predictive value for detection of recurrence on the surgical scar. MRM detected 13 lesions remote from the scar. The overall sensitivity, specificity, positive predictive value and negative predictive value of MRM for detection of breast malignancy were 93.8%, 90%, 62.5% and 98.8%, respectively. CONCLUSION: MRM is a sensitive method to differentiate recurrence from post-treatment changes at the prior lumpectomy site after conservative surgery and radiation therapy. The high negative predictive value of this technique can avoid unnecessary biopsies or surgical treatments. [Abstract/Link to Full Text]

Ural AU, Avcu F, Candir M, Guden M, Ozcan MA
In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells.
Breast Cancer Res. 2006;8(4):R52.
INTRODUCTION: Bisphosphonates are mostly used in the treatment of bone metastases. They have been shown to act synergistically with other chemotherapeutic agents. It is not known, however, whether similar synergistic effects exist with radiation on breast cancer cells. METHODS: Human MCF-7 breast cancer cells were treated with up to 100 microM zoledronic acid, were irradiated with up to 800 cGy or were exposed to combinations of both treatments to determine the antiproliferative effects of zoledronic acid and radiation. RESULTS: Zoledronic acid and radiation caused a dose-dependent and time-dependent decrease in cell viability (approximate 50% growth inhibition values were 48 microM and 20 microM for 24 hours and 72 hours, respectively, for zoledronic acid and 500 cGy for radiation). A synergistic cytotoxic effect of the combination of zoledronic acid and radiation was confirmed by isobologram analysis. CONCLUSION: These data constitute the first in vitro evidence for synergistic effects between zoledronic acid and radiation. This combination therapy might thus be expected to be more effective than either treatment alone in patients with metastatic breast carcinoma. [Abstract/Link to Full Text]

Zanetti-Dällenbach R, Vuaroqueaux V, Wight E, Labuhn M, Singer G, Urban P, Eppenberger U, Holzgreve W, Eppenberger-Castori S
Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples.
Breast Cancer Res. 2006;8(4):R51.
INTRODUCTION: Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor. METHODS: We quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB. RESULTS: In 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (rs > or = 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis. CONCLUSION: A GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance. [Abstract/Link to Full Text]


Symposium Mammographicum 2006, Bournemouth, United Kingdom, 9-11 July 2006. Abstracts.
Breast Cancer Res. 2006;8 Suppl 1P1-87. [Abstract/Link to Full Text]

Sun D, Chen G, Dellinger RW, Duncan K, Fang JL, Lazarus P
Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants.
Breast Cancer Res. 2006;8(4):R50.
INTRODUCTION: Tamoxifen (TAM) is an antiestrogen widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism of TAM and one of its major active metabolites, 4-hydroxytamoxifen (4-OH-TAM), is via glucuronidation. In the present study, the glucuronidating activities of three common variant isoforms encoded by the human UDP-glucuronosyltransferase (UGT) 1A4 gene were examined against TAM, trans-4-OH-TAM and cis-4-OH-TAM. METHODS: HPLC was used to detect glucuronide conjugates in microsomes from UGT1A4-overexpressing HK293 cells. The UGT1A4 wild-type cDNA was synthesized by RT-PCR using normal human liver total RNA. The UGT1A424Thr/48Leu and UGT1A424Pro/48Val variants were generated by site-directed mutagenesis of the pcDNA3.1/V5-His-TOPO plasmid expressing wild-type UGT1A424Pro/48Leu. Levels of UGT1A4 expression in UGT-overexpressing cell lines were measured by western blot analysis. RESULTS: Microsomes from wild-type UGT1A424Pro/48Leu-overexpressing HK293 cells exhibited significant levels of activity against TAM, trans-4-OH-TAM and cis-4-OH-TAM, forming exclusively the tamoxifen quaternary ammonium glucuronide (TAM-N+-glucuronide) and the 4-hydroxytamoxifen quaternary ammonium glucuronides (trans-4-OH-TAM-N+-glucuronide and cis-4-OH-TAM-N+-glucuronide) with apparent Km values of 2.0 microM, 2.2 microM, and 2.1 microM, respectively. Higher glucuronidation activities were found by kinetic analysis for microsomes from the variant UGT1A424Pro/48Val-overexpressing cell line as compared with microsomes from wild-type UGT1A424Pro/48Leu-overexpressing cells against TAM and against both the trans and cis isomers of 4-OH-TAM. A significantly (P < 0.02) lower Km value (approximately 1.6-fold to 1.8-fold) was observed for both 4-OH-TAM isomers, while a near-significant (P = 0.053) decrease in Km was observed for TAM for the UGT1A424Pro/48Val variant as compared with wild-type UGT1A4. The Vmax/Km ratio for the UGT1A424Pro/48Val variant was significantly (P < or = 0.005) higher than that observed for the wild-type UGT1A4 isoform for both the trans and cis isomers of 4-OH-TAM after normalization for UGT1A4 expression by western blotting. No significant effect on enzyme kinetics was observed for the UGT1A424Thr/48Leu variant against either isomer of 4-OH-TAM or with TAM. CONCLUSION: These data suggest that the UGT1A4 codon 48 Leu>Val polymorphism significantly alters glucuronidation rates against TAM and its active hydroxylated metabolites, and that this polymorphism may play an important role in individual pharmacological response to TAM therapy. [Abstract/Link to Full Text]

Booth BW, Smith GH
Estrogen receptor-alpha and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands.
Breast Cancer Res. 2006;8(4):R49.
INTRODUCTION: Stem cells of somatic tissues are hypothesized to protect themselves from mutation and cancer risk through a process of selective segregation of their template DNA strands during asymmetric division. Mouse mammary epithelium contains label-retaining epithelial cells that divide asymmetrically and retain their template DNA. METHOD: Immunohistochemistry was used in murine mammary glands that had been labeled with [3H]thymidine during allometric growth to investigate the co-expression of DNA label retention and estrogen receptor (ER)-alpha or progesterone receptor (PR). Using the same methods, we investigated the co-localization of [3H]thymidine and ER-alpha or PR in mammary tissue from mice that had received treatment with estrogen, progesterone, and prolactin subsequent to a long chase period to identify label-retaining cells. RESULTS: Label-retaining epithelial cells (LRECs) comprised approximately 2.0% of the entire mammary epithelium. ER-alpha-positive and PR-positive cells represented about 30-40% of the LREC subpopulation. Administration of estrogen, progesterone, and prolactin altered the percentage of LRECs expressing ER-alpha. CONCLUSION: The results presented here support the premise that there is a subpopulation of LRECs in the murine mammary gland that is positive for ER-alpha and/or PR. This suggests that certain mammary LRECs (potentially stem cells) remain stably positive for these receptors, raising the possibility that LRECs comprise a hierarchy of asymmetrically cycling mammary stem/progenitor cells that are distinguished by the presence or absence of nuclear steroid receptor expression. [Abstract/Link to Full Text]

Yamashita H, Toyama T, Nishio M, Ando Y, Hamaguchi M, Zhang Z, Kobayashi S, Fujii Y, Iwase H
p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer.
Breast Cancer Res. 2006;8(4):R48.
INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. MATERIALS AND METHODS: The expression of HER2, p53, and Ki67 was examined by immunohistochemistry in primary breast tumour specimens from 73 metastatic breast cancer patients who received first-line treatment with endocrine therapy on relapse, and analysed to determine whether expression of these molecular markers affected the response to endocrine therapy. RESULTS: Of the 73 invasive ductal carcinomas, 12.3%, 21.9%, and 35.6% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. All patients received endocrine therapy as first-line treatment for metastatic breast cancer; 34 patients (46.6%) responded. Patients with primary breast tumours that had p53 protein accumulation and Ki67 expression showed significantly more resistance to endocrine therapy (P = 0.0049 and P = 0.024, respectively). There were also tendencies for HER2 overexpression to correlate with resistance to endocrine therapy, but this did not reach significance. p53 protein accumulation and HER2 overexpression significantly reduced post-relapse survival (P < 0.0001 and P = 0.001, respectively), and these factors were also statistically significant in a multivariate analysis. CONCLUSION: These data suggest that p53 protein accumulation is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in hormone receptor-positive metastatic breast cancer. [Abstract/Link to Full Text]

Nottage MK, Kopciuk KA, Tzontcheva A, Andrulis IL, Bull SB, Blackstein ME
Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study.
Breast Cancer Res. 2006;8(4):R44.
INTRODUCTION: This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors--in particular younger age (< 40 years)--predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS). METHODS: A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18-75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type). RESULTS: During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 - 3.58), presence of intraductal disease (RR = 1.81, 95% CI = 1.15-2.85) and histological grade ('G2' or G3 versus G1: RR = 1.59, 95% CI = 0.87-2.94). In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR (RR = 2.58, 95% CI = 1.41-4.72), tumor size (1-2 cm versus < 1 cm: RR = 1.95, 95% CI = 1.05-3.64, > 2 cm versus < 1 cm: RR = 2.94, 95% CI = 1.56-5.56), progesterone receptor status (negative or equivocal versus positive or unknown: RR = 2.15, 95% CI = 1.36-3.39), lymphatic invasion (RR = 1.78, 95% CI = 1.17-2.72), and histological grade ('G2' or G3 versus G1: RR = 8.59, 95% CI = 2.09-35.36). The effects of competing risks could be ignored. CONCLUSION: The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate. [Abstract/Link to Full Text]

Martin RC, Ahn J, Nowell SA, Hein DW, Doll MA, Martini BD, Ambrosone CB
Association between manganese superoxide dismutase promoter gene polymorphism and breast cancer survival.
Breast Cancer Res. 2006;8(4):R45.
BACKGROUND: Manganese superoxide dismutase (MnSOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species, constituting a major cellular defense mechanism against agents that induce oxidative stress. A genetic polymorphism in the mitochondrial targeting sequence of this gene has been associated with increased cancer risk and survival in breast cancer. This base pair transition (-9 T > C) leads to a valine to alanine amino acid change in the mitochondrial targeting sequence. A polymorphism has also been identified in the proximal region of the promoter (-102 C>T) that alters the recognition sequence of the AP-2 transcription factor, leading to a reduction in transcriptional activity. The aim of our study was to investigate possible associations of the -102 C>T polymorphism with overall and relapse-free breast cancer survival in a hospital-based case-only study. MATERIALS AND METHODS: The relationship between the MnSOD -102 C>T polymorphism and survival was examined in a cohort of 291 women who received chemotherapy and/or radiotherapy for incident breast cancer. The MnSOD -102 C>T genotype was determined using a TaqMan allele discrimination assay. Patient survival was evaluated according to the MnSOD genotype using Kaplan-Meier survival functions. Hazard ratios were calculated from adjusted Cox proportional hazards modeling. All statistical tests were two-sided. RESULTS: In an evaluation of all women, there was a borderline significant reduction in recurrence-free survival with either one or both variant alleles (CT + TT) when compared with patients with wild-type alleles (CC) (odds ratio, 0.65; 95% confidence interval, 0.42-1.01). When the analysis was restricted to patients receiving radiation therapy, there was a significant reduction in relapse-free survival in women who were heterozygous for the MnSOD -102 genotype (relative risk, 0.40; 95% confidence interval, 0.18-0.86). Similarly, when the homozygous and heterozygous variant genotypes were combined, there remained a significant reduction in relapse-free survival in this group (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87). CONCLUSION: The MnSOD -102 variant allele appears to be associated with an improved recurrence-free survival in all patients, and more dramatically in subjects who received adjuvant radiation therapy. [Abstract/Link to Full Text]

Muńoz-de-Toro M, Durando M, Beldoménico PM, Beldoménico HR, Kass L, García SR, Luque EH
Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERalpha-positive breast carcinomas.
Breast Cancer Res. 2006;8(4):R47.
INTRODUCTION: Breast cancer is the most frequent malignant disease in women. Exposure to estrogens throughout a woman's life is a risk factor for the development of breast cancer. Organochlorine compounds (OCCs), such as pesticides and polychlorinated biphenyls, are persistent lipophilic chemicals identified as endocrine disruptors, mainly with estrogenic effects. To test the hypothesis that the amount and quality of organochlorine residues in adipose tissue adjacent to breast carcinoma affect the biological behavior of the tumor, we studied biomarker expression in breast carcinoma and the OCC body burden in patients from an urban area adjacent to Paraná fluvial system, Argentina. METHODS: The studied patients were 55 women who had undergone excision biopsies of a breast lesion diagnosed as invasive breast carcinoma. Analysis of OCC residues in breast adipose tissue was conducted by electron-capture gas-liquid chromatography. Estrogen receptor alpha (ERalpha), progesterone receptor (PR) and proliferative activity (Ki-67) levels were measured in paraffin-embedded biopsies of breast tumors by immunohistochemistry. RESULTS: All patients had high levels of organochlorine pesticides in their breast adipose tissue. The most frequently detected compounds were p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and beta-hexachlorocyclohexane. When the whole sample was analyzed, no correlation between ERalpha or PR expression and OCC levels were found. In the subgroup of ERalpha-positive breast carcinoma patients, however, there was a positive correlation between PR expression (an estrogen-induced protein) in the neoplastic cells and OCC levels in adipose tissue surrounding the tumor. More significantly, all the ERalpha-positive breast carcinomas from postmenopausal women exhibited high proliferation when organochlorine levels in the surrounding adipose tissue reached levels higher than 2600 ppb. No associations were found between the organochlorine body burden and any other marker of tumor aggressiveness, such as node involvement or tumor size. CONCLUSION: The present results support the hypothesis that organochlorine residues in adipose tissue adjacent to breast carcinoma generate an estrogenic microenvironment that may influence the biological behavior of the tumor through ERalpha activation and ERalpha-dependent proliferation. These findings may have therapeutic implications, since interference between organochlorine compounds and hormonal therapy could be expected to occur. [Abstract/Link to Full Text]

Shapira M, Kakiashvili E, Rosenberg T, Hershko DD
The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells.
Breast Cancer Res. 2006;8(4):R46.
INTRODUCTION: Loss of the cyclin-dependent kinase inhibitor p27 is associated with poor prognosis in breast cancer. The decrease in p27 levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit S phase kinase protein 2 (Skp2). The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphoinositol 3' kinase (PI3K)/Akt pathway that down-regulates p27 levels in breast cancer. Rapamycin was found to stabilize p27 levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression is unknown. METHODS: The expression of Skp2 mRNA and protein levels were examined in rapamycin-treated breast cancer cell lines. The effect of rapamycin on the degradation rate of Skp2 expression was examined in cycloheximide-treated cells and in relationship to the anaphase promoting complex/Cdh1 (APC\C) inhibitor Emi1. RESULTS: Rapamycin significantly decreased Skp2 mRNA and protein levels in a dose and time-dependent fashion, depending on the sensitivity of the cell line to rapamycin. The decrease in Skp2 levels in the different cell lines was followed by cell growth arrest at G1. In addition, rapamycin enhanced the degradation rate of Skp2 and down-regulated the expression of the APC\C inhibitor Emi1. CONCLUSION: These results suggest that Skp2, an important oncogene in the development and progression of breast cancer, may be a novel target for rapamycin treatment. [Abstract/Link to Full Text]

Galliher AJ, Schiemann WP
Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells.
Breast Cancer Res. 2006;8(4):R42.
INTRODUCTION: Transforming growth factor (TGF)-beta suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells (MECs). During the course of mammary tumorigenesis, genetic and epigenetic changes negate the cytostatic actions of TGF-beta, thus enabling TGF-beta to promote the acquisition and development of metastatic phenotypes. The molecular mechanisms underlying this conversion of TGF-beta function remain poorly understood but may involve signaling inputs from integrins. METHODS: beta3 Integrin expression or function in MECs was manipulated by retroviral transduction of active or inactive beta3 integrins, or by transient transfection of small interfering RNA (siRNA) against beta3 integrin. Altered proliferation, invasion, and epithelial-mesenchymal transition (EMT) stimulated by TGF-beta in control and beta3 integrin manipulated MECs was determined. Src involvement in beta3 integrin mediated alterations in TGF-beta signaling was assessed by performing Src protein kinase assays, and by interdicting Src function pharmacologically and genetically. RESULTS: TGF-beta stimulation induced alphavbeta3 integrin expression in a manner that coincided with EMT in MECs. Introduction of siRNA against beta3 integrin blocked its induction by TGF-beta and prevented TGF-beta stimulation of EMT in MECs. beta3 integrin interacted physically with the TGF-beta receptor (TbetaR) type II, thereby enhancing TGF-beta stimulation of mitogen-activated protein kinases (MAPKs), and of Smad2/3-mediated gene transcription in MECs. Formation of beta3 integrin:TbetaR-II complexes blocked TGF-beta mediated growth arrest and increased TGF-beta mediated invasion and EMT. Dual beta3 integrin:TbetaR-II activation induced tyrosine phosphorylation of TbetaR-II, a phosphotransferase reaction mediated by Src in vitro. Inhibiting Src activity in MECs prevented the ability of beta3 integrin to induce TbetaR-II tyrosine phosphorylation, MAPK activation, and EMT stimulated by TGF-beta. Lastly, wild-type and D119A beta3 integrin expression enhanced and abolished, respectively, TGF-beta stimulation of invasion in human breast cancer cells. CONCLUSION: We show that beta3 integrin alters TGF-beta signaling in MECs via Src-mediated TbetaR-II tyrosine phosphorylation, which significantly enhanced the ability of TGF-beta to induce EMT and invasion. Our findings suggest that beta3 integrin interdiction strategies may represent an innovative approach to re-establishing TGF-beta mediated tumor suppression in progressing human breast cancers. [Abstract/Link to Full Text]

Ma H, Bernstein L, Pike MC, Ursin G
Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies.
Breast Cancer Res. 2006;8(4):R43.
INTRODUCTION: Although reproductive factors have been known for decades to be associated with breast cancer risk, it is unclear to what extent these associations differ by estrogen and progesterone receptor (ER/PR) status. This report presents the first meta-analysis of results from epidemiological studies that have investigated parity, age at first birth, breastfeeding, and age at menarche in relation to ER+PR+ and ER-PR- cancer risk. MATERIALS AND METHODS: We calculated summary relative risks (RRs) and corresponding 95% confidence intervals (CIs) using a fixed effects model. RESULTS: Each birth reduced the risk of ER+PR+ cancer by 11% (RR per birth = 0.89, 95% CI = 0.84-0.94), and women who were in the highest age at first birth category had, on average, 27% higher risk of ER+PR+ cancer compared with women who were in the youngest age at first birth category (RR = 1.27, 95% CI = 1.07-1.50). Neither parity nor age at first birth was associated with the risk of ER-PR- cancer (RR per birth = 0.99, 95% CI = 0.94-1.05; RR of oldest versus youngest age at first birth category = 1.01, 95% CI = 0.85-1.20). Breastfeeding and late age at menarche decreased the risk of both receptor subtypes of breast cancer. The protective effect of late age at menarche was statistically significantly greater for ER+PR+ than ER-PR- cancer (RR = 0.72 for ER+PR+ cancer; RR = 0.84 for ER-PR- cancer, p for homogeneity = 0.006). CONCLUSION: Our findings suggest that breastfeeding (and age at menarche) may act through different hormonal mechanisms than do parity and age at first birth. [Abstract/Link to Full Text]

Alexe G, Alexe S, Axelrod DE, Bonates TO, Lozina II, Reiss M, Hammer PL
Breast cancer prognosis by combinatorial analysis of gene expression data.
Breast Cancer Res. 2006;8(4):R41.
INTRODUCTION: The potential of applying data analysis tools to microarray data for diagnosis and prognosis is illustrated on the recent breast cancer dataset of van 't Veer and coworkers. We re-examine that dataset using the novel technique of logical analysis of data (LAD), with the double objective of discovering patterns characteristic for cases with good or poor outcome, using them for accurate and justifiable predictions; and deriving novel information about the role of genes, the existence of special classes of cases, and other factors. METHOD: Data were analyzed using the combinatorics and optimization-based method of LAD, recently shown to provide highly accurate diagnostic and prognostic systems in cardiology, cancer proteomics, hematology, pulmonology, and other disciplines. RESULTS: LAD identified a subset of 17 of the 25,000 genes, capable of fully distinguishing between patients with poor, respectively good prognoses. An extensive list of 'patterns' or 'combinatorial biomarkers' (that is, combinations of genes and limitations on their expression levels) was generated, and 40 patterns were used to create a prognostic system, shown to have 100% and 92.9% weighted accuracy on the training and test sets, respectively. The prognostic system uses fewer genes than other methods, and has similar or better accuracy than those reported in other studies. Out of the 17 genes identified by LAD, three (respectively, five) were shown to play a significant role in determining poor (respectively, good) prognosis. Two new classes of patients (described by similar sets of covering patterns, gene expression ranges, and clinical features) were discovered. As a by-product of the study, it is shown that the training and the test sets of van 't Veer have differing characteristics. CONCLUSION: The study shows that LAD provides an accurate and fully explanatory prognostic system for breast cancer using genomic data (that is, a system that, in addition to predicting good or poor prognosis, provides an individualized explanation of the reasons for that prognosis for each patient). Moreover, the LAD model provides valuable insights into the roles of individual and combinatorial biomarkers, allows the discovery of new classes of patients, and generates a vast library of biomedical research hypotheses. [Abstract/Link to Full Text]

Ambrosone CB, Tian C, Ahn J, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Chang-Claude J
Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study.
Breast Cancer Res. 2006;8(4):R40.
INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998-2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04-4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes. [Abstract/Link to Full Text]

Hattrup CL, Gendler SJ
MUC1 alters oncogenic events and transcription in human breast cancer cells.
Breast Cancer Res. 2006;8(4):R37.
INTRODUCTION: MUC1 is an oncoprotein whose overexpression correlates with aggressiveness of tumors and poor survival of cancer patients. Many of the oncogenic effects of MUC1 are believed to occur through interaction of its cytoplasmic tail with signaling molecules. As expected for a protein with oncogenic functions, MUC1 is linked to regulation of proliferation, apoptosis, invasion, and transcription. METHODS: To clarify the role of MUC1 in cancer, we transfected two breast cancer cell lines (MDA-MB-468 and BT-20) with small interfering (si)RNA directed against MUC1 and analyzed transcriptional responses and oncogenic events (proliferation, apoptosis and invasion). RESULTS: Transcription of several genes was altered after transfection of MUC1 siRNA, including decreased MAP2K1 (MEK1), JUN, PDGFA, CDC25A, VEGF and ITGAV (integrin alphav), and increased TNF, RAF1, and MMP2. Additional changes were seen at the protein level, such as increased expression of c-Myc, heightened phosphorylation of AKT, and decreased activation of MEK1/2 and ERK1/2. These were correlated with cellular events, as MUC1 siRNA in the MDA-MB-468 line decreased proliferation and invasion, and increased stress-induced apoptosis. Intriguingly, BT-20 cells displayed similar levels of apoptosis regardless of siRNA, and actually increased proliferation after MUC1 siRNA. CONCLUSION: These results further the growing knowledge of the role of MUC1 in transcription, and suggest that the regulation of MUC1 in breast cancer may be more complex than previously appreciated. The differences between these two cell lines emphasize the importance of understanding the context of cell-specific signaling events when analyzing the oncogenic functions of MUC1, and caution against generalizing the results of individual cell lines without adequate confirmation in intact biological systems. [Abstract/Link to Full Text]

Souglakos J, Vamvakas L, Apostolaki S, Perraki M, Saridaki Z, Kazakou I, Pallis A, Kouroussis C, Androulakis N, Kalbakis K, Millaki G, Mavroudis D, Georgoulias V
Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status.
Breast Cancer Res. 2006;8(4):R36.
INTRODUCTION: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse. METHODS: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR. RESULTS: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007-0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51-101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97-12.84; P = 0.001) were independent predictive factors for CNS relapse. CONCLUSION: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs. [Abstract/Link to Full Text]

Calza S, Hall P, Auer G, Bjöhle J, Klaar S, Kronenwett U, Liu ET, Miller L, Ploner A, Smeds J, Bergh J, Pawitan Y
Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients.
Breast Cancer Res. 2006;8(4):R34.
BACKGROUND: Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization. METHODS: We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes--basal-like, ERBB2, luminal A/B and normal-like--and characterized these subtypes extensively with the use of conventional clinical variables. RESULTS: We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders. CONCLUSION: We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability. [Abstract/Link to Full Text]

Ma H, Bernstein L, Ross RK, Ursin G
Hormone-related risk factors for breast cancer in women under age 50 years by estrogen and progesterone receptor status: results from a case-control and a case-case comparison.
Breast Cancer Res. 2006;8(4):R39.
INTRODUCTION: It has been suggested that hormonal risk factors act predominantly on estrogen receptor and progesterone receptor (ER/PR)-positive breast cancers. However, the data have been inconsistent, especially in younger women. METHODS: We evaluated the impact of age at menarche, pregnancy history, duration of breastfeeding, body mass index, combined oral contraceptive use, and alcohol consumption on breast cancer risk by ER/PR status in 1,725 population-based case patients and 440 control subjects aged 20 to 49 years identified within neighborhoods of case patients. We used multivariable unconditional logistic regression methods to conduct case-control comparisons overall as well as by ER/PR status of the cases, and to compare ER+PR+ with ER-PR- case patients. RESULTS: The number of full-term pregnancies was inversely associated with the risk of ER+PR+ breast cancer (ptrend = 0.005), whereas recent average alcohol consumption was associated with an increased risk of ER+PR+ breast cancer (ptrend = 0.03). Neither of these two factors was associated with the risk of ER- PR- breast cancer. Late age at menarche and a longer duration of breastfeeding were both associated with decreased breast cancer risk, irrespective of receptor status (all ptrend< or = 0.03). CONCLUSION: Our results suggest that the number of full-term pregnancies and recent alcohol consumption affect breast cancer risk in younger women predominantly through estrogen and progesterone mediated by their respective receptors. Late age at menarche and breastfeeding may act through different hormonal mechanisms. [Abstract/Link to Full Text]

Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE
Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer.
Breast Cancer Res. 2006;8(4):R38.
INTRODUCTION: BRCA1 or BRCA2 germline mutations increase the risk of developing breast cancer. Tumour cells from germline mutation carriers have frequently lost the wild-type allele. This is predicted to result in genomic instability where cell survival depends upon dysfunctional checkpoint mechanisms. Tumorigenic potential could then be acquired through further genomic alterations. Surprisingly, somatic BRCA mutations are not found in sporadic breast tumours. BRCA1 methylation has been shown to occur in sporadic breast tumours and to be associated with reduced gene expression. We examined the frequency of BRCA1 methylation in 143 primary sporadic breast tumours along with BRCA1 copy number alterations and tumour phenotype. METHODS: Primary sporadic breast tumours were analysed for BRCA1alpha promoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1 and BRCA2 loci by microsatellite analysis and TP53 (also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1 methylated tumours were analysed for BRCA1 copy alterations by fluorescence in situ hybridisation and BRCA1 expression by immunostaining. RESULTS: BRCA1 methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1 methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1 AI (P = 0.0731) as well as young-age at diagnosis (< or = 55; P = 0.0898). BRCA1 methylation was not associated with BRCA2 AI (P = 0.5420), although a significant association was found between BRCA1 AI and BRCA2 AI (P < 0.0001).Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1 methylated tumours, most of which had BRCA1 deletion. An elevated TP53 mutation frequency was found among BRCA1 methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1 methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1. CONCLUSION: BRCA1 methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1 methylation to be associated with AI at the BRCA1 locus. Almost all BRCA1 methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1 deletion. Thus, epigenetic silencing and deletion of the BRCA1 gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1 methylated and familial BRCA1 tumours, based on BRCA1 deletion, TP53 mutations, ER status, young age at diagnosis and tumour grade. [Abstract/Link to Full Text]

Pugatsch T, Abedat S, Lotan C, Beeri R
Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways.
Breast Cancer Res. 2006;8(4):R35.
INTRODUCTION: Cardiac dysfunction is among the serious side effects of therapy with recombinant humanized anti-erbB2 monoclonal antibody. The antibody blocks ErbB-2, a receptor tyrosine kinase and co-receptor for other members of the ErbB and epidermal growth factor families, which is over-expressed on the surface of many malignant cells. ErbB-2 and its ligands neuregulin and ErbB-3/ErbB-4 are involved in survival and growth of cardiomyocytes in both postnatal and adult hearts, and therefore the drug may interrupt the correct functioning of the ErbB-2 pathway. METHODS: The effect of the rat-anti-erbB2 monoclonal antibody B-10 was studied in spontaneously beating primary myocyte cultures from rat neonatal hearts. Gene expression was determined by RT-PCR (reverse transcription polymerase chain reaction) and by rat stress-specific microarray analysis, protein levels by Western blot, cell contractility by video motion analysis, calcium transients by the FURA fluorescent method, and apoptosis using the TUNEL (terminal uridine nick-end labelling) assay. RESULTS: B-10 treatment induces significant changes in expression of 24 out of 207 stress genes analyzed using the microarray technique. Protein levels of ErbB-2, ErbB-3, ErbB-4 and neuregulin decreased after 1 day. However, both transcription and protein levels of ErbB-4 and gp130 increased several fold. Calreticulin and calsequestrin were overexpressed after three days, inducing a decrease in calcium transients, thereby influencing cell contractility. Apoptosis was induced in 20% cells after 24 hours. CONCLUSION: Blocking ErbB-2 in cultured rat cardiomyocytes leads to changes that may influence the cell cycle and affects genes involved in heart functions. B-10 inhibits pro-survival pathways and reduces cellular contractility. Thus, it is conceivable that this process may impair the stress response of the heart. [Abstract/Link to Full Text]

Lim KT, Cosgrave N, Hill AD, Young LS
Nongenomic oestrogen signalling in oestrogen receptor negative breast cancer cells: a role for the angiotensin II receptor AT1.
Breast Cancer Res. 2006;8(3):R33.
INTRODUCTION: Oestrogens can mediate some of their cell survival properties through a nongenomic mechanism that involves the mitogen-activated protein kinase (MAPK) pathway. The mechanism of this rapid signalling and its dependence on a membrane bound oestrogen receptor (ER), however, remains controversial. The role of G-protein-coupled receptor and epidermal growth factor (EGF) receptor in an ER-independent signalling pathway modulated by oestrogen was investigated. METHODS: ER-positive and ER-negative breast cancer cell lines (MCF-7 and SKBR3) and primary breast cancer cell cultures were used in this study. Cell proliferation was assessed using standard MTT assays. Protein and cAMP levels were detected by Western blotting and ELISA, respectively. Antigen localization was performed by immunocytochemistry, immunohistochemistry and immunofluorescence. Protein knockdown was achieved using small interfering RNA technologies. RESULTS: EGF and oestrogen, alone and in combination, induced cell proliferation and phosphorylation of MAPK proteins Raf and ERK (extracellular signal regulated kinase)1/2 in both ER-negative SKBR3 and ER-positive MCF-7 human breast cancer cell lines. Increased Raf phosphorylation was also observed in primary human breast cultures derived from ER-positive and ER-negative breast tumours. Oestrogen induced an increase in intracellular cAMP in ER-negative SKBR3 human breast cancer cells. Oestrogen-mediated cell growth and phosphorylation of MAPK was modified by the EGF receptor antagonist AG1478, the G-protein antagonist pertussis toxin, and the angiotensin II receptor antagonist saralasin. Knockdown of angiotensin II type 1 receptor (AT1) protein expression with small interfering RNA attenuated oestrogen-induced Raf phosphorylation in ER-negative cells. AT1 receptor was found to be expressed in the cell membrane of breast tumour epithelial cells. CONCLUSION: These findings provide evidence that, in breast cancer cells, oestrogen can signal through AT1 to activate early cell survival mechanisms in an ER-independent manner. [Abstract/Link to Full Text]

Gill JK, Maskarinec G, Pagano I, Kolonel LN
The association of mammographic density with ductal carcinoma in situ of the breast: the Multiethnic Cohort.
Breast Cancer Res. 2006;8(3):R30.
INTRODUCTION: It is well established that women with high mammographic density are at greater risk for breast cancer than are women with low breast density. However, little research has been done on mammographic density and ductal carcinoma in situ (DCIS) of the breast, which is thought to be a precursor lesion to some invasive breast cancers. METHOD: We conducted a nested case-control study within the Multiethnic Cohort, and compared the mammographic densities of 482 patients with invasive breast cancer and 119 with breast DCIS cases versus those of 667 cancer-free control subjects. A reader blinded to disease status performed computer-assisted density assessment. For women with more than one mammogram, mean density values were computed. Polytomous logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for two measurements of mammographic density: percentage density and dense area. RESULTS: Mammographic density was associated with invasive breast cancer and breast DCIS. For the highest category of percentage breast density (> or = 50%) as compared with the lowest (< 10%), the OR was 3.58 (95% CI 2.26-5.66) for invasive breast cancer and 2.86 (1.38-5.94) for breast DCIS. Similarly, for the highest category of dense area (> or = 45 cm2) as compared with the lowest (< 15 cm2), the OR was 2.92 (95% CI 2.01-4.25) for invasive breast cancer and 2.59 (1.39-4.82) for breast DCIS. Trend tests were significant for invasive breast cancer (P for trend < 0.0001) and breast DCIS (P for trend < 0.001) for both percentage density and dense area. CONCLUSION: The similar strength of association for mammographic density with breast DCIS and invasive breast cancer supports the hypothesis that both diseases may have a common etiology. [Abstract/Link to Full Text]

Cleator SJ, Powles TJ, Dexter T, Fulford L, Mackay A, Smith IE, Valgeirsson H, Ashworth A, Dowsett M
The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis.
Breast Cancer Res. 2006;8(3):R32.
INTRODUCTION: The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. MATERIALS AND METHODS: Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. RESULTS: Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%-13%, p < 0.05 on permutation). CONCLUSION: The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account. [Abstract/Link to Full Text]

Burcombe R, Wilson GD, Dowsett M, Khan I, Richman PI, Daley F, Detre S, Makris A
Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer.
Breast Cancer Res. 2006;8(3):R31.
INTRODUCTION: Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential. This study evaluated changes in Ki-67 labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy. METHODS: Twenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment. Tissue from pre-treatment biopsy, day 21 and surgery was analysed for Ki-67 index and AI. RESULTS: The objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histological criteria; two patients had a near-complete pathological response. A reduction in Ki-67 index was observed in 68% of patients at day 21 and 72% at surgery; Ki-67 index increased between day 21 and surgery in 54%. AI decreased in 50% of tumours by day 21, increased in 45% and was unchanged in one patient; 56% demonstrated rebound increases in AI by the time of surgery. Neither pre-treatment nor post-chemotherapy median Ki-67 index nor median AI at all three time points or relative changes at day 21 and surgery differed significantly between clinical or pathological responders and non-responders. Clinical responders had lower median Ki-67 indices at day 21 (11.4% versus 27.0%, p = 0.02) and significantly greater percentage reductions in Ki-67 at day 21 than did non-responders (-50.6% versus -5.3%, p = 0.04). The median day-21 Ki-67 was higher in pathological responders (30.3% versus 14.1%, p = 0.046). A trend toward increased AI at day 21 in pathological responders was observed (5.30 versus 1.68, p = 0.12). Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively). CONCLUSION: The clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive markers is available, clinical decision-making should not be based upon individual biological tumour marker profiles. [Abstract/Link to Full Text]

Grimm SL, Bu W, Longley MA, Roop DR, Li Y, Rosen JM
Keratin 6 is not essential for mammary gland development.
Breast Cancer Res. 2006;8(3):R29.
INTRODUCTION: Keratin 6 (K6) has previously been identified as a marker of early mammary gland development and has also been proposed to be a marker of mammary gland progenitor cells. However, the function of K6 in the mammary gland was not known, so we examined the expression pattern of the protein during both embryonic and postnatal mammary development, as well as the mammary gland phenotype of mice that were null for both K6a and K6b isoforms. METHOD: Immunostaining was performed to determine the expression pattern of K6a throughout mammary gland development, from the embryonic mammary bud to lactation. Double immunofluorescence was used to co-localize K6 with known markers of mammary gland development. Wild-type and K6ab-null mammary tissues were transplanted into the cleared fat pads of nude mice and the outgrowths were analyzed for morphology by whole-mount staining and for markers of mammary epithelium by immunostaining. Finally, progesterone receptor (PR) and bromodeoxyuridine co-localization was quantified by double immunofluorescence in wild-type and K6ab-null mammary outgrowths. RESULTS: Here we report that K6 is expressed earlier than described previously, by embryonic day 16.5. K6a is the predominant isoform expressed in the mammary gland, localized in the body cells and luminal epithelial cells but not in the cap cells or myoepithelial cells. Co-localization studies showed that most K6a-positive cells express steroid receptors but do not proliferate. When both the K6a and K6b genes are deleted, mammary gland development appears normal, with similar expression of most molecular markers examined in both the pubertal gland and the mature gland. Loss of K6a and K6b, however, leads to an increase in the number of steroid-receptor-positive cells, and increased co-localization of steroid receptor expression and proliferation was observed. CONCLUSION: Although K6a was not essential for mammary gland development, loss of both K6a and K6b resulted in an increase in PR-positive mammary epithelial cells and decreased proliferation after exposure to steroid hormones. There was also increased co-localization of PR and bromodeoxyuridine, suggesting alterations in patterning events important for normal lobuloalveolar development. [Abstract/Link to Full Text]

Tętu B, Brisson J, Wang CS, Lapointe H, Beaudry G, Blanchette C, Trudel D
The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis.
Breast Cancer Res. 2006;8(3):R28.
INTRODUCTION: Matrix metalloproteinase (MMP)-2 is very active at degrading extracellular matrix. It is under the influence of an activator, membrane type 1 MMP (MMP-14), and the tissue inhibitor of metalloproteases (TIMP)-2. We hypothesized that the individual expression of these three markers or their balance may help to predict breast cancer prognosis. METHODS: MMP-2, MMP-14 and TIMP-2 expression has been evaluated by 35S mRNA in situ hybridization on paraffin material of 539 breast cancers without distant metastasis at diagnosis and with a median follow-up of 9.2 years. RESULTS: MMP-2 and MMP-14 mRNA was detected primarily in reactive stromal cells whereas TIMP-2 mRNA was expressed by both stromal and cancer cells. Of the three molecules, an adjusted Cox model revealed that high MMP-14 mRNA (> or = 10% cells) alone predicted a significantly shorter overall survival (p = 0.031) when adjusted for clinical factors (tumor size and number of involved lymph nodes). Prognostic significance was lost when further adjusted for Her-2/neu and urokinase-type plasminogen activator (p = 0.284). Furthermore, when all three components were analyzed together, the survival was worst for patients with high MMP-2/high MMP-14/low TIMP-2 (5 year survival = 60%) and best with low MMP-2/low MMP-14/high TIMP-2 (5 year survival = 74%), but the difference did not reach statistical significance (p = 0.3285). CONCLUSION: Of the MMP-14/TIMP-2/MMP-2 complex, MMP-14 was the factor most significantly associated with the outcome of breast cancer and was an independent factor of poor overall survival when adjusted for clinical prognostic factors, but not for certain ancillary markers. [Abstract/Link to Full Text]

Apostolopoulos V, Pietersz GA, Tsibanis A, Tsikkinis A, Drakaki H, Loveland BE, Piddlesden SJ, Plebanski M, Pouniotis DS, Alexis MN, McKenzie IF, Vassilaros S
Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835].
Breast Cancer Res. 2006;8(3):R27.
INTRODUCTION: Mucin 1 (MUC1) is a high molecular weight glycoprotein overexpressed on adenocarcinoma cells and is a target for immunotherapy protocols. To date, clinical trials against MUC1 have included advanced cancer patients. Herein, we report a trial using early stage breast cancer patients and injection of oxidized mannan-MUC1. METHOD: In a randomized, double-blind study, 31 patients with stage II breast cancer and with no evidence of disease received subcutaneous injections of either placebo or oxidized mannan-MUC1, to immunize against MUC1 and prevent cancer reoccurrence/metastases. Twenty-eight patients received the full course of injections of either oxidized mannan-MUC1 or placebo. Survival and immunological assays were assessed. RESULTS: After more than 5.5 years had elapsed since the last patient began treatment (8.5 years from the start of treatment of the first patient), the recurrence rate in patients receiving the placebo was 27% (4/15; the expected rate of recurrence in stage II breast cancer); those receiving immunotherapy had no recurrences (0/16), and this finding was statistically significant (P = 0.0292). Of the patients receiving oxidized mannan-MUC1, nine out of 13 had measurable antibodies to MUC1 and four out of 10 had MUC1-specific T cell responses; none of the placebo-treated patients exhibited an immune response to MUC1. CONCLUSION: The results suggest that, in early breast cancer, MUC1 immunotherapy is beneficial, and that a larger phase III study should be undertaken. [Abstract/Link to Full Text]

Lose F, Lovelock P, Chenevix-Trench G, Mann GJ, Pupo GM, Spurdle AB
Variation in the RAD51 gene and familial breast cancer.
Breast Cancer Res. 2006;8(3):R26.
INTRODUCTION: Human RAD51 is a homologue of the Escherichia coli RecA protein and is known to function in recombinational repair of double-stranded DNA breaks. Mutations in the lower eukaryotic homologues of RAD51 result in a deficiency in the repair of double-stranded DNA breaks. Loss of RAD51 function would therefore be expected to result in an elevated mutation rate, leading to accumulation of DNA damage and, hence, to increased cancer risk. RAD51 interacts directly or indirectly with a number of proteins implicated in breast cancer, such as BRCA1 and BRCA2. Similar to BRCA1 mice, RAD51-/- mice are embryonic lethal. The RAD51 gene region has been shown to exhibit loss of heterozygosity in breast tumours, and deregulated RAD51 expression in breast cancer patients has also been reported. Few studies have investigated the role of coding region variation in the RAD51 gene in familial breast cancer, with only one coding region variant--exon 6 c.449G>A (p.R150Q)--reported to date. METHODS: All nine coding exons of the RAD51 gene were analysed for variation in 46 well-characterised, BRCA1/2-negative breast cancer families using denaturing high-performance liquid chromatography. Genotyping of the exon 6 p.R150Q variant was performed in an additional 66 families. Additionally, lymphoblastoid cell lines from breast cancer patients were subjected to single nucleotide primer extension analysis to assess RAD51 expression. RESULTS: No coding region variation was found, and all intronic variation detected was either found in unaffected controls or was unlikely to have functional consequences. Single nucleotide primer extension analysis did not reveal any allele-specific changes in RAD51 expression in all lymphoblastoid cell lines tested. CONCLUSION: Our study indicates that RAD51 is not a major familial breast cancer predisposition gene. [Abstract/Link to Full Text]

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Recent Articles in International Seminars in Surgical Oncology

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Thai DM, Kitagawa Y, Choong PF
Outcome of surgical management of bony metastases to the humerus and shoulder girdle: a retrospective analysis of 93 patients.
Int Semin Surg Oncol. 2006;35.
BACKGROUND: Metastatic disease to the shoulder girdle is a challenging problem because of the potential for pain, pathologic fracture and loss of function of that limb. Management of the bone disease centers around palliation, prevention of further complications and the preservation of residual function. A variety of surgical options exist for managing metastatic disease to the shoulder girdle and our experience with over 90 patients is reported. We focus on a preferred technique of combining rigid intramedullary nailing with cementation. METHODS: Patients with metastatic disease to the shoulder girdle were accrued over a 9 year period from 1996 to 2004. 93 patients were identified with 96 operations being performed. The median age was 63 years (range 33 - 89) and 54% were female. The commonest primary tumor to metastasize was breast, and the proximal and midshaft humerus was involved in 84% of cases. The median survival time was 8 months and at last review 82% of patients had died of their disease RESULTS: Operations performed were intramedullary nailing (n = 51), resection with or without prosthetic reconstruction (n = 34) or plate osteosynthesis (n = 9). The site of the metastasis was a guide to the most appropriate operation. Amputations (n = 2) were not done as the primary procedure.Median post operative hospitalization ranged from 3 to 6 days depending on the type of operation performed. Our preferred technique for diaphyseal lesions (intramedullary nailing plus cementation) achieved excellent results in terms of pain relief, functional restoration and minimal complications. Functional restriction was most notable for proximal humeral prostheses (35% of patients). CONCLUSION: Surgical treatment of metastases to the shoulder girdle can be successful, allowing prompt relief of pain and return to prehospital level of care. Proximal and midshaft humeral metastases are easily amenable to resection and reconstruction or intramedullary nailing with cementation. Relief of pain and preservation of function occurs for the majority of patients. [Abstract/Link to Full Text]

Helme S, Perry N, Mokbel K
Screening mammography in women aged 40-49: is it time to change?
Int Semin Surg Oncol. 2006;34.
There is little doubt that significant benefits can accrue from carrying out screening mammography of women aged 40-49 in the setting of a highly quality assured service delivery. This will best be achieved using digital mammography to maximise detection rates and trained and high volume reading expert radiologists to apply economic cushions of optimising specificity as well as sensitivity in addition to utilising modern and accurate assessment and tissue sampling techniques that have evolved. [Abstract/Link to Full Text]

Candelaria M, Chanona-Vilchis J, Cetina L, Flores-Estrada D, López-Graniel C, González-Enciso A, Cantú D, Poitevin A, Rivera L, Hinojosa J, de la Garza J, Dueńas-Gonzalez A
Prognostic significance of pathological response after neoadjuvant chemotherapy or chemoradiation for locally advanced cervical carcinoma.
Int Semin Surg Oncol. 2006;33.
BACKGROUND: Cisplatin-based chemoradiation is the standard of care for locally advanced cervical cancer patients; however, neoadjuvant modalities are currently being tested. Neoadjuvant studies in several tumor types have underscored the prognostic significance of pathological response for survival; however there is a paucity of studies in cervical cancer investigating this issue. METHODS: Four cohorts of patients with locally advanced cervical carcinoma (stages IB2-IIIB); included prospectively in phase II protocols of either neoadjuvant chemotherapy with 1) cisplatin-gemcitabine, 2) oxaliplatin-gemcitabine, 3) carboplatin-paclitaxel or 4) chemoradiation with cisplatin or cisplatin-gemcitabine followed by radical hysterectomy were analyzed for pathological response and survival. RESULTS: One-hundred and fifty three (86%) of the 178 patients treated within these trials, underwent radical hysterectomy and were analyzed. Overall, the mean age was 44.7 and almost two-thirds were FIGO stage IIB. Pathological response rates were as follows: Complete (pCR) in 60 cases (39.2%), Near-complete (p-Near-CR) in 24 (15.6 %) and partial (pPR) in 69 cases (45.1%). A higher proportion rate of pCR was observed in patients treated with chemoradiotherapy (with cisplatin [19/40, 47.5%]; or with cisplatin-gemcitabine [24/41, 58.5%] compared with patients receiving only chemotherapy, 6/23 (26%), 3/8 (37.5%) and 8/41 (19.5%) for cisplatin-gemcitabine, oxaliplatin-gemcitabine and carboplatin-paclitaxel respectively [p = 0.0001]). A total of 29 relapses (18.9%) were documented. The pathological response was the only factor influencing on relapse, since only 4/60 (6.6%) patients with pCR relapsed, compared with 25/93 (26.8%) patients with viable tumor, either pNear-CR or pPR (p = 0.001). Overall survival was 98.3% in patients with pCR versus 83% for patients with either pNear-CR or pPR (p = 0.009). CONCLUSION: Complete pathological response but no Near-complete and partial responses is associated with longer survival in cervical cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy. [Abstract/Link to Full Text]

Fyrmpas G, Barbetakis N, Efstathiou A, Konstantinidis I, Tsilikas C
Cutaneous metastasis to the face from colon adenocarcinoma. Case report.
Int Semin Surg Oncol. 2006;32.
BACKGROUND: Facial skin metastases from colorectal cancer are extremely rare and appear several years after resection of the primary tumour. They are an important finding, often being the first sign of metastasis from a previously treated colon cancer. CASE PRESENTATION: We describe a case of a 69 year old patient with cutaneous metastasis to the chin from a previously treated adenocarcinoma of the colon. The patient presented with dyspnoea, pleuritic pain and loss of weight. A chest x-ray revealed a right upper lobe mass of the lung which on subsequent surgical exploration proved to be metastatic from colorectal adenocarcinoma resected three years ago. During the postoperative course, a nodule was noted on the chin and excision biopsy revealed it was also a metastasis from the initial colorectal cancer. Palliative chemoradiotherapy was administered and the patient survived 8 months. CONCLUSION: High index of suspicion is necessary for the early detection of facial cutaneous metastases from colorectal cancer. The aim is to start treatment as soon as possible before widespread visceral metastases occur. Cutaneous metastases from colorectal cancer carry a better prognosis in comparison to those of other epithelial tumours. [Abstract/Link to Full Text]

Al Sarakbi W, Worku D, Escobar PF, Mokbel K
Breast papillomas: current management with a focus on a new diagnostic and therapeutic modality.
Int Semin Surg Oncol. 2006;31.
Breast papilloma is a term that describes an intraductal papillary configuration of the mammary epithelium on macroscopic or microscopic examination. It includes solitary intraductal papillomas, multiple papillomas, papillomatosis, and juvenile papillomatosis (JP).Recent advances in mammary ductoscopy (MD) have raised new possibilities in the diagnosis and treatment of breast papillomas. This technique represents an important diagnostic adjunct in patients with pathological nipple discharge (PND) by allowing direct visualisation and biopsy of intraductal lesions and guiding duct excision surgery.Treatment of breast papillomas often entails surgical duct excision for symptomatic relief and histopathological examination. Recently, more conservative approach has been adapted. MD-assisted microdochectomy should be considered the procedure of choice for a papilloma-related single duct discharge. Furthermore, there is increasing evidence that MD has the potential to reduce the number of duct excision procedures and minimise the extent of surgical resection. Imaging-guided vacuum-assisted core biopsy can be diagnostic and therapeutic for papillomas seen on mammography and/or ultrasound.Patients with multiple papillomas do have an increased risk of developing cancer and should be kept under annual review with regular mammography (preferably digital mammography) if treated conservatively. Magnetic resonance (MR) can be also used in surveillance in view of its high sensitivity. Because the risk is small, long term and affects both breasts, long-term follow-up is more appropriate than prophylactic mastectomy. Patients who prove to have solitary duct papilloma have insufficient increase in the risk of subsequent malignancy to justify routine follow-up. [Abstract/Link to Full Text]

Jack CM, Adwani A, Krishnan H
Tattoo pigment in an axillary lymph node simulating metastatic malignant melanoma.
Int Semin Surg Oncol. 2005;228.
We report a case of axillary lymphadenopathy thirty years after a decorative tattoo clinically mimicking metastatic melanoma. The importance of relying on histological confirmation of metastatic disease before altering extent of surgery is discussed. The importance of recording presence of decorative tattoos is stressed. [Abstract/Link to Full Text]

Adwani A, Ebbs SR, Burton S, Lowe S
Sentinel node biopsy should be supplemented by axillary sampling in patients with small breast cancers.
Int Semin Surg Oncol. 2005;227.
Axillary clearance provides important prognostic information but is associated with significant morbidity. Sentinel node biopsy can provide staging .141 patients with node negative early breast cancers-tumour size less than 1.5 cm measured clinically or by imaging had guided axillary sampling (sentinel lymph node biopsy in combination with axillary sampling). Four node axillary sampling improved the detection rate of axillary node metastases by 13.6% as compared to blue dye sentinel node biopsy alone. Positive sampled nodes strongly indicated the likelihood of further metastatic being revealed by axillary dissection (67%). Negative sampled nodes in combination with a positive sentinel node biopsy were associated with a much lower rate of further nodal involvement in the axillary clearance (8%). [Abstract/Link to Full Text]

Salhab M, Al Sarakbi W, Mokbel K
Skin and fat necrosis of the breast following methylene blue dye injection for sentinel node biopsy in a patient with breast cancer.
Int Semin Surg Oncol. 2005 Nov 28;226.
Sentinel lymph node biopsy (SLNB) is a simple technique that uses subdermal or peri-tumoral injection of vital blue dye and/or radioactive isotope to identify the first lymph node(s) draining the primary tumor. It has been shown to accurately predict axillary node status in patients with clinically node negative breast cancer. The SLNB is emerging as a new standard of care in patients with early breast cancer. However, the use of methylene blue (MB) dye can be associated with a number of local complications due to its tissue reactive properties. We report a rare case of skin and fat necrosis followed by a dry gangrene of the skin in a female patient with breast cancer who underwent SLNB localization using peri-tumoral injection of MB dye in another institution. This case and literature review suggest that the use of MB dye for SLNB identification should be avoided and replaced with alternative types of blue dye such as Patent Blue V preferably in conjunction with a radioactive isotope tracer. [Abstract/Link to Full Text]

Krynyckyi BR, Shafir MK, Kim SC, Kim DW, Travis A, Moadel RM, Kim CK
Lymphoscintigraphy and triangulated body marking for morbidity reduction during sentinel node biopsy in breast cancer.
Int Semin Surg Oncol. 2005 Nov 8;225.
Current trends in patient care include the desire for minimizing invasiveness of procedures and interventions. This aim is reflected in the increasing utilization of sentinel lymph node biopsy, which results in a lower level of morbidity in breast cancer staging, in comparison to extensive conventional axillary dissection. Optimized lymphoscintigraphy with triangulated body marking is a clinical option that can further reduce morbidity, more than when a hand held gamma probe alone is utilized. Unfortunately it is often either overlooked or not fully understood, and thus not utilized. This results in the unnecessary loss of an opportunity to further reduce morbidity. Optimized lymphoscintigraphy and triangulated body marking provides a detailed 3 dimensional map of the number and location of the sentinel nodes, available before the first incision is made. The number, location, relevance based on time/sequence of appearance of the nodes, all can influence 1) where the incision is made, 2) how extensive the dissection is, and 3) how many nodes are removed. In addition, complex patterns can arise from injections. These include prominent lymphatic channels, pseudo-sentinel nodes, echelon and reverse echelon nodes and even contamination, which are much more difficult to access with the probe only. With the detailed information provided by optimized lymphoscintigraphy and triangulated body marking, the surgeon can approach the axilla in a more enlightened fashion, in contrast to when the less informed probe only method is used. This allows for better planning, resulting in the best cosmetic effect and less trauma to the tissues, further reducing morbidity while maintaining adequate sampling of the sentinel node(s). [Abstract/Link to Full Text]

Kothari MS, Kosmoliaptsis V, Meyrick-Thomas J
Small bowel Gastrointestinal Stromal Tumors can physiologically alter gut motility before causing mechanical obstruction.
Int Semin Surg Oncol. 2005 Oct 26;224.
BACKGROUND: Gastro Intestinal Stromal Tumors (GISTs) are rare stromal neoplasms that represent the most common mesenchymal tumor of the G.I. tract, accounting for 5% of all sarcomas. Originating from interstitial cells of Cajal, which are regulators of gut peristalsis, they are preferentially located in the stomach and the small intestine and clinical presentation is variable, ranging from vague complaints to major G.I. bleeding. Surgical resection is the mainstay of treatment for patients with resectable GIST and 5-year survival ranges from 21% to 88% in different series depending on risk grading and completeness of surgical resection. Imatinib mesylate, a tyrosine kinase inhibitor, provides an encouraging option for treating high risk GISTs. CASE PRESENTATION: We report the case of a 62-year-old lady who had been diagnosed and being treated unsuccessfully for Irritable bowel syndrome for 11 years and eventually found to have an obstructing small bowel GIST. CONCLUSION: The symptoms from GIST may mimic those of irritable bowel syndrome. A physiological alteration in gut peristalsis resulting from neoplastic transformation of the interstitial cells of Cajal, is a hypothesis that could explain this presentation. An alternative diagnosis should be considered when treating patients with irritable bowel syndrome who fail to respond for a prolonged period. [Abstract/Link to Full Text]

Watkins G, Douglas-Jones A, Mansel RE, Jiang WG
Expression of thromboxane synthase, TBXAS1 and the thromboxane A2 receptor, TBXA2R, in human breast cancer.
Int Semin Surg Oncol. 2005 Oct 26;223.
BACKGROUND: Thromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostaglandin H(2), into thromboxanes. Some of the thromboxanes are known to be biologically active on cancer cells. The aim of the study was to investigate the expression of thromboxane synthases, TBXAS1 and the thromboxane A2 receptor, TBXA2R in a cohort of human breast cancer patients and also to assess their potential clinical relevance. METHODS: Human breast tumour tissues (n = 120) and non-neoplastic mammary tissues (n = 32) were studied. Levels of TBXA2R and TBXAS1 transcripts were quantified using quantitative real-time RT-PCR analysis and correlated with clinical/pathological information including nodal status, grade, prognosis and long term survival (median follow-up period 120 months). RESULTS: Breast tumour tissue expressed higher levels of TBXA2R compared with normal mammary tissues, although the difference was not statistically significant (p = 0.09). There was no difference between tumour and normal tissues for TBXAS1. However, TBXA2R expression was significantly increased in grade 3 tumours(p = 0.006 vs grade 1), while TBXAS1 was significantly reduced in grade 3 tumours (p = 0.026 vs grade 1 tumours). A similar differential expression pattern was seen in tumours from patients with different prognosis, in that patients with predicted poor prognosis had higher, but not statistically different, levels of TBXA2R, and significantly lower levels of TBXAS1 (p = 0.008). Finally, Kaplan-Meier survival analysis has shown that patients with high levels of TBXA2R had significantly shorter disease free survival (103.8 (79.1-128.5) months) compared with those with low levels (123.7 (112.0-135.3)) months, p = 0.043. CONCLUSION: Thromboxane synthases are differentially expressed in human breast cancer. While TBXA2R is highly expressed in aggressive tumours and linked with poor prognosis, TBXAS1 is expressed at significantly low levels in high grade tumours and tumour patients with poor prognosis. TBXA2R thus has a significant prognostic value in clinical breast cancer. [Abstract/Link to Full Text]

Atkin G, Scott MA, Mathur P, Mitchell IC
The rectus sling to prevent loop colostomy retraction: a case series.
Int Semin Surg Oncol. 2005 Oct 20;222.
Diverting stomas are being used increasingly in the management of rectal cancer, particularly with low anterior resection following neoadjuvant therapy. We describe a simple anchorage method for loop colostomy using a rectus fascial sling. This has been used successfully in fifteen patients with no complications or evidence of significant spill over of faecal contents into the efferent loop. [Abstract/Link to Full Text]

Kaya SO, Atalay H, Erbay HR, Ozcan AV, Goksin I, Kabay B, Tekin K
Exploring strategies to prevent post-lobectomy space: transient diaphragmatic paralysis using Botulinum toxin type A (BTX-A).
Int Semin Surg Oncol. 2005 Oct 19;221.
OBJECTIVE: Various techniques to reduce air space after pulmonary lobectomy especially for lung cancer have been an important concern in thoracic surgical practice. The aim of this study was to assess the effectiveness of Botulinum toxin A (BTX-A) injection into the diaphragm to reduce air space after right lower pulmonary lobectomy in an animal model. METHODS: Twelve male New Zealand rabbits were randomly allocated into two groups. All animals underwent right lower lobectomy. Then, normal saline of 0,1 ml and 10 units of 0,1 ml Botulinum toxin type A were injected into the muscular part of the right hemidiaphragm in control (n = 6) and BTX-A groups (n = 6) respectively. Residual air space and diaphragmatic elevation were evaluated with chest X-ray pre- and postoperatively. Diaphragmatic elevation was measured as a distance in millimetre from the line connecting the 10th ribs to the midpoint of the right hemidiaphragm. RESULTS: The mean diaphragmatic elevation in BTX-A and control groups were 7.0 +/- 2.5 and 1.3 +/- 1.2 millimetres respectively. Diaphragmatic elevations were significantly higher in BTX-A group (p = 0.0035). CONCLUSION: Intraoperative Botulinum toxin type A injection may reduce postlobectomy spaces effectively via hemidiaphragmatic paralysis in rabbits. Further studies are needed to validate the safe use of Botulinum toxin type A in human beings. [Abstract/Link to Full Text]

Mboto CI, Davies-Russell A, Fielder M, Jewell AP
Hepatocellular Carcinoma in The Gambia and the role of Hepatitis B and Hepatitis C.
Int Semin Surg Oncol. 2005 Oct 4;220.
OBJECTIVES: Hepatocellular Carcinoma is the commonest form of cancer in The Gambia, and although Hepatitis B and Hepatitis C are known risk factors, accurate baseline data on Hepatitis B and Hepatitis C distribution in the region are limited. Similarly data including information on the involvement of the viruses in HCC remains unknown. The current study was undertaken to estimate the risk of HCC in relation to HCV and HBV in The Gambia. METHODS: Thirteen patients with histological proven history of HCC and 39 healthy controls were enrolled in the study. Each subject blood was screened individually for anti-HCV using ORTHO HCV 3.0 ELISA test system (Ortho-Clinical Diagnostics, Inc, U.S.A) and for HBsAg using QUADRATECH CHECK 4-HBs one step generation hepatitis B surface antigen test kit (VEDALAB, France) following the manufacturers instructions. RESULTS: HBsAg and anti-HCV was detected in 38.5 % (5/13) and 7.7% (1/39) of the persons with a history of HCC respectively. HBsAg but not anti-HCV was detected in 12.8% (5/39 of the case control subjects. HBsAg and HCV rates among the HCC patients were higher in men than women. Rates were highest in patients 48 years and above (37.5%; 3/8). No patient was found with anti-HCV and anti-HBV. CONCLUSION: These results indicate that the involvement of HBV and HCV in HCC in the country is in a ratio of 5:1 and that these two viruses might be independently involved in the pathogenesis of the disease. The study revealed a statistically significant association (p = 0.04) between HBsAg and HCC patients. The results also indicate that up to 50% of HCC cases in the country may be due to non viral factors and calls for further studies in this regard. These findings call for provision of diagnostic facilities for these viruses in hospitals and for their routine screening in blood banks while intervention programmes should be put in place. [Abstract/Link to Full Text]

Sakellaridis T, Mathioulakis S, Antiochos C
Synchronous early primary adenocarcinoma of both rectum and gallbladder. Report of a case.
Int Semin Surg Oncol. 2005 Sep 14;219.
BACKGROUND: Synchronous early primary cancers are rare and in addition synchronous adenocarcinoma of both rectum and gallbladder is extremely rare. CASE REPORT: We report an unusual case of synchronous early primary adenocarcinoma of rectum and gallbladder. The patient was a 72-year-old woman with complaints of bloody stools and constipation. An endoscopy revealed adenocarcinoma of the lower rectum. A through preoperative investigation showed also cholelithiasis. The patient underwent abdominoperineal resection and cholecystectomy. The histopathological diagnosis was well to middle differentiate adenocarcinoma of the gallbladder (T2, N0, M0; stage II) and middle differentiate adenocarcinoma of the rectum (T2, N0, M0; stage II). CONCLUSION: For the cases of extracolonic primary cancer associated with colorectal primary carcinoma, Warren and Gates' diagnostic criteria are used. All patients with colorectal carcinoma, should undergo a throughout preoperative examination to exclude the possibility of synchronous early primary cancers. [Abstract/Link to Full Text]

Thyavihally YB, Tongaonkar HB, Desai SB
Benign mixed epithelial stromal tumor of the renal pelvis with exophytic growth: case report.
Int Semin Surg Oncol. 2005 Sep 9;218.
BACKGROUND: Mixed epithelial and stromal tumor (MEST) is a distinctive benign composite neoplasm of the kidney predominantly seen in females mostly in the perimenopausal period. Although these tumors are known to arise from renal pelvis, our case was distinct in that it had no intrapelvic component growing in exophytic fashion. CASE REPORT: A 35 year old female patient presented to us with vague abdominal pain. She had undergone excision of bilateral ovarian cystic masses for cystic teratoma twelve years earlier. A computed tomography scan of abdomen and pelvis showed a 9 x 7 cm uniformly solid mass with poor contrast enhancement situated in the inferomedial aspect of the left kidney. On exploration, the mass was arising from the inferior and anterior aspect of left renal pelvis, and was attached to it with a narrow pedicle. There was no adherence or attachment to the renal parenchyma. The mass was excised preserving the kidney. Microscopically, the tumor was composed of large collagenized areas containing bundles of spindle cells and several 'microcysts' lined by cuboidal epithelium suggestive of a benign mixed epithelial stromal tumor. DISCUSSION: Mixed epithelial tumors usually present in perimenopausal women as a partially cystic mass. Tumors are composed of irregular mixtures of cystic and solid areas, glands with variable complexity and distribution and the stromal component is characterized by a spindle cell proliferation. Commonly, it arises from the renal parenchyma and pelvis and nephrectomy is advocated to manage these tumors. CONCLUSION: MEST is a distinctive benign tumor of the kidney that should be distinguished from other renal neoplasms. MEST arising from the renal pelvis and growing exophytically is a rare entity. The overall prognosis is favorable. [Abstract/Link to Full Text]

Srkalovic G, Cameron MG, Deitcher SR, Kattke-Marchant K, Hussein MA
Incidence and risk factors of venous thromboembolism (VTD) in patients with amyloidosis.
Int Semin Surg Oncol. 2005 Sep 2;217.
BACKGROUND: Coagulation problems in amyloidosis are historically associated with bleeding tendencies (mostly Factor X abnormalities). Increased clotting was observed in isolated cases diagnosed with low-grade disseminated intravascular coagulation (DIC). Problem of venous thromboembolic disaease (VTD) in amyloidosis was not systematically investigated. METHODS: We evaluated frequency of VTD and risk factors for VTD in 56 consecutive amyloidosis patients with a documented disease evaluated and followed up at our Center from 1991-2001. Data was collected in 5 categories: (a) demographics, (b) disease and treatment, (c) thrombosis case information, (d) major risk factors for thrombosis and (e) baseline laboratory data. Univariable correlates of VTD were assessed using Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: Mean age of the patients was 67 (years range 21-83). Male/female percentage ratio was 70/30. 29% of the patients had high creatinine level (> 1.4 mg/dl). Personal or family history of VTD was recorded in 2 and 0% of patients, respectively. Known hypercoagulable state was present in 1 patient (2%). 8% of patients were smokers. Of 56 patients, 6 developed VTD (11%). Median time from diagnosis of amyloidosis to VTD was 12.5 month (range 1-107). Treatment was given within a median of 1 month (range 0-4) from the development of thrombosis. Only sites of VTD were lower extremities. No cases were associated with I.V. line. 1 case (17%) was identified postoperatively. We identified several univariable correlates of VTD in amyloid patients, including greater age at diagnosis (HR-2.99, P = .041), personal history of DVT (HR-47.7, P = .006) and immobility (HR-11.78, P = .006). Presence of circulating serum M-protein had protective role in our analysis (HR-.08, P = .031). There was no correlation with the type of treatment patients were receiving. CONCLUSION: Risk for thromboembolic diseases in patients with amyloidosis is similar to one previously described for multiple myeloma. Additional studies with higher number of thromboembolic events could help to further elucidate risk factors for VTD in this population of patients. [Abstract/Link to Full Text]

Botsios D, Zacharakis E, Lambrou I, Tsalis K, Christoforidis E, Kalfadis S, Zacharakis E, Betsis D, Dadoukis I
Our local experience with the surgical treatment of ampullary cancer.
Int Semin Surg Oncol. 2005 Aug 30;216.
BACKGROUND: The aim of this study is to report the outcome after surgical treatment of 32 patients with ampullary cancers from 1990 to 1999. METHODS: Twenty-one of them underwent pancreaticoduodenectomy and 9 local excision of the ampullary lesion. The remaining 2 patients underwent palliative surgery. RESULTS: When the final histological diagnosis was compared with the preoperative histological finding on biopsy, accurate diagnosis was preoperatively established in 24 patients. The hospital morbidity was 18.8% as 9 complications occurred in 6 patients. Following local excision of the ampullary cancer, the survival rate at 3 and 5 years was 77.7% and 33.3% respectively. Among the patients that underwent Whipple's procedure, the 3-year survival rate was 76.2% and the 5-year survival rate 62%. CONCLUSION: In this series, local resection was a safe option in patients with significant co-morbidity or small ampullary tumors less than 2 cm in size, and was associated with satisfactory long-term survival rates. [Abstract/Link to Full Text]

Al Sarakbi W, Salhab M, Thomas V, Mokbel K
Is preoperative core biopsy accurate in determining the hormone receptor status in women with invasive breast cancer?
Int Semin Surg Oncol. 2005 Aug 22;215.
BACKGROUND: The objective of this study was to determine the concordance rate between core needle biopsy (CNB) and surgical excision of invasive breast cancer regarding the oestrogen receptor (ER) and Progesterone receptor (PgR) status as determined by Immunohistochemistry (IHC). METHODS: Hormone receptor status was established using IHC (using quickscore system 0-8) on preoperative CNB and subsequent surgical excision in 93 patients with invasive breast cancer. Results were compared taking into account tumour's size, grade, and patient's age. RESULTS: The ER concordance rate between CNB and surgical excisions was 95%. The PgR concordance rate was 89%. This shows that CNB has a sensitivity of 97% for ER and 95% for PgR. There is a positive correlation of ER and PgR between CNB and surgical excision (p < 0.000001). There was no significant difference in the number of core biopsies between concordant and discordant cases. CONCLUSION: Preoperative core biopsy is highly sensitive for the IHC detection of ER and PgR in invasive breast cancer. The concordance rate is higher for ER than PgR, which could be due to the fact that ER is more homogeneously distributed. [Abstract/Link to Full Text]

Salhab M, Al Sarakbi W, Perry N, Mokbel K
Pneumothorax after a clinical breast fine-needle aspiration of a lump in a patient with Poland's syndrome.
Int Semin Surg Oncol. 2005 Aug 19;214.
We report the first case in the medical literature of a pneumothorax complicating fine needle aspiration cytology (FNAC) of a breast lump in a woman with a mild form of Poland's syndrome. The pneumothorax was treated conservatively. This is the first case of breast FNA-related pneumothorax seen in our clinical practice. We believe that the absence of pectoral muscles has increased the risk of this complication. We have also diagnosed an incidental screen-detected breast cancer affecting the ipsilateral breast in the same patient. We conclude that caution should be exercised when performing FNAC of breast lesions in patients with Poland's syndrome. The procedure should be preferably performed under image guidance in such patients in order to minimise the risk of this complication. [Abstract/Link to Full Text]

Hillenbrand A, Sträter J, Henne-Bruns D
Frequency, symptoms and outcome of intestinal metastases of bronchopulmonary cancer. Case report and review of the literature.
Int Semin Surg Oncol. 2005 Jun 6;213.
BACKGROUND: We report a new case of small bowel metastases from primary lung cancer. Such metastases are not exceptional, but their clinical manifestations are rare. CASE PRESENTATION: The case involved a 56-year-old man with a squamous cell carcinoma of the lung (stage IV) that had been treated with chemotherapy. He presented fourteen months after diagnosis with an acute abdominal pain. Abdominal CT-scan demonstrated a perforated jejunum and he underwent emergency surgery. Postoperative pathologic analysis confirmed the diagnosis of metastatic pulmonary carcinoma. The patient was discharged after ten days, but died 8 weeks after surgery at home on tumor progression. CONCLUSION: We were able to find 58 documented similar cases in the literature. Most cases presented with bowel perforation or obstruction. Squamous cell carcinoma was the most common histological cell type followed by large cell carcinoma. Other metastases are often present, and the prognosis is mostly fatal at short term. [Abstract/Link to Full Text]

Nath SV, Prince HM, Choong PF, Toner GC
Durable remissions are rare following high dose therapy with autologous stem cell transplantation for adults with "paediatric" bone and soft tissue sarcomas.
Int Semin Surg Oncol. 2005 May 31;2(1):12.
BACKGROUND: The role of high dose therapy (HDT) with autologous stem cell transplantation (AuSCT) for the treatment of bone and soft tissue sarcomas remains investigational. There are few reports examining this strategy focusing on the adult population. METHODS: We retrospectively reviewed our experience of adult patients undergoing HDT and AuSCT for 'paediatric' sarcomas. RESULTS: A total of 17 patients (14 male, 3 female) with median age at transplant of 24 years (range 20 - 41) were identified. The diagnosis was Ewings sarcoma/PNET (10), osteosarcoma (5) and rhabdomyosarcoma (2). Status prior to HDT, following conventional-dose chemotherapy +/- surgery +/- radiotherapy, was complete remission (CR) (6), partial remission (PR) (6), stable disease (1) and progressive disease (4). There was no transplant-related mortality. Two patients remain disease free beyond four years and both received HDT as part of their primary therapy (CR1 and PR1) however, the median progression free survival and overall survival following AuSCT for the entire cohort was only 7 months (range: 2-92 months) and 13 months (range: 2 - 92 months), respectively. CONCLUSION: HDT and AuSCT infrequently achieves prolonged remissions in adult patients and should only be considered in patients who are in a PR or CR following conventional-dose therapy. Further studies are required to define the role of HDT with AuSCT for adult patients with sarcoma. [Abstract/Link to Full Text]

Salhab M, Al Sarakbi W, Mokbel K
Breast weight and hormone receptor status in women with breast cancer.
Int Semin Surg Oncol. 2005 May 16;2(1):11. [Abstract/Link to Full Text]

Amukotuwa S, Choong PF, Smith PJ, Powell GJ, Slavin J, Schlicht SM
Tuberculosis masquerading as malignancy: a multimodality approach to the correct diagnosis - a case report.
Int Semin Surg Oncol. 2005 May 7;2(1):10.
BACKGROUND: Extrapulmonary tuberculosis is one of the great mimickers of medicine, and often masquerades as malignancy. As a result, patients may be referred to oncologists and surgeons for further evaluation and management, delaying the institution of appropriate anti-tuberculous drug therapy. CASE PRESENTATION: We present the case of a 21 year old man with tuberculous osteomyelitis, who was referred to the Bone and Soft Tissue Sarcoma Service at our institution with a provisional diagnosis of malignancy. Further investigation revealed extensive retroperitoneal abdominal and pelvic lymphadenopathy. The recognition of certain patterns on imaging, and finally the isolation of Mycobacterium tuberculosis from tissue samples obtained under image guidance, enabled the correct diagnosis to be made. CONCLUSION: This case highlights the importance of remaining cognisant of the protean manifestations of extrapulmonary tuberculosis, and illustrates the advantage of a clinically directed multi-modality imaging approach to diagnosis. [Abstract/Link to Full Text]

Yuen A, Ek ET, Choong PF
Research: Is resection of tumours involving the pelvic ring justified? : A review of 49 consecutive cases.
Int Semin Surg Oncol. 2005 Apr 9;2(1):9.
INTRODUCTION: Pelvic surgery is challenging and impacts significantly on limb and visceral function, thus, raising the question "is heroic surgery justifiable". This study assessed the functional, oncologic and surgical outcomes following pelvis tumour resections. METHODS: Between 1996-2003, 49 patients (mean age 43 years) underwent pelvic tumour resections- 38 primary malignant tumours, 5 secondary tumours and 6 benign tumours. Bone tumours comprised 5 osteosarcomas, 5 Ewings sarcomas, and 12 chondrosarcomas. Of the soft tumours, 9 were of neural origin. Tumours involved the ilium, acetabulum, pubic bones, sacrum or a combination of these. Functional assessment was performed and no patient had metastases at presentation. RESULTS: There were 41 limb sparing resections and 8 hindquarter amputations. Surgical margins were intralesional (1), marginal (13), wide (26), and radical (3). Of limb sparing surgery, prosthetic reconstructions were performed in 10 patients, biologic reconstructions in 6, a combination of these in 3 and no reconstruction in others. There was 1 intraoperative death, 7 local recurrences and 19 metastases. Death from disease occurred at a mean of 14.2 months with a mean followup of 27 (1-96) months. Amputation and periacetabular resections had worse functional outcomes. Emotional acceptance was surprisingly high. CONCLUSION: Pelvic resections are complex. Functional outcome is significantly affected by surgery. Disease control is similar to limb tumours. Emotional acceptance of surgery in survivors was surprisingly high. Major pelvic resection for malignancy appears justified. [Abstract/Link to Full Text]

Salhab M, Al Sarakbi W, Mokbel K
The evolving role of the dynamic thermal analysis in the early detection of breast cancer.
Int Semin Surg Oncol. 2005 Apr 8;2(1):8.
It is now recognised that the breast exhibits a circadian rhythm which reflects its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian and that a circadian to ultradian shift may be a general correlation to neoplasia.Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development.The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer.This article focuses on dynamic thermal analysis as an evolving method in breast cancer detection in pre-menopausal women with dense breast tissue. Prospective multi-centre trials are required to validate this promising modality in screening.The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy. [Abstract/Link to Full Text]

Leondi A, Koutsikos J, Zerva C
Interpretation of the post-surgical Somatostatin Receptor Scintigram of a Primary Neuroendocrine Tumor of the Thymus: a case report and literature review.
Int Semin Surg Oncol. 2005 Mar 23;2(1):7.
A case of a thymic neuroendocrine tumor and the interpretation problems in a post-surgical Somatostatin Receptor Scintigraphy are presented. In a 53-year-old man with superior vena cava obstruction syndrome an atypical carcinoid of the thymus (neuroendocrine carcinoma of intermediate grade 2), was found at surgery.During his first year of follow-up a Somatostatin Receptor Scintigraphy was recommended. An area of abnormal concentration of the radiopharmaceutical was revealed in the mediastinum at this time.A thorough understanding of the mechanisms of the radiopharmaceutical uptake and of the various clinical settings in which uptake can occur are essential for a proper evaluation of the scintigraphic findings and result in the optimal use of this valuable modality.The literature review provides an overview of this rare type of tumor and insight into the clinical significance of Somatostatin Receptor Scintigraphy. [Abstract/Link to Full Text]

Memon MA, Anwar S, Shiwani MH, Memon B
Gallbladder carcinoma: a retrospective analysis of twenty-two years experience of a single teaching hospital.
Int Semin Surg Oncol. 2005 Mar 17;2(1):6.
BACKGROUND: The purpose of this study was to retrospectively evaluate our experience with gallbladder cancer since the establishment of a tumour registry in our institute. METHODS: Between 1975 and 1998, 23 consecutive patients with gallbladder cancer were identified using the tumour registry database. There were 18 females (78%) and 5 (22%) males. The mean age at diagnosis was 70.6 (range 42-85) years. The diagnosis was achieved either intra-operatively or following the histological analysis of the gallbladder (n = 17), following gallbladder or liver biopsy (n = 4) or at autopsy (n = 2). Presenting symptoms included upper abdominal pain, weight loss, nausea, vomiting, fever, painless jaundice, hepatomegaly, upper abdominal mass, upper abdominal tenderness, and gastrointestinal haemorrhage. RESULTS: Histological examination revealed 20 adenocarcinomas (87%), 2 squamous cell carcinomas (9%) and one spindle cell sarcoma (4%). At presentation, 14 (61%) gallbladder cancers were stage IV, 5 (22%) were stage III and 4 (17%) were stage II. Kaplan Meier analysis revealed a mean survival of 3.2, 7.8 and 8.2 months for stage IV, III, and II disease respectively. Out of 14 patients with stage IV disease, 8 patients received adjuvant chemotherapy and survived for 4.6 months whereas six patients who did not receive adjuvant chemotherapy survived for 1.3 months. This difference was statistically significant (p = 0.04). CONCLUSION: The majority of patients with gallbladder cancer presented with advanced stage disease (stage IV) which carries a dismal prognosis. Patients who received chemotherapy with stage IV disease, however, did better than those who did not, but this is probably a reflection of patient selection. [Abstract/Link to Full Text]

Atkin G, Chopada A, Mitchell I
Colorectal cancer metastasis: in the surgeon's hands?
Int Semin Surg Oncol. 2005 Feb 24;2(1):5.
BACKGROUND: Lymphovascular ligation before tumour manipulation during colorectal cancer resection is termed the 'no-touch isolation' technique. It aims to reduce the intra-operative dissemination of colorectal cancer cells. Recently, the detection of circulating tumour cells has been enhanced by molecular biology techniques. This paper reviews the evidence for the no-touch isolation technique in light of the recent developments in circulating tumour cell detection. METHODS: Studies investigating the effect of colorectal cancer surgery on circulating tumour cells were identified by a Medline search using the subject headings colorectal neoplasms and neoplasm circulating cells together with the map term 'no-touch isolation technique'. Further references were obtained from key articles. RESULTS: Molecular biological techniques have improved the detection of circulating colorectal cancer cells. There is a trend towards reduced tumour cell dissemination with the no-touch technique compared with the conventional method. However the benefit in terms of improved patient survival remains unproven. CONCLUSION: The no-touch isolation technique reduces circulating tumour cell dissemination but further work is needed to determine the significance of this with regards to patient survival. [Abstract/Link to Full Text]

Hargunani R, Al-Dujaily S, Abdulla A, Osborne D
Haematuria as a presentation of metastatic oesophageal carcinoma.
Int Semin Surg Oncol. 2005 Feb 20;2(1):4.
Haematuria is a classical symptom of urological disease often signifying a primary bladder cancer. Rarely, however, the presence of blood in the urine can be due to secondary spread of tumours into the bladder from distant sites. Notably this has been reported to occur in breast cancer, malignant melanoma and gastric cancers. Haematuria due to spread from a primary oesophageal cancer to the bladder has never been reported. We present a case of haematuria confirmed histologically to be due to metastases from a primary oesophageal tumour. Oesophageal cancer is capable of spread to all three neighbouring compartments (abdomen, chest and neck) and therefore has the potential to spread to unusual sites. Clinicians should always carefully regard haematuria in a patient previously treated for cancer and retain a high index of suspicion for distant metastases as being the cause. [Abstract/Link to Full Text]

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Recent Articles in World Journal of Surgical Oncology

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Takeyama H, Sawai H, Wakasugi T, Takahashi H, Matsuo Y, Ochi N, Yasuda A, Sato M, Okada Y, Funahashi H, Akamo Y, Manabe T
Successful paclitaxel-based chemotherapy for an alpha-fetoprotein-producing gastric cancer patient with multiple liver metastases.
World J Surg Oncol. 2007;579.
BACKGROUND: Alpha-fetoprotein (AFP)-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis. CASE PRESENTATION: A 64-year-old Japanese man admitted to our hospital was diagnosed with gastric cancer with liver metastases. He underwent a total gastrectomy with splenectomy, and pathological stage IV disease according to the classification proposed by the Japanese Gastric Cancer Association was assigned. The histological diagnosis was poorly differentiated adenocarcinoma, and tumor production of AFP was confirmed by immunohistochemical staining. Following surgery, the patient received combination chemotherapy consisting of TS-1 and paclitaxel. Initially, AFP levels decreased dramatically and computed tomography (CT) revealed regression of liver metastases. However, multiple new liver metastases appeared and serum AFP levels increased after 5 months. A regimen of 5-FU plus paclitaxel followed by paclitaxel monotherapy was used next. Serum AFP levels once again decreased and CT showed regression or disappearance of liver metastases. The patient currently has a very good quality of life, and is receiving weekly paclitaxel monotherapy as an outpatient. No progression of liver metastases has been observed to date. CONCLUSION: We consider this rare case to have significant value with respect to treatment of AFP-producing gastric cancer with multiple liver metastases, and propose that combining surgery with chemotherapeutic agents such as paclitaxel may lead to a better prognosis in such cases. [Abstract/Link to Full Text]

John SK, Basu S, Lawrance RJ, Davies N
An unusual presentation of a Gastrointestinal stromal tumour (GIST).
World J Surg Oncol. 2007;578.
ABSTRACT: BACKGROUND: Gastrointestinal stromal tumours (GIST) are rare tumours, now more frequently identified with the new imaging modalities like computerised tomography (CT) and magnetic resonance imaging (MRI). We report a rare presentation of a GIST with an unusual diagnostic workup in a multidisciplinary setting leading to a definitive diagnosis and treatment. CASE PRESENTATION: A 55-year-old lady was admitted under the general surgeons, with 3-day history of abdominal pain, three-week history of loss of appetite and weight. The patient was sequentially investigated with ultrasonography, computerised tomography and finally selective angiogram in a multidisciplinary setting. The selective angiogram showed a GIST with intratumour bleed, leading to successful surgical excision and being recurrence free at 22 month follow up. CONCLUSION: Clinical presentation of these tumours can be varied and gastrointestinal bleeding is the commonest mode described in the literature. The clinician needs to be aware of much more rare presentations of the GIST including an intra tumour bleed. A structured multidisciplinary approach would lead to successful diagnosis and treatment. [Abstract/Link to Full Text]

Hyer SL, McAleese J, Harmer CL
Neuroendocrine carcinoma arising in soft tissue: three case reports and literature review.
World J Surg Oncol. 2007;577.
ABSTRACT: BACKGROUND: Neuroendocrine tumours (NET) are tumours arising from neuroendocrine cells of neural crest origin. They are characterised by the presence of neurosecretory granules which react positively to silver stains and to specific markers including neuron specific enolase, synaptophysin and chromogranin. Metastasis to the skin occurs infrequently but primary soft tissue NET is excessively rare. CASE PRESENTATION: We report our experience with 3 such cases. In the first case, the NET originated in muscle and was treated with wide surgical excision and adjuvant radiotherapy. The second case presented as a subcutaneous mass in the foot and the tumour was positive on 123I mIBG scan. She has had prolonged recurrence-free survival following primary hypo-fractionated radiotherapy. In the third case, a cutaneous nodule proved to be a NET and at surgery, lymph node disease was present. He has remained disease-free after surgical excision without the need for external beam radiotherapy. CONCLUSION: These tumours appear to have a good prognosis. Complete excision offers potentially curative treatment. Adjuvant radiotherapy may be helpful when the tumour margin is narrow. For patients with unresectable disease or where surgery would not be appropriate, radiotherapy appears to be an effective therapeutic option. [Abstract/Link to Full Text]

Tartaglia F, Blasi S, Sgueglia M, Polichetti P, Tromba L, Berni A
Retroperitoneal liposarcoma associated with small plaque parapsoriasis.
World J Surg Oncol. 2007;576.
BACKGROUND: Extremely rare cases of paraneoplastic syndromes or ectopic production of proteins associated with liposarcoma are reported in literature. Production of Granulocyte-Colony Stimulating Factor, alpha-fetoprotein, paraneoplastic pemphigus and leucocytosis, Acrokeratosis paraneoplastica (Bazex's syndrome) are reported.The present report describes a case of retroperitoneal liposarcoma associated with small plaque parapsoriasis. Our search in the English literature of such a kind of association did not reveal any case reported. CASE PRESENTATION: A 74 year male patient was admitted to our hospital because of the presence of an abdominal mass in right iliac fossa. He also complained of a two-year history of psoriasiform eruptions. The CT scan showed a retroperitoneal pelvic mass. Therefore surgical resection of the tumor was performed. After surgery, the skin eruptions disappeared completely in seven days and so a diagnosis of parapsoriasis syndrome was done. CONCLUSION: Parallel disappearing of skin eruptions after surgery, typical clinical picture and not specific histology of the cutaneous lesions suggest the diagnosis of small plaque parapsoriasis. Therefore we propose to add Small Plaque Parapsoriasis to the list of paraneoplastic syndromes associated to liposarcoma. [Abstract/Link to Full Text]

Jones GE, Strauss DC, Forshaw MJ, Deere H, Mahedeva U, Mason RC
Breast cancer metastasis to the stomach may mimic primary gastric cancer: report of two cases and review of literature.
World J Surg Oncol. 2007;575.
BACKGROUND: The stomach is an infrequent site of breast cancer metastasis. It may prove very difficult to distinguish a breast cancer metastasis to the stomach from a primary gastric cancer on the basis of clinical, endoscopic, radiological and histopathological features. It is important to make this distinction as the basis of treatment for breast cancer metastasis to the stomach is usually with systemic therapies rather than surgery. CASE PRESENTATIONS: The first patient, a 51 year old woman, developed an apparently localised signet-ring gastric adenocarcinoma 3 years after treatment for lobular breast cancer with no clinical evidence of recurrence. Initial gastric biopsies were negative for both oestrogen and progesterone receptors. Histopathology after a D2 total gastrectomy was reported as T4 N3 Mx. Immunohistochemistry for Gross Cystic Disease Fluid Protein was positive, suggesting metastatic breast cancer. The second patient, a 61 year old woman, developed a proximal gastric signet-ring adenocarcinoma 14 years after initial treatment for breast cancer which had subsequently recurred with bony and pleural metastases. In this case, initial gastric biopsies were positive for both oestrogen and progesterone receptors; subsequent investigations revealed widespread metastases and surgery was avoided. CONCLUSION: In patients with a history of breast cancer, a high index of suspicion for potential breast cancer metastasis to the stomach should be maintained when new gastrointestinal symptoms develop or an apparent primary gastric cancer is diagnosed. Complete histopathological and immunohistochemical analysis of the gastric biopsies and comparison with the original breast cancer pathology is important. [Abstract/Link to Full Text]

Vaughan A, Dietz JR, Moley JF, Debenedetti MK, Aft RL, Gillanders WE, Eberlein TJ, Ritter J, Margenthaler JA
Metastatic disease to the breast: the Washington University experience.
World J Surg Oncol. 2007;574.
BACKGROUND: Metastases to the breast occur rarely, but may be increasing in incidence as patients live longer with malignant diseases. The aim of this study is to characterize metastatic disease to the breast and to describe the management and prognosis of patients who present with this diagnosis. METHODS: A retrospective review of our institution's pathology and breast cancer databases was performed in order to identify patients with breast malignancies that were not of primary breast origin. Chart review provided additional information about the patients' primary malignancies and course of illness. RESULTS: Between 1991 and 2006, eighteen patients with metastatic disease to the breast of non-hematologic origin were identified and all had charts available for review. Among the 18 patients with disease metastatic to the breast, tissues of origin included 3 ovarian, 6 melanoma, 3 medullary thyroid, 3 pulmonary neuroendocrine, 1 pulmonary small cell, 1 oral squamous cell, and 1 renal cell. Overall mean survival after diagnosis of metastatic disease to the breast was 22.4 months. Treatment of metastases varied and included combinations of observation, surgery, radiation, and chemotherapy. Five patients (27.8%) required a change in management of their breast disease for local control. CONCLUSION: Due to the variable course of patients with metastatic disease, a multi-disciplinary approach is necessary for each patient with disease metastatic to the breast to determine optimal treatment. Based on our review, many patients survive for long periods of time and local treatment of metastases to the breast may be beneficial in these patients to prevent local complications. [Abstract/Link to Full Text]

Andreoni B, Chiappa A, Bertani E, Bellomi M, Orecchia R, Zampino M, Fazio N, Venturino M, Orsi F, Sonzogni A, Pace U, Monfardini L
Surgical outcomes for colon and rectal cancer over a decade: results from a consecutive monocentric experience in 902 unselected patients.
World J Surg Oncol. 2007;573.
BACKGROUND: This study evaluates the surgical morbidity and long-term outcome of colorectal cancer surgery in an unselected group of patients treated over the period 1994-2003. METHODS: A consecutive series of 902 primary colorectal cancer patients (489 M, 413 F; mean age: 63 years +/- 11 years, range: 24-88 years) was evaluated and prospectively followed in a university hospital (mean follow-up 36 +/- 24 months; range: 3-108 months). Perioperative mortality, morbidity, overall survival, curative resection rates, recurrence rates were analysed. RESULTS: Of the total, 476 colorectal cancers were localized to the colon (CC, 53%), 406 to the rectum (RC, 45%), 12 (1%) were multicentric, and 8 were identified as part of HNPCC (1%). Combining all tumours, there were 186 cancers (20.6%) defined as UICC stage I, 235 (26.1%) stage II, 270 (29.9%) stage III and 187 (20.6%) stage IV cases. Twenty-four (2.7%) cases were of undetermined stage. Postoperative complications occurred in 38% of the total group (37.8% of CC cases, 37.2% of the RC group, 66.7% of the synchronous cancer patients and 50% of those with HNPCC, p = 0.19) Mortality rate was 0.8%, (1.3% for colon cancer, 0% for rectal cancer; p = 0.023). Multivisceral resection was performed in 14.3% of cases. Disease-free survival in cases resected for cure was 73% at 5-years and 72% at 8 years. The 5- and 8-year overall survival rates were 71% and 61% respectively (total cases). At 5-year analysis, overall survival rates are 97% for stage I disease, 87% for stage II, 73% for stage III and 22% for stage IV respectively (p < 0.0001). The 5-year overall survival rates showed a marked difference in R0, R1+R2 and non resected patients (82%, 35% and 0% respectively, p < 0.0001). On multivariate analysis, resection for cure and stage at presentation but not tumour site (colon vs. rectum) were independent variables for overall survival (p < 0.0001). CONCLUSION: A prospective, uniform follow-up policy used in a single institution over the last decade provides evidence of quality assurance in colorectal cancer surgery with high rates of resection for cure where only stage at presentation functions as an independent variable for cancer-related outcome. [Abstract/Link to Full Text]

De Tommasi A, Occhiogrosso G, De Tommasi C, Luzzi S, Cimmino A, Ciappetta P
A polycystic variant of a primary intracranial leptomeningeal astrocytoma: case report and literature review.
World J Surg Oncol. 2007;572.
BACKGROUND: Primary leptomeningeal astrocytomas are rare intracranial tumors. These tumors are believed to originate from cellular nests which migrate by means of aberration, ultimately settling in the leptomeningeal structure. They may occur in both solitary and diffuse forms. The literature reports only fifteen cases of solitary primary intracranial leptomeningeal astrocytomas. CASE PRESENTATION: The authors report the case of a seventy-eight year-old woman with a polycystic variant of a solitary primary intracranial leptomeningeal astrocytoma. The first neurological signs were seizures and aphasia. CT and MRI scans demonstrated a fronto-parietal polycystic tumor adherent to the sub arachnoid space. A left fronto-temporo-parietal craniotomy revealed a tight coalescence between the tumor and the arachnoid layer which appeared to wrap the mass entirely. Removal of the deeper solid part of the tumor resulted difficult due to the presence of both a high vascularity and a tight adherence between the tumor and the ventricular wall. CONCLUSION: A new case of a solitary primitive intracranial leptomeningeal astrocytoma of a rare polycystic variant is reported. Clinical, surgical, pathologic and therapeutic aspects of this tumor are discussed. [Abstract/Link to Full Text]

Behtash N, Karimi Zarchi M
Dysgerminoma in three patients with Swyer syndrome.
World J Surg Oncol. 2007;571.
BACKGROUND: Dysgerminoma is the most common malignant germ cell tumor of the ovary. This malignancy can be associated with pure gonadal dysgenesis or Swyer syndrome, mixed gonadal dysgenesis and partial gonadal dysgenesis. CASE PRESENTATION: Dysgerminoma developed in 3 phenotypic female patients with 46 XY pure gonadal dysgenesis. All patients presented first with abdominopelvic mass. Laparatomy was done. 46 XY karyotype was made by lymphocyte culture. Then these patients underwent gonadectomy that histopathology results were streak ovaries without evidence for malignancy. Two patients received postoperative adjuvant therapy. CONCLUSION: In Patients with Swyer syndrome the risk of dysgerminoma is high and gonadectomy is recommended. Also 5% of dysgerminomas are discovered in phenotypic female and 46 XY karyotype, thus in adolescent with dysgerminoimas and amenorrhea, karyotype should be done. [Abstract/Link to Full Text]

Ojima H, Ootake S, Yokobori T, Mochida Y, Hosouchi Y, Nishida Y, Kuwano H
Treatment of multiple liver metastasis from gastric carcinoma.
World J Surg Oncol. 2007;570.
BACKGROUND: The efficacy of operative resection of liver metastasis from colorectal cancer has been established. However, a treatment for liver metastasis from gastric cancer has not yet been established. In this study, we evaluated the efficacy of hepatic arterial infusion for synchronous hepatic metastasis from gastric cancer. PATIENTS AND METHODS: This study consisted of 37 patients [HAI group; 18 and non-HAI group; 19] with synchronous multiple liver metastases from gastric cancer at Gunma Prefecture Saiseikai-Maebashi Hospital. We retrospectively analyzed the efficacy of HAI. RESULTS: Response rate (CR + PR) of HAI was 83%. However, HAI treatment did not affect any improvement in the survival rate. CONCLUSION: HAI is an effective treatment for control of liver metastasis specifically. The factor effective for an improvement in the survival rate was possibly that of gastrectomy. [Abstract/Link to Full Text]

Ogun GO, Oyetunde O, Akang EE
Cavernous lymphangioma of the breast.
World J Surg Oncol. 2007;569.
BACKGROUND: Cavernous lymphangioma is a rare lesion in the breast of adults. Only a few cases have been documented in literature. CASE PRESENTATION: We describe a 38-year-old woman who presented with a palpable breast lump, which measured 5 x 4 cm. A local excision of the lump was performed and a diagnosis of cavernous lymphangioma was made. The patient is alive and well, after five years of follow-up, with no complaints or recurrence. CONCLUSION: To the best of our knowledge, this is the first case to be documented in a black African woman. Complete surgical excision seems to be the best modality of treatment of this lesion. [Abstract/Link to Full Text]

Nanni C, Zamagni E, Cavo M, Rubello D, Tacchetti P, Pettinato C, Farsad M, Castellucci P, Ambrosini V, Montini GC, Al-Nahhas A, Franchi R, Fanti S
11C-choline vs. 18F-FDG PET/CT in assessing bone involvement in patients with multiple myeloma.
World J Surg Oncol. 2007;568.
BACKGROUND: Multiple Myeloma (MM) is a B cell neoplasm causing lytic or osteopenic bone abnormalities. Whole body skeletal survey (WBSS), Magnetic resonance (MR) and 18F-FDG PET/CT are imaging techniques routinely used for the evaluation of bone involvement in MM patients. AIM: As MM bone lesions may present low 18F-FDG uptake; the aim of this study was to assess the possible added value and limitations of 11C-Choline to that of 18F-FDG PET/CT in patients affected with MM. METHODS: Ten patients affected with MM underwent a standard 11C-Choline PET/CT and an 18F-FDG PET/CT within one week. The results of the two scans were compared in terms of number, sites and SUVmax of lesions. RESULTS: Four patients (40%) had a negative concordant 11C-Choline and 18F-FDG PET/CT scans. Two patients (20%) had a positive 11C-Choline and 18F-FDG PET/CT scans that identified the same number and sites of bone lesions. The remaining four patients (40%) had a positive 11C-Choline and 18F-FDG PET/CT scan, but the two exams identified different number of lesions. Choline showed a mean SUVmax of 5 while FDG showed a mean SUVmax of 3.8 (P = 0.042). Overall, 11C-Choline PET/CT scans detected 37 bone lesions and 18F-FDG PET/CT scans detected 22 bone lesions but the difference was not significant (P = 0.8). CONCLUSION: According to these preliminary data, 11C-Choline PET/CT appears to be more sensitive than 18F-FDG PET/CT for the detection of bony myelomatous lesions. If these data are confirmed in larger series of patients, 11C-Choline may be considered a more appropriate functional imaging in association with MRI for MM bone staging. [Abstract/Link to Full Text]

Akçay MN, Sa?lam L, Polat P, Erdo?an F, Albayrak Y, Povoski SP
Mammary tuberculosis - importance of recognition and differentiation from that of a breast malignancy: report of three cases and review of the literature.
World J Surg Oncol. 2007;567.
BACKGROUND: While tuberculosis of the breast is an extremely uncommon entity seen in western populations, it accounts for up to 3% of all treatable breast lesions in developing countries. CASE PRESENTATIONS: We reviewed three female cases of mammary tuberculosis that were diagnosed and treated in Turkey during the same calendar year. All three patients presented with a painful breast mass. In all cases, fine needle aspiration was nondiagnostic for mammary tuberculosis. However, the diagnosis of mammary tuberculosis was confirmed by histopathologic evaluation at the time of open surgical biopsy. All three patients were treated with antituberculous therapy for six months. At the end of the treatment period, each patient appeared to be clinically and radiologically without evidence of residual disease. CONCLUSION: The diagnosis of mammary tuberculosis rests on the appropriate clinical suspicion and the histopathologic findings of the breast lesion. Its recognition and differentiation from that of a breast malignancy is absolutely necessary. Antituberculous chemotherapy, initiated immediately upon diagnosis, forms the mainstay of treatment for mammary tuberculosis. [Abstract/Link to Full Text]

Chintamani V, Bansal A, Bhatnagar D, Saxena S
Isolated colostomy site recurrence in rectal cancer-two cases with review of literature.
World J Surg Oncol. 2007;552.
BACKGROUND: Colostomy site carcinomas are rare with only eight cases reported in the world literature. Various etiological factors like adenoma-cancer sequence, bile acids, recurrent and persistent physical damage at the colostomy site by faecal matter due to associated stomal stenosis have been considered responsible. Two such cases are being reported and in both cases there was no evidence of any local recurrence in the pelvis or liver and distant metastasis. Both patients had received adjuvant chemotherapy following surgery. CASE PRESENTATION: First case was a 30-year-old male that had reported with large bowel obstruction due to an obstructing ulcero-proliferative growth (poorly differentiated adenocarcinoma) at the colostomy site after abdomino-perineal resection, performed for low rectal cancer six years previously. Wide local excision with microscopically free margins was performed with a satisfactory outcome. Four years later he presented with massive malignant ascites, cachexia and multiple liver metastasis and succumbed to his disease. Second case was a 47-year-old male that presented with acute large bowel obstruction due to an annular growth (well differentiated adenocarcinoma) in the upper rectum. He was managed by Hartmann's operation and the sigmoid colostomy was closed six months later. Five years following closure of colostomy, he presented with two parietal masses at the previous colostomy site scar, which, on fine needle aspiration cytology were found to be well-differentiated adenocarcinomas of colorectal type. Surgery in the form of wide local resection with free margins was performed. He presented again after five years with recurrence along the previous surgery scar and an incisional hernia and was managed by wide local excision along with hernioplasty. Follow-up of nine years following first surgery is satisfactory. CONCLUSIONS: Colostomy site/scar recurrence of rectal carcinoma is rare and could be due to various etiological factors, although the exact causative mechanism is not known. Surgery with microscopically free margins is recommended in the absence of metastatic disease. Stenosis of the stoma is considered as one of the most important contributory factors and should be followed carefully. [Abstract/Link to Full Text]

Todoroki T, Sano T, Sakurai S, Segawa A, Saitoh T, Fujikawa K, Yamada S, Hirahara N, Tsushima Y, Motojima R, Motojima T
Primary omental gastrointestinal stromal tumor (GIST).
World J Surg Oncol. 2007;566.
BACKGROUND: We report herein a rare case of primary omental gastrointestinal stromal tumor (GIST). CASE PRESENTATION: A 65 year-old man was referred to our hospital with a huge abdominal mass occupying the entire left upper abdomen as shown by sonography. On computed tomography (CT), this appeared as a heterogeneous low-density mass with faint enhancement. Abdominal angiography revealed that the right gastroepiploic artery supplied the tumor. With such an indication of gastric GIST, liposarcoma, leiomyosarcoma or mesothelioma laparotomy was performed and revealed that this large mass measured 20 x 17 x 6 cm, arising from the greater omentum. It was completely resected. Histopathologically, it was composed of proliferating spindle and epithelioid cells with an interlacing bundle pattern. Immunohistochemically, the tumor was positive for myeloid stem cell antigen (CD34), weakly positive for c-KIT (CD117) and slightly positive for neuron-specific enolase (NSE), but negative for cytokeratin (CK), alpha-smooth muscle actin (SMA) and S-100 protein. A mutation was identified in the platelet-derived growth factor alpha (PDGFRA) juxtamembrane domain (exon 12, codon561) and the tumor was diagnosed as an omental GIST. The postoperative course was uneventful. The patient is treated by Glevec(R) and is alive well with no sign of relapse. CONCLUSION: Our case demonstrated a weak immunohistochemical expression of c-kit (CD117) and a point mutation in PDGFRA exon 12 resulting in an Asp for Val561 substitution. Imatinib therapy as an adjuvant to complete resection has been carried out safely. Because of the rarity of primary omental GISTs, it is inevitable to analyze accumulating data from case reports for a better and more detailed understanding of primary omental GISTs. [Abstract/Link to Full Text]

Gulec SA, Hoenie E, Hostetter R, Schwartzentruber D
PET probe-guided surgery: applications and clinical protocol.
World J Surg Oncol. 2007;565.
INTRODUCTION: Parallel to the advances in diagnostic imaging using positron emission tomography (PET), and availability of new systemic treatment options, the treatment paradigm in oncology has shifted towards more aggressive therapeutic interventions to include cytoreductive techniques and metastasectomies. Intraoperative localization of PET positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe. MATERIALS AND METHODS: Records of patients who underwent PET probe-guided surgery were reviewed. Surgical indications and operative targets were determined based on diagnostic PET/PET-CT images performed prior to probe-guided surgical planning. PET probe-guided surgery was performed on a separate day using a high-energy gamma probe (PET probe, Care Wise Medical, Morgan Hills CA) 2-6 hours post-injection of 5-15 mCi FDG. Probe count rates, target-to-background ratios, and lesion detection success were analyzed. RESULTS: Twenty-four patients underwent PET probe-guided surgery; one patient had two PET-probe guided surgeries resulting in a total of 25 cases (5 colorectal cancer cases, 4 thyroid cancer cases, 6 lymphoma cancer cases, and 10 other cancer cases). Surgical indication was diagnostic exploration in 6 cases with lymphoma and 1 case with head and neck cancer (28%). The remaining 18 cases (72%) underwent PET probe-guided surgery with a therapeutic intent in a recurrent or metastatic disease setting. All the lesions identified and targeted on a preoperative FDG-PET scan were detected by the PET probe with satisfactory in-vivo lesion count rates and a TBR of >/= 1.5. PET probe allowed localization of lesions that were non-palpable and non-obvious at surgical exploration in 8 patients. CONCLUSION: The use of the PET probe improves the success of surgical exploration in selected indications. Separate day protocol is clinically feasible allowing for flexible operating room scheduling. [Abstract/Link to Full Text]

Sarikaya I, Bloomston M, Povoski SP, Zhang J, Hall NC, Knopp MV, Martin EW
FDG-PET scan in patients with clinically and/or radiologically suspicious colorectal cancer recurrence but normal CEA.
World J Surg Oncol. 2007;564.
BACKGROUND: Although frequently used for tumor surveillance, the sensitivity of carcinoembryonic antigen (CEA) to detect recurrent colorectal cancer (CRC) is not optimal. Fluorine 18-fluoro-2-deoxy-glucose-positron emission tomography (18F FDG-PET) scans promise to improve recurrent CRC detection. We aimed to review PET scans of patients with clinically and/or radiologically suspicious tumor recurrence but normal CEA. METHODS: A retrospective review of an electronic database of 308 patients with CRC who had PET scans was performed. Only PET studies of patients with normal CEAs and suspected tumor recurrence who had pathological verification were selected for further analysis. Thirty-nine patients met the inclusion criteria. RESULTS: PET was positive in 26 patients (67%) and normal in 13 (33%). Histopathologic evidence of tumor recurrence was seen in 27 of the 39 patients (69%). When correlated with histopathology, PET was true positive in 22 patients, false positive in 4, true negative in 8 and false negative in 5. Overall, the accuracy of PET was 76.9%, negative predictive value (NPV) was 61.5%, and positive predictive value (PPV) was 84.6%. PPV value of PET for liver metastases was 88.8% compared to 73.3% for local recurrence. In two patients with confirmed recurrence, CEA became positive 2 months after PET scan indicating earlier detection of disease with PET. The false positive PET findings were mainly in the bowel and were secondary to acute/chronic inflammation and granulation tissue. In 3 patients with false negative PET, histopathology was consistent with mucinous adenocarcinoma. CONCLUSION: PET yields high PPV for recurrent CRC, particularly for liver metastases, in spite of normal CEA levels and should be considered early in the evaluation of patients with suspected tumor recurrence. [Abstract/Link to Full Text]

Slupski M, Piotrowiak I, Wlodarczyk Z
Local recurrence and distant metastases 18 years after resection of the greater omentum hemangiopericytoma.
World J Surg Oncol. 2007;563.
BACKGROUND: Hemangiopericytoma occurs with increasing frequency in 5th decade of life and has prediction for retroperitoneum and extremities. A case of a local recurrence and metastases of hemangiopericytoma is described. CASE PRESENTATION: Recurrence of hemangiopericytoma in the greater omentum and the jejunal mesentery as well as metastases in the retroperitoneal space were diagnosed in a 61-year-old patient who had a hemangiopericytoma of the greater omentum excised 18 years before. CONCLUSION: Because of the rarity of this disease and its typical clinical course associated with late recurrence and metastases, the authors decided to present this case emphasizing the necessity of systematic oncological follow-up after the end of treatment. [Abstract/Link to Full Text]

Valassiadou K, Morgan DA, Robertson JF, Pinder SE, Cheung KL
Successful management of elderly breast cancer patients treated without radiotherapy.
World J Surg Oncol. 2007;562.
BACKGROUND: Breast cancer in the elderly may follow a less aggressive course. There are data suggesting that radiotherapy (RT) following breast conserving surgery (BCS) for invasive carcinoma may not be necessary in some elderly patients. The addition of RT to surgery might constitute an imposition to such patients due to age-related factors. The aim of this study was to assess the efficacy of BCS without adjuvant RT in this group of patients. PATIENTS AND METHODS: A retrospective review of 92 elderly (median age 75 years; range: 70 - 87 years) patients (analysed as 93 'patients' due to one patient having bilateral cancers) managed in a dedicated breast clinic and who underwent BCS for invasive carcinoma was carried out. Eighty-three patients did not receive postoperative RT to the breast (no-RT group) whereas the remaining 10 had RT (RT-group). RESULTS: The median age in this group was 75 (range 70 - 87) years. The mean tumour size was 18 mm with a median follow-up of 37 (range 6 - 142) months. In the no RT group, adjuvant endocrine therapy with tamoxifen was given to 40/53 patients. No patients in the oestrogen receptor (ER) negative group received tamoxifen. The local recurrence (LR) rate in this group was 8.4% (2.4% per year, n = 7/83), with median time to LR of 17 months. In this no-RT group LR was correlated to ER status (2/53 ER+, 5/26ER-, p = 0.024) and margins of excision (n = 1/54 >5 mm, 2/17 1-5 mm, 4/12 <1 mm, p = 0.001). Within the ER positive group the LR rate was 0.92% per annum (0.62% per annum in patients treated with adjuvant tamoxifen, regardless of margin status). Breast cancer specific survival was correlated to histological grade (p < 0.05) and ER status (p < 0.05). CONCLUSION: It would appear that omission of RT following successful BCS in elderly patients with ER positive tumours receiving adjuvant tamoxifen may be acceptable. The LR rate as shown in this retrospective study is highly comparable to that of younger patients treated by conventional therapy. This concept is now being evaluated prospectively following a change in treatment practice. [Abstract/Link to Full Text]

Koukoutsis I, Tamijmarane A, Bellagamba R, Bramhall S, Buckels J, Mirza D
The impact of splenectomy on outcomes after distal and total pancreatectomy.
World J Surg Oncol. 2007;561.
BACKGROUND: Several authors advocate spleen preserving distal pancreatectomy, because of the increased complication rate after splenectomy. METHODS: Postoperative complications and survival after distal and total pancreatectomy, were recorded and retrospectively analyzed according to spleen preservation. Patients, who underwent distal and total pancreatectomy without histologically proven adenocarcinoma, or extrapancreatic disease, were included in the cohort which was divided into splenectomy and no splenectomy groups. Statistical analysis was performed using Fisher's test. RESULTS: The study group consisted of 62 patients who underwent distal and total pancreatectomy between 26/11/1987 to 6/1/2006. Splenectomy was performed in 35 out of 62 patients (56.5%), distal pancreatectomy was performed in 49 out of 62 patients (79%). Morbidity rate was 28.6% in splenectomy group and 14.8% in the no splenectomy group (p = 0.235), while 30 days mortality rate was 2.9%; one patient died in the splenectomy group (p = 1). CONCLUSION: Spleen-preservation did not influence the outcomes after distal and total pancreatectomy in our series. [Abstract/Link to Full Text]

Hirose Y, Sasa M, Bando Y, Hirose T, Morimoto T, Kurokawa Y, Nagao T, Tangoku A
Bilateral male breast cancer with male potential hypogonadism.
World J Surg Oncol. 2007;560.
BACKGROUND: Male breast cancer is a comparatively rare disease, and simultaneous bilateral male breast cancer is considered to be an extremely rare event. Risk factors are said to be genetic factors and hormonal abnormalities due to obesity or testicular diseases. CASE PRESENTATION: The patient was a 47-year-old Japanese male. His family had no history of female breast cancer. This patient also had hypospadias and hormonal examination indicated the presence of primary testicular potential hypogonadism, and these hormonal abnormalities seemed to be present since childhood or the fetal period. The bilateral breast cancer developed in this man at a comparatively young age, and histopathological studies of multiple sections showed that there was almost no normal epithelial cell in the ducts, while the ducts were almost completely filled with breast cancer cells. CONCLUSION: It is thought that male breast cancer is caused by an imbalance between estrogen and testosterone. We cannot rule out the possibility that the breast cancer developed due to the effect of the slight elevation of estrogen over a long period of time, but the actual causative factors in this patient were unable to be definitively identified. In the future, we hope to further elucidate the causes of male breast cancer. [Abstract/Link to Full Text]

Watanabe T, Segami K, Sasaki T, Kawashima H, Enomoto T, Jinnouchi Y, Koizumi S, Tobe N, Sakurai J, Shimamura T, Suda T, Asakura T, Nakano H, Ichiroh T, Otsubo T
A rare case of concomitant huge exophytic gastrointestinal stromal tumor of the stomach and Kasabach-Merritt phenomenon.
World J Surg Oncol. 2007;559.
BACKGROUND: We report an extremely rare case of concomitant huge exophytic GIST of the stomach and Kasabach-Merritt phenomenon (KMP). CASE PRESENTATION: The patient was a 67-year-old man experiencing abdominal distension since September 2006. A physical examination revealed a 25 x 30 cm hard mass that was palpable in the middle and lower left abdomen minimal intrinsic mobility and massive ascites. Since the admitted patient was diagnosed with DIC, surgery could not be performed. The patient received a platelet transfusion and the DIC was treated. Due to this treatment, the platelet count recovered to 7.0 x 10(4); tumor resection was performed at 16 days after admission. Laparotomy revealed a huge extraluminal tumor arising from the greater curvature of the stomach that measured 25 x 30 cm and had not ruptured into the peritoneal cavity or infiltrated other organs. Partial gastric resection was performed. The resected mass measured 25 x 25 x 20 cm. In cross section, the tumor appeared hard and homogenous with a small polycystic area. Histopathology of the resected specimen showed large spindle cell GIST with >5/50 HPF (high-power field) mitotic activity. The postoperative course was uneventful, and the coagulopathy improved rapidly. CONCLUSION: Since the characteristic of tumor in this case was hypervascularity with bleeding and necrotic lesions, coagulopathy was thought to be caused by the trapping of platelets within a large vasculized tumor mass. [Abstract/Link to Full Text]

Ibekwe TS, Kokong DD, Ngwu BA, Akinyemi OA, Nwaorgu OG, Akang EE
Nasal septal teratoma in a child.
World J Surg Oncol. 2007;558.
BACKGROUND: Teratoma is a rare developmental neoplasm that arises from totipotential tumor stem cells. Head and neck teratomas constitute about 10% of all cases. Only two cases of mature teratoma of the nasal septum have previously been documented in the world literature. CASE PRESENTATION: We present a case of histologically confirmed mature teratoma arising from the nasal septum in an eighteen month old Nigerian female who presented with a history of noisy breathing associated with recurrent rhinorrhea since birth. Physical examination revealed obstruction of the right nasal cavity by a pale fleshy mass. She underwent a total surgical excision and to date, after thirty one months follow-up, she is free from recurrence. CONCLUSION: The prognosis for benign teratoma of the nasal septum is good following total surgical excision. [Abstract/Link to Full Text]

Zagouri F, Sergentanis TN, Zografos GC
Precursors and preinvasive lesions of the breast: the role of molecular prognostic markers in the diagnostic and therapeutic dilemma.
World J Surg Oncol. 2007;557.
Precursors and preinvasive lesions of the breast include atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular neoplasia (LN). There is a significant debate regarding the classification, diagnosis, prognosis and management of these lesions. This review article describes the current theories regarding the pathogenesis and molecular evolution of these lesions. It reviews the implication of a variety of molecules in the continuum of breast lesions: estrogen receptors (ER-alpha and ER-beta), c-erb-B2 (Her2/neu), p53, Ki-67, bcl-2, E-cadherin, transforming growth factor-beta (TGF-beta), p27 (Kip1), p16 (INK4a), p21 (Waf1), vascular endothelial growth factor (VEGF). With respect to the aforementioned molecules, this article reviews their pathophysiological importance, and puts the stress on whether they confer additional risk for invasive breast cancer or not. This knowledge has the potential to be of importance in the therapeutic decisions presenting in the common clinical practice. [Abstract/Link to Full Text]

Kuraparthy S, Reddy KM, Yadagiri LA, Yutla M, Venkata PB, Kadainti SV, Reddy RP
Epidemiology and patterns of care for invasive breast carcinoma at a community hospital in Southern India.
World J Surg Oncol. 2007;556.
BACKGROUND: Breast cancer incidence in India is on rise. We report epidemiological, clinical and survival patterns of breast cancer patients from community perspective. METHODS: All breast cancer patients treated at this hospital from July 2000 to July 2005 were included. All had cytological or histological confirmation of breast cancer. TNM guidelines for staging and Immunohistochemistry to assess the receptor status were used. Either lumpectomy with axillary lymph node dissection or Modified radical mastectomy (MRM) was done for operable breast cancer, followed by 6 cycles of adjuvant chemotherapy with FAC or CMF regimens to patients with pT >1 cm or lymph node positive or estrogen receptor negative and radiotherapy to patients after breast conservation surgery, pT size > 5 cm, 4 or more positive nodes and stage IIIB disease. Patients with positive Estrogen receptor or Progesterone receptor were advised Tamoxifene 20 mg per day for 3 years. Descriptive analysis was performed. Independent T test and Chi-square test were used. Overall survival time was computed by Kaplan - Meier method. RESULTS: Of 1488 cancer patients, 122 (8.2%) had breast cancer. Of 122 patients, 96.7% had invasive breast carcinoma and 3.3% had sarcoma. 94% came from the rural and semi urban areas. Premenopausal women were 27%. The median age was 50 years. Stage I-6.8%, II-45.8%, III-22%, IV-6.8%, Bilateral breast cancer - 2.5%. The mean pT size was 3.9 cm. ER and PR were positive in 31.6% and 28.1% respectively. MRM was done in 93.8%, while 6.3% patients underwent breast conservation surgery. The mean of the lymph nodes dissected were 3. CMF and FAC regimens were used in 48.8% and 51.2% of patients respectively. FAC group were younger than the CMF group (43.6 yr vs. 54 yrs, P = 0.000). Toxicities were more in FAC than CMF group, alopecia (100% vs. 26.2%), grade2 or more emesis (31.8% vs. 9.2%), grade2 or more fatigue (40.9% vs.19%), anemia (43.1% vs. 16.6%). Median Survival for the cohort was 50.8 months. ER positive patients had better median survival (P = 0.05). CONCLUSION: MRM was the most frequent surgical option. CMF and FAC showed equivalent survival. FAC chemotherapy was more toxic than CMF. ER positive tumors have superior survival. Overall 3 year survival was 70 percent. [Abstract/Link to Full Text]

Scheingraber S, Justinger C, Stremovskaia T, Weinrich M, Igna D, Schilling MK
The standardized surgical approach improves outcome of gallbladder cancer.
World J Surg Oncol. 2007;555.
BACKGROUND: The objective of this study was to examine the extent of surgical procedures, pathological findings, complications and outcome of patients treated in the last 12 years for gallbladder cancer. METHODS: The impact of a standardized more aggressive approach compared with historical controls of our center with an individual approach was examined. Of 53 patients, 21 underwent resection for cure and 32 for palliation. RESULTS: Overall hospital mortality was 9% and procedure related mortality was 4%. The standardized approach in UICC stage IIa, IIb and III led to a significantly improved outcome compared to patients with an individual approach (Median survival: 14 vs. 7 months, mean+/-SEM: 26+/-7 vs. 17+/-5 months, p = 0.014). The main differences between the standardized and the individual approach were anatomical vs. atypical liver resection, performance of systematic lymph dissection of the hepaticoduodenal ligament and the resection of the common bile duct. CONCLUSION: Anatomical liver resection, proof for bile duct infiltration and, in case of tumor invasion, radical resection and lymph dissection of the hepaticoduodenal ligament are essential to improve outcome of locally advanced gallbladder cancer. [Abstract/Link to Full Text]

Konishi Y, Suzuki K, Wada H, Watanabe H, Ogura H, Sugamori Y, Bashar AH, Yamashita K, Kobayashi T, Kazui T
How do we manage the gastrectomy for gastric cancer after coronary artery bypass grafting using the right gastroepiploic artery? Report of two cases and a review of the literature.
World J Surg Oncol. 2007;554.
BACKGROUND: Recently, the right gastroepiploic artery (RGEA) has been used in coronary artery bypass grafting (CABG) as an alternative arterial graft. Unfortunately, an increased incidence of gastric cancers has been reported after CABG using the RGEA. Handling of the RGEA during gastrectomy in these patients may cause lethal complications, which sometimes reduces the feasibility of curative dissection of lymph nodes at the base of the graft. CASE PRESENTATIONS: We describe two cases of gastric cancer undergoing gastrectomy after CABG with the use of RGEA. To avoid the potentially fatal coronary event during gastrectomy, safe handling of the conduit including preparations for injuries and prevention of vessel spasm was performed in both cases, accompanied by an adequate monitoring of the systemic circulation. Intraoperative frozen section examination showed no lymph node metastasis around the graft in any of the cases; therefore, complete lymph node dissection at the base of the graft was not undertaken. No complications occurred during the operation. In addition to these two cases, twenty-four cases reported in the literatures were reviewed (a total of 26 cases). Ten early and 16 advanced gastric cancers were included. Among the 16 advanced gastric cancer cases, an alternative graft was employed in 8 due to the resection of an original graft to complete lymph node dissection. Mere handling of a graft often caused lethal complications suggesting that the operation should be completed by isolation of the graft. A pedicled graft harvesting via the ante-gastric route was popular. However, a skeletonized harvesting with resection of the pyloric branches of the RGEA would be better because this would interrupt the original lymph flow, which could eliminate the need for lymph node dissection and graft isolation. Among the 10 cases having early gastric cancers, 6 were found within 1.5 years after CABG. Early detection in these 6 cases was possible due to the use of gastric fiberscopic examination before and after CABG, which gave them opportunities to receive a less extensive operation such as endoscopic mucosal resection. CONCLUSION: Adequate intraoperative care as well as an optimal lymph node dissection considering the graft harvesting method at the first CABG leads to successful gastrectomy after CABG using the RGEA graft. Therefore, this operation should be carried out with careful management by both gastrointestinal and cardiovascular surgeons. [Abstract/Link to Full Text]

Zografos GC, Zagouri F, Sergentanis TN, Koulocheri D, Nonni A, Oikonomou V, Domeyer P, Kotsani M, Fotiadis C, Bramis J
Is zero underestimation feasible? Extended Vacuum-Assisted Breast Biopsy in solid lesions - a blind study.
World J Surg Oncol. 2007;553.
BACKGROUND: Vacuum-Assisted Breast Biopsy (VABB) is effective for the preoperative diagnosis of non-palpable mammographic solid lesions. The main disadvantage is underestimation, which might render the management of atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) difficult. This study aims to develop and assess a modified way of performing VABB. PATIENTS AND METHODS: A total of 107 women with non-palpable mammographic breast solid tumors BI-RADS 3 and 4 underwent VABB with 11G, on the stereotactic Fischer's table. 54 women were allocated to the recommended protocol and 24 cores were obtained according to the consensus meeting in Nordesterdt (1 offset-main target in the middle of the lesion and one offset inside). 53 women were randomly allocated to the extended protocol and 96 cores were excised (one offset-main target in the middle of the lesion and 7 peripheral offsets). A preoperative diagnosis was established. Women with a preoperative diagnosis of precursor/preinvasive/invasive lesion underwent open surgery. A second pathologist, blind to the preoperative results and to the protocol made the postoperative diagnosis. The percentage of the surface excised via VABB was retrospectively calculated on the mammogram. The discrepancy between preoperative and postoperative diagnoses along with the protocol adopted and the volume removed were evaluated by Fisher's exact test and Mann-Whitney-Wilcoxon test, respectively. RESULTS: Irrespectively of the protocol adopted, 82.2% of the lesions were benign. 14.0% of the lesions were malignancies (5.1% of BI-RADS 3, 5.3% of BI-RADS 4A, 25% of BI-RADS 4B, and 83.3% of BI-RADS 4C lesions). 3.7% of the biopsies were precursor lesions. There was no evidence of underestimation in either protocols. In the standard protocol, the preoperative/postoperative diagnoses were identical. In the extended protocol, the postoperative diagnosis was less severe than the preoperative in 55.5% of cases (55.5% vs. 0%, p = 0.029), and preoperative ADH was totally removed. The phenomenon of discrepancy between diagnoses was associated with larger volume removed (8.20 +/- 1.10 vs. 3.32 +/- 3.50 cm3, p = 0.037) and higher removed percentage of the lesion (97.83 +/- 4.86% vs. 74.34 +/- 23.43%, p = 0.024) CONCLUSION: The extended protocol seems to totally excise precursor lesions, with minimal underestimation. This might possibly point to a modified management of ADH lesions. [Abstract/Link to Full Text]

Jones M, Helliwell P, Pritchard C, Tharakan J, Mathew J
Helicobacter pylori in colorectal neoplasms: is there an aetiological relationship?
World J Surg Oncol. 2007;551.
BACKGROUND: This pilot study was carried out to determine whether Helicobacter pylori can be detected in normal colon or in association with colorectal neoplasia. METHODS: Paraffin processed colonic tissue blocks of normal colonic mucosa (n = 60), and patients diagnosed as adenoma (n = 60), and adenocarcinoma (n = 60) were retrieved from our archive; the adenoma group included tubular (n = 20), tubulovillous (n = 20) and villous adenomas (n = 20). 4 mum sections were stained by immunohistochemical methods using anti-Helicobacter pylori antibodies (polyclonal NCL-HPp and monoclonal NCL-C-jejuni). RESULTS: Significant numbers of Helicobacter pylori were identified in tubular adenomas (OR = 11.13; 95%CI = 1.62-76.70), tubulovillous adenomas (OR = 10.45; 95%CI = 1.52-71.52) and adenocarcinomas (OR = 8.13; 95%CI = 1.40-46.99) compared to controls: there was no association in numbers of Helicobacter pylori and villous adenomas (OR = 2.95; 95%CI = 0.29-9.96). CONCLUSION: We conclude that although, in this pilot study, there appears to be an association in the prevalence of Helicobacter pylori with some, but not all, colorectal neoplasms, we can not infer causality from these results. These findings need to be further substantiated with a prospective study and the use of molecular biological techniques to determine a causal association. [Abstract/Link to Full Text]

Chandramohan K, Agarwal M, Gurjar G, Gatti RC, Patel MH, Trivedi P, Kothari KC
Gastrointestinal stromal tumour in Meckel's diverticulum.
World J Surg Oncol. 2007;550.
BACKGROUND: Meckel's Diverticulum is the most commonly encountered congenital anomaly of the small intestine, occurring in approximately 2% of the population. Occasionally Meckel's diverticulum harbors neoplasms. CASE PRESENTATION: A 65 year old gentleman, presented with a pelvic mass. On exploratory laparotomy, it turned out to be gastrointestinal stromal tumour (GIST) arising from Meckel's diverticulum. Short history and review of literature are discussed. CONCLUSION: Neoplasms occurring from Meckel's diverticulum, even though rare, should be considered as differential diagnosis of pelvic masses arising from bowel, wherever imaging modalities fail to give a definitive diagnosis. [Abstract/Link to Full Text]

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Recent Articles in Journal of Carcinogenesis

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Potti A, Ganti AK, Tuchman SA, Sholes K, Langness E, Koka V, Koch M
HER-2/neu and CD117 (c-kit) overexpression in patients with pesticide exposure and extensive stage small cell lung carcinoma (ESSCLC).
J Carcinog. 2005 Jun 9;48.
BACKGROUND: The rate of detection of HER-2/neu and CD117 (c-kit) overexpression in small cell lung cancer (SCLC) has varied widely; between 5-35% and 21-70% respectively. METHODS: To evaluate the relationship between pesticide exposure and HER-2/neu and CD117 overexpression in extensive stage SCLC (ESSCLC), we identified patients with ESSCLC and assessed pesticide exposure using a predetermined questionnaire. An exposure index (hours/day x days/year x years) > or = 2400 hours was considered as 'exposed.' HER-2/neu overexpression was evaluated on archival tissue using the DAKO Hercep test, and CD117 testing was performed using immunohistochemistry (A4052 polyclonal antibody). RESULTS: 193 ESSCLC patients were identified. Pesticide exposure data could be obtained on 174 patients (84 females and 109 males) with a mean age of 68.5 years. 53/174 (30.4%) revealed HER-2/neu overexpression. 54/174 (31.03%) specimens showed CD117 overexpression by IHC. On multivariate analysis, HER-2/neu overexpression was associated with diminished survival (p < 0.001). In comparison, CD117 expression did not have an adverse prognostic value (p = 0.025). 41/53 (77.4%) patients with HER-2/neu overexpression and 47/121 (38.8%) patients without overexpression had exposure to pesticides (odds ratio: 5.38; p < 0.01). Among the cohort tested for CD117, 29/54 (53.7%) patients with CD117 overexpression and 59/120 (49.2%) patients without CD117 overexpression had pesticide exposure (odds ratio: 1.18; p = 0.12). CONCLUSION: Pesticide exposure affects HER-2/neu but not CD117 overexpression. Future studies are needed to determine specific pesticide(s)/pesticide components that are responsible for HER-2/neu overexpression in ESSCLC, and to validate our findings in other solid tumors that overexpress HER-2/neu. [Abstract/Link to Full Text]

Elkak A, Al Sarakbi W, Mokbel K
SYK expression in human breast cancer.
J Carcinog. 2005 Apr 20;4(1):7.
BACKGROUND: Syk (Splenic Tyrosine Kinase) is an intracellular receptor protein kinase involved in cell proliferation, differentiation and phagocytosis. It has been studied in T and B lymphocytes, NK cells and platelets. The strong expression of Syk in mammary gland prompted research into its potential role in mammary carcinogenesis. There have been very few studies about its role in breast cancer with conflicting results. This study aims to investigate the hypothesis that Syk expression is down-regulated in breast cancer compared with ANCT and the association between its expression and clinicopathological parameters. MATERIALS AND METHODS: mRNA was extracted from 48 breast cancer specimens. Relative Syk to ribosomal RNA expression was determined by RT-PCR and Taqman methodology. Mann-Whitney U test was used to examine the association between Syk expression in cancer and ANCT. Spearman's rank correlation test was used to examine the association between Syk expression in tumours and patients' age, tumour size, tumour grade, estrogen and progesterone receptor status, lymph node metastasis, vascular invasion and clinical outcome. RESULTS: The median for the relative value of Syk expression was 0.17 and 0.18 (range: 0.12 - 0.56 and 0.0 - 1.77) for tumours and ANCT respectively. There was no significant association between Syk expression in cancers and ANCT (p= 0.598) nor between Syk expression in tumours and patients' age, tumour size, tumour grade, estrogen and progesterone receptor status, lymph node metastasis, vascular invasion or prognosis. CONCLUSION: This study shows that Syk mRNA expression does not seem to vary between breast tumours and ANCT. Furthermore, we observed no significant association between Syk expression and clinicopathological parameters. [Abstract/Link to Full Text]

Jhavar SG, Sarin R, Chopra S, Kotnis A, Mulherkar R, A'hern R, Agarwal JP, Shrivastava SK, Dinshaw KA
Females with paired occurrence of cancers in the UADT and genital region have a higher frequency of either Glutathione S-transferase M1/T1 null genotype.
J Carcinog. 2005 Mar 24;4(1):6.
Upper Aero digestive Tract (UADT) is the commonest site for the development of second cancer in females after primary cervical cancer. Glutathione S-transferase (GSTM1 and / or T1) null genotype modulates the risk of developing UADT cancer (primary as well as second cancer). The aim of this study was to evaluate the difference in GST null genotype frequencies in females with paired cancers in the UADT and genital region as compared to females with paired cancers in the UADT and non-genital region. Forty-nine females with a cancer in the UADT and another cancer (at all sites-genital and non-genital) were identified from a database of patients with multiple primary neoplasms and were analyzed for the GSTM1 and T1 genotype in addition to known factors such as age, tobacco habits, alcohol habits and family history of cancer. Frequencies of GSTM1 null, GSTT1 null, and either GSTM1/T1 null were higher in females with paired occurrence of cancer in the UADT and genital site (54%, 33% and 75% respectively) in comparison to females with paired occurrence of cancer in the UADT and non-genital sites (22%, 6% and 24% respectively). The significantly higher inherited frequency of either GSTM1/T1 null genotype in females with a paired occurrence of cancers in UADT and genital region (p = 0.01), suggests that these females are more susceptible to damage by carcinogens as compared to females who have UADT cancers in association with cancers at non-genital sites. [Abstract/Link to Full Text]

Wada R, Yamaguchi T, Tadokoro K
Colonic Paneth cell metaplasia is pre-neoplastic condition of colonic cancer or not?
J Carcinog. 2005 Feb 12;4(1):5.
ABSTRACTS: BACKGROUND: The carcinogenesis of colorectal cancer has been accepted by a model for a cascade of genetic alterations, named the adenoma-carcinoma sequence. In order to elucidate the carcinogenesis of the colorectal cancer more clearly, the genetic abnormalies of the non-neoplastic mucosal epithelium of the colon and rectum should be investigated. It has been speculated that colonic Paneth cell metaplasia (PaM) is one of the pre-neoplastic mucosa of colonic cancer. Therefore, we studied the propria mucosa of the right colon with PaM from the standpoints of the frequency of the K-ras codon 12 mutations (K-ras), which is initial genetic abnormality in colorectal cancer, and the loss of heterozygosity of microsatellite markers (LOH-MS), which has a relationship to development of colorectal cancer. METHODS: Fifty-two regions with PaM histopathologically from 12 surgically resected right colon specimens were studied. DNA extraction of the colonic mucosa with PaM was obtained using a microdissection method, and the frequency of the K-ras of PaM was investigated by enriched polymerase chain reaction-enzyme linked mini-sequence assay, and the frequency of the LOH-MS (D2S123, D17S250 and D5S346) of PaM was examined by high resolution fluorescenced labeled PCR primers. RESULTS: K-ras mutation was detected in fifteen regions among 52 PaM (28.9%). All mutations were a single mutation and GGT changed to AGT in eleven and GAT in four. LOH-MS were detected in twenty-one regions among 52 PaM (40.4%) (D2S123: 35.4%, 17/48 regions, D17S250: 13.7%, 7/51 regions, and D5S346: 0%, 0/52 regions). No K-ras mutations and LOH-MS were detected in the controls (Colorectal mucosa with no PaM). CONCLUSIONS: Colonic mucosa with Paneth cell metaplasia may be one of the pre-neoplastic mucosa in the development of the colonic epithelial neoplasia. [Abstract/Link to Full Text]

Wahnschaffe U, Bitsch A, Kielhorn J, Mangelsdorf I
Mutagenicity testing with transgenic mice. Part II: Comparison with the mouse spot test.
J Carcinog. 2005 Jan 27;4(1):4.
The mouse spot test, an in vivo mutation assay, has been used to assess a number of chemicals. It is at present the only in vivo mammalian test system capable of detecting somatic gene mutations according to OECD guidelines (OECD guideline 484). It is however rather insensitive, animal consuming and expensive type of test. More recently several assays using transgenic animals have been developed. From data in the literature, the present study compares the results of in vivo testing of over twenty chemicals using the mouse spot test and compares them with results from the two transgenic mouse models with the best data base available, the lacI model (commercially available as the Big Blue(R) mouse), and the lacZ model (commercially available as the Mutatrade mark Mouse). There was agreement in the results from the majority of substances. No differences were found in the predictability of the transgenic animal assays and the mouse spot test for carcinogenicity. However, from the limited data available, it seems that the transgenic mouse assay has several advantages over the mouse spot test and may be a suitable test system replacing the mouse spot test for detection of gene but not chromosome mutations in vivo. [Abstract/Link to Full Text]

Wahnschaffe U, Bitsch A, Kielhorn J, Mangelsdorf I
Mutagenicity testing with transgenic mice. Part I: Comparison with the mouse bone marrow micronucleus test.
J Carcinog. 2005 Jan 17;4(1):3.
As part of a larger literature study on transgenic animals in mutagenicity testing, test results from the transgenic mutagenicity assays (lacI model; commercially available as the Big Blue(R) mouse, and the lacZ model; commercially available as the Mutatrade markMouse), were compared with the results on the same substances in the more traditional mouse bone marrow micronucleus test. 39 substances were found which had been tested in the micronucleus assay and in the above transgenic mouse systems. Although, the transgenic animal mutation assay is not directly comparable with the micronucleus test, because different genetic endpoints are examined: chromosome aberration versus gene mutation, the results for the majority of substances were in agreement. Both test systems, the transgenic mouse assay and the mouse bone marrow micronucleus test, have advantages and they complement each other. However, the transgenic animal assay has some distinct advantages over the micronucleus test: it is not restricted to one target organ and detects systemic as well as local mutagenic effects. [Abstract/Link to Full Text]

Hemminki K, Försti A, Lorenzo Bermejo J
Single nucleotide polymorphisms (SNPs) are inherited from parents and they measure heritable events.
J Carcinog. 2005 Jan 17;4(1):2.
Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence is not conclusive but it is consistent in pointing to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. Empirical familial risks should be used as guidance for the planning of SNP studies. We provide calculations for the assessment of familial risks for assumed allele frequencies and gene effects (odds ratios) for different modes of inheritance. Based on these data, we discuss the gene effects that could account for the unexplained proportion of familial breast and lung cancer. As a conclusion, we are concerned about the indiscriminate use of a genetic tool to cancers, which are mainly environmental in origin. We consider the likelihood of a successful application of SNPs in gene-environment studies small, unless established environmental risk factors are tested on proven candidate genes. [Abstract/Link to Full Text]

Felty Q, Roy D
Estrogen, mitochondria, and growth of cancer and non-cancer cells.
J Carcinog. 2005 Jan 15;4(1):1.
In this review, we discuss estrogen actions on mitochondrial function and the possible implications on cell growth. Mitochondria are important targets of estrogen action. Therefore, an in-depth analysis of interaction between estrogen and mitochondria; and mitochondrial signaling to nucleus are pertinent to the development of new therapy strategies for the treatment of estrogen-dependent diseases related to mitochondrial disorders, including cancer. [Abstract/Link to Full Text]

Bentz BG, Hammer ND, Radosevich JA, Haines GK
Nitrosative stress induces DNA strand breaks but not caspase mediated apoptosis in a lung cancer cell line.
J Carcinog. 2004 Dec 23;3(1):16.
BACKGROUND: Key steps crucial to the process of tumor progression are genomic instability and escape from apoptosis. Nitric oxide and its interrelated reactive intermediates (collectively denoted as NOX) have been implicated in DNA damage and mutational events leading to cancer development, while also being implicated in the inhibition of apoptosis through S-nitrosation of key apoptotic enzymes. The purpose of this study was to explore the interrelationship between NOX-mediated DNA strand breaks (DSBs) and apoptosis in cultured tumor cell lines. METHODS: Two well-characterized cell lines were exposed to increasing concentrations of exogenous NOX via donor compounds. Production of NOX was quantified by the Greiss reaction and spectrophotometery, and confirmed by nitrotyrosine immunostaining. DSBs were measured by the alkaline single-cell gel electrophoresis assay (the COMET assay), and correlated with cell viability by the MTT assay. Apoptosis was analyzed both by TUNEL staining and Annexin V/propidium iodine FACS. Finally, caspase enzymatic activity was measured using an in-vitro fluorogenic caspase assay. RESULTS: Increases in DNA strand breaks in our tumor cells, but not in control fibroblasts, correlated with the concentration as well as rate of release of exogenously administered NOX. This increase in DSBs did not correlate with an increase in cell death or apoptosis in our tumor cell line. Finally, this lack of apoptosis was found to correlate with inhibition of caspase activity upon exposure to thiol- but not NONOate-based NOX donor compounds. CONCLUSIONS: Genotoxicity appears to be highly interrelated with both the concentration and kinetic delivery of NOX. Moreover, alterations in cell apoptosis can be seen as a consequence of the explicit mechanisms of NOX delivery. These findings lend credence to the hypothesis that NOX may play an important role in tumor progression, and underscores potential pitfalls which should be considered when developing NOX-based chemotherapeutic agents. [Abstract/Link to Full Text]

Mason JA, Yancy HF, Lashley K, Jett M, Day AA
Comparative study of matrix metalloproteinase expression between African American and Caucasian Women.
J Carcinog. 2004 Oct 29;3(1):15.
To date there are 26 human matrix metalloproteinases (MMPs) which are classified according to their substrate specificity and structural similarities. The four major subgroups of MMPs are gelatinases, interstitial collagenases, stromelysins, and membrane-type matrix metalloproteinases (MT-MMPs). This study investigates the expression of 26 MMPs, which have been shown to play a role in cancer metastasis. Breast tissues and cell lines derived from African American patients and Caucasian patients were assayed to demonstrate alterations in the transcription of genes primarily responsible for degrading the extracellular matrix (ECM). The expression levels of the extracellular matrix and adhesion molecules were analyzed using the gene array technology. Steady state levels of mRNAs were validated by RT-PCR analysis. Total RNA was isolated from tissue and cell lines and used in the RT-PCR assays. From this data, differential expression of MMPs between 6 breast cancer cell lines and 2 non-cancer breast cell lines was demonstrated. We have performed an in vitro comparison of MMP expression and established differences in 12 MMPs (3, 7, 8, 9, 11-15, 23B, 26, and 28) expression between African American and Caucasian breast cell lines. Thus, evidence indicates that altered expression of MMPs may play a role in the aggressive phenotype seen in African American women. [Abstract/Link to Full Text]

Linz AL, Xiao R, Parker JG, Simpson PM, Badger TM, Simmen FA
Feeding of soy protein isolate to rats during pregnancy and lactation suppresses formation of aberrant crypt foci in their progeny's colons: interaction of diet with fetal alcohol exposure.
J Carcinog. 2004 10 15;3(1):14.
Soy protein isolate (SPI) in the diet may inhibit colon tumorigenesis. We examined azoxymethane (AOM)-induced aberrant crypt foci (ACF) in male rats in relation to lifetime, pre-weaning, or post-weaning dietary exposure to SPI and also within the context of fetal alcohol exposure. Pregnant Sprague Dawley rats were fed AIN-93G diets containing casein (20%, the control diet) or SPI (20%) as the sole protein source starting on gestation day 4 (GD 4). Progeny were weaned on postnatal day (PND) 21 to the same diet as their dams and were fed this diet until termination of the experiment at PND 138. Rats received AOM on PND 89 and 96. Lifetime (GD 4 to PND 138) feeding of SPI led to reduced frequency of ACF with 4 or more crypts in the distal colon. Progeny of dams fed SPI only during pregnancy and lactation or progeny fed SPI only after weaning exhibited similarly reduced frequency of large ACF in distal colon. Number of epithelial cells, in the distal colon, undergoing apoptosis was unaffected by diet. SPI reduced weight gain and adiposity, but these were not correlated with fewer numbers of large ACF. Lifetime SPI exposure similarly inhibited development of large ACF in Sprague Dawley rats whose dams were exposed to ethanol during pregnancy. In summary, feeding of SPI to rat dams during pregnancy and lactation suppresses numbers of large ACF in their progeny, implying a long-term or permanent change elicited by the maternal diet. Moreover, results support the use of ACF as an intermediate endpoint for elucidating effects of SPI and its biochemical constituents in colon cancer prevention in rats. [Abstract/Link to Full Text]

Wodarz D, Iwasa Y, Komarova NL
On the emergence of multifocal cancers.
J Carcinog. 2004 10 1;3(1):13.
Several tumors can exist as multiple lesions within a tissue. The lesions may either arise independently, or they may be monoclonal. The importance of multiple lesions for tumor staging, progression, and treatment is subject to debate. Here we use mathematical models to analyze the emergence of multiple, clonally related lesions within a single tissue. We refer to them as multi-focal cancers. We find that multifocal cancers can arise through a dynamical interplay between tumor promoting and inhibiting factors. This requires that tumor promoters act locally, while tumor inhibitors act over a longer range. An example of such factors may be angiogenesis promoters and inhibitors. The model further suggests that multifocal cancers represent an intermediate stage in cancer progression as the tumor evolves away from inhibition and towards promotion. Different patterns of progression can be distinguished: (i) If tumor inhibition is strong, the initial growth occurs as a unifocal and self contained lesion; progression occurs through bifurcation of the lesion and this gives rise to multiple lesions. As the tumor continues to evolve and pushes the balance between inhibition and promotion further towards promotion, the multiple lesions eventually give rise to a single large mass which can invade the entire tissue. (ii) If tumor inhibition is weaker upon initiation, growth can occur as a single lesion without the occurrence of multiple lesions, until the entire tissue is invaded. The model suggests that the sum of the tumor sizes across all lesions is the best characteristic which correlates with the stage and metastatic potential of the tumor. [Abstract/Link to Full Text]

Falahatpisheh M, Kerzee J, Metz R, Donnelly K, Ramos K
Inducible cytochrome P450 activities in renal glomerular mesangial cells: biochemical basis for antagonistic interactions among nephrocarcinogenic polycyclic aromatic hydrocarbons.
J Carcinog. 2004 Aug 17;3(1):12.
BACKGROUND: Benzo(a)pyrene (BaP), anthracene (ANTH) and chrysene (CHRY) are polynuclear aromatic hydrocarbons (PAHs) implicated in renal toxicity and carcinogenesis. These PAHs elicit cell type-specific effects that help predict toxicity outcomes in vitro and in vivo. While BaP and ANTH selectively injure glomerular mesangial cells, and CHRY targets cortico-tubular epithelial cells, binary or ternary mixtures of these hydrocarbons markedly reduce the overall cytotoxic potential of individual hydrocarbons. METHODS: To study the biochemical basis of these antagonistic interactions, renal glomerular mesangial cells were challenged with BaP alone (0.03 - 30 microM) or in the presence of ANTH (3 microM) or CHRY (3 microM) for 24 hr. Total RNA and protein will be harvested for Northern analysis and measurements of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activity, respectively, to evaluate cytochrome P450 mRNA and protein inducibility. Cellular hydrocarbon uptake and metabolic profiles of PAHs were analyzed by high performance liquid chromatography (HPLC). RESULTS: Combined hydrocarbon treatments did not influence the cellular uptake of individual hydrocarbons. ANTH or CHRY strongly repressed BaP-inducible cytochrome P450 mRNA and protein expression, and markedly inhibited oxidative BaP metabolism. CONCLUSION: These findings indicate that antagonistic interactions among nephrocarcinogenic PAHs involve altered expression of cytochrome P450s that modulate bioactivation profiles and nephrotoxic/ nephrocarcinogenic potential. [Abstract/Link to Full Text]

Pillai AA, Bhattacharya RN, Radhakrishnan VV, Banerjee M
Molecular signatures of cell cycle transcripts in the pathogenesis of Glial tumors.
J Carcinog. 2004 Jun 17;3(1):11.
BACKGROUND: Astrocytic brain tumors are among the most lethal and morbid tumors of adults, often occurring during the prime of life. These tumors form an interesting group of cancer to understand the molecular mechanism of pathogenesis. Histological grading of Astrocytoma based on WHO classification does not provide complete information on the proliferation potential and biological behavior of the tumors. It is known that cancer results from the disruption of the orderly regulated cycle of replication and division. In the present study, we made an attempt to identify the cell cycle signatures and their involvement in the clinical aggressiveness of gliomas. METHODS: The variation in expression of various cell cycle genes was studied in different stages of glial tumor progression (low and high grades), and the results were compared with their corresponding expression levels in the normal brain tissue. Macroarray analysis was used for the purpose. RESULTS: Macroarray analysis of 114 cell cycle genes in different grades of glioma indicated differential expression pattern in 34% of the gene transcripts, when compared to the normal tissue. Majority of the transcripts belong to the intracellular kinase networks, cell cycle regulating kinases, transcription factors and transcription activators. CONCLUSION: Based on the observation in the expression pattern in low grade and high grade gliomas, it can be suggested that the upregulation of cell cycle activators are seen as an early event in glioma; however, in malignancy it is not the cell cycle activators alone, which are involved in tumorigenesis. Understanding the molecular details of cell cycle regulation and checkpoint abnormalities in cancer could offer an insight into potential therapeutic strategies. [Abstract/Link to Full Text]

Chen Y, Hu J, Boorman D, Klein-Szanto A, O'Brien TG
Therapy of murine squamous cell carcinomas with 2-difluoromethylornithine.
J Carcinog. 2004 Jun 2;3(1):10.
Targeted overexpression of an ornithine decarboxylase (ODC) transgene to mouse skin (the K6/ODC mouse) significantly enhances susceptibility to carcinogenesis. While in most strain backgrounds the predominant tumor type resulting from initiation-promotion protocols is benign squamous papilloma, K6/ODC mice on a FVB/N background develop malignant squamous cell carcinomas (SCCs) rapidly and in high multiplicity after carcinogen treatment. We have investigated the utility of polyamine-based therapy against SCCs in this model using the ODC inhibitor 2-difluoromethylornithine delivered orally. At a 2% concentration in drinking water, DFMO caused rapid tumor regression, but in most cases, tumors eventually regrew rapidly even in the presence of DFMO. The tumors that regrew were spindle cell carcinomas, an aggressive undifferentiated variant of SCC. At 1% DFMO in the drinking water, tumors also responded rapidly, but tumor regrowth did not occur. The majority of DFMO-treated SCCs were classified as complete responses, and in some cases, apparent tumor cures were achieved. The enzymatic activity of ODC, the target of DFMO, was substantially reduced after treatment with 1% DFMO and the high SCC polyamine levels, especially putrescine, were also significantly lowered. Based on the results of BrdUrd labeling and TUNEL assays, the effect of DFMO on SCC growth was accompanied by a significant reduction in tumor proliferation with no increase in the apoptotic index. These results demonstrate that SCCs, at least in the mouse, are particularly sensitive to polyamine-based therapy. [Abstract/Link to Full Text]

Wang C, Youssef J, Cunningham M, Badr M
Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643.
J Carcinog. 2004 May 24;3(1):9.
BACKGROUND: The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPARalpha agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPARalpha agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. METHODS: Male B6C3F1 mice were given Wy-14,643 (100 ppm), rotenone (600 ppm) or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU), marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar x40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. RESULTS: Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI), and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI), which provides an accurate reflection of the animal's thyroid status, was 5.0 +/- 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 +/- 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 +/- 0.9. FTI values decreased to 3.4 +/- 0.8 in mice receiving both rotenone and Wy-14,643. CONCLUSION: A strong correlation was observed between the animal thyroid status and both, hepatocyte proliferation (r2 = 0.62), and hepatocyte surface area (r2 = 0.83). These results support the hypothesis that the thyroid status of the animal plays a role in PPARalpha-induced hepatocellular proliferation and liver cell enlargement. Both these events are known to contribute to the expression of liver cancer in response to the activation of PPARalpha. [Abstract/Link to Full Text]

Van Erk MJ, Teuling E, Staal YC, Huybers S, Van Bladeren PJ, Aarts JM, Van Ommen B
Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells.
J Carcinog. 2004 May 12;3(1):8.
BACKGROUND: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling. METHODS: Gene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours). Gene expression changes after short-term exposure (3 or 6 hours) to curcumin were also studied in a second cell type, Caco-2 cells. RESULTS: Gene expression changes (>1.5-fold) were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. CONCLUSIONS: This study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase-II genes). Moreover, potential new leads to genes and pathways that could play a role in colon cancer prevention by curcumin were identified. [Abstract/Link to Full Text]

Boerrigter ME
Mutagenicity of the peroxisome proliferators clofibrate, Wyeth 14,643 and di-2-ethylhexyl phthalate in the lacZ plasmid-based transgenic mouse mutation assay.
J Carcinog. 2004 May 5;3(1):7.
BACKGROUND: Peroxisome proliferators are considered rodent carcinogens that are putative human non-carcinogens based on the presumed absence of direct genetic toxicity in rodent and human cells and the resistance of human cells to the induction of peroxisomes by peroxisome proliferators. The highly sensitive lacZ plasmid-based transgenic mouse mutation assay was employed to investigate the mutagenicity of several peroxisome proliferators based on several lines of evidence suggesting that these agents may in fact exert a genotoxic effect. METHODS: Male and female lacZ-plasmid based transgenic mice were treated at 4 months of age with 6 doses of 2,333 mg di-2-ethylhexyl phthalate (DHEP), 200 mg Wyeth-14,643, or 90 mg clofibrate per kg of bodyweight, respectively, over a two-week period. Control animals were treated with the respective vehicles only (35% propyl glycol for DEHP and Wyeth-14,643 treatment controls and sterile water for clofibrate treatment controls).The mutant frequency in liver, kidney and spleen DNA was determined as the proportion of retrieved mutant and wild-type lacZ plasmids expressed in Escherichia Coli C host cells employing a positive selection system for mutant plasmids. RESULTS: Exposure to DEHP or Wyeth-14,643 significantly increased the mutant frequency in liver, but not in kidney or spleen, of both female and male mice. Treatment with clofibrate did not lead to an increased mutant frequency in any of the organs studied. CONCLUSION: The results indicate that some peroxisome proliferators display an organ-specific mutagenicity in lacZ plasmid-based transgenic mice consistent with historical observations of organ- and compound-specific carcinogenicity. [Abstract/Link to Full Text]

Houben R, Becker JC, Kappel A, Terheyden P, Bröcker EB, Goetz R, Rapp UR
Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis.
J Carcinog. 2004 Mar 26;3(1):6.
BACKGROUND: Genes of the Raf family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Recently, it was shown that activating mutations of BRaf are found with high frequency in human melanomas. The Ras family member most often mutated in melanoma is NRas. METHODS: The constitutive activation of the Ras/Raf signaling pathway suggests an impact on the clinical course of the tumor. To address this notion, we analyzed tumor DNA from 114 primary cutaneous melanomas and of 86 metastatic lesions obtained from 174 patients for mutations in BRaf (exons 15 and 11) and NRas (exons 1 and 2) by direct sequencing of PCR products and correlated these results with the clinical course. RESULTS: In 57.5% of the tumors either BRaf or NRas were mutated with a higher incidence in metastatic (66.3%) than in primary lesions (50.9%). Although the majority of BRaf mutations affected codon 599, almost 15% of mutations at this position were different from the well-described exchange from valine to glutamic acid. These mutations (V599R and V599K) also displayed increased kinase and transforming activity. Surprisingly, the additional BRaf variants D593V, G465R and G465E showed a complete loss of activity in the in vitro kinase assay; however, cells overexpressing these mutants displayed increased Erk phosphorylation. The correlation of mutational status and clinical course revealed that the presence of BRaf/NRas mutations in primary tumors did not negatively impact progression free or overall survival. In contrast, however, for metastatic lesions the presence of BRAF/NRAS mutations was associated with a significantly poorer prognosis, i.e. a shortened survival. CONCLUSION: We demonstrate a high - albeit lower than initially anticipated - frequency of activating BRaf mutations in melanoma in the largest series of directly analyzed tumors reported to date. Notably, the clinical course of patients harboring activating BRaf mutations in metastatic melanoma was significantly affected by the presence of a constitutive BRaf activation in these. [Abstract/Link to Full Text]

Jacob JH, Khalil AM, Maslat AO
In vitro cytogenetic testing of an organoselenium compound and its sulfur analogue in cultured rat bone marrow cells.
J Carcinog. 2004 Mar 15;3(1):5.
BACKGROUND: Selenium (Se) is a non-metal element, occurring in varying degrees in the environment and it has been found to be a component of several enzymes. Different selenium compounds have been associated with carcinogenicity, toxicity, modification of metal toxicity and prevention of cancer. Organoselenium compounds had substantially greater bioavailability and less toxicity than that of inorganic selenium. From a chemical point of view, Se resembles sulfur (S) in many of its properties, thus, Se and S may be considered to be isosteric. The ability of a synthetic organoselenium compound; cyclopenta-dienyldicarbonyl ironselenoterephthalic acid (CSe) and its sulfur analogue (CS) in the range of 10-8 to 10-5 M, to induce sister-chormatid exchanges (SCE) and alter cell division expressed as mitotic index (MI) as well as cell survival has been investigated. METHODS: Rat bone marrow cells were cultured in the presence of CSe and CS in the range of 10-8 to 10-5 M with a total exposure time of 4, 16 or 28 h at 37 degrees C. Fluorescence-plus-Giemsa (FPG) technique was used to visualize chromosomes for SCE analysis and MI determination. Trypan blue exclusion technique was used to determine cell viability. RESULTS: At the three exposure times, cell survival progressively decreased with increasing concentration, but the effect of either chemical was not significant (ANOVA; P < 0.05) as compared to the negative control. Significant reductions in MI were calculated at the highest concentration (10-5 M) when either chemical was applied for 16 or 28 h. Furthermore, the mean SCE increased with longer exposure times and, in general, CSe had slightly greater effect on cell survival and caused higher frequencies of SCE than CS. The exception was the 10-8 M treatment. However, both CSe and CS failed to induce 2-fold SCE as that of the negative control and therefore they are not considered as mutagens. CONCLUSION: Both CSe and CS in the range of 10-8 to 10-5 M could not double the SCE rate of the negative control and therefore not considered as mutagens at these experimental conditions. [Abstract/Link to Full Text]

Singh KP, Roy D
Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting.
J Carcinog. 2004 Mar 5;3(1):4.
Kidney tumors from stilbene estrogen (diethylstilbestrol)-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR) fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors). The presence of mutated loci in uninvolved (non-tumor) surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental models. Although the exact functional importance of mutated loci is unknown, this study indicates that these altered loci may participate during tumor progression in the kidney. [Abstract/Link to Full Text]

Kovvali G
To eat or not to eat: The NICE way.
J Carcinog. 2004 Feb 26;3(1):3. [Abstract/Link to Full Text]

Geter DR, Chang LW, Hanley NM, Ross MK, Pegram RA, DeAngelo AB
Analysis of in vivo and in vitro DNA strand breaks from trihalomethane exposure.
J Carcinog. 2004 Feb 17;3(1):2.
BACKGROUND: Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of two major causes of human mortality, colorectal and bladder cancer. Trihalomethanes (THMs) are by-products formed when chlorine is used to disinfect drinking water. The purpose of this study was to examine the ability of the THMs, trichloromethane (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and tribromomethane (TBM), to induce DNA strand breaks (SB) in (1) CCRF-CEM human lymphoblastic leukemia cells, (2) primary rat hepatocytes (PRH) exposed in vitro, and (3) rats exposed by gavage or drinking water. METHODS: DNA SB were measured by the DNA alkaline unwinding assay (DAUA). CCRF-CEM cells were exposed to individual THMs for 2 hr. Half of the cells were immediately analyzed for DNA SB and half were transferred into fresh culture medium and incubated for an additional 22 hr before testing for DNA SB. PRH were exposed to individual THMs for 4 hr then assayed for DNA SB. F344/N rats were exposed to individual THMs for 4 hr, 2 weeks, and to BDCM for 5 wk then tested for DNA SB. RESULTS: CCRF-CEM cells exposed to 5- or 10-mM brominated THMs for 2 hr produced DNA SB. The order of activity was TBM>DBCM>BDCM; TCM was inactive. Following a 22-hr recovery period, all groups had fewer SB except 10-mM DBCM and 1-mM TBM. CCRF-CEM cells were found to be positive for the GSTT1-1 gene, however no activity was detected. No DNA SB, unassociated with cytotoxicity, were observed in PRH or F344/N rats exposed to individual THMs. CONCLUSION: CCRF-CEM cells exposed to the brominated THMs at 5 or 10 mM for 2 hr showed a significant increase in DNA SB when compared to control cells. Additionally, CCRF-CEM cells exposed to DBCM and TBM appeared to have compromised DNA repair capacity as demonstrated by an increased amount of DNA SB at 22 hr following exposure. CCRF-CEM cells were found to be positive for the GSTT1-1 gene, however no activity was detected. No DNA SB were observed in PRH or F344/N rats exposed to individual THMs. [Abstract/Link to Full Text]

Kirkpatrick KL, Newbold RF, Mokbel K
The mRNA expression of hTERT in human breast carcinomas correlates with VEGF expression.
J Carcinog. 2004 Jan 22;3(1):1.
BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase) is the rate-limiting determinant of telomerase reactivation. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any correlation between hTERT and the negative prognostic indicators VEGF and PCNA by quantitatively measuring the mRNA expression of these genes in human breast cancer and in adjacent non-cancerous tissue (ANCT). MATERIALS AND METHODS: RNA was extracted from 38 breast carcinomas and 40 ANCT. hTERT and VEGF165, VEGF189 and PCNA mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR) and Taqman methodology. RESULTS: The level of expression of VEGF-165 and PCNA was significantly higher in carcinoma tissue than ANCT (p = 0.02). The ratio of VEGF165/189 expression was significantly higher in breast carcinoma than ANCT (p = 0.025). hTERT mRNA expression correlated with VEGF-189 mRNA (p = 0.008) and VEGF165 (p = 0.07). CONCLUSIONS: hTERT mRNA expression is associated with the expression of the VEGF189 and 165 isoforms. This could explain the poorer prognosis reported in breast tumours expressing high levels of hTERT. The relative expression of the VEGF isoforms is significantly different in breast tumour to ANCT, and this may be important in breast carcinogenesis. [Abstract/Link to Full Text]

Grandics P
Cancer: a single disease with a multitude of manifestions?
J Carcinog. 2003 Nov 18;2(1):9.
The relationships of critical nutrients such as plant phenolics, vitamins, minerals and lipids are considered with respect to the incidence of a variety of cancers, and analyzed in terms of how these nutrient deficiencies alter immune function, DNA integrity and cell proliferation. With a significant correlation found between cancer and these nutrient deficiencies, the hypothesis is presented here that nutrition could provide a unifying perception of cancer and recast it as a single disease. This further suggests that a coordinated administration of specific, critical nutrients to cancer patients could lead to the reversal of the disease. It is also proposed that the concurrent presence of a variety of nutritional deficiencies in cancer patients requires a multilevel, systemic approach to this disease as opposed to the single active therapeutic agent approach that is the cornerstone of contemporary research and pharmacology. [Abstract/Link to Full Text]

Meyer P, Sergi C, Garbe C
Polymorphisms of the BRAF gene predispose males to malignant melanoma.
J Carcinog. 2003 Nov 14;2(1):7.
The incidence of malignant melanoma has rapidly increased in recent years. Evidence points to the role of inheritance in melanoma development, but specific genetic risk factors are not well understood. Recent reports indicate a high prevalence of somatic mutations of the BRAF gene in melanomas and melanocytic nevi. Here we report that germ-line single nucleotide polymorphisms (SNPs) in BRAF are significantly associated with melanoma in German males, but not females. At-risk haplotypes of BRAF are shown. Based upon their frequencies, we estimate that BRAF could account for a proportion attributable risk of developing melanoma of 4% in the German population. The causal variant has yet to be determined. The burden of disease associated with this variant is greater than that associated with the major melanoma susceptibility locus CDKN2A, which has an estimated attributable risk of less than 1%. [Abstract/Link to Full Text]

Potti A, Hille RC, Koch M
Immunohistochemical determination of HER-2/neu overexpression in malignant melanoma reveals no prognostic value, while c-Kit (CD117) overexpression exhibits potential therapeutic implications.
J Carcinog. 2003 Nov 16;2(1):8.
BACKGROUND: HER-2/neu and c-kit (CD117) onco-protein are increasingly being recognized as targets for therapy in solid tumors, but data on their role in malignant melanoma is currently limited. We studied the prevalence of overexpression of HER-2/neu and c-Kit in 202 patients with malignant melanoma to evaluate a possible prognostic value of these molecular targets in malignant melanoma. METHODS: Overexpression of HER-2/neu and c-Kit was evaluated using immunohistochemical assays in 202 archival tissue specimens. RESULTS: Between 1991 and 2001, 202 subjects (109 males; 54% and 93 females; 46%) with malignant melanoma were studied with a mean age of 57 years (age range: 15-101 years). The most common histologic type was amelanotic melanoma (n = 62; 30.7%) followed by superficial spreading melanoma (n = 54; 26.7%). The depth of penetration of melanoma (Breslow thickness, pT Stage) ranged from 0.4 mm (stage pT1) to 8.0 mm (stage pT4A). Mean thickness was 2.6 mm (stage pT3A). The ECOG performance scores ranged from 0 to 3. Only 2 patients (0.9%) revealed HER-2/neu overexpression, whereas 46 (22.8%) revealed c-Kit overexpression. Multivariate analysis performed did not show a significant difference in survival between c-Kit positive and negative groups (p = 0.36). Interestingly, not only was c-Kit more likely to be overexpressed in the superficial spreading type, a preliminary association between the presence or absence of c-Kit overexpression and the existence of another second primary tumor was also observed. CONCLUSIONS: The results of our large study indicate that the HER-2/neu onco-protein neither has a role in melanogenesis nor is a potential target for clinical trials with monoclonal antibody therapy. This indicates there is no role for its testing in patients with malignant melanoma. Although c-Kit, expressed preferentially in the superficial spreading type, may not have prognostic value, it does have significant therapeutic implications as a molecular target warranting further investigation. [Abstract/Link to Full Text]

Iddamaldeniya SS, Wickramasinghe N, Thabrew I, Ratnatunge N, Thammitiyagodage MG
Protection against diethylnitrosoamine-induced hepatocarcinogenesis by an indigenous medicine comprised of Nigella sativa, Hemidesmus indicus and Smilax glabra: a preliminary study.
J Carcinog. 2003 Oct 18;2(1):6.
BACKGROUND: A decoction comprised of Nigella sativa seeds, Hemidesmus indicus root and Smilax glabra rhizome is used to treat cancer patients in Sri Lanka. However, the anti-carcinogenic properties of this decoction have not been experimentally confirmed. The purpose of this study was to determine whether the above decoction could protect against chemically induce hepatocarcinogenesis. METHODS: The effects of this decoction on diethylnitrosamine (DEN) induced hepatocarcinogenesis were examined in male Wistar rats using the medium term bioassay system of Ito, based on a 2-step model of hepatocarcinogenesis. Rats were randomly divided into 6 groups of 10 each. Groups 1 to 4 were injected with DEN (200 mg/kg) to initiate carcinogenesis. Twenty-four hours later groups 1 and 2 were administered the decoction at 4 g/kg body weight/day (dose 1) and 6 g/kg body weight/day (dose 2), respectively. Group 3 and group 4 were given distilled water instead of the decoction and a suspension of garlic powder (20 g/kg body weight/day) in distilled water (positive control), respectively. Group 5 and 6 were injected with normal saline and twenty-four hours later group 5 was given distilled water (normal control) while group 6 was given decoction dose 2 (decoction control). Oral feeding continued for two weeks after which all rats were subjected to 2/3 partial hepatectomy to promote carcinogenesis. Oral feeding continued for eight more weeks. At the end of the 10th week, rats were sacrificed and samples of livers taken for immunohistochemical studies.Carcinogenic potential was scored by comparing the number, area and staining intensity of glutathione S-transferase placental form (GST-P) positive foci and the number of cells/cm2 of the positive foci in the livers of the six groups of rats. RESULTS: The number and area of DEN-mediated GST-P positive foci, number of cells/cm2 of foci and staining intensity of the foci were significantly (P > 0.001) reduced by the decoction and garlic in the order dose 2 = garlic >dose 1. CONCLUSION: Overall results indicate that the decoction comprised of N. sativa, S. glabra and H. indicus has the potential to protect rat liver against DEN induced hepatocarcinogenesis [Abstract/Link to Full Text]

Boettger MB, Sergi C, Meyer P
BRCA1/2 mutation screening and LOH analysis of lung adenocarcinoma tissue in a multiple-cancer patient with a strong family history of breast cancer.
J Carcinog. 2003 Oct 2;2(1):5.
BACKGROUND: Germline mutations in BRCA1/2 greatly elevate risks of breast and ovarian cancers, but the role of these genes in tumourigenesis of other cancer types is still being investigated. OBJECTIVE: We report on an investigation of BRCA1/2 mutations and their loss of heterozygosity (LOH) in a patient with a strong family history of breast cancer who was diagnosed with consecutive primary cervical, ovarian and lung carcinomas. METHODS AND RESULTS: BRCA1/2 mutation screening of the proband revealed a common familial breast- and ovarian cancer-associated germline BRCA2 mutation (3034del4bp). We then performed LOH analysis for BRCA2 in lung adenocarcinoma tissue of the patient. Using the laser-capture microdissection (LCM) technique, we obtained pure populations of neoplastic cells from which DNA could be extracted. Mutation analysis by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing revealed loss of the mutant allele in the adenocarcinoma tumour tissue. CONCLUSION: To our knowledge, this is the first report of investigation for LOH for BRCA2 in primary lung adenocarcinoma tissue of a patient with multiple primary tumours related to a familial germline BRCA2 mutation. Interestingly, it was the mutant, not the wild-type, allele which was lost in the lung adenocarcinoma tissue. [Abstract/Link to Full Text]

Potti A, Panwalkar AW, Langness E
Prevalence of pesticide exposure in young males (</= 50 years) with adenocarcinoma of the prostate.
J Carcinog. 2003 Jul 15;2(1):4.
Evidence implicating pesticides as causative agents of prostate cancer is controversial, and specifically, data in young adults is lacking. Hence, we performed a preliminary study evaluating the relationship between pesticide exposure and prostate cancer in young males. After approval from the University of North Dakota Institutional Review Board and Human Subjects Committee, a retrospective study was performed on all young males (</ = 50 years) with a biopsy-proven diagnosis of carcinoma of the prostate. The records of all patients aged less than/equal to 50 years, with a diagnosis of adenocarcinoma of the prostate, from January 1991 through December 2001 were reviewed. Pesticide risk assessment interviews were performed by a single member of the team, for consistency, via telephone on the basis of a pre-determined questionnaire investigating occupations and hobbies with special emphasis on: Duration of exposure. An exposure index was calculated for each interviewed subject according to the following formula: hours/day x days/year x years. Patients with an exposure index >2400 hours were considered as 'exposed.' The 2400 hour cut-off value was chosen on the basis of previous reports indicating that this figure represents heavy exposure to genotoxic agents. Statistical analysis was obtained using SPSS-10ledR;. Between 1991 and 2001, 61 young males with adenocarcinoma of the prostate were identified, of whom 56 patients with a mean age of 47 years (range: 40-49) had complete records of treatment and could be contacted for completion of the questionnaire. The most common stage at presentation was Stage III and the mean Gleason's score was 7.5 (range 5-9). Interestingly, almost a third (16/56, 28.6%) of patients had stage IV disease at presentation. 37/56 (66.1%) patients had 'significant' exposure in our study. In addition, interestingly, the mean survival in the subgroup of patients with pesticide exposure was 11.3 months (SD: +/- 2.3 months), while the mean survival in the patients without pesticide exposure (n = 19) was 20.1 months (SD: +/- 3.1 months), with p-value <0.01. Although our study is relatively small, it does reveal preliminary evidence linking pesticide exposure to the early development of, possibly aggressive, prostate adenocarcinoma. Future, larger, epidemiological studies are needed to confirm the findings of our study. [Abstract/Link to Full Text]

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Trends for inflammatory breast cancer: is survival improving?
Oncologist. 2007 Aug;12(8):904-12.
The purpose of this study was to evaluate whether the survival of women with inflammatory breast cancer (IBC) treated at our institution has improved over the past 30 years. Three-hundred ninety-eight patients with IBC were treated between 1974 and 2005. Patient characteristics and outcomes were tabulated and compared among decades of diagnosis. Survival outcomes were estimated with the Kaplan-Meier product limit method and compared among groups with the log-rank statistic. Cox proportional hazards models were fit to determine the association between year of diagnosis and survival outcomes after adjustment for patient and disease characteristics and treatments received. The median follow-up was 5.8 years (range, 0.3-23.8 years). There were 238 recurrences and 236 deaths. The median recurrence-free survival (RFS) duration was 2.3 years and the median overall survival (OS) time was 4.2 years. In the models for RFS and OS, after adjustment for patient and disease characteristics, increasing year of diagnosis was not associated with a decrease in the risk for recurrence (hazard ratio, [HR], 1.00; 95% confidence interval [CI], 0.97-1.04) or death (HR, 0.97; 95% CI, 0.94-1.01). Our data show that there has not been an important change in the prognosis of patients with IBC in the last 30 years. Clinical trials focusing on the management of this aggressive disease are warranted. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Chabner BA
Orange alert for oncologists.
Oncologist. 2007 Aug;12(8):902-3. [Abstract/Link to Full Text]

Eichler AF, Loeffler JS
Multidisciplinary management of brain metastases.
Oncologist. 2007 Jul;12(7):884-98.
Metastatic brain tumors are the most common intracranial neoplasms in adults. The incidence of brain metastases appears to be rising as a result of superior imaging modalities, earlier detection, and more effective treatment of systemic disease. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Treatment decisions must take into account clinical prognostic factors in order to maximize survival and neurologic function whilst avoiding unnecessary treatments. The goal of this article is to review important prognostic factors that may guide treatment selection, discuss the roles of surgery, radiation, and chemotherapy in the treatment of patients with brain metastases, and present new directions in brain metastasis therapy under active investigation. In the future, patients will benefit from a multidisciplinary approach focused on the integration of surgical, radiation, and chemotherapeutic options with the goal of prolonging survival, preserving neurologic and neurocognitive function, and maximizing quality of life. [Abstract/Link to Full Text]

Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, Canniff PC, Sharma A, Gomez-Navarro J
Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer.
Oncologist. 2007 Jul;12(7):873-83.
Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG(2) isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Preclinical testing in vitro and in large animal models predicted the target concentrations of circulating antibody in humans necessary for a pharmacodynamic effect. Phase I clinical trials provided evidence of dose- or exposure-related effects consistent with the anticipated mechanism of action. Further clinical development has led to two ongoing registration trials in patients with metastatic melanoma: a phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a phase II trial of tremelimumab in previously treated patients with advanced melanoma. [Abstract/Link to Full Text]

Weber J
Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events.
Oncologist. 2007 Jul;12(7):864-72.
The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. Preclinical and early clinical studies of patients with advanced melanoma show that ipilimumab promotes antitumor activity as monotherapy and in combination with treatments such as chemotherapy, vaccines, or cytokines. Emerging data on the kinetics of response to ipilimumab and associated adverse events are increasing our understanding about how to manage patients treated with this therapy. For example, short-term tumor progression prior to delayed regression has been observed in ipilimumab-treated patients, and objective responses may be of prolonged duration. In some patients clinical improvement manifests as stable disease, which may also extend for months or years. Immune-related adverse events (IRAEs) have been observed in patients after CTLA-4 blockade and most likely reflect the drug mechanism of action and corresponding effects on the immune system. Early clinical data suggest a correlation between IRAEs and response to ipilimumab treatment. This paper briefly reviews the results from several ongoing and completed ipilimumab clinical trials, provides a synopsis of current trials, and presents several cases that demonstrate the kinetics of antitumor responses and the relationship to IRAEs in patients receiving ipilimumab. [Abstract/Link to Full Text]

Ceresoli GL, Gridelli C, Santoro A
Multidisciplinary treatment of malignant pleural mesothelioma.
Oncologist. 2007 Jul;12(7):850-63.
The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and staging, especially of early disease, have thwarted the development of a universally accepted therapeutic approach. Single modality therapies (surgery, radiotherapy, chemotherapy) have generally failed to significantly prolong patient survival. As a result, multimodality treatment regimens have been developed. Radical surgery with extrapleural pneumonectomy and adjuvant treatments has become the preferred option in early disease, but the benefits of such an aggressive approach have been questioned because of significant treatment-related morbidity and mortality. In the past few years, there have been several major advances in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens with definite activity such as antifolate (pemetrexed or raltitrexed)-platinum combinations, and new radiotherapy techniques such as intensity-modulated radiation therapy. Induction chemotherapy followed by surgery and adjuvant radiotherapy has shown promising results. A number of molecular alterations occurring in MPM have been reported, providing broader insights into its biology and leading to the identification of new targets for therapy. However, currently available treatments still appear to have modest results. Further studies are needed to provide evidence-based recommendations for the treatment of early and advanced stages of this disease. [Abstract/Link to Full Text]

Gridelli C, Bareschino MA, Schettino C, Rossi A, Maione P, Ciardiello F
Erlotinib in non-small cell lung cancer treatment: current status and future development.
Oncologist. 2007 Jul;12(7):840-9.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Standard treatment approaches such as chemotherapy, radiotherapy, and surgery have reached a plateau in this disease. Therefore, alternatives to conventional treatment, such as new molecular-targeted therapies, are needed. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years. There are two EGFR tyrosine kinase inhibitors approved for the treatment of advanced NSCLC: gefitinib and erlotinib. Of these, erlotinib has shown a significant improvement in median survival, quality of life, and related symptoms in an unselected population of advanced and metastatic NSCLC patients in the second- or third-line setting. Furthermore, erlotinib has significant antitumor activity in first-line treatment. Moreover, factors that predict the efficacy of erlotinib, including clinical, pathologic, and molecular features, have been investigated. A series of studies is planned to contribute to our understanding of the role of erlotinib in NSCLC treatment. Major areas of clinical research are the assessment of erlotinib: in adjuvant treatment, combined with chemotherapy and/or radiotherapy in locally advanced disease, in the first-line therapy of advanced disease, and in combination and/or sequence with cytotoxic treatments and/or other molecular target agents. [Abstract/Link to Full Text]

Kemeny N
Presurgical chemotherapy in patients being considered for liver resection.
Oncologist. 2007 Jul;12(7):825-39.
The liver is a frequent site of metastatic disease for colorectal cancer patients. Approximately 15% of patients have liver metastases at diagnosis and another 50% develop metastatic disease to the liver over the course of their disease. Advances in systemic chemotherapy and surgical techniques for hepatic resection have led to longer survival times for these patients. There is no doubt that unresectable patients benefit from systemic chemotherapy. For patients who have resectable disease, the timing of chemotherapy is still not clear. This review addresses the pros and cons of presurgical chemotherapy. The benefits of preoperative chemotherapy include decreasing tumor size, controlling micrometastatic disease, assessing activity of chemotherapy, improving chemotherapy tolerance, and perhaps allowing some prediction of the success of liver resection. The risks for presurgical chemotherapy include liver toxicity, the risk for progression or growth of new sites, secondary splenomegaly, selection of resistant clones, and the possibility of leaving behind active tumor that is no longer seen because of a complete radiographic response. The challenge for the future is to develop a multidisciplinary team approach that can design the best treatment plan for patients with liver metastases. [Abstract/Link to Full Text]

Martin S, Ulrich C, Munsell M, Taylor S, Lange G, Bleyer A
Delays in cancer diagnosis in underinsured young adults and older adolescents.
Oncologist. 2007 Jul;12(7):816-24.
BACKGROUND: In the U.S., adolescents and young adults diagnosed with cancer have had less survival improvement than older or younger patients, a deficit that may be a result of delays in diagnosis in an age group with the lowest rates of health insurance. METHODS: The relationship between health insurance status and the time from the onset of first cancer-specific symptom or sign to definitive diagnosis (lagtime) was retrospectively compared with other sociodemographic factors in newly diagnosed cancer patients aged 15-29 years who were evaluated between June 2001 and June 2003. Data on 270 patients with the six most common cancer types in this cohort (leukemia, Hodgkin's and non-Hodgkin's lymphoma, sarcoma, brain tumors, thyroid cancer) were retrospectively collected in 2004. RESULTS: Lagtimes were evaluable in 235 (88%) patients. In multivariate analysis, the type of cancer and health insurance were significantly associated with lagtime, whereas race/ethnicity, age, gender, marital status, and surrogate measures of socioeconomic status were not. The mean lagtime in patients with public or no health insurance was 13.1 weeks longer than in patients with private health insurance, and longer in four of six evaluable histology-specific types of cancer. In cancers evaluable for stage at diagnosis, advanced stage was associated with longer lagtimes. CONCLUSION: In the U.S., older adolescents and young adults with cancer are likely to have a delay in diagnosis because of inadequate health insurance and consequently present with a more advanced stage of disease. [Abstract/Link to Full Text]

Chattopadhyay S, Tamari R, Min SH, Zhao R, Tsai E, Goldman ID
Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.
Oncologist. 2007 Jul;12(7):808-15.
Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed is administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish the activity of this agent. The current study demonstrates, in several human solid tumor cell lines, that when extracellular 5-formyltetrahydrofolate levels are increased in vitro, within the range of normal human blood levels, there is a substantial decrease in pemetrexed activity upon continuous exposure to the drug. This was accompanied by a comparable lower level of trimetrexate activity consistent with an expansion of tumor cell folate pools. Likewise, when cells were exposed to pemetrexed with a schedule that simulates in vivo pharmacokinetics, there was markedly less cell killing with higher extracellular folate levels. Data are provided to indicate that 5-formyltetrahydrofolate is an acceptable surrogate for 5-methyltetrahydrofolate, the major blood folate, for this type of in vitro study. These observations and other reports suggest that, in view of the rise in serum folate and fall in serum homocysteine that has accompanied folic acid supplementation of food in the U.S., the addition of folic acid to regimens with pemetrexed should be limited to the lowest recommended level that provides optimal protection from pemetrexed toxicity. [Abstract/Link to Full Text]

Dimitrov NV, Colucci P, Nagpal S
Some aspects of the endocrine profile and management of hormone-dependent male breast cancer.
Oncologist. 2007 Jul;12(7):798-807.
The management of hormone-dependent male breast cancer is insufficiently understood by practicing oncologists. This article provides a review of the endocrine profile of male breast cancer, and outlines the differences between hormone-dependent female and male breast cancers. A concise review of the past, present, and possible future management of hormone-dependent male breast cancer is presented. For a better understanding of this disease, more information on the natural history and biological behaviors of patients with male breast cancer is needed. This could be accomplished by the development of a specific multi-institutional tumor registry and execution of prospective clinical trials. [Abstract/Link to Full Text]

Verma S, Clemons M
First-line treatment options for patients with HER-2 negative metastatic breast cancer: the impact of modern adjuvant chemotherapy.
Oncologist. 2007 Jul;12(7):785-97.
The management of early breast cancer has evolved rapidly in recent years. Consequently, the range of first-line treatment options for metastatic breast cancer (MBC) is becoming increasingly complicated and therapy depends on a complex interaction of tumor, patient, and physician variables. Arguably one of the most important factors determining choice of first-line chemotherapy is prior adjuvant therapy. We have reviewed data from large, randomized clinical trials to identify the most effective regimens and help clinicians to select first-line treatment based on previous adjuvant therapy. In this review we provide recommendations on the most appropriate first-line therapy according to the type of previous adjuvant therapy. With such a wide array of treatment options available, none is likely to become the gold-standard first-line treatment for MBC. Furthermore, as increasing emphasis is placed on the quality as well as the duration of survival after development of MBC, treatment decisions should take into account tumor characteristics, toxicity, convenience, potential impact on quality of life, and patient preference, in addition to robust efficacy data. [Abstract/Link to Full Text]

Robertson JF
Fulvestrant (Faslodex) how to make a good drug better.
Oncologist. 2007 Jul;12(7):774-84.
Fulvestrant (Faslodex); AstraZeneca Pharmaceuticals, Wilmington, DE) is an estrogen receptor (ER) antagonist with a novel mode of action; it binds, blocks, and increases degradation of ER. Fulvestrant (at the approved dose [250 mg/month]) is at least as effective as anastrozole (1 mg/day) in the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (HR(+) ABC) progressing or recurring on antiestrogen therapy, and is also an active first-line treatment. Although fulvestrant (250 mg/month) is clearly effective, it takes 3-6 months to achieve steady-state plasma levels. Steady-state concentrations are approximately twofold higher than those achieved with a single dose; reaching this earlier, for example, via a loading-dose (LD) regimen (250 mg/month plus 500 mg on day 0 and 250 mg on day 14 of month 1), may allow responses to be achieved more quickly and limit the possibility of early relapse. Fulvestrant high-dose (HD) regimens (500 mg/month) offer the possibility of greater antitumor activity, because (a) ER downregulation is a dose-dependent process (an approximately 70% reduction is observed with a single 250 mg dose of fulvestrant) and (b) evidence correlates greater ER downregulation with superior efficacy. A fulvestrant HD regimen offers the potential of achieving near 100% ER downregulation. There is also potential to increase fulvestrant-ER binding by reducing plasma estrogen levels, for example, with concomitant aromatase inhibitor treatment. Several ongoing trials use LD, HD, and combination regimens; results from these studies are awaited with interest. Meanwhile, fulvestrant (250 mg/month) remains a valuable additional endocrine treatment for postmenopausal women with HR(+) ABC recurring or progressing on antiestrogen therapy. [Abstract/Link to Full Text]

Gori S, Rimondini S, De Angelis V, Colozza M, Bisagni G, Moretti G, Sidoni A, Basurto C, Aristei C, Anastasi P, Crinň L
Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors.
Oncologist. 2007 Jul;12(7):766-73.
BACKGROUND: A higher incidence of central nervous system (CNS) metastases in HER-2-positive metastatic breast cancer (MBC) has recently been reported. MATERIALS AND METHODS: Aims of this observational study were to evaluate the incidence of CNS metastases in HER-2-positive MBC patients, to define the outcome of patients with CNS metastases, and to identify the risk factors for CNS relapse. RESULTS: Between April 1999 and June 2005 we treated 122 consecutive HER-2-positive MBC patients with chemotherapy and trastuzumab. At a median follow-up of 28 months from the occurrence of metastatic disease, 43 patients (35.2%) developed CNS metastases. The median time to death from the diagnosis of CNS metastases was 23.46 months. At multivariate analysis we found that only premenopausal status at diagnosis of breast cancer and visceral metastases as the dominant site at relapse were significantly associated with a higher risk for CNS metastases. CONCLUSION: The CNS metastasis incidence is very high in HER-2-positive MBC, but the survival after CNS relapse in these patients is longer than in patients unselected for HER-2 status, because of the better control of extracranial disease obtained by trastuzumab. The identified risk factors for CNS relapse could allow us to select a subgroup of HER-2-positive MBC patients as candidates for active surveillance for CNS progression (by computed tomography or magnetic resonance imaging) and/or as candidates for accrual in trials of prevention of CNS relapse. [Abstract/Link to Full Text]

Moy B, Goss PE
Lapatinib-associated toxicity and practical management recommendations.
Oncologist. 2007 Jul;12(7):756-65.
Lapatinib is an oral receptor tyrosine kinase inhibitor, inhibiting both the ErbB-1 and ErbB-2 receptors. Lapatinib has been shown to have activity in ErbB-2-overexpressing breast cancer in several phase II and III clinical trials. Specifically, lapatinib is effective in patients with metastatic breast cancer, with inflammatory breast cancer, and possibly, with brain metastases. An ongoing clinical trial and another anticipated clinical trial will investigate lapatinib as adjuvant treatment in early-stage disease. Lapatinib has specific toxicities, the most common being diarrhea and rash. Cardiac toxicity is rarely seen with lapatinib. This paper reviews lapatinib-associated toxicities and provides practical management recommendations based on available data. [Abstract/Link to Full Text]

Mustian KM, Morrow GR, Carroll JK, Figueroa-Moseley CD, Jean-Pierre P, Williams GC
Integrative nonpharmacologic behavioral interventions for the management of cancer-related fatigue.
Oncologist. 2007;12 Suppl 152-67.
Cancer-related fatigue (CRF) is a debilitating, multi-faceted biopsychosocial symptom experienced by the majority of cancer survivors during and after treatment. CRF begins after diagnosis and frequently persists long after treatments end, even when the cancer is in remission. The etiological pathopsychophysiology underlying CRF is multifactorial and not well delineated. Mechanisms may include abnormal accumulation of muscle metabolites, dysregulation of the homeostatic status of cytokines, irregularities in neuromuscular function, abnormal gene expression, inadequate ATP synthesis, serotonin dysregulation, abnormal vagal afferent nerve activation, as well as an array of psychosocial mechanisms, including self-efficacy, causal attributions, expectancy, coping, and social support. An important first step in the management of CRF is the identification and treatment of associated comorbidities, such as anemia, hypothyroidism, pain, emotional distress, insomnia, malnutrition, and other comorbid conditions. However, even effective clinical management of these conditions will not necessarily alleviate CRF for a significant proportion of cancer survivors. For these individuals, intervention with additional therapeutic modalities may be required. The National Comprehensive Cancer Network guidelines recommend that integrative nonpharmacologic behavioral interventions be implemented for the effective management of CRF. These types of interventions may include exercise, psychosocial support, stress management, energy conservation, nutritional therapy, sleep therapy, and restorative therapy. A growing body of scientific evidence supports the use of exercise and psychosocial interventions for the management of CRF. Research on these interventions has yielded positive outcomes in cancer survivors with different diagnoses undergoing a variety of cancer treatments. The data from trials investigating the efficacy of other types of integrative nonpharmacologic behavioral therapies for the management of CRF, though limited, are also encouraging. This article provides an overview of current research on the relative merits of integrative nonpharmacologic behavioral interventions for the effective clinical management of CRF and makes recommendations for future research.Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Carroll JK, Kohli S, Mustian KM, Roscoe JA, Morrow GR
Pharmacologic treatment of cancer-related fatigue.
Oncologist. 2007;12 Suppl 143-51.
Fatigue is the most commonly reported symptom in patients with cancer, with a prevalence of over 60% reported in the majority of studies. This paper systematically reviews pharmacologic agents in the treatment of cancer-related fatigue (CRF). We conducted a literature review of clinical trials that assessed pharmacologic agents for the treatment of CRF. These agents include hematopoietics (for anemia), corticosteroids, and psychostimulants. Other therapeutic agents that are less well studied for CRF but are currently the focus of clinical trials include l-carnitine, modafinil, bupropion, and selective serotonin reuptake inhibitors such as paroxetine.Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Roscoe JA, Kaufman ME, Matteson-Rusby SE, Palesh OG, Ryan JL, Kohli S, Perlis ML, Morrow GR
Cancer-related fatigue and sleep disorders.
Oncologist. 2007;12 Suppl 135-42.
Sleep disorders, such as difficulty falling asleep, problems maintaining sleep, poor sleep efficiency, early awakening, and excessive daytime sleepiness, are prevalent in patients with cancer. Such problems can become chronic in some patients, persisting for many months or years after completion of cancer therapy. For patients with cancer, sleep is potentially affected by a variety of factors, including the biochemical changes associated with the process of neoplastic growth and anticancer treatments, and symptoms that frequently accompany cancer, such as pain, fatigue, and depression.Fatigue is highly prevalent and persistent in patients with cancer and cancer survivors. Although cancer-related fatigue and cancer-related sleep disorders are distinct, a strong interrelationship exists between these symptoms, and a strong possibility exists that they may be reciprocally related. The majority of studies that have assessed both sleep and fatigue in patients with cancer provide evidence supporting a strong correlation between cancer-related fatigue and various sleep parameters, including poor sleep quality, disrupted initiation and maintenance of sleep, nighttime awakening, restless sleep, and excessive daytime sleepiness.This paper reviews the data from these studies with a view toward suggesting further research that could advance our scientific understanding both of potential interrelationships between sleep disturbance and cancer-related fatigue and of clinical interventions to help with both fatigue and sleep disturbance.Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K, Morrow GR
Mechanisms of cancer-related fatigue.
Oncologist. 2007;12 Suppl 122-34.
Cancer-related fatigue (CRF) is one of the most prevalent symptoms patients with cancer experience, both during and after treatment. CRF is pervasive and affects patients' quality of life considerably. It is important, therefore, to understand the underlying pathophysiology of CRF in order to develop useful strategies for prevention and treatment. At present, the etiology of CRF is poorly understood and the relative contributions of the neoplastic disease, various forms of cancer therapy, and comorbid conditions (e.g., anemia, cachexia, sleep disorders, depression) remain unclear. In any individual, the etiology of CRF probably involves the dysregulation of several physiological and biochemical systems. Mechanisms proposed as underlying CRF include 5-HT neurotransmitter dysregulation, vagal afferent activation, alterations in muscle and ATP metabolism, hypothalamic-pituitary-adrenal axis dysfunction, circadian rhythm disruption, and cytokine dysregulation. Currently, these hypotheses are largely based on evidence from other conditions in which fatigue is a characteristic, in particular chronic fatigue syndrome and exercise-induced fatigue. The mechanisms that lead to fatigue in these conditions provide a theoretical basis for future research into the complex etiology of this distressing and debilitating symptom. An understanding of relevant mechanisms may offer potential routes for its prevention and treatment in patients with cancer.Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Jean-Pierre P, Figueroa-Moseley CD, Kohli S, Fiscella K, Palesh OG, Morrow GR
Assessment of cancer-related fatigue: implications for clinical diagnosis and treatment.
Oncologist. 2007;12 Suppl 111-21.
Cancer-related fatigue (CRF) is a highly prevalent and debilitating symptom experienced by most cancer patients during, and often for considerable periods after, treatment. The recognition of the importance of CRF to patients' psychosocial and cognitive functioning, as well as to their quality of life, has driven the development of a wide range of assessment tools for screening and diagnosis of CRF. Over 20 different measures have been used to assess CRF from either a unidimensional or multi-dimensional perspective. Unidimensional measures are often single-question scales that generally focus on identifying the occurrence and severity of CRF, whereas multidimensional measures may also examine the effect of CRF across several domains of physical, socio-emotional, and cognitive functioning. This paper provides an overview and critique of measures commonly used to assess CRF. Single-question assessment is the most commonly used and the most useful methodology. Strategies to facilitate reliable assessment of CRF are also discussed.Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR
Cancer-related fatigue: the scale of the problem.
Oncologist. 2007;12 Suppl 14-10.
Fatigue is one of the most common and debilitating symptoms experienced by patients with cancer. Cancer-related fatigue (CRF) is characterized by feelings of tiredness, weakness, and lack of energy, and is distinct from the "normal" drowsiness experienced by healthy individuals in that it is not relieved by rest or sleep. It occurs both as a consequence of the cancer itself and as a side effect of cancer treatment, although the precise underlying pathophysiology is largely unknown. CRF may be an early symptom of malignant disease and is reported by as many as 40% of patients at diagnosis. Virtually all patients expect fatigue from cancer therapy. Up to 90% of patients treated with radiation and up to 80% of those treated with chemotherapy experience fatigue. CRF continues for months and even years ollowing completion of treatment in approximately one third of the patients with cancer. The impact of CRF on a patient's quality of life (QoL), particularly in relation to physical functioning and the ability to perform activities of daily living, is both profound and pervasive. In addition, CRF is associated with considerable psychological distress and can impose a significant financial burden by limiting a patient's ability to work. These effects can extend to caregivers and family members, who may also have to reduce their working capacity in order to provide additional care for a patient with CRF. This paper examines the prevalence of CRF and explores the impact of this distressing symptom on patients' functioning and QoL.Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Morrow GR
Cancer-related fatigue: causes, consequences, and management.
Oncologist. 2007;12 Suppl 11-3. [Abstract/Link to Full Text]

Steinmetz T, Hellmich M, Neise M, Aldaud A, Lerchenmüller C, Tsamaloukas A, Fandel F, Weiligmann C, Totzke U, Schmitz S
Prediction of the responsiveness to treatment with erythropoiesis-stimulating factors: a prospective clinical study in patients with solid tumors.
Oncologist. 2007 Jun;12(6):748-55.
OBJECTIVE: Treatment with erythropoiesis-stimulating factors (ESFs) can ameliorate anemia associated with cancer and chemotherapy. However, half of anemic cancer patients do not respond even to high doses. To determine factors that are predictive of a treatment response, a multicenter, prospective study was performed. PATIENTS AND METHODS: Investigated factors were baseline erythropoietin, reticulocytes and soluble transferrin receptor (sTfR) after 2 weeks, and reticulocytes and hemoglobin after 4 weeks. Anemic patients with solid tumors received 150 microg/week of darbepoetin concomitantly with chemotherapy. The dose was doubled if hemoglobin did not increase by >1 g/dl after 4 weeks. Patients were considered responders if hemoglobin increased by >or=2 g/dl or reached a level >or=12 g/dl within 8-12 weeks. RESULTS: In total, 196 patients were enrolled; 61% of the intention-to-treat (ITT) and 68% of the per-protocol population were responders. In the ITT population, the hemoglobin increase after 4 weeks indicated an 11-fold higher chance of response (odds ratio, 11.0; 95% confidence interval [CI], 5.1-23.6; sensitivity, 88%; specificity, 60%). In a multiple logistic regression model including all factors, the area under the receiver operating characteristic curve was 0.78 (95% CI, 0.71-0.84). The combination of sTfR after 2 weeks and hemoglobin after 4 weeks was as predictive as the combination of all five tested factors. CONCLUSION: So far, an early hemoglobin increase remains the single most predictive factor for response to ESF treatment. In contrast to anemic patients with lymphoproliferative malignancies, serum erythropoietin had little predictive value in patients with solid tumors. [Abstract/Link to Full Text]

Kouvaris JR, Kouloulias VE, Vlahos LJ
Amifostine: the first selective-target and broad-spectrum radioprotector.
Oncologist. 2007 Jun;12(6):738-47.
After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions. [Abstract/Link to Full Text]

Charu V, Belani CP, Gill AN, Bhatt M, Tomita D, Rossi G, Ben-Jacob A
Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial.
Oncologist. 2007 Jun;12(6):727-37.
This randomized, controlled trial evaluated the effect of darbepoetin alfa on hospitalization days, transfusion requirements, hemoglobin levels, and fatigue in patients with anemia of cancer (AOC). Eligible patients were anemic (hemoglobin <or=11 g/dl) due to cancer, >or=18 years old, and had not received chemotherapy or radiotherapy within 4 weeks of study screening. Patients were randomized 4:1 to receive darbepoetin alfa, 3.0 microg/kg every 2 weeks (Q2W) (n = 226), or observation only for 12 weeks (n = 59), followed by an optional 9 weeks of darbepoetin alfa, 3.0 microg/kg Q2W. Endpoints were compared between the two treatment arms at week 13. A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect, so the study was terminated early. Therefore, results for the primary endpoint should be interpreted cautiously. The hospitalization rate was similar (0.5 days) for both the darbepoetin alfa and observation groups (p = .73). Transfusion incidence (weeks 5-12) was significantly lower for darbepoetin alfa patients (8%) than for observation patients (22%) (p = .0092). By week 13, hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa, compared with 0.1 g/dl in the observation group p < .0001. Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy-Fatigue score (mean change in score at week 13: darbepoetin alfa, 6.0; observation, 2.2; p < .05). Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC, resulting in significant improvements in health-related quality of life. [Abstract/Link to Full Text]

Sleijfer S, Wiemer E, Seynaeve C, Verweij J
Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment.
Oncologist. 2007 Jun;12(6):719-26.
Gastrointestinal stromal tumor (GIST) is one of the first solid tumor types in which a tyrosine kinase inhibitor, imatinib, has become standard of care for patients with advanced disease. Although imatinib yields antitumor activity in the vast majority of patients, it is likely that all patients eventually experience progressive disease given enough time. In recent years, major progress has been made in the elucidation of mechanisms conferring resistance to imatinib that result in progressive disease. Insight into these resistance mechanisms has already resulted in the availability of strategies that can be applied in cases of progressive disease and it is likely that more approaches will be defined in the next years. Additionally, it can be anticipated that in the near future treatment will be guided according to factors determining sensitivity to imatinib. This review focuses on the factors inducing imatinib resistance that have been elucidated so far, the currently available and potential novel treatment options for patients with progressive disease, and how insight into resistance mechanisms may allow individualized treatment in the near future for patients with advanced GISTs. [Abstract/Link to Full Text]

Cohen MH, Gootenberg J, Keegan P, Pazdur R
FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer.
Oncologist. 2007 Jun;12(6):713-8.
On October 11, 2006, the U.S. Food and Drug Administration granted approval for bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), administered in combination with carboplatin and paclitaxel, for the initial treatment of patients with unresectable, locally advanced, recurrent, or metastatic, nonsquamous, non-small cell lung cancer (NSCLC). Approval is based on a significant improvement in overall survival (OS). A randomized, open label, multicenter clinical trial, conducted by the Eastern Cooperative Oncology Group (ECOG), in chemotherapy-naďve patients with stage IIIB/IV nonsquamous NSCLC, evaluated bevacizumab plus carboplatin and paclitaxel (BV/CP, n = 434) versus carboplatin and paclitaxel alone (CP, n = 444). Exclusion of patients with squamous or predominantly squamous histology was based on life-threatening or fatal hemoptysis occurring in 4 of 13 patients with squamous histology who received a BV/CP regimen in a phase II study. Among the 878 randomized patients, the median age was 63, 46% were female, 76% had stage IV disease, 12% had stage IIIB disease with malignant pleural effusion, 11% had recurrent disease, and 40% had an ECOG performance status score of 0. OS was significantly longer in patients receiving BV/CP than in those receiving CP alone (median OS, 12.3 versus 10.3 months; hazard ratio [HR], 0.80; p = .013, stratified log rank test). Although a consistent effect was observed across most subgroups, in an exploratory analysis, evidence of a survival benefit was not observed in women (HR, 0.99; 95% confidence interval, 0.79-1.25). Severe and life-threatening adverse events occurring more frequently in patients receiving BV/CP were neutropenia (27% versus 17%), fatigue (16% versus 13%), hypertension (8% versus 0.7%), infection without neutropenia (7% versus 3%), thrombosis/embolism (5% versus 3%), pneumonitis or pulmonary infiltrate (5% versus 3%), infection with grade 3 or 4 neutropenia (5% versus 2%), febrile neutropenia (5% versus 2%), hyponatremia (4% versus 1%), proteinuria (3% versus 0), and headache (3% versus 0.5%). Fatal, treatment-related adverse events in patients receiving bevacizumab were pulmonary hemorrhage (2.3% versus 0.5%), gastrointestinal hemorrhage, central nervous system infarction, gastrointestinal perforation, myocardial infarction, and neutropenic sepsis. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, congestive heart failure, and neutropenic sepsis. The most common adverse events in patients receiving bevacizumab are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria. [Abstract/Link to Full Text]

Wouters A, Pauwels B, Lardon F, Vermorken JB
Review: implications of in vitro research on the effect of radiotherapy and chemotherapy under hypoxic conditions.
Oncologist. 2007 Jun;12(6):690-712.
As it is now well established that human solid tumors frequently contain a substantial fraction of cells that are hypoxic, more and more in vitro research is focusing on the impact of hypoxia on the outcome of radiotherapy and chemotherapy. Indeed, the efficacy of irradiation and many cytotoxic drugs relies on an adequate oxygen supply. Consequently, hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy. Moreover, efforts have been made to exploit hypoxia as a potential difference between malignant and normal tissues.Nowadays, a body of evidence indicates that oxygen deficiency clearly influences some major intracellular pathways such as those involved in cell proliferation, cell cycle progression, apoptosis, cell adhesion, and others. Obviously, when investigating the effects of radiotherapy or chemotherapy or both combined under hypoxic conditions, it is essential to consider the influences of hypoxia itself on the cell.In this review, we first focus on the effects of hypoxia per se on some critical biological pathways. Next, we sketch an overview of preclinical and clinical research on radiotherapy, chemotherapy, and chemoradiation under hypoxic conditions. [Abstract/Link to Full Text]

Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K
New drugs for myeloma.
Oncologist. 2007 Jun;12(6):664-89.
Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide plus dexamethasone is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been approved, in combination with dexamethasone, for the treatment of patients who have received one prior therapy; this regimen has shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these drugs in the treatment of newly diagnosed and advanced multiple myeloma. [Abstract/Link to Full Text]

Reddy SK, Tyler DS, Pappas TN, Clary BM
Extended resection for pancreatic adenocarcinoma.
Oncologist. 2007 Jun;12(6):654-63.
Adenocarcinoma of the pancreas presents a number of therapeutic challenges. Given the poor long-term outcomes after pancreaticoduodenectomy (PD), many surgeons have sought to improve survival via a radical or "extended" pancreatectomy which may include (a) total pancreatectomy (TP), (b) extended lymph node dissection (ELND), and (c) portal/mesenteric vascular resections. These themes of "extended" resection are addressed in this review. TP should not be performed for most cases of adenocarcinoma of the pancreatic head because of the nominal incidence of lymph node involvement along the body and tail of the pancreas, the scarcity of multicentric disease, and the better management of pancreatic leaks after PD. Most studies show no difference in long-term survival and demonstrate greater postoperative morbidity after TP than after PD. Performing ELND in addition to PD is not worthwhile because most studies do not demonstrate any long-term benefits from ELND and the circumferential dissection around the mesenteric vessels required to harvest distant lymph nodes increases postoperative morbidity. Major arterial resection increases postoperative morbidity after PD and worsens long-term survival as the need for arterial resection to achieve negative resection margins indicates more aggressive disease. In contrast, portal and/or mesenteric venous resection does not increase the morbidity after PD or impact long-term survival as venous resection is often performed because of tumor location and not extent of disease. The disappointing experience with extended resections underscores the need for better adjuvant systemic strategies and the interdisciplinary care of patients with pancreatic adenocarcinoma. [Abstract/Link to Full Text]

Suliburk JW, Perrier ND
Primary hyperparathyroidism.
Oncologist. 2007 Jun;12(6):644-53.
Primary hyperparathyroidism (PHPT) is classically thought of as the somatic manifestation of hypercalcemia in which patients suffer from a variety of complaints including abdominal pain, nephrolithiasis, osteopenia, and mental status changes. Contemporary PHPT patients are generally free of somatic manifestations and are most often diagnosed when routine biochemical testing shows an elevated serum calcium level. The modern day patient may present with much more subtle neurocognitive symptoms including fatigue, lethargy, muscle weakness, depression, and cognitive impairment. Advances in imaging technology, intraoperative parathyroid hormone measurement, and surgical technique now allow parathyroidectomy to be performed using a focused approach without the absolute need of a four-gland exploration. Minimally invasive techniques allow the procedure to be accomplished under local anesthesia on an outpatient basis. This brief review summarizes the presentation, biochemical evaluation, operative intervention, and follow-up care of the modern day PHPT patient. [Abstract/Link to Full Text]

Tacca O, Penault-Llorca F, Abrial C, Mouret-Reynier MA, Raoelfils I, Durando X, Achard JL, Gimbergues P, Curé H, Chollet P
Changes in and prognostic value of hormone receptor status in a series of operable breast cancer patients treated with neoadjuvant chemotherapy.
Oncologist. 2007 Jun;12(6):636-43.
The aim of this study was to detect and analyze changes in hormone receptor (HR) status after treatment of operable breast cancer with neoadjuvant chemotherapy (NCT). Patients were treated from 1982 to 2004 with different NCT combinations, mainly in successive prospective phase II trials. HR status before and after NCT was retested and reviewed in a blinded fashion by two pathologists, for 420 patients from a database of 710 patients. Among these 420 tumors, 145 (35%) were HR negative and 275 (65%) were HR positive before NCT. The HR status had changed after treatment in 98 patients (23%): 61 patients (42%) initially HR negative became HR positive. This HR-positive switch was significantly correlated with better overall survival (OS), compared with patients with unchanged HR-negative tumors. Moreover, this HR-positive switch also had an effect on disease-free survival (DFS). Conversely, 37 patients (13%) initially HR positive became HR negative after NCT. However, this group of previously positive patients still had a survival advantage for OS, but not for DFS. The Allred score was evaluated before and after chemotherapy. An increase in Allred score after NCT was significantly correlated with better DFS but not OS. It was previously shown, for other tumor parameters, that residual disease after NCT, rather than parameters evaluated on the initial biopsy, must be considered for patient prognosis. In this work, NCT induced variations in HR status in 23% of patients. A positive switch in HR status after NCT could be an indicator of better prognosis for patient outcome. [Abstract/Link to Full Text]

Paik S
Development and clinical utility of a 21-gene recurrence score prognostic assay in patients with early breast cancer treated with tamoxifen.
Oncologist. 2007 Jun;12(6):631-5.
Although patients diagnosed with axillary node-negative estrogen receptor-positive breast cancer have an excellent prognosis, about 15% of them fail after 5 years of tamoxifen treatment. Clinical trials have provided evidence that there is a significant benefit from chemotherapy for these patients, but it would be significant overtreatment if all of them were treated with chemotherapy. Therefore, context-specific prognostic assays that can identify those who need chemotherapy in addition to tamoxifen, or those who are essentially cured by tamoxifen alone, and can be performed using routinely processed tumor biopsy tissue would be clinically useful. Using a stepwise approach of going through independent model-building and validation sets, a 21-gene recurrence score (RS), based on monitoring of mRNA expression levels of 16 cancer-related genes in relation to five reference genes, has been developed. The RS identified approximately 50% of the patients who had excellent prognosis after tamoxifen alone. Subsequent study suggested that high-risk patients identified with the RS preferentially benefit from chemotherapy. Ideally the RS should be used as a continuous variable. A prospective study-the Trial Assigning Individualized Options for Treatment (Rx) (TAILORx)-to examine whether chemotherapy is required for the intermediate-risk group defined by the RS is accruing in North America. [Abstract/Link to Full Text]

Rha SY, Jeung HC, Choi YH, Yang WI, Yoo JH, Kim BS, Roh JK, Chung HC
An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients.
Oncologist. 2007 Jun;12(6):622-30.
PURPOSE: We examined the pattern of single-nucleotide polymorphisms (SNPs) of gemcitabine metabolism-related and target genes in breast cancer patients and evaluated their association with drug response or toxicity. PATIENTS AND METHODS: SNPs in deoxycytidine kinase (dCK), deoxycytidine monophosphate deaminase (DCTD), and ribonucleotide reductase M1 polypeptide (RRM1) were analyzed with genomic DNA of 10 breast cancer cell lines, 74 peripheral blood mononuclear cell (PBMC) samples from advanced breast cancer patients treated with gemcitabine, and 56 PBMC samples from healthy volunteers. RESULTS: The incidences of SNPs of breast cancer patients were 1.4% in dCK (626 A>G), 10.8% in DCTD (315 T>C), 40.5% in the first RRM1 (1082 C>A), 44.6% in the second RRM1 (2455 A>G), 44.6% in the third RRM1 (2464 G>A), and 23% in two RRM1 sites (2455 A>G and 2464 G>A) that were similar to those of the normal control group. We found a double SNP of RRM1 (2455 A>G and 2464 G>A) to be the novel haplotype that was associated with a lower frequency of chemotherapy-induced toxicity, such as neutropenia (p < .01) and G-CSF requirement (p < .005). CONCLUSION: RRM1 haplotype showed an association with susceptibility to gemcitabine monotherapy in breast cancer patients. [Abstract/Link to Full Text]

Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME
Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management.
Oncologist. 2007 May;12(5):610-21.
Epidermal growth factor receptor inhibitors (EGFRIs) have demonstrated improved overall survival in patients with non-small cell lung cancer, pancreatic cancer, and colorectal cancer; however, their use is associated with dermatologic reactions of varying severity. The similar spectrum of events observed with monoclonal antibodies and tyrosine kinase inhibitors suggests such toxicities are a class effect. While such reactions do not necessarily require any alteration in EGFRI treatment, being best addressed through symptomatic treatment, there is limited evidence on which to base such therapies. In October 2006, at an international and interdisciplinary EGFRI dermatologic toxicity forum, the underlying mechanisms of these toxicities were discussed and commonly used therapeutic interventions were evaluated. Our aim was to reach a current consensus on management strategies. A three-tiered, EGFRI-focused toxicity grading system is suggested for the purposes of therapeutic decision making, and as a framework on which to build a stepwise approach to intervention. This approach to successful management is specifically tailored to accurately categorize dermatologic toxicity associated with EGFRIs, and can be easily applied by all health care professionals. The goal is to maximize quality of life in patients who are being treated with these agents--many of whom will be on these drugs for several months or even years. [Abstract/Link to Full Text]

Lenz HJ
Management and preparedness for infusion and hypersensitivity reactions.
Oncologist. 2007 May;12(5):601-9.
BACKGROUND: Like nearly all systemic cancer therapies, monoclonal antibodies are associated with hypersensitivity reactions. This article reviews the characteristics and management of hypersensitivity reactions to monoclonal antibodies and commonly used chemotherapy agents. METHODS: MEDLINE was searched for recent studies and reviews pertaining to hypersensitivity reactions with monoclonal antibodies (cetuximab, rituximab, trastuzumab, panitumumab, bevacizumab), platinum compounds (carboplatin, oxaliplatin), and taxanes (paclitaxel, docetaxel). Emphasis was placed on articles that provided practical information on hypersensitivity reaction management. Data found in the literature were supplemented with information from the package insert for each agent. RESULTS: Severe hypersensitivity reactions are rare, with an incidence of < or =5%, provided patients receive proper premedication, close monitoring, and prompt intervention when symptoms occur. Hypersensitivity reactions to platinum compounds are generally consistent with type 1 hypersensitivity, occurring after multiple cycles of therapy. Reactions to taxanes and monoclonal antibodies produce similar symptoms, but are generally immediate, occurring during the first few minutes of the first or second infusion. However, 10%-30% of reactions to monoclonal antibodies are delayed, and may occur in later infusions, indicating the importance of close observation of the patient following administration. Mild-to-moderate reactions can be managed by temporary infusion interruption, reduction of the infusion rate, and symptom management. Rechallenge should be considered after complete resolution of all symptoms. Severe reactions may require treatment discontinuation. CONCLUSION: Hypersensitivity or infusion reactions to platinum compounds are acquired; reactions to taxanes and monoclonal antibodies are immediate and typically occur during the first few minutes of the first infusion. The different time of onset should be considered when developing strategies for preventing and managing hypersensitivity reactions. The decision to rechallenge or discontinue treatment after a reaction occurs depends on the severity of the reaction and other clinical factors. [Abstract/Link to Full Text]

Garcia JM, Polvino WJ
Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers.
Oncologist. 2007 May;12(5):594-600.
PURPOSE: RC-1291 is a novel, oral ghrelin mimetic and growth hormone (GH) secretagogue being developed to increase appetite and lean muscle mass in patients with cancer-associated anorexia/cachexia. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation phase I study in healthy volunteers evaluated RC-1291 once daily (qd) and twice daily (bid) for effect on body weight and safety. METHODS: The study was conducted with three sequential groups of volunteers. Panel A subjects (n = 8) received placebo or RC-1291, 25 mg qd, for 5 days. Panel B subjects received RC-1291, 25 mg bid or 50 mg qd, for 6 days then crossed over to the other dosage for 5 days (n = 12); three subjects received placebo for all 11 doses to maintain double-blinding. Panel C subjects (n = 9) received placebo or RC-1291, 75 mg qd, for 6 days. RESULTS: Subjects who received RC-1291, 50 or 75 mg, had significant dose-related weight gain after 6 days versus placebo, with the greatest increases seen with daily dosing. The mean increase in weight from baseline after 50 mg qd was 1.25 +/- 0.725 kg (p = .0022 versus placebo), and after 75 mg qd it was 1.16 +/- 0.651 kg (p = .0022 versus placebo). One subject in the 50 mg qd group had moderate transient elevation in aspartate aminotransferase and alanine aminotransferase levels. No other laboratory or clinical adverse events of consequence were reported. CONCLUSIONS: Results indicate that RC-1291 produces dose-related increases in body weight with no dose-limiting adverse effects, and may be an effective treatment for anorexia/cachexia. [Abstract/Link to Full Text]

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Recent Articles in CA: A Cancer Journal for Clinicians

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Hoffman B
Cancer survivors at work: a generation of progress.
CA Cancer J Clin. 2005 Sep-Oct;55(5):271-80.
Before the 1970s, a substantial percentage of cancer survivors faced blatant employment discrimination with little legal recourse, a paucity of support services, and limited medical options for curative treatment. Since then, survivors have benefited from improvements in cancer treatment, the passage of state and federal antidiscrimination laws, and a sea change in perceptions about living with and beyond cancer. Consequently, cancer survivors now face fewer barriers to employment opportunities. Because millions of cancer survivors, more than ever before, are now working age adults, advocacy efforts should shift from expanding legal protection from cancer-based discrimination to providing resources to help survivors meet their individual employment-related concerns. [Abstract/Link to Full Text]

Patel SG, Shah JP
TNM staging of cancers of the head and neck: striving for uniformity among diversity.
CA Cancer J Clin. 2005 Jul-Aug;55(4):242-58; quiz 261-2, 264.
The sixth edition of the tumor-node-metastasis staging system for head and neck cancers incorporates some significant shifts in philosophy. As treatment paradigms shift and data from ongoing clinical and basic research become available, further revisions may be expected in the future. The purpose of this review is to highlight the complexities involved in developing a user-friendly staging system and to report the major changes in the new version. The authors also discuss some areas of current interest that may have the potential to lead to future modifications. [Abstract/Link to Full Text]

Lim ST, Levine AM
Recent advances in acquired immunodeficiency syndrome (AIDS)-related lymphoma.
CA Cancer J Clin. 2005 Jul-Aug;55(4):229-41; 260-1, 264.
Human immunodeficiency virus-infected patients are at an increased risk for developing both Hodgkin and non-Hodgkin lymphoma when compared with the general population. With the remarkable decrease in the incidence of opportunistic infections since the availability of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome-related lymphoma (ARL) is now the second most common cancer associated with human immunodeficiency virus after Kaposi sarcoma. Over the last few years, advances in our understanding of the molecular biology of this heterogeneous group of lymphomas have led to the adoption of new classification systems. The prognosis of patients with ARL has improved dramatically with the availability of HAART, and the survival of many of these patients is now comparable to patients in the general population. Apart from the contribution of HAART, this improvement in prognosis can also be attributed to new initiatives in treatment of these patients, such as the use of effective infusional regimens, the feasibility of high-dose therapy with peripheral stem cell rescue for relapsed or refractory disease, and better supportive care. Nonetheless, several controversial issues persist, including the optimal timing of HAART with combination chemotherapy, the role of rituximab when incorporated into treatment regimens, and the optimal therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma. This article reviews the changes in the epidemiology of ARL in the era of HAART, advances in the biology of ARL, new developments in the management of patients with ARL, and several of the controversial issues that oncologists may encounter in the care of these patients. [Abstract/Link to Full Text]

Simon B, Lee SJ, Partridge AH, Runowicz CD
Preserving fertility after cancer.
CA Cancer J Clin. 2005 Jul-Aug;55(4):211-28; quiz 263-4.
In this review, the reproductive impact of treatments for several common cancers and options to maintain fertility in women and men undergoing treatment for these cancers will be discussed. The options available to any particular cancer survivor will depend on her or his age at the time of diagnosis and treatment, cancer type and primary site, stage, and type of treatment. [Abstract/Link to Full Text]


Hormonal therapy for breast cancer.
CA Cancer J Clin. 2005 May-Jun;55(3):195-8. [Abstract/Link to Full Text]

Ghobrial IM, Witzig TE, Adjei AA
Targeting apoptosis pathways in cancer therapy.
CA Cancer J Clin. 2005 May-Jun;55(3):178-94.
Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. These novel agents include those targeting the extrinsic pathway such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1, and those targeting the intrinsic Bcl-2 family pathway such as antisense bcl-2 oligonucleotides. Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001. Because these pathways may be preferentially altered in tumor cells, there is potential for a selective effect in tumors sparing normal tissue. This article reviews the current understanding of the apoptotic pathways, including the extrinsic (cytoplasmic) and intrinsic (mitochondrial) pathways, and the agents being developed to target these pathways. [Abstract/Link to Full Text]

Back AL, Arnold RM, Baile WF, Tulsky JA, Fryer-Edwards K
Approaching difficult communication tasks in oncology.
CA Cancer J Clin. 2005 May-Jun;55(3):164-77.
Effective communication skills enable physicians to improve patients' understanding of their illnesses, improve patient adherence to treatment regimens, use time efficiently, avoid burnout, and increase professional fulfillment. Common communication pitfalls include blocking, lecturing, depending on a routine, collusion, and premature reassurance. Fundamental communication skills include "ask-tell-ask," "tell me more," and responding empathetically. Key communication tasks that are linked to the illness trajectory include: the first visit, giving bad news, making anticancer treatment decisions, offering clinical trials, completing anticancer therapy, and discontinuing palliative chemotherapy. While enhancing or acquiring new skills ultimately requires practice and feedback over time, this article provides a cognitive map for important communication skills that physicians need over the course of caring for a person with cancer. [Abstract/Link to Full Text]

Kudachadkar R, O'Regan RM
Aromatase inhibitors as adjuvant therapy for postmenopausal patients with early stage breast cancer.
CA Cancer J Clin. 2005 May-Jun;55(3):145-63.
Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues. [Abstract/Link to Full Text]

Bucci MK, Bevan A, Roach M
Advances in radiation therapy: conventional to 3D, to IMRT, to 4D, and beyond.
CA Cancer J Clin. 2005 Mar-Apr;55(2):117-34.
Modern advances in computers have fueled parallel advances in imaging technologies. The improvements in imaging have in turn allowed a higher level of complexity to be incorporated into radiotherapy treatment planning systems. As a result of these changes, the delivery of radiotherapy evolved from therapy designed based primarily on plain (two dimensional) x-ray images and hand calculations to three-dimensional x-ray based images incorporating increasingly complex computer algorithms. More recently, biologic variables based on differences between tumor metabolism, tumor antigens, and normal tissues have been incorporated into the treatment process. In addition, greater awareness of the challenges to the accuracy of the treatment planning process, such as problems with set-error and organ movement, have begun to be systematically addressed, ushering in an era of so-called Four-Dimensional Radiotherapy. This review article discusses how these advances have changed the way the most common neoplasms are treated now and will be treated in the near future. [Abstract/Link to Full Text]

Deng G, Cassileth BR
Integrative oncology: complementary therapies for pain, anxiety, and mood disturbance.
CA Cancer J Clin. 2005 Mar-Apr;55(2):109-16.
Many people with cancer experience pain, anxiety, and mood disturbance. Conventional treatments do not always satisfactorily relieve these symptoms, and some patients may not be able to tolerate their side effects. Complementary therapies such as acupuncture, mind-body techniques, massage, and other methods can help relieve symptoms and improve physical and mental well-being. Self-hypnosis and relaxation techniques help reduce procedural pain. Acupuncture is well documented to relieve chronic cancer pain. Massage and meditation improve anxiety and other symptoms of distress. Many dietary supplements contain biologically active constituents with effects on mood. However, not all complementary therapies are appropriate or useful, and even helpful complementary modalities may not be optimal under some circumstances. Situations when precaution is indicated include acute onset of symptoms and severe symptoms, which require immediate mainstream intervention. Dietary supplements are associated with serious negative consequences under some circumstances. The authors summarize the research on these modalities and discuss the rationale, expectation, and necessary precautions involved with combining complementary therapies and mainstream care. Practical clinical issues are addressed. [Abstract/Link to Full Text]

Parkin DM, Bray F, Ferlay J, Pisani P
Global cancer statistics, 2002.
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108.
Estimates of the worldwide incidence, mortality and prevalence of 26 cancers in the year 2002 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. The results are presented here in summary form, including the geographic variation between 20 large "areas" of the world. Overall, there were 10.9 million new cases, 6.7 million deaths, and 24.6 million persons alive with cancer (within three years of diagnosis). The most commonly diagnosed cancers are lung (1.35 million), breast (1.15 million), and colorectal (1 million); the most common causes of cancer death are lung cancer (1.18 million deaths), stomach cancer (700,000 deaths), and liver cancer (598,000 deaths). The most prevalent cancer in the world is breast cancer (4.4 million survivors up to 5 years following diagnosis). There are striking variations in the risk of different cancers by geographic area. Most of the international variation is due to exposure to known or suspected risk factors related to lifestyle or environment, and provides a clear challenge to prevention. [Abstract/Link to Full Text]

Chen YC, Hunter DJ
Molecular epidemiology of cancer.
CA Cancer J Clin. 2005 Jan-Feb;55(1):45-54; quiz 57.
Epidemiology is very successful in identifying environmental and lifestyle factors that increase or reduce risk of specific cancers, leading to cancer prevention strategies. However, the etiology of many types of cancer is still poorly understood, despite extensive use of questionnaires and interview-based approaches in conventional epidemiologic studies. The integration of molecular techniques into epidemiology studies may provide new insights and has been referred to as molecular epidemiology. For instance, our ability to make connections between lifestyle and cancer risk is limited by difficulty in accurately measuring exposure to many carcinogens-newer molecular markers of exposure may provide better information. The completion of the Human Genome Project gives us knowledge of the genetic variations that presumably underlie the fact that a family history of cancer is a risk factor for most cancer types. Some of this excess risk has been explained over the last decade by identification of mutations in genes that give rise to a very high familial risk. Molecular epidemiologists are searching for genes that may give rise to much smaller increases in individual risk, but account for much of the residual risk associated with family history. These genes may also interact with environment and lifestyle factors such that cancer risk is not equally elevated in all persons exposed to an environmental factor (but not genetically susceptible), or all gene carriers (but not exposed to the environmental factor). Molecular markers may help to differentiate tumors with the same histologic appearance into different etiologic subtypes. Finally, response to treatment may be determined by molecular subtypes of the tumor, or inherited variation in drug metabolism. Examples will be given of how use of molecular techniques is informative in epidemiological studies of cancer and is predicted to lead to improvements in cancer incidence, early detection, and mortality. [Abstract/Link to Full Text]

Smith RA, Cokkinides V, Eyre HJ
American Cancer Society Guidelines for the Early Detection of Cancer, 2005.
CA Cancer J Clin. 2005 Jan-Feb;55(1):31-44; quiz 55-6.
Each January, the American Cancer Society (ACS) publishes a summary of its recommendations for early cancer detection, including guideline updates, emerging issues that are relevant to screening for cancer, and a summary of the most current data on cancer screening rates for US adults. In 2004, there were no updates to ACS guidelines. In this article, we summarize the current guidelines, discuss recent evidence and policy changes that have implications for cancer screening, and provide an update of the most recent data pertaining to participation rates in cancer screening by age, gender, and insurance status from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System. [Abstract/Link to Full Text]

Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ
Cancer statistics, 2005.
CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,372,910 new cancer cases and 570,280 deaths are expected in the United States in 2005. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for persons younger than 85 since 1999. When adjusted to delayed reporting, cancer incidence rates stabilized in men from 1995 through 2001 but continued to increase by 0.3% per year from 1987 through 2001 in women. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease from the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and from breast and colorectal cancers in women. Lung cancer mortality among women has leveled off after increasing for many decades. In analyses by race and ethnicity, African American men and women have 40% and 20% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population. [Abstract/Link to Full Text]

Sener SF
Disease without borders.
CA Cancer J Clin. 2005 Jan-Feb;55(1):7-9. [Abstract/Link to Full Text]


Patient pages. Colorectal cancer staging.
CA Cancer J Clin. 2004 Nov-Dec;54(6):362-5. [Abstract/Link to Full Text]

McDonald S, Saslow D, Alciati MH
Performance and reporting of clinical breast examination: a review of the literature.
CA Cancer J Clin. 2004 Nov-Dec;54(6):345-61.
Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression, when treatment is more effective and treatment options are greater than for later stage disease. Evidence suggests that, for some women, CBE can be an important complement to mammography in the earlier detection of breast cancer; CBE identifies some cancers missed by mammography and provides an important screening tool among women for whom mammography is not recommended or women who do not receive high-quality screening mammography according to recommended guidelines. But CBE performance and reporting approaches are inconsistent. Health care providers indicate that they are not confident in their CBE skills and would welcome training. Studies demonstrate that training can enhance CBE performance, measured in terms of execution of CBE components and accuracy. This literature review provides evidence to the extent that it is available, to support the specific recommendations of Saslow, et al. for optimizing CBE performance and reporting and to guide further research on CBE performance characteristics, reporting systems, barriers to high-quality CBE performance, and training. [Abstract/Link to Full Text]

Saslow D, Hannan J, Osuch J, Alciati MH, Baines C, Barton M, Bobo JK, Coleman C, Dolan M, Gaumer G, Kopans D, Kutner S, Lane DS, Lawson H, Meissner H, Moorman C, Pennypacker H, Pierce P, Sciandra E, Smith R, Coates R
Clinical breast examination: practical recommendations for optimizing performance and reporting.
CA Cancer J Clin. 2004 Nov-Dec;54(6):327-44.
Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression. Treatment options for earlier-stage cancers are generally more numerous, include less toxic alternatives, and are usually more effective than treatments for later-stage cancers. For average-risk women aged 40 and younger, earlier detection of palpable tumors identified by CBE can lead to earlier therapy. After age 40, when mammography is recommended, CBE is regarded as an adjunct to mammography. Recent debate, however, has questioned the contributions of CBE to the detection of breast cancer in asymptomatic women and particularly to improved survival and reduced mortality rates. Clinicians remain widely divided about the level of evidence supporting CBE and their confidence in the examination. Yet, CBE is practiced extensively in the United States and continues to be recommended by many leading health organizations. It is in this context that this report provides a brief review of evidence for CBE's role in the earlier detection of breast cancer, highlights current practice issues, and presents recommendations that, when implemented, could contribute to greater standardization of the practice and reporting of CBE. These recommendations may also lead to improved evidence of the nature and extent of CBE's contribution to the earlier detection of breast cancer. [Abstract/Link to Full Text]

Sifri R, Gangadharappa S, Acheson LS
Identifying and testing for hereditary susceptibility to common cancers.
CA Cancer J Clin. 2004 Nov-Dec;54(6):309-26.
Hereditary cancer syndromes account for an estimated 5% of breast, ovarian, and colon cancers. The rapid discovery of cancer-related genes in the last 15 years has propelled the field of cancer genetic risk assessment forward. With patients becoming increasingly aware of available genetic testing options, it is important that various health professionals become knowledgeable in identifying and advising patients at increased risk for a hereditary cancer syndrome. This article will outline the components of providing a hereditary cancer risk assessment with a focus on hereditary breast and ovarian cancer syndrome and hereditary colon cancer. [Abstract/Link to Full Text]

Compton CC, Greene FL
The staging of colorectal cancer: 2004 and beyond.
CA Cancer J Clin. 2004 Nov-Dec;54(6):295-308.
Stage is the strongest predictor of survival for patients with colorectal cancer. Accurate staging also is critical for appropriate patient management and meaningful clinical research. Uniform staging criteria applied in a uniform manner are essential for accurate evaluation of therapies and outcomes. Historically, numerous different staging systems for colorectal cancer have been employed, but a single internationally recognized system is required to ensure a common language for cancer that is understood by clinicians in all specialties. For the tumor, node, metastasis system to remain relevant, it has to continuously undergo critical evaluation and change when clinically indicated. [Abstract/Link to Full Text]

Dewilde LF, Russell C
The "Welcome to Medicare" physical: a great opportunity for our seniors.
CA Cancer J Clin. 2004 Nov-Dec;54(6):292-4. [Abstract/Link to Full Text]

Thun MJ, Sinks T
Understanding cancer clusters.
CA Cancer J Clin. 2004 Sep-Oct;54(5):273-80.
Each year, state and local health departments respond to more than 1,000 inquiries about suspected cancer clusters. Three quarters of these reports involve situations that are clearly not clusters and can be resolved by telephone. For the remainder, follow-up is needed, first to confirm the number of persons affected, their age, type of cancer, dates of diagnosis, and other factors, and then to compare cancer incidence in the affected population with background rates in state tumor registries. In approximately 5% to 15% of the reported situations, formal statistical testing confirms that the number of observed cases exceeds the number expected in a specific area, given the age, sex, and size of the affected population. Even in these instances, however, chance remains a plausible explanation for many clusters, and further epidemiologic investigation almost never identifies the underlying cause of disease with confidence. The few exceptions have involved clusters of extremely rare cancers occurring in well-defined occupational or medical settings, generally involving intense and sustained exposure to an unusual chemical, occupation, infection, or drug. This article discusses the resources and scientific tools currently available to investigate cancer clusters. It also provides a framework for understanding cancer clusters and a realistic appraisal of what cluster investigations can and cannot provide in the context of community expectations. [Abstract/Link to Full Text]

Cheson BD
What is new in lymphoma?
CA Cancer J Clin. 2004 Sep-Oct;54(5):260-72.
The lymphomas are a diverse group of malignant disorders that vary with respect to their molecular features, genetics, clinical presentation, treatment approaches, and outcome. Over the past few years, there have been major advances in our understanding of the biology of these diseases, leading to a universally adopted World Health Organization classification system. New therapies are now available with the potential to improve patient outcome, and the International Prognostic Index and standardized response criteria help make clinical trials interpretable. Most notably, the chimeric antiCD20 monoclonal antibody rituximab has altered our therapeutic paradigms for B-cell disorders. Combinations of this antibody with chemotherapy and other biologic agents have shown promise in treating lymphoma. Other antibodies, radioimmunoconjugates (such as Y-90 ibritumomab tiuxetan and I-131 tositumomab), and oblimerson sodium (a BCL-2 antisense oligonucleotide) have all shown promise. New chemotherapy regimens such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), agents such as gemcitabine, and monoclonal antibodies directed against CD30 are also being studied in Hodgkin Lymphoma. The challenge of clinical research is to optimize the use of these agents, select patients most likely to respond, and develop multitargeted strategies based on sound scientific rational, with the potential to increase the cure rate of patients with lymphomas. [Abstract/Link to Full Text]

Anhang R, Goodman A, Goldie SJ
HPV communication: review of existing research and recommendations for patient education.
CA Cancer J Clin. 2004 Sep-Oct;54(5):248-59.
The potential for human papillomavirus (HPV) DNA testing in cervical cancer prevention programs has been a topic at the forefront of cervical cancer policy discussions in recent years. To prevent some of the anxiety and psychological distress often experienced on HPV diagnosis and during the period of management, mass patient education must accompany the incorporation of HPV DNA testing into screening protocols. To contribute to a growing body of work that provides an empiric basis for development of effective counseling messages about HPV and HPV testing, this paper highlights women's most common information gaps and psychosocial concerns and describes the different perspectives offered by women's usual sources of information about HPV, including the crucial role of the clinical community in creating a shared decision making environment in which screening decisions and results can be discussed. [Abstract/Link to Full Text]

Harper DM
Why am I scared of HPV?
CA Cancer J Clin. 2004 Sep-Oct;54(5):245-7. [Abstract/Link to Full Text]

Oeffinger KC, Hudson MM
Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors.
CA Cancer J Clin. 2004 Jul-Aug;54(4):208-36.
Survivors of childhood and adolescent cancer are one of the higher risk populations seen by health care professionals. The curative therapy administered for the cancer also affects growing and developing tissues. Following chemotherapy, radiation therapy, and surgery, many survivors will experience chronic or late-occurring health problems, often not becoming clinically apparent until decades after therapy. Survivors face an increased risk of morbidity, mortality, and diminished quality of life associated with their previous cancer therapy. Risk is further modified by the survivor's genetics, lifestyle habits, and comorbid health conditions. Over their lifetime, survivors will see health care professionals from an array of specialties and disciplines. The aim of this review is threefold: (1) to convey a sense of the risk faced by survivors to clinicians unfamiliar with the population; (2) to provide an up-to-date tool for clinicians, regardless of specialty or discipline, when providing care for a survivor; and (3) to complement the recently completed recommendations for screening, prevention, and management of childhood cancer survivors. [Abstract/Link to Full Text]

Eyre H, Kahn R, Robertson RM
Preventing cancer, cardiovascular disease, and diabetes: a common agenda for theAmerican Cancer Society, the American Diabetes Association, and the American Heart Association.
CA Cancer J Clin. 2004 Jul-Aug;54(4):190-207.
Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two-thirds of all deaths in the United States and about 700 billion US dollars in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity-the major risk factors for these diseases-and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the American Cancer Society, the American Diabetes Association, and the American Heart Association review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment. [Abstract/Link to Full Text]

Vance RB
Common interests and common goals: achieving greater progress in preventive health through strategic collaborations.
CA Cancer J Clin. 2004 Jul-Aug;54(4):188-9. [Abstract/Link to Full Text]


Quitting smoking.
CA Cancer J Clin. 2003 Nov-Dec;53(6):372-5. [Abstract/Link to Full Text]

Eysenbach G
The impact of the Internet on cancer outcomes.
CA Cancer J Clin. 2003 Nov-Dec;53(6):356-71.
Each day, more than 12.5 million health-related computer searches are conducted on the World Wide Web. Based on a meta-analysis of 24 published surveys, the author estimates that in the developed world, about 39% of persons with cancer are using the Internet, and approximately 2.3 million persons living with cancer worldwide are online. In addition, 15% to 20% of persons with cancer use the Internet "indirectly" through family and friends. Based on a comprehensive review of the literature, the available evidence on how persons with cancer are using the Internet and the effect of Internet use on persons with cancer is summarized. The author distinguishes four areas of Internet use: communication (electronic mail), community (virtual support groups), content (health information on the World Wide Web), and e-commerce. A conceptual framework summarizing the factors involved in a possible link between Internet use and cancer outcomes is presented, and future areas for research are highlighted. [Abstract/Link to Full Text]

Ghafoor A, Jemal A, Ward E, Cokkinides V, Smith R, Thun M
Trends in breast cancer by race and ethnicity.
CA Cancer J Clin. 2003 Nov-Dec;53(6):342-55.
In this article, the American Cancer Society (ACS) describes trends in incidence, mortality, and survival rates of female breast cancer in the United States by race and ethnicity. It also provides estimates of new cases and deaths and shows trends in screening mammography. The incidence and survival data derive from the National Cancer Institute's Surveillance, Epidemiology, and End Results program; mortality data are from the National Center for Health Statistics. Approximately 211,300 new cases of invasive breast cancer, 55,700 in situ cases, and 39,800 deaths are expected to occur among women in the United States in 2003. Breast cancer incidence rates have increased among women of all races combined and white women since the early 1980s. The increasing rate in white women predominantly involves small (< or = 2 cm) and localized-stage tumors, although a small increase in the incidence of regional-stage tumors and those larger than five cm occurred since the early 1990s. The incidence rate among African American women stabilized during the 1990s for all breast cancers and for localized tumors. African American women are more likely than white women to be diagnosed with large tumors and distant-stage disease. Other racial and ethnic groups have lower incidence rates than do either white or African American women. However, the proportion of disease diagnosed at advanced stage and with larger tumor size in all minorities is greater than in white persons. Death rates decreased by 2.5% per year among white women since 1990 and by 1% per year among African American women since 1991. The disparity in mortality rates between white and African American women increased progressively between 1980 and 2000, so that by 2000 the age-standardized death rate was 32% higher in African Americans. Clinicians should be aware that 63% and 29% of breast cancers are diagnosed at local- and regional-stage disease, for which the five-year relative survival rates are 97% and 79%, respectively. This information, coupled with decreasing mortality rates and improvements in treatment, may motivate women to have regular mammographic and clinical breast examinations. Continued efforts are needed to increase the availability of high-quality mammography and treatment to all segments of the population. [Abstract/Link to Full Text]

Hurria A, Kris MG
Management of lung cancer in older adults.
CA Cancer J Clin. 2003 Nov-Dec;53(6):325-41.
Lung cancer is the leading cause of cancer death in the United States. At the time of diagnosis, most patients are older than 65 years and have Stage III or IV disease. More than 80% of patients have non-small cell lung cancer and the rest have small cell lung cancer. Age is not a significant prognostic factor for overall survival and response to treatment for patients with either type of lung cancer. Treatment options should be tailored to older patients based on the same selection process and benefits seen in the population as a whole. This article reviews the available data regarding surgery, radiation, and systemic treatment for older patients with lung cancer and considers the role of geriatric assessment in the evaluation of older patients. [Abstract/Link to Full Text]

Balducci L
Lung cancer in the elderly: so many patients, so little time!
CA Cancer J Clin. 2003 Nov-Dec;53(6):322-4. [Abstract/Link to Full Text]

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Recent Articles in Cancer Control: Journal of the Moffitt Cancer Center

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Miranda-Sousa AJ, Davila HH, Lockhart JL, Ordorica RC, Carrion RE
Sexual function after surgery for prostate or bladder cancer.
Cancer Control. 2006 Jul;13(3):179-87.
BACKGROUND: Compromised sexual function is often a side effect for patients following radical surgical procedures for bladder or prostate cancer. METHODS: The authors review the classification and physiology of sexual function and dysfunction. Moreover, they explain the possible pathophysiology directly resulting from surgery, and they discuss several approaches available to address these problems. RESULTS: Options for male sexual dysfunction, primarily erectile dysfunction resulting from radical prostatectomy or surgery for bladder cancer, range from patient education to penile prosthesis implantation. Female sexual dysfunction caused by surgical intervention for bladder cancer includes problems with libido, arousal, orgasm, and dyspareunia. Treatment options for women can include sex therapy, hormonal therapy, and preventive strategies. However, no consensus has been established on the most effective agents and time points to treat male or female sexual dysfunction following radical cystectomies or prostatectomies. The chronic intermittent treatment of erectile dysfunction following radical prostatectomy has been commonly referred to as penile rehabilitation. CONCLUSIONS: Additional research is needed to obtain further data concerning sexual dysfunction in both men and women following radical pelvic surgeries. Modification of surgical techniques, the use of various treatment modalities for sexual dysfunction, and the development of new agents will help to successfully minimize or prevent damage and restore normal sexual function after local surgical therapy for prostate or bladder cancer in the future. [Abstract/Link to Full Text]

Rodriguez A, Pow-Sang JM
Laparoscopic surgery in urologic oncology.
Cancer Control. 2006 Jul;13(3):169-78.
BACKGROUND: Techniques in genitourinary oncologic surgery have evolved over the past several years, shifting from traditional open approaches toward minimally invasive routes by laparoscopy. METHODS: We reviewed the literature on laparoscopic surgery for genitourinary cancer, with emphasis on contemporary indications, complications, and oncologic outcome of laparoscopic surgery for urologic malignancies. RESULTS: All urologic oncology procedures have been performed laparoscopically. Laparoscopic radical nephrectomy is becoming the preferred approach for managing kidney cancer. The initial experience with nephroureterectomy is encouraging. Laparoscopic radical prostatectomy is rapidly becoming the standard in Europe and is the procedure of choice in many centers in the United States. CONCLUSIONS: When following the open oncologic principles for the surgical treatment of malignancies, laparoscopy offers similar oncologic clinical outcomes, less morbidity, improved operative precision, and reduced convalescence time. [Abstract/Link to Full Text]

Delongchamps NB, Singh A, Haas GP
The role of prevalence in the diagnosis of prostate cancer.
Cancer Control. 2006 Jul;13(3):158-68.
BACKGROUND: The worldwide incidence of prostate cancer has been rising rapidly, likely due to intensified effort in early detection and screening. Intense effort is also directed at novel schemas of chemoprevention and therapy. Incidence data are insufficient to identify the true magnitude of prostate cancer in a given population. The true prevalence of prostate cancer must be identified. METHODS: We reviewed the latest worldwide epidemiologic data and clinical studies on prostate cancer studying the true prevalence of this disease. RESULTS: The incidence of prostate cancer is increasing worldwide, with strong variation among regions. Prevalence studies based on autopsy data have confirmed a high frequency of latent prostate cancer in men of all ages. More aggressive screening measures using a lower prostate-specific antigen (PSA) threshold, together with an increasing number of biopsies, have escalated the detection of these latent cancers. CONCLUSIONS: Recent improvements in prostate cancer detection narrow the gap between the incidence and true prevalence of prostate cancer. This, however, raises concerns about the risk of over detection of latent cancers and thus identifying a need for improvement in screening strategies to better identify clinically significant disease. [Abstract/Link to Full Text]

Martin P, Kelly CM, Carney D
Epidermal growth factor receptor-targeted agents for lung cancer.
Cancer Control. 2006 Apr;13(2):129-40.
BACKGROUND: Approximately 150,000 people were diagnosed with non-small cell lung cancer (NSCLC) in the United States in 2005. Most presented with inoperable advanced-stage disease. Although combination chemotherapy remains the standard treatment, median survival with these regimens is only 8 to 10 months. Recent advances in our understanding of lung cancer on a molecular level have led to the introduction of targeted therapies. METHODS: We reviewed the mechanism of action of gefitinib and erlotinib as well as the results of phase I, II, and III trials with these drugs. RESULTS: No survival advantage was seen with the addition of gefitinib or erlotinib to combination chemotherapy in first-line treatment of advanced NSCLC. Erlotinib has shown a survival advantage over placebo in patients with NSCLC after first- or second-line chemotherapy. Recently, mutations in the epidermal growth factor receptor-tyrosine kinase domain have been identified. Patients who express these mutations have shown a higher probability of response to gefitinib. CONCLUSIONS: Combination chemotherapy remains the first-line treatment of advanced NSCLC. The benefit of alternating drug schedules and combinations has been small. Targeted therapies such as gefitinib and erlotinib, although to date have shown no survival advantage when combined with chemotherapy in the first-line setting, remain promising. Ongoing studies of patient characteristics of responding patients and molecular studies of tumors may help to identify patients most likely to respond to these therapies. [Abstract/Link to Full Text]

Patel KN, Shaha AR
Poorly differentiated and anaplastic thyroid cancer.
Cancer Control. 2006 Apr;13(2):119-28.
BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic (undifferentiated) thyroid carcinoma (ATC) comprise a small subset of thyroid tumors that are associated with a poor prognosis and account for a significant portion of the morbidity and mortality related to thyroid cancer. Since management strategies vary between these two entities, it is important for clinicians to be able to differentiate PDTC from ATC. METHODS: We reviewed the literature on PDTC and ATC and compared clinical and histopathologic features important in defining the disease process. RESULTS: Both PDTC and ATC display aggressive behavior with increased locoregional and distant disease. In most cases, patients are older and have large, locally advanced tumors. PDTC may represent an intermediate entity in the progression of well-differentiated thyroid carcinoma to ATC. The use of surgical management may be curative or palliative and differs between PDTC and ATC. The roles of radiotherapy and chemotherapy have not been well described. CONCLUSIONS: PDTC and ATC are rare diseases that carry a poor prognosis. Recognition of their different clinicopathologic features is important to the optimal management of these tumors. [Abstract/Link to Full Text]

Patel KN, Singh B
Genetic considerations in thyroid cancer.
Cancer Control. 2006 Apr;13(2):111-8.
BACKGROUND: Recent molecular studies have described a number of abnormalities associated with the progression and dedifferentiation of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development. A better understanding of the mechanisms involved in thyroid cancer pathogenesis may help to translate these discoveries toward improvements in patient care. METHODS: We reviewed the literature on the molecular pathogenesis of thyroid cancer and compared clinical, histopathologic, and genetic features important in defining the disease process. RESULTS: The progression of thyroid cancer from well-differentiated to poorly differentiated and undifferentiated carcinoma represents a biological continuum. Specific genetic events serve as early initiating and late triggering events. Poorly differentiated thyroid carcinomas occupy an intermediate position in this progression model. CONCLUSIONS: With sophisticated genetic tools generating a wealth of information, we have gained better insight into the mechanisms driving thyroid tumor progression. Recognition of these features is crucial to the management of patients with thyroid cancer. Novel treatments are being designed based on our enhanced understanding of this disease process. [Abstract/Link to Full Text]

Malchoff CD, Malchoff DM
Familial nonmedullary thyroid carcinoma.
Cancer Control. 2006 Apr;13(2):106-10.
BACKGROUND: Nonmedullary thyroid carcinomas (NMTCs) originate from the thyroid epithelial cells and, until recently, were thought to arise sporadically without an inherited genetic predisposition. However, evidence of a familial predisposition to NMTC is accumulating. METHODS: This review addresses the strengths, weaknesses, and clinical implications of the observations indicating an inherited genetic predisposition to NMTC. These observations include epidemiologic studies, descriptions of large kindreds, and genetic analyses. RESULTS: Familial NMTC (FNMTC) may be caused by an inherited genetic predisposition and can be divided into two groups. The first group has an increased prevalence of NMTC within a familial cancer syndrome with a preponderance of nonthyroidal tumors. In the second group the predominant neoplasm is NMTC, although other neoplasms may occur with increased frequency. These disorders are the focus of this review. CONCLUSIONS: A family history in NMTC patients should be directed at detecting those familial tumor syndromes with a preponderance of NMTC as well as those familial tumor syndromes enriched in NMTC but with a preponderance of nonthyroidal tumors. Since the recurrence rates may be greater in FNMTC than in sporadic NMTC, careful monitoring is indicated for affected individuals. The advantages and disadvantages of screening asymptomatic members of FNMTC kindreds with thyroid ultrasound are discussed, and the final decision is deferred to the treating physicians and their patients. It is hoped that positional cloning research will identify the FNMTC susceptibility genes. [Abstract/Link to Full Text]

Slough CM, Randolph GW
Workup of well-differentiated thyroid carcinoma.
Cancer Control. 2006 Apr;13(2):99-105.
BACKGROUND: Well-differentiated thyroid carcinoma (WDTC) includes three main entities: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and Hurthle cell carcinoma (HCC). A thorough knowledge of the natural history and presentation of these carcinomas is vital to the thyroid surgeon. METHODS: This review details the preoperative workup of patients having or suspected to have WDTC. We review the history, physical examination, laboratory, and radiographic evaluations that optimally prepare the surgeon to determine the ideal surgical thyroid and neck treatment for patients with WDTC. RESULTS: A fiberoptic evaluation of the larynx is integral to the physical examination, and a laryngeal assessment is performed for all patients who will undergo thyroid surgery. It must be noted that vocal cord paralysis can be subtle and does not always present with clear dysphagia or voice change. Ultrasound and FNA are the primary tools of preoperative assessment. Given that patients with preoperative FNA positive for papillary cancer are expected to have clinically significant nodal disease in one third of cases, radiographic evaluation must be appropriately aggressive. The combination of US and CT allows assessment of the central and lateral neck nodes and the thyroid's relationship to central neck viscera. CONCLUSIONS: The overriding principle in the surgical treatment of WDTC is that the surgeon recognizes and encompasses all gross disease in the thyroid and neck nodes at first surgery. The extent of thyroidectomy is tailored not only to the patient's risk group and gross operative findings but also to the progress of the specific surgery in terms of parathyroid and recurrent laryngeal nerve preservation. [Abstract/Link to Full Text]

Lansford CD, Teknos TN
Evaluation of the thyroid nodule.
Cancer Control. 2006 Apr;13(2):89-98.
BACKGROUND: Thyroid nodules are common, yet treatment modalities range from observation to surgical resection. Because thyroid nodules are frequently found incidentally during routine physical examination or imaging performed for another reason, physicians from a diverse range of specialties encounter thyroid nodules. Clinical decision making depends on proper evaluation of the thyroid nodule. METHODS: The current literature was reviewed and synthesized. RESULTS: Current evidence allows the formulation of recommendations and a general algorithm for evaluating the incidental thyroid nodule. CONCLUSIONS: Only a small percentage of thyroid nodules require surgical management. Diagnosis and treatment selection require a risk stratification by history, physical examination, and ancillary tests. Nodules causing airway compression or those at high risk for carcinoma should prompt evaluation for surgical treatment. In nodules larger than 1 cm, fine-needle aspiration biopsy is central to the evaluation as it is accurate, low risk, and cost effective. Subcentimeter nodules, often found incidentally on imaging obtained for another purpose, can usually be evaluated by ultrasonography. Other laboratory and imaging evaluations have specific and more limited roles. An algorithm for the evaluation of the thyroid nodule is presented. [Abstract/Link to Full Text]

Strosberg JR, Choi J, Cantor AB, Kvols LK
Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors.
Cancer Control. 2006 Jan;13(1):72-8.
BACKGROUND: Prognosis in patients with carcinoid and pancreatic endocrine tumors with diffuse, unresectable liver metastases is poor. Palliation is often difficult despite the use of somatostatin analogs, interferon alpha, or systemic chemotherapy. Several reviews have suggested that hepatic artery embolization, with or without intraarterial chemotherapy, can be used for control of symptoms and for cytoreduction in patients with liver dominant metastases. METHODS: Between 2000 and 2002, 161 embolizations using polyvinyl alcohol or microspheres were performed on 84 patients with carcinoid or pancreatic endocrine tumors metastatic to the liver. A retrospective review was performed to evaluate symptomatic response, biochemical response, adverse effects, and duration of survival. Baseline and follow-up computed tomography scans were also assessed to determine radiographic response rates. Further analysis of survival was performed to assess the possible impact of various postembolization therapies. RESULTS: Eighty-four patients underwent bland hepatic artery embolizations during the study period. Among 55 symptomatic patients, 44 patients had fewer symptoms, and among 35 patients whose tumor markers were followed, 28 had a major biochemical response. Objective radiographic responses were observed in 11 of 23 patients. No deaths occurred during therapy, and major toxicities were rare. Median overall survival was 36 months from time of initial embolization. CONCLUSIONS: Hepatic artery embolization frequently results in clinical and radiographic responses in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors. Morbidity is low when appropriate supportive care is provided. Hepatic artery embolization often results in regressions in patients with unresectable liver metastases from carcinoid or pancreatic endocrine tumors. [Abstract/Link to Full Text]

Hodul P, Malafa M, Choi J, Kvols L
The role of cytoreductive hepatic surgery as an adjunct to the management of metastatic neuroendocrine carcinomas.
Cancer Control. 2006 Jan;13(1):61-71.
BACKGROUND: Patients with metastatic neuroendocrine cancers to the liver often present with disabling endocrinopathies and pain associated with bulky disease. Quality of life for these patients is poor and can require long-term therapy with somatostatin analogs for control of their symptoms. Alternative therapies to decrease tumor burden and subsequent hormone release have been investigated. Of these, cytoreductive surgery was found to have the most consistent and profound impact on symptom regression and overall survival. METHODS: Several cases are reported that illustrate an aggressive multimodality approach in the treatment of metastatic neuroendocrine cancers to the liver. The literature is reviewed and the role of cytoreductive surgery in the management of hepatic neuroendocrine metastases is discussed. RESULTS: Cytoreductive surgery can be performed safely with minimal morbidity and mortality. Regression of symptoms occurs in the majority of patients and survival is prolonged. CONCLUSIONS: Surgical intervention as part of an aggressive multimodality treatment plan results in improved outcomes for patients with advanced hepatic metastases of neuroendocrine origin. Future directions may include earlier surgical intervention with adjuvant therapies reserved for aggressive recurrent disease. [Abstract/Link to Full Text]

Nasir A, Stridsberg M, Strosberg J, Su PH, Livingston S, Malik HA, Kelley ST, Centeno BA, Coppola D, Malafa ME, Yeatman TJ, Kvols LK
Somatostatin receptor profiling in hepatic metastases from small intestinal and pancreatic neuroendocrine neoplasms: immunohistochemical approach with potential clinical utility.
Cancer Control. 2006 Jan;13(1):52-60.
BACKGROUND: The expression of somatostatin receptors (SSTRs) on endocrine tumor (ET) cells forms the basis for somatostatin analog treatment of patients with SSTR-positive, hormonally active ETs. In patients with SSTR-negative ETs, the clinical response is generally absent or suboptimal, while nonfunctioning ETs with SSTR positivity show a variable response to such therapy. METHODS: We retrospectively studied SSTR subtype expression in hepatic metastases from 14 adult patients with primary endocrine carcinomas (ECAs) of the small intestine and pancreas and compared SSTR subtype expression among the primary and metastatic ECAs. Polyclonal antibodies against the 5 SSTR subtypes were used on formalin-fixed, paraffin sections from each primary and metastatic ECA. Both qualitative and semiquantitative evaluation of the stained ECA sections was carried out. RESULTS: Eleven (61%) of 18 hepatic metastases from small intestinal and pancreatic ECAs were positive for SSTR-1, 15 (83%) for SSTR-2, 13 (72%) for SSTR-3, 10 (56%) for SSTR-4, and 15 (83%) for SSTR-5. Among 11 hepatic ECA metastases from small intestinal ECAs (carcinoids), 7 (63%) expressed SSTR-1, 9 (81%) expressed SSTR-2, 8 (72%) expressed SSTR-3, 6 (54%) expressed SSTR-4, and 10 (91%) expressed SSTR-5. Of 7 hepatic ECA metastases from pancreatic ECAs, 4 expressed SSTR-1, 6 expressed SSTR-2, and 5 expressed SSTR-3 and SSTR-5 each. We also observed the immunohistochemical evidence of heterogeneity of expression of various SSTR subtypes in the primary enteropancreatic ECAs and their hepatic metastases. CONCLUSIONS: SSTR subtype expression needs to be correlated to somatostatin analog therapy. Immunohistochemical profiling of various SSTR subtypes as a part of routine surgical pathologic analysis of enteropancreatic ETs may become a useful predictor of responsiveness of ETs to various SSTR analogs. [Abstract/Link to Full Text]

Feliberti EC, Wagman LD
Radiofrequency ablation of liver metastases from colorectal carcinoma.
Cancer Control. 2006 Jan;13(1):48-51.
BACKGROUND: Most patients with colorectal carcinoma will develop liver metastases. Radiofrequency ablation (RFA) has been utilized in metastatic CRC to help improve the survival gap between resectable and unresectable tumor. METHODS: The current use of RFA in selected patient populations is reviewed. RESULTS: RFA provides a survival benefit in patients with unresectable hepatic metastases from CRC compared with chemotherapy alone. It offers effective local tumor destruction in appropriately selected lesions and minimizes the morbidity and mortality of an open resection. Common complications are abdominal bleeding (1.6%), abdominal infection (1.1%), and injury to the biliary tree (1.0%). Mortality ranges from 0% to 0.5%. CONCLUSIONS: Trials are underway to compare chemotherapy plus local ablation to chemotherapy alone. RFA is a tool that should be utilized by experienced individuals to achieve optimal oncologic outcomes. [Abstract/Link to Full Text]

Homsi J, Garrett CR
Hepatic arterial infusion of chemotherapy for hepatic metastases from colorectal cancer.
Cancer Control. 2006 Jan;13(1):42-7.
BACKGROUND: Sixty percent of colon cancer patients develop liver metastasis. Only 25% of those have potentially resectable hepatic metastases, and approximately 58% of those patients relapse. METHODS: We review the indications and the technical aspects of hepatic artery infusion (HAI) of chemotherapy, as well as the efficacy, morbidity, and outcomes. RESULTS: HAI of chemotherapy has been used following hepatic metastasectomy, in patients with unresectable metastases, or in combination with other agents. Floxuridine, the chemotherapeutic agent most studied, is administered through an implantable subcutaneous infusion pump connected to a surgically placed hepatic artery catheter, which delivers the chemotherapeutic agents at a slow fixed rate. Treatment-related toxicities include chemical hepatitis, biliary sclerosis, and peptic ulceration. Some trials report a survival benefit for HAI over systemic chemotherapy with acceptable toxicity. CONCLUSIONS: Regional perfusion chemotherapy can be logistically and technically complicated to deliver. The development of newer systemic agents with superior efficacy in the treatment of metastatic colorectal cancer will likely diminish the role of regional perfusion therapy in the future. [Abstract/Link to Full Text]

McLoughlin JM, Jensen EH, Malafa M
Resection of colorectal liver metastases: current perspectives.
Cancer Control. 2006 Jan;13(1):32-41.
BACKGROUND: Metastases to the liver is the leading cause of death in patients with colorectal cancer. METHODS: The authors review the data on diagnosis and management of this clinical problem, and they discuss management options that can be considered. RESULTS: Complete surgical resection of metastases from colorectal cancer that are localized to the liver results in 5-year survival rates ranging from 26% to 40%. CONCLUSIONS: By adding modalities such as targeted systemic therapy and other "local" treatments for liver metastases, further gains in survival are anticipated. [Abstract/Link to Full Text]

Alvarado MD, Jensen EH, Yeatman TJ
The potential role of gene expression in the management of primary and metastatic colorectal cancer.
Cancer Control. 2006 Jan;13(1):27-31.
BACKGROUND: Although there have been recent advances in treatment of colorectal cancer, microarray technology has the potential to improve the application of these therapies by interrogating tumor-specific molecular "fingerprints." METHODS: The future applications and benefits of gene expression profiling are discussed. RESULTS: Potential uses include determining who will benefit from chemotherapy, further classifying patients into responders and nonresponders, predicting apoptotic response, developing classifiers to recognize chemosensitive tumors, identifying genes that portend a poor prognosis, revealing genes associated with metastases, predicting the outcome according to clinical stage, and avoiding surgery in patients who would not benefit from resection. CONCLUSIONS: Recent research has been aimed at not only finding new molecularly targeted agents, but also identifying specific signatures to predict sensitivity and resistance to therapy. Future care may soon incorporate the data derived from a single microarray chip or similar technology that will describe a patient's tumor, predict prognosis, and direct specific therapy. [Abstract/Link to Full Text]

Centeno BA
Pathology of liver metastases.
Cancer Control. 2006 Jan;13(1):13-26.
BACKGROUND: The liver is the most frequent site of metastatic disease, and metastatic disease to the liver is far more common than primary liver carcinoma in the United States. Pathologic evaluation of biopsy samples is key to establishing a correct diagnosis for patient management. Morphologic and immunoperoxidase studies, which are the standard for pathologic practice, accurately classify most tumors. Subclassification of carcinoma of unknown primary remains problematic. METHODS: The author reviewed the literature for articles pertaining to liver biopsy, diagnosis of specific tumor types, utility of immunohistochemical markers, and microarray and proteomic analysis. RESULTS: Sampling of liver lesions is best accomplished by combining fine-needle aspiration and needle core biopsy. Many malignancies have distinct morphologic and immunohistochemical patterns and can be correctly subclassified. Adenocarcinoma of unknown primary remains enigmatic since current immunohistochemical markers for this differential diagnosis lack specificity. Microarray analysis and proteomic analysis of tumors can provide distinct gene or protein expression profiles, respectively, for tumor classification. These technologies can be used with fine-needle aspiration and needle core biopsy samples. CONCLUSIONS: Most metastatic malignancies in the liver may be correctly diagnosed using standard morphology and immunohistochemical techniques. However, subtyping of some carcinomas and identification of site of unknown primary remains problematic. New technologies may help to further refine our diagnostic capabilities. [Abstract/Link to Full Text]

Choi J
Imaging of hepatic metastases.
Cancer Control. 2006 Jan;13(1):6-12.
BACKGROUND: Imaging plays an important role not only in screening, evaluating, staging, and monitoring disease, but also in surveillance following tumor ablation. Advances in imaging techniques have increased our ability to detect and characterize focal liver lesions, resulting in improvements in diagnostic capability and improved monitoring of liver metastases. This has led to increased interest in both hepatic imaging and image-guided hepatic interventions. METHODS: Several imaging options are reviewed according to their effective application, notably computed tomography (CT), CT during arterial portography, ultrasound, magnetic resonance imaging, positron emission tomography, and integrated PET/CT imaging. RESULTS: Although there are exceptions regarding imaging options based on patient selection and on institution preference and expertise, multidetector helical CT scanning remains the dominant modality in the evaluation of suspected hepatic metastases, and for preoperative planning, treatment monitoring, and posttreatment follow-up. CONCLUSIONS: Ultimately, the choice of imaging modality must be based not only on the patient and the clinical situation, but also on the imaging expertise within each institution. [Abstract/Link to Full Text]

Kripalani S, Sharma J, Justice E, Justice J, Spiker C, Laufman LE, Jacobson TA, Weinberg AD
Prostate cancer screening in a low-literacy population: does informed decision making occur?
Cancer Control. 2005 Nov;12 Suppl 2116-7. [Abstract/Link to Full Text]

Clay KS, Newlin K, Leeks KD
Pastors' wives as partners: an appropriate model for church-based health promotion.
Cancer Control. 2005 Nov;12 Suppl 2111-5. [Abstract/Link to Full Text]

Borrayo EA, Lawsin C, Coit C
Latinas' appraisal of participation in breast cancer prevention clinical trials.
Cancer Control. 2005 Nov;12 Suppl 2107-10. [Abstract/Link to Full Text]

Brandt HM, McCree DH, Lindley LL, Sharpe PA, Hutto BE
An evaluation of printed HPV educational materials.
Cancer Control. 2005 Nov;12 Suppl 2103-6. [Abstract/Link to Full Text]

Bradley PK, Kash KM, Piccoli CW, Myers RE
Preparing African American women for breast biopsy.
Cancer Control. 2005 Nov;12 Suppl 2100-2. [Abstract/Link to Full Text]

Ka'opua LS, Anngela L
Developing a spiritually based breast cancer screening intervention for native Hawaiian women.
Cancer Control. 2005 Nov;12 Suppl 297-9. [Abstract/Link to Full Text]

Hudson SV, Momperousse D, Leventhal H
Physician perspectives on cancer clinical trials and barriers to minority recruitment.
Cancer Control. 2005 Nov;12 Suppl 293-6. [Abstract/Link to Full Text]

Daza P, Mazas C, Nguyen L, Wetter DW
Categorizing race among Hispanic smokers.
Cancer Control. 2005 Nov;12 Suppl 291-2. [Abstract/Link to Full Text]

Holt CL, Haire-Joshu DL, Lukwago SN, Lewellyn LA, Kreuter MW
The role of religiosity in dietary beliefs and behaviors among urban African American women.
Cancer Control. 2005 Nov;12 Suppl 284-90.
The relationship between religiosity and health has been investigated in many studies, with most finding positive associations. However, little is known about the role of religiosity in dietary factors, particularly among African American women. We used a self-administered questionnaire to examine the association between religiosity and dietary beliefs and behaviors among African American women. Women with strong religious beliefs and behaviors reported more interest in eating more fruits and vegetables, perceived their consumption as being more important, and consumed more fruits and vegetables than women low in religious beliefs and behaviors. These findings highlight the role of both religious beliefs and behaviors as they relate to diet-related beliefs and behaviors in this population. [Abstract/Link to Full Text]

Fernandez ME, Palmer RC, Leong-Wu CA
Repeat mammography screening among low-income and minority women: a qualitative study.
Cancer Control. 2005 Nov;12 Suppl 277-83.
Regular mammography screening can reduce breast cancer mortality, yet low-income African American and Hispanic women underutilize mammography screening and are often diagnosed at a later stage, resulting in increased mortality. We used qualitative research methods to identify factors influencing regular breast cancer screening among African American and Hispanic women. Predisposing factors (including fear of mastectomy and lack of knowledge), enabling factors (including cost and social support) and a reinforcing factor were identified and categorized utilizing the PRECEDE framework. The study identified factors associated with the decision to complete regular mammography screening, and examined differences between African American and Hispanic women who participated in the interviews. Future research should seek to better understand the influence of family/friends, risk perception, and fatalistic beliefs on the decision to obtain regular mammograms. [Abstract/Link to Full Text]

Burhansstipanov L, Christopher S, Schumacher SA
Lessons learned from community-based participatory research in Indian country.
Cancer Control. 2005 Nov;12 Suppl 270-6.
The purpose of this article is to share lessons learned from implementing community-based participatory research (CBPR) in Indian Country that may be generalizable to other medically underserved communities. CBPR is currently included in multiple grant announcements by the National Institute of Health and Centers for Disease Control and Prevention, but information about this methodology vs traditional research methodology is often misleading. This article addresses some common mistakes made by academic research institutes by sharing what we have learned about how CBPR can be implemented in a respectful manner. The majority of tribal Nations prefer, if not mandate, that CBPR be used in most proposed studies involving their communities today. [Abstract/Link to Full Text]

Bowie JV, Curbow BA, Garza MA, Dreyling EK, Benz Scott LA, McDonnell KA
A review of breast, cervical, and colorectal cancer screening interventions in older women.
Cancer Control. 2005 Nov;12 Suppl 258-69.
Although cancer-screening guidelines recommend periodic testing for women 50 years of age and older, these tests are underused. A search of databases identified 156 community-based breast, cervical, and colorectal cancer screening intervention studies published before April 2003. Most were conducted in the United States. More than half used randomization procedures or pre-post measures, and one third used both. Most reported significant intervention effects. Cervical and combined cervical and breast studies had higher rates of pre-post designs, and breast studies had the highest percentage using randomization. Although effective community-based breast and cervical interventions have been conducted, there is an urgent need for amplification of colorectal cancer screening. [Abstract/Link to Full Text]

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Recent Articles in Pathology Oncology Research

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Lumniczky K, Sáfrány G
Cancer gene therapy: combination with radiation therapy and the role of bystander cell killing in the anti-tumor effect.
Pathol Oncol Res. 2006;12(2):118-24.
Current anti-cancer modalities such as surgery, chemo- and radiation therapies have only limited success in cancer treatment. Gene therapy is a promising new tool to improve outcomes. In this review, first we summarize the various strategies to kill tumor cells, and then focus on the bystander effect of gene therapy. A variety of strategies, such as gene-directed enzyme pro-drug therapy, activation of an anti-tumor immune attack, application of replication-competent and oncolytic viral vectors, tumor-specific as well as radiation- and hypoxiainduced gene expression, might be applied to target tumor cells. We put special emphasis on the combination of these approaches with local tumor irradiation. Using the available vector systems, only a small portion of cancer cells contains the therapeutic genes under clinical situations. However, cells directly targeted by gene therapy will transfer death signals to neighboring cancer cells. This bystander cell killing improves the efficiency of cancer gene therapy. Death signals are delivered by cell-to-cell communication through gap junction intercellular contacts, release of toxic metabolites into the neighborhood or to larger distances, phagocytosis of apoptotic bodies, and the activation of the immune system. Bystander cell killing can be enhanced by the introduction of gap junction proteins into cells, by further activating the immune system with immune-stimulatory molecules, or by introducing genes that help the transfer of cytotoxic genes and/or metabolites into bystander cells. In conclusion, although bystander cell killing can improve therapeutic effects, there should be additional developments in cancer gene therapy for a more efficient clinical application. [Abstract/Link to Full Text]

Merkli H, Pál E, Gáti I, Czopf J
Distal myopathy with rimmed vacuoles and cerebellar atrophy.
Pathol Oncol Res. 2006;12(2):115-7.
Distal myopathies constitute a clinically and pathologically heterogeneous group of genetically determined neuromuscular disorders, where the distal muscles of the upper or lower limbs are affected. The disease of a 41-year-old male patient started with gait disturbances, when he was 25. The progression was slow, but after 16 years he became seriously disabled. Neurological examination showed moderate to severe weakness in distal muscles of all extremities, marked cerebellar sign and steppage gait. Muscle biopsy resulted in myopathic changes with rimmed vacuoles. Brain MRI scan showed cerebellar atrophy. This case demonstrates a rare association of distal myopathy and cerebellar atrophy. [Abstract/Link to Full Text]

Vargas-Gonzalez R, Sanchez-Sosa S
Fibrocartilaginous dysplasia (fibrous dysplasia with extensive cartilaginous differentiation).
Pathol Oncol Res. 2006;12(2):111-4.
Fibrocartilaginous dysplasia is a variant of fibrous dysplasia in which extensive cartilaginous differentiation is identified. The amount of cartilage varies from case to case, however, no percentage has been proposed to consider this diagnosis. We present a 6-year-old girl with a two-year history of hip pain. Initial imaging studies of the right femur revealed a lucent lesion of the proximal shaft that extended into the femoral neck with ill-defined borders but well maintained cortex. Computed tomography scan demonstrated increased density of the medullary cavity but the cortex appeared intact. Curettage of the lesion was performed and fragments with cartilaginous appearance were obtained, weighing 45 g in total. Microscopically, the tumor revealed a cartilaginous (60%) and a fibro-osseous (40%) component; the former had increased cellularity and some chondrocytes displayed moderate atypia and binucleation, while the latter showed features of fibrous dysplasia. Areas of endochondral ossification and calcification were also identified. After five years of surgery this child is well and without evidence of recurrence. We discuss the differential diagnosis of this variant of fibrous dysplasia in the pediatric group. [Abstract/Link to Full Text]

Glisi? A, Atanackovi? J
Krukenberg tumor in pregnancy. The lethal outcome.
Pathol Oncol Res. 2006;12(2):108-10.
Krukenberg tumor refers to gastrointestinal cancer metastatic to the ovaries and its prognosis is uniformly poor. This case report concerns a 38-year-old pregnant woman suffering from abdominal pain and iterative vomiting episodes. She presented with a large abdominopelvic tumor. Because of suspected ovarian torsion, we performed urgent surgery. At laparotomy, bilateral ovarian tumors, ascites and gastric cancer located at the cardia and the lesser curvature invading the serosa were identified. We performed right ovariectomy, resection of the left ovary, and gastric biopsy. Histological examination of the specimen yielded diagnosis of Krukenberg tumor. Ten days later the patient underwent an elective Cesarean section in the 25th gestational week because of fetal asphyxia and very poor maternal life prognosis. We performed Cesarean delivery and extracted a vital female newborn of 31 cm, 600 g, Ap score 3, with virilization. Few days later the baby died at the intensive care unit. Two weeks later the mother died because of pulmonary failure. [Abstract/Link to Full Text]

Dundar E, Acikalin MF, Can C
The nested variant of urothelial carcinoma: an aggressive tumor closely simulating benign lesions.
Pathol Oncol Res. 2006;12(2):105-7.
The "nested" variant is a rare form of urothelial carcinoma and its biologic behavior is highly aggressive. Herein two new cases of nested variant of urothelial carcinoma with immunohistochemical examination are presented. In one of the cases, the tumor extended through the bladder wall into the perivesicular soft tissue, prostatic urethra and left vesicula seminalis, and metastasized to obturator lymph nodes. In the other case, invasion of muscular layer was observed and three recurrences were developed during a follow-up period of 23 months. Both tumors of our study demonstrated high p53 and Ki-67 indices, supporting the aggressive nature of such tumors. [Abstract/Link to Full Text]

Borka K, Patai K, Rendek A, Sobel G, Paulin F
Pleomorphic rhabdomyosarcoma of the uterus in a postmenopausal patient.
Pathol Oncol Res. 2006;12(2):102-4.
Pure rhabdomyosarcomas occurring in the adult uterus are very rare, with poor prognosis. We present a case of a 67-year-old woman with postmenopausal vaginal bleeding caused by pleomorphic rhabdomyosarcoma of the uterus, treated with hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymphadenectomy and partial sigmoidectomy. Postoperative chemotherapy (Doxorubicin) was given according to protocol. Follow-up examinations one year after surgery revealed no abnormalities or tumor recurrence. The rarity of this histological entity makes the presented case worthy of publication. [Abstract/Link to Full Text]

Kahán Z, Varga K, Dudás R, Nyári T, Thurzó L
Collaborative/active participation per se does not decrease anxiety in breast cancer.
Pathol Oncol Res. 2006;12(2):93-101.
The information needs of breast cancer patients on their disease, its treatment, the prognosis, and their attitude to decision-making concerning treatment were assessed. One hundred and fifty early and 45 metastatic breast cancer patients were recruited into the study. The amount of information and role in the treatment decision-making process preferred by the patient were independently estimated by the patient and the oncologist, using questionnaires. Information was provided in accordance with the wishes of the patient as perceived by the physician. Test of anxiety was performed before, and one week after the consultation. Most of the patients claimed to anticipate the provision of extensive information and an active role in the decision-making, but real interest during the consultation was found less frequently. The post-consultation anxiety test revealed a significant decrease in situational anxiety; this was not related to the patient's information needs or her attitude to the decision-making concerning treatment. Our study demonstrates that a significant decrease in anxiety may be achieved via a consultation tailored to the needs of the patient. Loading the patient with information and involvement in the decision regarding therapy as much as the patient seems comfortable with lowers distress. [Abstract/Link to Full Text]

Hiraishi Y, Wada T, Nakatani K, Negoro K, Fujita S
Immunohistochemical expression of EGFR and p-EGFR in oral squamous cell carcinomas.
Pathol Oncol Res. 2006;12(2):87-91.
Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family, which is expressed or highly expressed in a variety of solid tumors, including oral cancers. High EGFR expression has been correlated with tumor size, metastasis and survival. In recent years, EGFR has been considered a promising target for monoclonal antibody therapy. A total of 52 patients with oral squamous cell carcinoma (OSCC) were selected for EGFR and phosphorylated EGFR (p-EGFR) detection. Immunohistochemical staining was performed to evaluate EGFR and p-EGFR expression. Positive EGFR and p-EGFR staining was present in 92.3% (48/52) and 98.0% (51/52) of all cases, respectively. High EGFR and p-EGFR expression was present in 63.4% (33/52) and 69.2% (36/52) of all cases, respectively. EGFR and p-EGFR expression did not correlate with the clinical factors tumor stage, regional lymph node metastasis, or distant metastasis. However, a statistically significant correlation was identified between high EGFR expression and the pathologic factor tumor invasion. As a conclusion, the majority of OSCCs highly express EGFR and p-EGFR, indicating the importance of studying the efficacy of anticancer therapy targeting these signal factors. [Abstract/Link to Full Text]

Sughayer MA, Al-Khawaja MM, Massarweh S, Al-Masri M
Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan.
Pathol Oncol Res. 2006;12(2):83-6.
The management and prognosis of breast cancer nowadays require the evaluation of Estrogen (ER), Progesterone Receptors (PR) and HER2/neu. Ethnic variation in the expression of these receptors is well documented. The aim of this study is to determine the prevalence of ER, PR and HER2/neu among Jordanian women with breast cancer of ductal and lobular types. A retrospective analysis was performed on 267 cases of breast cancer referred for treatment at King Hussein Cancer Center, Jordan between the period of June 2003 and June 2004. Standard immune stains were used for evaluation of hormone receptors and HER2/neu. In addition, evaluation of HER2/neu was done by FISH in selected cases. Of these 267 cases, 240 (89.9%) were ductal carcinomas of various histological grades, 122 (50.8%) of which were ER-positive, 138 (57.5%) PRpositive and 42 (17.5%) HER2/neu-positive. Twentytwo (8.2%) of all cases were lobular carcinomas, 15 (68%) of which were ER-positive, 20 (90.9%) PRpositive and 3 (13.6%) HER2/neu-positive. Five (1.9%) of the total cases were of mixed lobular and ductal types, 4 (80%) of which were ER-positive, 3 (60%) PR-positive and none were positive for HER2/neu. The prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations and close to other populations such as the Chinese and the minor ethnic groups of Northern America (African Americans). [Abstract/Link to Full Text]

Baccar Harrath A, Yacoubi Loueslati B, Troudi W, Hmida S, Sedkaoui S, Dridi A, Jridi A, Ben Ayed F, Ben Rhomdhane K, Ben Ammar Elgaaied A
HLA class II polymorphism: protective or risk factors to breast cancer in Tunisia?
Pathol Oncol Res. 2006;12(2):79-81.
HLA system plays a key role in the tumor cells' escape from immune surveillance. Herein is the first report on the correlation of the susceptibility to breast cancer with HLA class II markers in Tunisia. Molecular typing of HLA-DRB1 and -DQB1 loci was undertaken for 70 Tunisian female patients. Comparison of allele and haplotype distribution between patients and 70 female control subjects reveals a negative association between HLADRB1* 07-DQB1*02 and the incidence of breast cancer in the Tunisian population. [Abstract/Link to Full Text]

Székely E, Török V, Székely T, Riesz P, Romics I
E-cadherin expression in transitional cell carcinomas.
Pathol Oncol Res. 2006;12(2):73-7.
The authors analyzed the expression of E-cadherin, one of the most important cell adhesion molecules, on histological slides of tumors of bladder cancer patients. The aim of the study was to see whether there is any association between E-cadherin expression and tumor grade, stage, age and gender of the patients, number of recurrences, or overall survival. The samples were examined in 51 primary bladder transitional cell carcinomas (TCC) of 50 patients, resected by transurethral resection (TUR) between January 1, 1996 and January 1, 1997. Immunoreactions were performed with monoclonal anti-human E-cadherin antibody. Forty of the fifty patients could be clinically followed. The analysis of the results on these forty patients was performed by contingency analysis and significance was assessed by chi2 test. No significant association between E-cadherin expression and tumor grade, stage, age or gender of the patients, the number of recurrences, or overall survival could be seen. [Abstract/Link to Full Text]

Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak M, Sulkowski S
Leptin--from regulation of fat metabolism to stimulation of breast cancer growth.
Pathol Oncol Res. 2006;12(2):69-72.
Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptin-induced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogen-activated protein kinase) and ERKs (extracellular signal-regulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor alpha (ERalpha) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors, therefore, it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer, the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary, we provide refreshed interpretation of intensively reported scientific queries of the topic. [Abstract/Link to Full Text]

Szilasi M, Dolinay T, Nemes Z, Strausz J
Pathology of chronic obstructive pulmonary disease.
Pathol Oncol Res. 2006;12(1):52-60.
Chronic obstructive pulmonary disease is one of the leading causes of death and morbidity worldwide. Despite intensive investigation, its pathology and pathophysiology are not well understood. The hallmarks of the disease are irreversible airflow limitation and chronic inflammation. Small airway obstruction due to progressive inflammation and fibrosis, and the loss of elastic recoil mediated by elastolysis and apoptosis equally contribute to pathologic changes. However, it is debated to what extent the obstruction of large airways leads to altered lung function. Three morphologic entities are described in the literature under one disease; chronic bronchitis, obstructive bronchiolitis and emphysema may appear in the same patient at the same time. The authors review pathologic changes observed in chronic obstructive pulmonary disease, including acute exacerbations and secondary pulmonary hypertension as severe but common complications of the disease. Furthermore, we detail recent scientific evidences for major cellular and molecular inflammatory pathway activation. These mechanisms result in accelerated apoptosis, remodeling and increased proinflammatory cytokine release. Targeting intracellular pathological changes may lead to the discovery of a new generation of drugs that could reduce chronic obstruction before airway irreversibility is established. [Abstract/Link to Full Text]

Culhaci N, Ozkara E, Yüksel H, Ozsunar Y, Unal E
Spontaneously ruptured uterine angioleiomyoma.
Pathol Oncol Res. 2006;12(1):50-1.
Angioleiomyoma is an uncommon type of leiomyoma of the uterus that originates from smooth muscle cells and contains thick-walled vessels. A 45-year-old woman with the complaint of lower abdominal pain was admitted to the hospital. In the operation a ruptured, bleeding uterine tumor was seen. She underwent total hysterectomy and bilateral salpingo-oophorectomy. On pathologic examination of the specimen, the tumor was diagnosed as angioleiomyoma. Here, an unusual clinical presentation of uterine angioleiomyoma was reported. [Abstract/Link to Full Text]

Sobel G, Halász J, Bogdányi K, Szabó I, Borka K, Molnár P, Schaff Z, Paulin F, Bánhidy F
Prenatal diagnosis of a giant congenital primary cerebral hemangiopericytoma.
Pathol Oncol Res. 2006;12(1):46-9.
Congenital primary intracranial hemangiopericytomas are exceptionally rare tumors. We present a case of a fetus, with the prenatal sonogram at 33 weeks of gestation revealing a large cerebral tumor. Because of the enlarged head, a cesarean section was performed. The tumor was confirmed by postnatal ultrasound, magnetic resonance imaging (MRI) and biopsy. Elevated intracranial pressure and hemorrhage led to death on the 11th day. Autopsy revealed a 10x9 cm large inhomogeneous tumor located centrally, mainly in the posterior fossa. Histology showed a hypercellular and hypervascular tumor with extended necrosis and high mitotic rate. The tumor cells were positive for vimentin and CD34 antigens and negative for several neurological markers, desmin and CD31. The diagnosis of a congenital primary cerebral hemangiopericytoma was confirmed. [Abstract/Link to Full Text]

Saqui-Salces M, Martinez-Benitez B, Gamboa-Dominguez A
EBV+ lymphoepithelial carcinoma of the parotid gland in Mexican Mestizo patients with chronic autoimmune diseases.
Pathol Oncol Res. 2006;12(1):41-5.
Lymphoepithelial carcinomas of the salivary gland are rare tumors constantly associated with Epstein-Barr virus (EBV) and mainly identified in Asiatic and Greenlander population. Four cases have been described in Caucasians, only two with EBV infection. We describe two cases of parotid gland lymphoepithelial carcinomas in Mexican mestizo women in which chronic latent EBV infection was documented by immunohistochemistry and in situ hybridization. One patient had primary Sjögren's syndrome and the other systemic lupus erythematosus of six and three years of evolution, respectively. Epithelial neoplastic cells showed latency pattern II (LMP1+, EBNA-2-, EBER+) with a dense inflammatory infiltrate composed mainly by CD8+ T lymphocytes. Follow-up excluded nasopharyngeal involvement in both patients. This report expands the ethnic groups in which salivary lymphoepithelial carcinomas associated with chronic latent EBV infection have been described, and illustrates for the first time its association with autoimmune diseases in two women living in a region non-endemic for this unusual neoplasm. [Abstract/Link to Full Text]

Pál J, Nyárády Z, Marczinovits I, Pár A, Ali YS, Berencsi G, Kvell K, Németh P
Comprehensive regression analysis of hepatitis B virus X antigen level and anti-HBx antibody titer in the sera of patients with HBV infection.
Pathol Oncol Res. 2006;12(1):34-40.
Although the pathogenetic significance of hepatitis B virus x protein (HBxAg) in chronic hepatitis, liver cirrhosis, and primary hepatocellular carcinoma has already been studied, the comparative analyses of both the actual serum HBxAg levels and antibody production against various HBx epitopes have been examined to lesser extent. We have simultaneously investigated the relationship between antibody production (IgG and IgM) against the HBxAg fragments and HBxAg level in the sera of patients with acute (14) or chronic hepatitis (80) and symptomless carriers (12). A recently developed sandwich-type ELISA was used for the quantitative measurements of HBxAg. Overlapping recombinant and synthetic antigens were used to map the fine epitope specificities of circulating anti-HBx antibodies. In acute hepatitis, we have found high and homogenous correlation in the IgM type immune responses against all the examined HBxAg regions. Moreover, strong correlation has been observed between IgG type immune responses to a characteristic C-terminal region (C1: 79-117) and the longest fragment (X: 10-143). Moderate correlation has been found between HBxAg concentration and the IgG type anti-HBx antibody levels against C-terminus of HBxAg in patients with chronic hepatitis. In the case of symptomless carriers, there were also demonstrable associations in the immune responses against the C-terminal sequences; however, significant correlations were found for antibody production against the N-terminal region as well. The examinations show that the C-terminal sequence, responsible for transactivation, promotes an efficient IgG antibody response in all three groups of patients, whereas the negative regulator N-terminal part of the HBxAg molecule for the most part does not trigger antibody production. This suggests that the immune responses against various - biologically active - epitopes of the HBxAg may have a different role in the pathogenesis of hepatitis and may be used as prognostic markers in human HBV infections. [Abstract/Link to Full Text]

Pezeshki A, Sari-Aslani F, Ghaderi A, Doroudchi M
p53 codon 72 polymorphism in basal cell carcinoma of the skin.
Pathol Oncol Res. 2006;12(1):29-33.
Basal cell carcinoma (BCC) is the most prevalent cancer in Iran. A common polymorphism at codon 72 of exon 4 of p53 tumor suppressor gene has been reported to be associated with increased inheritable susceptibility to several cancers. In the present study the frequency of p53 codon 72 polymorphism in 91 patients with BCC of skin, compared to 465 healthy normal individuals, was investigated. In total, there was no significant difference in the p53 genotypes between patients and controls. However, there was an apparent increase in the Arg/Arg genotype among those BCC patients who had a history of occupational sun exposure, compared to non-exposed patients (46.3% vs. 23.1%, P=0.11). A trend of increase in the frequency of Arg allele among sun-exposed patients was also observed (69.4% vs. 53.8%, P=0.07). Comparison of the genotype frequencies between sunexposed patients and normal controls confirmed the accumulation of Arg/Arg genotype in these patients (46.3% vs. 34.8%, P = 0.07). In addition, the frequency of Arg allele was significantly higher in sunexposed patients compared to controls (69.4% vs. 58.2%, P=0.03). Our results suggest that Arg allele at codon 72 of p53 gene might affect the risk of ultraviolet-induced basal cell carcinoma. [Abstract/Link to Full Text]

Elagoz S, Egilmez R, Koyuncu A, Muslehiddinoglu A, Arici S
The intratumoral microvessel density and expression of bFGF and nm23-H1 in colorectal cancer.
Pathol Oncol Res. 2006;12(1):21-7.
It has previously been reported that intratumoral microvessel density (IMD), and the expression of bFGF and nm23-H1 are useful prognostic markers in colorectal cancer (CRC). In this study, a total of 100 CRCs were evaluated histopathologically, and IMD, bFGF and nm23-H1 expression were assessed by immunohistochemistry. IMD of patients increased with grade and stage, and this increase was statistically significant (p<0.05). A significantly higher incidence of high bFGF expression scores was also associated with increasing grade and stage (p<0.05). However, there was no significant difference between the grades in nm23-H1 expression (p=0.234). nm23-H1 expression occurred with lower incidence in stages C1, C2 and D than in stages B1 and B2 (p<0.05). Thus, a negative correlation was found between nm23-H1 expression and stage or lymph node metastasis (LNM) (p<0.05). IMD and bFGF expression were positively correlated with grade, stage, LNM, and lymphovascular invasion. Although positive correlation was found between IMD and bFGF, nm23-H1 expression negatively correlated with both of them. As a result, in clinical practice, increased IMD and bFGF expression and decreased nm23-H1 expression may provide valuable information in characterizing the malignant phenotype. [Abstract/Link to Full Text]

Koksal IT, Ates M, Danisman A, Sezer C, Ciftcioglu A, Karpuzoglu G, Sevuk M
Reduced E-cadherin and alpha-catenin expressions have no prognostic role in bladder carcinoma.
Pathol Oncol Res. 2006;12(1):13-9.
In various human cancers, dysfunction of the E-cadherin-catenin complex is associated with a decrease in cellular and tissue differentiation, and with higher invasive and metastatic potentials. The objective of this study was to investigate E-cadherin and alpha-catenin expression in superficial noninvasive papillary TCC and invasive TCC, and correlate these results with pathological and clinical parameters. We have used immunohistochemistry to localize Ecadherin and alpha-catenin in 56 formalin-fixed, paraffin-embedded tissue blocks from 41 patients with superficial bladder cancer and 15 with invasive bladder cancer. The 46 male and 10 female patients had a mean age of 67 years, with range of 40 to 82 years. The mean follow-up time was 33.4 (range 5-120) months. Tumor grade 1:2:3 ratios were 5:32:19. In superficial bladder tumor, abnormal expression of E-cadherin and alpha-catenin was demonstrated in 37 and 71% of the tumors, respectively. In advanced bladder tumor, abnormal expression of E-cadherin and alpha-catenin was demonstrated in 80 and 100% of the tumors, respectively. Differences in expression of E-cadherin and alpha-catenin could be discerned between superficial and advanced bladder tumors (p=0.004, p=0.024, respectively). However, the association between E-cadherin and alpha-catenin expression and tumor grade was not statistically significant (p>0.05). In addition, the expression of E-cadherin and alpha-catenin did not correlate with tumor number and size (p>0.05). We have demonstrated that abnormal expression of E-cadherin and/or alpha-catenin occurs in more than 85% of bladder carcinomas and correlates significantly only with advanced stage. Nevertheless, these observations need to be confirmed in larger prospective clinical studies. [Abstract/Link to Full Text]

Kopper L, Tímár J
Genomics of renal cell cancer-- does it provide breakthrough?
Pathol Oncol Res. 2006;12(1):5-11.
It is a strong hope that the more we characterize the pathways in an individual tumor, the better we will be able to evaluate the response to a specific therapy. Different array technologies could be powerful tools to achieve this goal, i.e. selecting patients on the basis of the genomic and/or proteomic profiles who would really benefit from the target-designed therapy. Genomic analysis of RCC accumulated ample of data which now can be exploited in clinical management of a previously almost uncontrollable disease. Beside the previously identified genetic abnormalities (VHL, MET, EGFR), CAIX seems to be a novel molecular marker of RCC. Array studies also outlined a small set of tumor markers, vimentin, galectin-3, CD74 and parvalbumin, which can define the individual histologic subtypes of RCC. We are at the beginning to take advantage of the genomic results. Some new approaches will interfere with the progression of RCC (anti-VEGF, anti-VEGFR or anti-EGFR therapies). Further novel molecular targets are available, such as HIF, HSP90 or the IFN-regulated genes, which can be used to the fine-tuning of RCC therapy. [Abstract/Link to Full Text]

Ates LE, Kapran Y, Erbil Y, Barbaros U, Dizdaroglu F
Cystic lymphangioma of the right adrenal gland.
Pathol Oncol Res. 2005;11(4):242-4.
Lymphangiomas are benign malformations of the vessels. They are commonly located in the neck, axillary region and mediastinum. Lymphangioma of the adrenal gland is very rare. These lesions were first discovered as incidental autopsy findings. As the imaging techniques have improved, they now appear as incidental findings at abdominal ultrasonography and computed tomography scan examinations. They are usually asymptomatic. We present a 26-year-old woman admitted to the hospital, complaining of weakness, putting on weight, and lumbago. Her laboratory findings were within normal limits. Radiological examination revealed a 7 cm cystic lesion located in the right adrenal gland. Right adrenalectomy was performed. Histopathological examination and immunohistochemical analysis of the cystic lesion was consistent with a lymphangioma. [Abstract/Link to Full Text]

Ghayumi SM, Mehrabi S, Doroudchi M, Ghaderi A
Diagnostic value of tumor markers for differentiating malignant and benign pleural effusions of Iranian patients.
Pathol Oncol Res. 2005;11(4):236-41.
In order to evaluate the diagnostic yield of tumor markers in differentiating malignant and benign pleural effusions, we carried out a prospective study in a group of Iranian people. Pleural and serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA 15-3), neuron-specific enolase (NSE) and cancer antigen 125 (CA 125) were assayed prospectively in patients with pleural effusion (40 malignant and 37 benign). The highest sensitivity was obtained with a combination of CA 15-3 in serum, and CA 15-3 and CEA in pleural fluid (80%), also with combination of CA 15-3 in serum, and CA 15-3, NSE and CEA in pleural fluid (80%). The highest specificity was obtained with combination of CA 15-3 in serum, and CA 15-3 and NSE in pleural fluid (100%), and also with combination of CA 15-3 in serum, and CA15-3, NSE and CEA in pleural fluid (100%). [Abstract/Link to Full Text]

Behrem S, Zarkovi? K, Eskinja N, Jonji? N
Distribution pattern of tenascin-C in glioblastoma: correlation with angiogenesis and tumor cell proliferation.
Pathol Oncol Res. 2005;11(4):229-35.
Tenascin-C (TN-C) is an extracellular matrix protein which participates in different processes like normal fetal development, wound healing, inflammation, keloids and rheumatoid arthritis. Furthermore, the immunostaining for TN-C is seen in the stroma of various malignant tumors as in glioblastoma multiforme (GBM), however, the significance of these findings is still not clear. In this study 62 GBM samples were analyzed immunohistochemically for distribution patterns of TN-C and correlated with angiogenesis and tumor cell proliferation. Tenascin-C in GBM localizes in two compartments, perivascular and intercellular space. Intercellular tenascin-C (TN-C ic) showed focal distribution in 66%, and diffuse one in 34% of cases. Perivascular tenascin-C (TN-C pv) showed strong correlation with microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression. Moreover, it seems that TN-C pv enhanced the effect of VEGF. Intercellular TN-C did not correlate with MVD and VEGF expression, but showed strong correlation with proliferation index. Furthermore, tumors with diffuse TN-C ic expression had higher proliferation indices than tumors with focal TN-C expression. Our results indicate that TN-C plays a role in angiogenesis and tumor cell proliferation, but beside the intensity of expression, the distribution patterns are also important in these processes. This study also suggests that perivascular and intercellular TN-C compartments have probably different sources and different roles in GBM. [Abstract/Link to Full Text]

Yilmaz Z, Sahin FI, Atalay B, Ozen O, Caner H, Bavbek M, Demirhan B, Altinörs N
Chromosome 1p36 and 22qter deletions in paraffin block sections of intracranial meningiomas.
Pathol Oncol Res. 2005;11(4):224-8.
Meningiomas are the most frequent benign tumors of the intracranial cavity. The classification and underlying pathogenetic mechanisms have been reported to be investigated by both pathological and genetic methods. In this study, we aimed to detect 1p36 and 22qter deletions by fluorescence in situ hybridization (FISH) in archival materials of 50 intracranial meningioma patients. The clinical material consisted of paraffin-embedded tissue sections from 50 patients who were surgically treated and had histopathologic diagnosis of an intracranial meningioma. We observed 1p36 deletion in 23/50 (46%) and 22qter deletion in 33/50 (66%) patients. In addition, we observed 22qter deletion in 26/36 (72.2%) patients with meningothelial meningioma. This finding implies that 22qter deletion might play an important role in the pathogenesis of meningothelial meningioma. On the other hand, no alterations were documented in the frequency of these chromosomal alterations according to the grade of meningiomas, suggesting that malignant progression of these tumors depends on other, more relevant, genetic changes. [Abstract/Link to Full Text]

Rásó E, Tóvári J, Ladányi A, Varga N, Tímár J
Ligand-mimetic anti-alphaIIb beta3 antibody PAC-1 inhibits tyrosine signaling, proliferation and lung colonization of melanoma cells.
Pathol Oncol Res. 2005;11(4):218-23.
Beta3 integrin expression is the hallmark of melanoma and may serve as a potential therapeutic target. While alphav beta3 integrin expression seems to be constitutive in melanoma, ectopic expression of platelet-alphaIIb beta3 is dependent on progression. B16a murine melanoma is a suitable model for studies on alphaIIb beta3 treatment strategies since alphav beta3 is not expressed in this cell line. Here we have used a ligand-mimetic anti-alphaIIb beta3 monoclonal antibody, PAC-1, to test the biological consequences of alphaIIb beta3 modulation in melanoma cells. We have previously reported that in B16a cells FAK is constitutively active and tyrosine-phosphorylated. Upon PAC-1 binding to the surface alphaIIb beta3, which is in the active conformation, FAK became dephosphorylated through a process of PKC-dependent phosphatase activation. Furthermore, PAC-1 binding to B16a cells induced a significant decrease in phosphotyrosine-positive melanoma cells within 30 min. Treatment of B16a cells in vitro with PAC-1 significantly inhibited proliferation by decreasing the mitotic index but not affecting apoptotic rate. Incubation of B16a cells with PAC-1 decreased their lung colonization potential, suggesting a profound alteration in their biological behavior under the effect of this antibody. These preclinical data suggest that the ectopic expression of alphaIIb beta3 in melanoma cells can be exploited as a novel target of antibody therapy of melanoma. [Abstract/Link to Full Text]

Naghibalhossaini F, Pakdel A, Ghaderi AA, Saberi Firoozi M
Effective production of carcinoembryonic antigen by conversion of the membrane-bound into a recombinant secretory protein by site-specific mutagenesis.
Pathol Oncol Res. 2005;11(4):211-7.
Carcinoembryonic antigen (CEA), the most widely used human tumor marker, is a heavily glycosylated protein over-expressed by a wide range of tumors. It has been indicated that CEA might be a useful target for human anti-tumor immunotherapy. CEA assay for research as well as clinical trials demands a continuous source of CEA protein preparations. In a multi-purpose research program to provide a reliable source for large production of CEA, we converted the membrane-bound carcinoembryonic antigen into a secretory protein by site-specific mutagenesis. We made the secretory CEA protein by introducing a new stop codon at 99 bp upstream of the original stop codon in CEA cDNA by PCR-based mutagenesis. The glycosylation of recombinant CEA proteins, especially those destined for administration to human trials is crucially important. To produce CEA with the same glycosylation pattern and immunogenicity as the native CEA expressed by human tumors in vivo, the truncated CEA cDNA which does not encode the last C-terminal 33-amino acid hydrophobic domain was transfected into HT29, a human colon carcinoma cell line by the calcium phosphate method. Stable transfectants were selected and pooled. CEA secretion from the cells was verified by analysis of the transfectant culture supernatant for CEA protein. As determined by ELISA, 16 microg/L of recombinant CEA was secreted per 106 transfectants within 48 hrs, an increase over 40 times relative to the untransfected cells. The size of the recombinant CEA secreted by HT29 transfectants in our experiment is identical to that of reference CEA secreted from tumors and is fully antigenic. It seems that the C-terminal truncation does not affect CEA glycosylation in HT29 cells. It is predicted that human cancer immunotherapy using recombinant CEA expressed in this system would be more effective than the commercial protein which is usually prepared from bacterial or other heterologous expression systems. [Abstract/Link to Full Text]

Méhes G
Chromosome abnormalities with prognostic impact in B-cell chronic lymphocytic leukemia.
Pathol Oncol Res. 2005;11(4):205-10.
The detailed analysis of the biologic features led to a rapid increase in clinically relevant information in CLL. The recognition of the prognostic role of IgVH hypermutation status and related phenotypic changes (CD38, ZAP-70 expression) as well as of chromosome abnormalities defined by cytogenetic analysis enabled a refined classification of the disease. Improvements in karyotyping and the introduction of fluorescence in situ hybridization (FISH) in routine hematological diagnostics raised the detection rate of chromosomal aberrations to approx. 60-80% in CLL. Among them, deletions of 17p and 11q have been associated with unfavorable prognosis. The deletion of the p53 locus (17p13) was described as the strongest independent predictor for aggressive behavior, resistance to chemotherapy and early death. On the contrary, an isolated deletion at 13q14 or a normal karyotype was related with a long survival. Classical and molecular cytogenetic analysis became an important tool for individual risk estimation. Unlike any other approaches, cytogenetic monitoring reflects the genetic heterogeneity and clonal growth dynamics during the course of the disease. [Abstract/Link to Full Text]

Kopper L, Tímár J
Genomics of prostate cancer: is there anything to "translate"?
Pathol Oncol Res. 2005;11(4):197-203.
This review provides an up-dated collection of data concerning the genetic and epigenetic changes during development, growth and progression of prostate cancer. Hereditary and susceptibility factors have a long list, similarly to the expression of single genes connected to various cell functions. It was a hope that covering a large set of genes, array technologies would clarify very rapidly the role of genetics in malignant diseases, offering targets for molecular diagnostics and therapy. The power of high-throughput techniques for the detection and global analysis of gene expression is unquestionable, interesting, astonishing as well as puzzling data have already been obtained. However, the standardization of the procedures is still missing and the reproducibility is rather low in many instances. Moreover, the different array methods can select different gene expression profiles, which makes the decision rather difficult. Another important question is, coming again from the array technologies, how far the genotype (the gene profiles or fingerprints) can reflect the actual phenotype in a highly complex and readily changing disease as cancer. Proteomics will provide a closer look to this seemingly unanswerable problem. We are at the beginning of the exploration of the behavior of cancer cells in order to apply a more effective therapy based on a more reliable set of diagnostic and prognostic informations. [Abstract/Link to Full Text]

Nagy Z
Zoledronic acid(ZOMETA): a significant improvement in the bone metastases.
Pathol Oncol Res. 2005;11(3):186-7. [Abstract/Link to Full Text]

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Recent Articles in Indian Journal of Cancer

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Niloofar A, Mosalaei A, Shapour O, Mohammadianpanah M
Role of external irradiation in high-risk resected colon cancer.
Indian J Cancer. 2005 Jul-Sep;42(3):133-7.
BACKGROUND / AIM: The best therapeutic modality for colon cancer "one of the most common malignancies of human being" is surgical resection of primary tumor. Adjuvant chemotherapy can help surgery to have a higher control and survival rate in high-risk resected patients, but the role of radiation therapy is the place of debate. This study was carried out to evaluate the possible role of adjuvant radiotherapy in such cases. MATERIALS AND METHODS: This retrospective trial evaluated 65 eligible patients with surgically resected high-risk colon carcinoma (serosal and/or lymph node involvement), from May 1986 to February 2000. The patients were categorized into two groups. The first group was treated with chemotherapy alone and the other with chemo-radiotherapy. Chemotherapy included 5.FU 500 mg/m2sub/5days for 6-8 courses and radiotherapy consisted 45-55 Gy with 1.5-2 Gy/fraction. Minimum follow-up was 36 months. RESULTS: Mean event-free survival was 140 and 101 months in chemotherapy and combined-therapy groups, respectively (P = 0.099). Local recurrence rate was detected as 9.7% in the chemotherapy arm and 23.5% in the combined-therapy arm (P > 0.1). Treatment-related morbidity and mortality has been significantly higher in the radiation arm (P CONCLUSION: Postoperative external radiation as adjuvant treatment does not improve local control of the patients with colon carcinoma. [Abstract/Link to Full Text]

Anant M, Guleria R, Pathak AK, Bhutani M, Pal H, Charu M, Kochupillai V
Quality of life measures in lung cancer.
Indian J Cancer. 2005 Jul-Sep;42(3):125-32.
Lung cancer is one of the leading causes of cancer death worldwide. Survival has not improved significantly in spite of newer therapies. In view of the high-symptom burden and severe morbidity, evaluation of quality of life (QOL) becomes important in these patients. Several instruments are now available for this purpose, and have demonstrated good correlation with performance status, symptoms, and survival. Quality of life assessments also help in comparing different therapeutic regimes, thus allowing selection of the appropriate modality. Problems of inconsistent interpretability and high-patient dropout rate poses a challenging problem that needs to be tackled. In spite of these drawbacks, QOL is now considered to be an essential component of lung cancer management and should be performed routinely. Such a practice will help the physician plan appropriate treatment strategies and set practical therapeutic goals. [Abstract/Link to Full Text]

Ghosh S, Advani SH
T- cell prolymphocytic leukemia - a rare case.
Indian J Cancer. 2005 Apr-Jun;42(2):104-6.
T- cell Prolymhocytic leukemia (T-PLL) is a rare mature post-thymic T-cell malignancy that is usually reported in the elderly and follows an aggressive course. A 68 year old male presented with a history of weakness and weight loss of two months duration. Clinical examination revealed pallor, enlarged cervical and axillary lymph nodes and splenomegaly. He also had a maculo- papular skin rash. There was marked leucocytosis, anemia and thrombocytopenia (WBC 445 x 103 sub/ml, Hb 8.5 gm/dl, Platelet 25 x 103 sub/microl) with 60% prolymphocytes in the peripheral blood. Bone marrow was hypercellular with an excess of prolymphocytes. Flow cytometric analysis of the bone marrow showed positivity for CD2, CD3, CD4, CD5 and CD 7. T- PLL is a rare T cell disorder with characteristic clinical and laboratory features. Currently, no optimal treatment exists although there has been some success with 2'- deoxycoformycin or Campath-1H. [Abstract/Link to Full Text]

Scott JX, Moses PD, Somashekar HR, Sathish Kumar T
Paraneoplastic papilloedema in a child with neuroblastoma.
Indian J Cancer. 2005 Apr-Jun;42(2):102-3.
Non-metastatic neurological disease complicating neuroblastoma is well recognized. Gross papilloedema in the absence of intracranial disease as initial manifestation of neuroblastoma is reported in adults. We report for the first time a case of bilateral papilloedema in a child with neuroblastoma in the absence of intracranial disease and hypertension. [Abstract/Link to Full Text]

Rekhi B, Saxena S
Gastric outlet obstruction and cutaneous metastasis in adenocarcinoid tumor of stomach - unusual presentations with cytologic and ultra structural findings.
Indian J Cancer. 2005 Apr-Jun;42(2):99-101.
Neuroendocrine tumors, including carcinoids account for less than 1% of gastric tumors. Various subtypes of gastric carcinoids have been reported earlier. The present case deals with two unusual presentations, diagnosis and course of a gastric neuroendocrine tumor in an adult patient. A 35-years-old male initially presented with gastric outlet obstruction for an antral growth in the emergency ward. He underwent radical gastrectomy and was diagnosed with a gastric carcinoid tumor, on histopathology. After 6 months, he developed hepatic along with nodular cutaneous lesions over the scalp. Aspiration cytology (FNAC) from these metastatic lesions showed two distinct cell types with rosette formation. Ultrastructural findings showed neurosecretory granules in some cells. Subsequently, he underwent 2 cycles of chemotherapy. After a total duration of 9 months, he finally succumbed to the disease. We present a case of a gastric adenocarcinoid tumor, with 2 rare presentations. The metastatic lesions exhibited neuroendocrine features on cytology and electron microscopy. [Abstract/Link to Full Text]

Sushma C, Sharang C
Pan masala advertisements are surrogate for tobacco products.
Indian J Cancer. 2005 Apr-Jun;42(2):94-8.
BACKGROUND: Pan masala is a comparatively recent habit in India and is marketed with and without tobacco. Advertisements of tobacco products have been banned in India since 1st May 2004. The advertisements of plain pan masala, which continue in Indian media, have been suspected to be surrogate for tobacco products bearing the same name. The study was carried out to assess whether these advertisements were for the intended product, or for tobacco products with same brand name. MATERIALS AND METHODS: The programme of a popular television Hindi news channel was watched for a 24-h period. Programmes on the same channel and its English counterpart were watched on different days to assess whether the advertisements were repeated. The total duration of telecast of a popular brand of plain pan masala (Pan Parag) was multiplied by the rate charged by the channel to provide the cost of advertisement of this product. The total sale value of the company was multiplied by the proportion of usage of plain pan masala out of gutka plus pan masala habit as observed from a different study, to provide the annual sale value of plain pan masala product under reference. RESULTS: The annual sale value of plain Pan Parag was estimated to be Rs. 67.1 million. The annual cost of the advertisement of the same product on two television channels was estimated at Rs. 244.6 million. CONCLUSION: The advertisements of plain pan masala seen on Indian television are a surrogate for the tobacco products bearing the same name. [Abstract/Link to Full Text]

Mehrotra R, Singh M, Gupta RK, Singh M, Kapoor AK
Trends of prevalence and pathological spectrum of head and neck cancers in North India.
Indian J Cancer. 2005 Apr-Jun;42(2):89-93.
BACKGROUND: Head and neck neoplasia constitute one of the commonest cancers in India. Use of smokeless tobacco (Pan masala, Zarda etc.) is on the increase in North India, especially in Uttar Pradesh, and is responsible for the large majority of these tumours. AIM: To assess the patients' characteristics, yearly prevalence and histopathological subtypes of the head and neck neoplasia (excluding oral cavity) in Allahabad and surrounding regions. SETTINGS AND DESIGN: A retrospective study of 11 years from 1990 to 2000 was designed. Data was collected year-wise using the tumor registry data. MATERIAL AND METHODS: All biopsies submitted for histopathology to the Pathology department were reviewed and analyzed for demographic data, site and diagnosis. STATISTICAL ANALYSIS: The Kolmogorov-Smirnov Two-Sample Test was utilized to determine whether two distributions are the same. RESULTS: A total of 40559 biopsies were examined in the department, of which, lesions of the head and neck region, excluding the oral cavity, constituted 694 biopsies (409 males and 285 females). One hundred and forty-four malignant lesions were reported, 114 being males and 30 females. A comparison of the age-specific prevalence rates of cancer during the study period showed that the prevalence was highest in patients belonging to the 50-59 years age group and squamous cell carcinoma Grade II was the most prevalent type. On an average, 58 new biopsies per annum were received. CONCLUSIONS: Properly structured site-specific data like this can augment the National Cancer Registry Programme and is an essential indicator for the magnitude and the pattern of the cancer problem in India. [Abstract/Link to Full Text]

Ozkan K, Turkkan E, Ender K, Mutlu D, Murat A, Nalan B, Abdulmecit Y, Osman M
5-Fluorouracil, epirubicin and cisplatin in the treatment of metastatic gastric carcinoma: a retrospective analysis of 68 patients.
Indian J Cancer. 2005 Apr-Jun;42(2):85-8.
BACKGROUND: Gastric cancer is one of the most common types of cancer and one of the most frequent causes of cancer-related death. The majority of gastric cancers show distant metastasis at the time of diagnosis. At present, there is no general agreement over one standard chemotherapy regimen for metastatic gastric cancer. AIMS: We evaluated the activity and toxicity of the combination of 5-Fluorouracil (5-FU), epirubicin and cisplatin (FEP) in previously untreated patients with metastatic gastric cancer. SETTING AND DESIGN: Medical Oncology Department of Uludag University Faculty of Medicine, Bursa; retrospective study. MATERIAL AND METHODS: Sixty-eight patients received 5-FU 300 mg/m2 on Days 1-5, epirubicin 50 mg/m2 on Day 1 and cisplatin 60 mg/m2 on Day 1, every 4 weeks. A median of 3.5 cycles was administered. The response rate, time to disease progression, survival and toxic effects were analyzed. STATISTICAL ANALYSIS USED: Overall survival and time to progression were estimated using Kaplan-Meier method. RESULTS: There were 4 partial responses and 1 complete response (overall response rate 7.3%); 16 patients had stable disease. Median progression-free and overall survival rates were 3.1 months (95% CI 1.9-4) and 6 months (95% CI 4.2-7), respectively. The principal toxicity was myelosupression. Grade 3-4 neutropenia occurred in 27.9%, anemia in 17.6%, and thrombocytopenia in 11.7% of patients. Non-hematological toxicity was mild and manageable. CONCLUSIONS: We concluded that FEP combination as used at the doses and schedules in this study has inferior activity against metastatic gastric cancer. [Abstract/Link to Full Text]

Biswas G, Laskar S, Banavali SD, Gujral S, Kurkure PA, Muckaden M, Parikh PM, Nair CN
Desmoplastic small round cell tumor: extra abdominal and abdominal presentations and the results of treatment.
Indian J Cancer. 2005 Apr-Jun;42(2):78-84.
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare malignant neoplasm of adolescent males. Current multimodality treatment prolongs life and rarely achieves cure. AIM: To review the presenting features, histopathology and outcome of 18 patients with DSRCT treated at a single institution. SETTING AND DESIGN: This is a retrospective observational study of patients with DSRCT who presented at the Tata Memorial Hospital between January 1994 to January 2005. MATERIALS AND METHODS: Eighteen patients of DSRCT seen during this period were evaluated for their clinical presentation, response to chemotherapy and other multimodality treatment and overall survival. The cohort of 18 patients included 11 males (61%) and 7 females (39%) with a mean age of 16 years (Range 1(1/2)--30 years). Majority (83%) presented with abdomino-pelvic disease. The others, involving chest wall and extremities. There were 6 patients (33%) with metastatic disease at presentation. RESULTS: The treatment primarily included a multimodality approach using a combination of multiagent chemotherapy with adjuvant surgery and radiotherapy as applicable. A response rate of 39% (CR-1, PR-6), with chemotherapy was observed. The overall response rate after multimodality treatment was 39% (CR-5, PR-2). The overall survival was poor except in patients who had complete excision of the tumor. Conclusion:0 Abdomino-pelvic site was the commonest presentation, the disease can occur at other non-serosal surfaces also. Despite aggressive treatment the outcome was poor. However, complete surgical excision seems to provide a better survival. [Abstract/Link to Full Text]

Datta NR, Rajkumar A, Basu R
Variations in clinical estimates of tumor volume regression parameters and time factor during external radiotherapy in cancer cervix: does it mimic the linear-quadratic model of cell survival?
Indian J Cancer. 2005 Apr-Jun;42(2):70-7.
BACKGROUND: Tumor regression parameters and time factor during external radiotherapy (EXTRT) are of paramount importance. AIMS: To quantify the parameters of tumor regression and time factor during EXTRT in cancer cervix. SETTINGS AND DESIGN: Patients, treated solely with radiotherapy and enrolled for other prospective studies having weekly tumor regressions recorded were considered. MATERIALS AND METHODS: Seventy-seven patients received 50 Gy of EXTRT followed by intracavitary brachytherapy. Loco-regional regressions were assessed clinically and regression fraction (RF) was represented as RF=c + a 1D + a 2 D2 sub - a 3T, with c, D and T as constant, cumulative EXTRT dose and treatment time respectively. STATISTICAL ANALYSIS USED: Step wise linear regression was performed for RF. Scatter plots were fitted using linear-quadratic fit. RESULTS: Coefficients of parameters D, D2 sub and T were computed for various dose intervals, namely 0--20 Gy, 0--30 Gy, 0--40 Gy and 0--50 Gy. At 0--20 Gy and 0--30 Gy, only the coefficient of D2 was significant (P 2 sub and T turned significant (P 2 sub and T showed significance, leading to an estimate of 26 Gy for a1/a2 and 0.96 Gy/day for a3/a1. CONCLUSIONS: As with alpha/beta and gamma/alpha of post-irradiation cell survival curves, a1/a2 and a3/a1 represents the cumulative effect of various radiobiological factors influencing clinical regression of tumor during the course of EXTRT. The dynamic changes in the coefficients of D, D2 sub and T, indicate their relative importance during various phases of EXTRT. [Abstract/Link to Full Text]

Shama G, Bhagwat R, Pai SK, Kurkure PA, Nair CN, Parikh PM, Mukaden MA, Banavali SD
Isolated testicular relapse in acute lymphoblastic leukemia - effective treatment with the modified CCG-112 protocol.
Indian J Cancer. 2005 Apr-Jun;42(2):65-9.
BACKGROUND: The testes have been considered a sanctuary site for leukemic cells and testicular relapses used to account for a major proportion of the poor outcome of boys with acute lymphoblastic leukemia. With use of aggressive chemotherapy which includes intermediate or high dose methotrexate, the incidence of testicular relapses has declined. However once these patients have received cranial irradiation as a part of the front line protocol, high dose methotrexate needs to be avoided because of risk of developing leucoencephalopathy. AIM: To study the use of non cross resistant chemotherapeutic agents along with a regimen containing lower doses of methotrexate in patients of isolated testicular relapse (ITR). MATERIALS AND METHODS: This is a retrospective analysis of 12 consecutive patients with ITR treated with modified version of the CCG-112 protocol which consists of intensive systemic chemotherapy, cranial chemoprophylaxis along with testicular irradiation. RESULTS: One patient died of regimen related toxicity. Two patients relapsed in the bone marrow during maintenance. Of the nine patients who completed treatment, eight are alive and in remission. One patient had a bone marrow relapse two months after completing treatment. The Kaplan Meier estimates give us an Event Free Survival (EFS) of 66.7% at 10 yrs. CONCLUSIONS: Thus, though the incidence is very low, patients with ITR should be treated aggressively since they have an excellent chance of achieving a long term EFS. [Abstract/Link to Full Text]

Basu S, Nair N
(18)FDG PET in primary oat cell carcinoma of the esophagus.
Indian J Cancer. 2005 Jan-Mar;42(1):60-2.
The role of FDG-PET in oat cell carcinoma of the esophagus is hitherto unexplored. A MEDLINE search using the terms "small cell carcinoma" or "oat cell carcinoma" combined with "FDG-PET" yielded no report on this issue till date. We report, in this article, two cases depicting the usefulness of this modality in the management of this uncommon neoplasm. While reevaluation of unsuspected metastatic sites missed by other modalities suggest its role in M staging, whole body FDG PET (both baseline as well as post treatment) may find important role in treatment monitoring and evaluation in residual viable disease, taking into account the systemic nature of the disease. [Abstract/Link to Full Text]

Khodadad K, Sadeghipour A, Aghili N
Generalized neutrophilic dermatosis: a rare presentation of myelodysplastic syndrome.
Indian J Cancer. 2005 Jan-Mar;42(1):57-9.
We present a 30-year-old man admitted with generalized cutaneous lesions, fever and cough. Examination of skin biopsies of a papular lesion revealed dense neutrophilic infiltration of the upper dermis, so these lesions were diagnosed as neutrophilic dermatosis. Peripheral blood examination and bone marrow findings confirmed the diagnosis of myelodysplastic syndrome with excess blasts. The cutaneous lesions improved after administration of corticosteroid and follow-up bone marrow examination revealed a normocellular marrow. One year later he referred with acute myelogenous leukemia (AML-M0). Unfortunately, he did not respond to treatment and died a few months later due to disease progression. [Abstract/Link to Full Text]

Badakh DK, Grover AH
The efficacy of postoperative radiation therapy in patients with carcinoma of the buccal mucosa and lower alveolus with positive surgical margins.
Indian J Cancer. 2005 Jan-Mar;42(1):51-6.
PURPOSE: A retrospective analysis to determine the efficacy of postoperative radiation therapy, in patients of carcinoma of the buccal mucosa and lower alveolus with pathologically verified positive surgical margins (PSM). MATERIALS AND METHODS: Ninety-four patients were analysed, who underwent surgery plus postoperative radiation therapy. Twenty-nine patients (31%) had PSM. Other pathological factors like nodal stage, number of nodes, bone involvement etc. were also analysed. RESULTS: Disease free survival (DFS) of patients with a PSM was significantly worse when compared with those with negative surgical margins (NSM). Poor DFS was also observed for variables like nodal stage, number of nodes and extranodal extension and radiation dose. In multivariate analysis only two variables showed significant impact on DFS, those were surgical margins and number of nodes. CONCLUSION: To conclude in our study median dose of 60 Gy in PSM patients was not able to improve DFS and showed poor results as compared with NSM patients. There is also evidence from other studies, to suggest that post-operative radiation doses upto 60 Gy may not be sufficient to overcome this poor prognostic factor. To overcome this poor prognostic group patients, we in our institution are now employing radiation dose intensification and altered fractionation in an effort to improve our results. In physically fit patients we are trying to administer concomitant chemotherapy along with radiation treatment. [Abstract/Link to Full Text]

Uppal G, Raina V, Sharma A, Anand M, Kumar R, Khaitan BK, Grover JK
Use of simple hematological, biochemical and clinical parameters to monitor response of multiple myeloma patients on high dose thalidomide therapy.
Indian J Cancer. 2005 Jan-Mar;42(1):46-50.
BACKGROUND: Evidence of increased bone marrow vascularity in multiple myeloma (MM) has led to the use of anti-angiogenic drugs especially thalidomide in relapsed or refractory patients. Currently, parameters such as serum/ urine electrophoresis for M (monoclonal) proteins, bone marrow biopsy with touch preparation and b2 microglobulin are routinely used to assess response to therapy. These investigations are expensive, invasive and require high technical setup. AIM: To correlate simple and routine hematological and biochemical parameters with the key marker of disease i.e. M proteins. SETTINGS AND DESIGN: This is an open label, uncontrolled, single-arm study. MATERIALS AND METHODS: Twenty nine refractory or relapsed multiple myeloma patients of both sexes (M=20, F=9) with age ranging between 35-72 years were initiated on 200 mg/day of thalidomide with fortnightly increments of 200 mg to a maximum tolerated dose not exceeding 800 mg/day. All hematological and biochemical parameters were monitored at monthly intervals for one year. STATISTICAL ANALYSIS: Correlation analysis was performed between hemoglobin (Hb), total leukocyte count (TLC), absolute neutrophil count (ANC), platelet count (PC), total proteins (TP), serum albumin and serum globulin on one hand and M protein levels on the other using Pearsons Correlation test by SPSS version 7.5. RESULT: Hb, TLC, ANC, PC and serum albumin levels showed a significant negative correlation with M proteins. A highly significant positive correlation existed between M proteins on one hand and TP and globulin levels on the other. Dryness of skin indicated positive response to therapy. These correlations were found to be significant at the end of one month of therapy in all the above-mentioned parameters except in TLC where it was significant after 2 months of thalidomide therapy. CONCLUSION: Results suggest that sustained efficacy of thalidomide therapy may be amenable to monitoring by these simple, inexpensive and easily available investigations after ascertaining an initial response by M protein and marrow plasmacytosis as these parameters closely follow M protein levels. However more studies are required to further substantiate these findings. [Abstract/Link to Full Text]

Raina V, Bhutani M, Bedi R, Sharma A, Deo SV, Shukla NK, Mohanti BK, Rath GK
Clinical features and prognostic factors of early breast cancer at a major cancer center in North India.
Indian J Cancer. 2005 Jan-Mar;42(1):40-5.
BACKGROUND: Data on the clinical profile of early breast cancer (EBC) from India is scant. Due to differences in genetics, environment, lifestyle, socio-demographic structure and ethnicity, the presentation and behavior of breast cancer in India may be different. AIMS: To analyze the clinical presentation and outcome of EBC patients. SETTINGS AND DESIGN: A single center retrospective study. MATERIALS AND METHODS: Data from 487 EBC patients registered and treated at our institute from 1993 through 1999 were analyzed. Cox's multivariate regression test was used to determine prognostic factors for overall and disease-free survival (OS & DFS). RESULTS: The median age was 47 years and 49.7% patients were pre-menopausal. Ninety-six per cent patients presented with a lump. Stages I, IIa, and IIb comprised 7.8%, 38.8%, and 47.6% respectively. Only 11.3% patients opted for breast-conserving surgery (BCS) while the remaining 88.7% underwent modified radical mastectomy (MRM). Adjuvant chemotherapy was administered to 275 (56.5%), and radiotherapy to 146 (29.9%). Estrogen receptor status was known in 173, of whom 93 (53.7%) were positive. Most patients were prescribed Tamoxifen for 5 years. At a median follow-up of 48 months, 126 (25.9%) patients had relapsed (systemic 107, loco-regional 19) and 94 (19.3%) had died. Five-year DFS and OS were 73% and 78%, respectively. On multivariate analysis, four positive nodes adversely influenced survival (P< 0.01). CONCLUSIONS: The median age at presentation was 47 years, significantly lower than most Western figures. The majority (86.4%) had a lump size > two cm. BCS was done in only 11% and the rest underwent MRM. Nodal involvement was the significant prognostic factor. [Abstract/Link to Full Text]

Mistry RC, Qureshi SS, Gupta S, Gupta S
Juvenile nasopharyngeal angiofibroma: a single institution study.
Indian J Cancer. 2005 Jan-Mar;42(1):35-9.
BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a rare tumor of adolescent males and there is a paucity of Indian studies on this subject. AIMS: To present the experience of management of JNA at a single institution. SETTING AND DESIGN: This is a retrospective observational study of patients with JNA who presented at the Tata Memorial Hospital between May 1988 and August 2001. MATERIALS AND METHODS: Thirty-two patients with JNA were treated in the study period. Since the time period was prolonged and diagnostic and therapeutic protocols had undergone many changes, the patients were divided into two groups, namely 1988-1996 and 1997-2001. The age distribution, disease patterns, management approaches and treatment outcomes of patients in the two groups were recorded. Statistical analyses were done using students 't' test and test for proportion. RESULTS: The mean age at presentation was 16 years and more than 90% of the patients had Stage III or IV disease. Preoperative embolization was carried out in 19 patients. The surgical approaches used were median maxillectomy, infratemporal fossa, transpalatal, maxillary swing and craniofacial approach. The recurrence rate, complete resection rate and cure rates were 12.5%, 41% and 63% respectively. CONCLUSION: Surgery is the mainstay of treatment of JNA. Preoperative embolization and newer surgical approaches result in less blood loss and complete resection. Aggressive re-resection should be done for resectable recurrences reserving radiotherapy for unresectable, recurrent/ residual disease. [Abstract/Link to Full Text]

Viswambharan JK, Kadambari D, Iyengar KR, Srinivasan K
Feasibility of breast conservation surgery in locally advanced breast cancer downstaged by neoadjuvant chemotherapy: a study in mastectomy specimens using simulation lumpectomy.
Indian J Cancer. 2005 Jan-Mar;42(1):30-4.
BACKGROUND: The response of locally advanced breast cancer (LABC) to neoadjuvant chemotherapy (NACT) offers these patients previously treated by mastectomy, the chance for breast conservation. AIM: This study aims to assess the feasibility of lumpectomy in patients with LABC treated by NACT, with residual tumor < or =5 cm. SETTINGS, DESIGN: Single group prospective study from August 2001 to June 2003 in a teaching hospital. MATERIALS AND METHODS: Thirty patients with LABC whose tumors reduced with NACT to 5 cm were included. Simulation lumpectomy was performed on the mastectomy specimens to achieve 1 to 2 cm clearance from tumor and hence margin negativity. Multiple sections of the inked margin were studied. STATISTICAL ANALYSIS: Margin positivity was correlated with patient factors. Chi square test and Fisher's exact test used as appropriate. P value 0.05 was considered significant. RESULTS AND CONCLUSIONS: After three cycles of NACT, 4 patients (13%) had complete clinical response including 2 with complete pathological response. Twenty-two (73%) showed partial response and 4, no response. Fourteen out of thirty (47%) had tumor involvement of margins. Tumors with post-chemotherapy size> 4 cm were margin positive in 10/13 (77%). Tumors with post-chemotherapy size>3 cm were margin positive in 13/24 (54%). Tumors with post-chemotherapy size 3 cm were margin negative in 5/6 (83%). Pre-chemotherapy tumor size and post-chemotherapy tumor size were significantly associated with margin positivity (P=0.003). Tumors in the subareolar location had significantly higher incidence of residual tumor in the nipple areola complex. (P=0.04). Margin positivity of lumpectomy on downstaged tumors can be reduced by removing the nipple areola complex in subareolar tumors and by limiting breast conservation to tumors with post-chemotherapy size < or =3 cm. [Abstract/Link to Full Text]

Desai SS, Sarkar S, Borges AM
A study of histopathological features of medullary carcinoma of the thyroid: cases from a single institute in India.
Indian J Cancer. 2005 Jan-Mar;42(1):25-9.
BACKGROUND: The microscopic features of medullary carcinoma have been described in world literature, together with its behavior and molecular biology. However, no large study has been reported from India. AIMS: This study aims to analyse the clinical, and especially the pathological features of medullary carcinoma of the thyroid, and the surrounding thyroid. MATERIALS AND METHODS: In this study a total of 234 cases of medullary thyroid carcinoma (MTC) were gathered over a period of 3 decades. The clinical presentation, the microscopic features and the clinical outcome were analyzed. RESULTS: MTC was found to be twice as common in men as in women and for some reason it occurred 10 years earlier in women. The histology revealed certain interesting features like the presence of apoptosis in over half of the tumors, in addition to the other common and not so common histological findings (encapsulated variant, small cell variants, follicular pattern, rosettes, oncocytic change, osteosarcoma-like pattern, and cribriform pattern). The adjacent thyroid in about 19% of the cases showed optically clear nuclei in the follicles that were close to the tumor cells. These features were similar to those seen in papillary thyroid carcinoma. CONCLUSIONS: The thyroid adjacent to MTC showed nuclear changes, which are also found in papillary carcinoma of the thyroid. The occasional concurrent occurrence of these two tumors and the involvement of the RET gene in both medullary and papillary carcinomas, makes this observation worth discussing and studying further. [Abstract/Link to Full Text]

Ray A
Cancer preventive role of selected dietary factors.
Indian J Cancer. 2005 Jan-Mar;42(1):15-24.
Dietary behavior seems to be an important modifiable determinant for the risk of cancer. The evidences from several epidemiological studies suggest that higher intakes of fruits and vegetables have been associated with lower risk of cancer. Dietary phenolic and polyphenolic substances, terpenoids, dietary fibers, fish oils, some micronutrients present in foods of both plant and animal origin, and a reduction of caloric intake appear to inhibit the process of cancer development. Many dietary factors possess antioxidant and anti-inflammatory properties and cause induction of phase II enzymes like glutathione-S-transferases. It has been suggested that cruciferous vegetables play an important role in cancer prevention, and their chemopreventive effects are due to high glucosinolate content which under enzymatic hydrolysis produces bioactive compound isothiocyanates. Further, isothiocyanates of a wide variety of cruciferous vegetables are powerful inhibitors of carcinogenesis in experimental animal models. Several flavonoids present in fruits, tea, soya beans, etc. may be useful as cancer preventive agents. Similarly, ellagic acid, perillyl alcohol and resveratrol found in various fruits may have chemoprotective effect. Moreover, different vanilloids such as curcumin and gingerol have been shown to possess antioxidative properties. Nevertheless, in spite of several studies, still the effects of various ingredients are not clearly distinguished. In human, little convincing evidence has been established for the proposed protective effects of dietary constituents. It is an important future research goal to provide necessary evidences to support the chemopreventive role of different dietary factors, and also to clarify misunderstandings in this perplexing area. [Abstract/Link to Full Text]

Venkataraman G, Ananthanaranayanan V
Tissue microarrays: potential in the Indian subcontinent.
Indian J Cancer. 2005 Jan-Mar;42(1):9-14.
Tissue microarrays (TMAs) are a means of combining hundreds of specimens of tissue on to a single slide for analysis simultaneously. The evolution of this technology to validate the results of cDNA microarrays has impacted tremendously in accurately identifying prognostic indicators significant in determining survival demographics for patients. TMAs can be generated from archival paraffin blocks, combined with sophisticated image analysis software for reading TMA immunohistochemistry, and a staggering amount of useful information can be generated in terms of the biomarkers useful in predicting patient outcome. There is a wide range of uses for the TMA technology including profiling of specific proteins in cancerous tissues and non-cancerous tissues. Given the wide variety of tissue resources available in India, investment in a dedicated TMA facility will be of immense use in the research arena in India. This review article discusses the basics of TMA construction, design, the software available for the analysis of this technology and its relevance to Indian scientists. A potential workflow structure for setting up a TMA facility is also included. [Abstract/Link to Full Text]

Qureshi SS, Chaukar DA, Pathak KA, Sanghvi VD, Sheth T, Merchant NH, Dcruz AK
Hemangioma of base of tongue.
Indian J Cancer. 2004 Oct-Dec;41(4):181-3.
Although vascular malformations of the tongue comprise a significant portion of head and neck angiodysplastic lesions, hemangioma of base of tongue is rare. We report a case of hemangioma of base of tongue extending to the supraglottis, which necessitated an extended supraglottic laryngectomy. Patient had an uneventful recovery and at three year, follow-up has a normal speech and no difficulty in swallowing or aspiration. More importantly, there was no recurrence of hemangioma or bleeding. Although hemangiomas may be treated by various conservative methods, occasionally patient may require surgical excision as in the present case due to the repeated bleeding episode and difficult access. A high index of suspicion and radiological investigations should be performed if the clinical presentation is atypical for malignancy, as in our case. [Abstract/Link to Full Text]

Srivastava A, Murari M, Datta NR
Early occurrence of acute myeloid leukemia following adjuvant radiotherapy and higher cumulative dose of cyclophosphamide in carcinoma breast.
Indian J Cancer. 2004 Oct-Dec;41(4):178-80.
We report a case of cancer breast developing acute myeloid leukemia (AML) within a relatively short interval of two and a half years of her primary treatment. This could be attributed to post operative radiotherapy and a higher cumulative dose of cyclophosphamide (14.4 gm) which had to be given as a part of her combination chemotherapy regimen, initially as adjuvant and then later as salvage chemotherapy. The successful salvage therapy for secondary AML instituted in this case is also discussed. [Abstract/Link to Full Text]

Gupta S, Punia RS, Kaushik R
Gastrointestinal stromal tumour of the colon presenting with intestinal obstruction.
Indian J Cancer. 2004 Oct-Dec;41(4):175-7.
Gastrointestinal Stromal Tumours are the commonest mesenchymal tumors of the gastrointestinal tract, the stomach and small intestine being the favored sites. They rarely occur in the colon and rectum and esophagus. The diagnosis is difficult, especially in the rarer sites, since there are no pathognomic features to suggest GIST on preoperative clinical examination and investigations, and only a detailed histopathological analysis of the specimen reveals their true nature. The case of a young female patient who presented with intestinal obstruction due a GIST of the transverse colon is reported. The relevant literature is briefly reviewed. [Abstract/Link to Full Text]

Badhe PB, Chauhan PP, Mehta NK
Brainstem gliomas--a clinicopathological study of 45 cases with p53 immunohistochemistry.
Indian J Cancer. 2004 Oct-Dec;41(4):170-4.
BACKGROUND: Brainstem tumors represent 10% of central nervous system tumors, accounting for 30% of pediatric posterior fossa tumors. AIMS: The aim of this study was to clinicopathologically correlate 45 cases of brain stem gliomas and determine the occurrence and prognostic significance of p53 expression. MATERIALS AND METHOD: 45 cases of brain stem gliomas encountered during a 19-year period. 30 were diagnosed by surgical biopsy and 15 at autopsy. In 25 cases p53 immunohistochemistry (Avidin Biotinylated technique) was performed. The WHO brain tumor classification and Stroink's CT classification were applied. STATISTICAL ANALYSIS USED: Chi square test. RESULTS AND CONCLUSIONS: 51 % of gliomas were observed in the first decade of life. The female to male ratio was 1.04: 1. The commonest presenting features were cranial nerve palsies (33%) and cerebellar signs (29.8%). 55.55% of cases were located in the pons, 31.01% in the medulla and 13.33% in the midbrain. Diffuse astrocytomas were seen in 40 cases (5% were Grade I, 47.5%Grade II, 32.5% Grade III and 15% Grade IV) and pilocytic astrocytomas in 5 cases. Grade IV patients had 2- 3 mitoses /10 high power fields and had a poorer survival rate. Grade II astrocytomas were treated with excision and radiotherapy, while grade III and IV tumors were treated with radiotherapy and chemotherapy (CCNU). Improvement was noted in 20% of patients postoperatively. The outcome was better in patients who were treated surgically. p53 is a frequently mutated gene in brain stem astrocytomas. It was found in 50 % of glioblastoma multiforme, 28.57% of grade III astrocytoma and 12.5% of grade II astrocytoma, while grade 1 astrocytomas failed to express p53 protein. p53 positivity was more in high grade lesions, decreasing significantly in lower grade lesions. [Abstract/Link to Full Text]

Thakur B, Zhang CS, Tan ZB
Omentoplasty versus no omentoplasty for esophagogastrostomy after surgery for cancer of cardia and esophagus.
Indian J Cancer. 2004 Oct-Dec;41(4):167-9.
BACKGROUND: The standard of care of patients with cancer of cardia and esophagus still remains surgery in early stage. One of the most feared complications after such procedure is anastomotic leak. AIM: We present our experience with omental wrapping of anastomosis (omentoplasty) to decrease the anastomotic leak. SETTINGS AND DESIGN: Retrospective study. MATERIALS AND METHODS: An analysis of 50 consecutive patients, who underwent surgical resection for cancer of cardia and esophagus at BPKMCH, is done. For cancer of esophagus, a 10 cm proximal tumor free margin and for lesions of cardia, at least 5 cm margin was achieved. A 5 cm distal tumor free margin was achieved in each case. A subset of patients was considered for omentoplasty after completion of anastomosis. RESULTS: There were 29 male and 21 female with a mean age of 56.3 years. The average postoperative stay was 13.14 days. The stomach was the organ of substitute in 48 and jejunum in 2 cases. Omentoplasty was done in 37 cases, whereas in 13 cases, no omental wrapping was done. The rate of anastomotic leak was 6%. There was no leak from anastomosis placed at chest, whereas three cases of leak was observed in the anastomosis at the level of neck (P=.013). Overall, there was no leak in omentoplasty group, whereas there were three cases with leak in the group without omentoplasty (P=0.003). CONCLUSION: Omentoplasty should be considered in every case after surgical resection for cancer of cardia and esophagus. [Abstract/Link to Full Text]

Sharma R, Pednekar MS, Rehman AU, Gupta R
Tobacco use among school personnel in Rajasthan, India.
Indian J Cancer. 2004 Oct-Dec;41(4):162-6.
BACKGROUND: A very little information about tobacco use among school personnel is available. This is a step to have cross country and within country data using standardized methodology. AIMS: To obtain baseline information about tobacco use prevalence, knowledge and attitude among school personnel. STUDY DESIGN: Two stage cluster sample. SETTING: A state of Rajasthan. MATERIALS AND MATERIALS AND METHODS: A cross-sectional study, using anonymous self-administered questionnaire. A sample of schools with probability proportional to the enrollment in grades 8-10. All school personnel in sampled schools were eligible to participate. STATISTICAL ANALYSIS: Percentage, 95% confidence interval. RESULTS: School response rate was 97.4% (75/77) and school personnel response rate was 67.2% (909/1352). Majority of school personnel (men 69%, women 31%) were school teachers (78.3%). The prevalence of ever any tobacco use was reported by 35.9%, more among men than women (46.2% vs. 13.0%). The prevalence of current daily smoking was reported by 14.4% (men 20.6%, women 0.8%) and occasional by 7.3%, where as current daily smokeless tobacco use was 11.7% (men 16.4%, women 1.1%) and occasional 13.6%. Current daily tobacco use was significantly more among men than women. Four out of nine reported their schools have a tobacco prohibiting policy for both students (48.4%) as well as for school personnel (44.4%) and about same (47.2%) reported their schools enforce its tobacco policy or rule. Over 85% of all school personnel strongly support the tobacco control policies and wanted training in tobacco cessation and prevention. CONCLUSION: First study from Rajasthan to report tobacco use among school personnel. School personnel not only strongly support the tobacco control policies but also ready to work for its successful implementation with proper training. [Abstract/Link to Full Text]

Eras M, Yenigun M, Acar C, Kumbasar B, Sar F, Bilge T
Pancreatic involvement in Von Hippel-Lindau disease.
Indian J Cancer. 2004 Oct-Dec;41(4):159-61.
BACKGROUND: Involvement of the pancreas in Von Hippel-Lindau disease that is a tumor predisposing syndrome mentioned in literature with some morbid and mortal progression. AIMS: For evaluation the faith of the pancreatic involvement in VHL disease we analysed our patient population with VHL disease. MATERIALS AND METHODS: 12 of the 56 patients that were evaluated in our institute with the diagnosis of Von Hippel-Lindau disease had pancreatic involvement. They are periodically examined for 5 years follow up period. Their retrospective analysis was accomplished. RESULTS AND CONCLUSIONS: Pancreatic involvement in our patient population disclosed lesions that were multicysts or serous cystadenomas. During follow up period, we did not observe significant morbidity related to pancreatic involvement. Repeated radiological examination of pancreatic lesions disclosed insignificant modifications such as slight increase or decrease in size. Whereas we considered morbidity and mortality related to renal and central nervous system pathologies in VHL disease. Shortly, even pancreatic involvement in VHL disease requires close clinical follow up, morbidity and mortality in this case is not severe as in renal and the central nervous system involvement. [Abstract/Link to Full Text]

Gokhale S, Gatalica Z, Mohammad A, Rampy AI, Velagaleti Gopalrao VN
FISH for HER-2/neu in breast cancer: standardization makes the difference!
Indian J Cancer. 2004 Oct-Dec;41(4):152-8.
CONTEXT: Overexpression of HER-2/neu oncogene in breast cancer patients is correlated with disease free survival (DFS) and overall survival (OS). The most commonly used methods for the detection of HER-2/neu status are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). However, therse is a lot of controversy with regard to the best method. Most of the FISH studies chose arbitrary cut-off levels for positive results (10%) and had no validation. AIM: In order to address these issues, we designed a pilot study of 38 samples with known IHC status representing all 4 categories. SETTINGS AND DESIGN: FISH was performed using Vysis Pathvysion probe. For validation, 5 cases of reduction mammoplasty were analyzed using same protocols. RESULTS: Our results showed significant discordance between FISH and IHC. The rate of discordance was much higher in the 0, 1+, and 2+ categories compared to published literature. This could be due to the lower cut-off rates for positive amplification established by validation in our study (5.7% vs 10%). Our analysis showed that FISH positive and IHC negative patients have a poor prognosis in terms of DFS and OS compared to FISH negative and IHC negative patients. Further, our results also showed that IHC in comparison to FISH has a comparable specificity (98%), but has a very low sensitivity (46%). CONCLUSION: Based on these results, we consider FISH to be the gold standard for detecting HER-2/neu status in breast cancer. [Abstract/Link to Full Text]

Rai A, Mohapatra SC, Shukla HS
A review of association of dietary factors in gallbladder cancer.
Indian J Cancer. 2004 Oct-Dec;41(4):147-51.
Gallbladder cancer (GBC) is the prominent malignancy of hepato-biliary tract, being the fifth most common carcinoma for gastrointestinal tract in United States. Epidemiological studies world wide have implicated dietary factors in the development of gallbladder cancer. The ecological evidences indicate considerable geographic variation in the incidence of gallbladder cancer. However the variations in GBC incidence of different populations might be partly determined by their dietary variations. Higher intake of energy and carbohydrate possibly increase the risk of gallbladder cancer. Obesity plays an important role in the causation of GBC. Adequate intake of fruits and vegetables probably reduce the risk of GBC. This nutritional preventive effect against GBC could be attributed to high content of vitamins, carotenes and fibers. They can not be too emphatically stated as the sole determinants of GBC. It is apparently clear that a variety of essential nutrients can significantly modify the carcinogenic process. Furthermore, an attempt has been made to establish an association between dietary factors and the occurrence of gallbladder cancer. [Abstract/Link to Full Text]