free full text journal articles: cancer
(skip the 90 most recent)

Advertisement

 

Google
 
Web www.neurotransmitter.net
Recent Articles in BMC Cancer

Tischkowitz M, Brunet JS, Bégin LR, Huntsman DG, Cheang MC, Akslen LA, Nielsen TO, Foulkes WD
Use of immunohistochemical markers can refine prognosis in triple negative breast cancer.
BMC Cancer. 2007;7134.
BACKGROUND: Basal-like breast cancer has been extensively characterized on the basis of gene expression profiles, but it is becoming increasingly common for these tumors to be defined on the basis of immunohistochemical (IHC) staining patterns, particularly in retrospective studies where material for expression profiling may not be available. The IHC pattern that best defines basal-like tumors is under investigation and various combinations of ER, PR, HER2-, CK5/6+ and EGFR+ have been tested. METHODS: Using datasets from two different hospitals we describe how using different combinations of immunohistochemical patterns has different effects on estimating prognosis at different time intervals after diagnosis. As our baseline, we used two IHC patterns ER-/PR-/HER2-("triple negative phenotype", TNP) and ER-/HER2-/CK5/6+ and/or EGFR+ ("core basal phenotype", CBP). RESULTS: There was no overall difference in survival between the two hospital-based series, but there was a difference between the TNP and non-TNP groups which was most marked at 3 years (76.8% vs 93.5%, p < .0001). This difference reduced with time, suggesting that long term survivors (beyond 10 years) in the TNP group may have comparable survival to non-TNP cases. A similar difference was seen if CBP was used instead of TNP. However when CK5/6 and/or EGFR expressing tumors were analyzed without consideration of ER/PR status, the reduction in survival increased with time, becoming more pronounced at 10 years than at 3 years. CONCLUSION: Our findings suggests that CK5/6 and/or EGFR expressing tumor types have a persistently poorer prognosis over the longer term, an observation that may have important therapeutic implications as drugs that target the EGFR are currently being evaluated in breast cancer. [Abstract/Link to Full Text]

Costa VL, Henrique R, Ribeiro FR, Pinto M, Oliveira J, Lobo F, Teixeira MR, Jerónimo C
Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors.
BMC Cancer. 2007;7133.
BACKGROUND: Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors. METHODS: A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP) in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC), 13 papillary (pRCC), 10 chromophobe (chRCC), and 10 oncocytomas) and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters. RESULTS: Significant differences in methylation levels among the four subtypes of renal tumors were found for CDH1 (p = 0.0007), PTGS2 (p = 0.002), and RASSF1A (p = 0.0001). CDH1 hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (p = 0.00016 and p = 0.0034, respectively), whereas PTGS2 methylation levels were significantly higher in ccRCC compared to pRCC (p = 0.004). RASSF1A methylation levels were significantly higher in pRCC than in normal tissue (p = 0.035). In pRCC, CDH1 and RASSF1A methylation levels were inversely correlated with tumor stage (p = 0.031) and nuclear grade (p = 0.022), respectively. CONCLUSION: The major subtypes of renal epithelial neoplasms display differential aberrant CDH1, PTGS2, and RASSF1A promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses. [Abstract/Link to Full Text]

Palomba G, Cossu A, Friedman E, Budroni M, Farris A, Contu A, Pisano M, Baldinu P, Sini MC, Tanda F, Palmieri G
Origin and distribution of the BRCA2-8765delAG mutation in breast cancer.
BMC Cancer. 2007;7132.
BACKGROUND: The BRCA2-8765delAG mutation was firstly described in breast cancer families from French-Canadian and Jewish-Yemenite populations; it was then reported as a founder mutation in Sardinian families. We evaluated both the prevalence of the BRCA2-8765delAG variant in Sardinia and the putative existence of a common ancestral origin through a haplotype analysis of breast cancer family members carrying such a mutation. METHODS: Eight polymorphic microsatellite markers (D13S1250, centromeric, to D13S267, telomeric) spanning the BRCA2 gene locus were used for the haplotype analysis. Screening for the 8765delAG mutation was performed by PCR-based amplification of BRCA2-exon 20, followed by automated sequencing. RESULTS: Among families with high recurrence of breast cancer (> or = 3 cases in first-degree relatives), those from North Sardinia shared the same haplotype whereas the families from French Canadian and Jewish-Yemenite populations presented distinct genetic assets at the BRCA2 locus. Screening for the BRCA2-8765delAG variant among unselected and consecutively-collected breast cancer patients originating from the entire Sardinia revealed that such a mutation is present in the northern part of the island only [9/648 (1.4%) among cases from North Sardinia versus 0/493 among cases from South Sardinia]. CONCLUSION: The BRCA2-8765delAG has an independent origin in geographically and ethnically distinct populations, acting as a founder mutation in North but not in South Sardinia. Since BRCA2-8765delAG occurs within a triplet repeat sequence of AGAGAG, our study further confirmed the existence of a mutational hot-spot at this genomic position (additional genetic factors within each single population might be involved in generating such a mutation). [Abstract/Link to Full Text]

Vinayagam R, Sibson DR, Holcombe C, Aachi V, Davies MP
Association of oestrogen receptor beta 2 (ER beta 2/ER beta cx) with outcome of adjuvant endocrine treatment for primary breast cancer--a retrospective study.
BMC Cancer. 2007;7131.
BACKGROUND: Oestrogen receptor beta (ERbeta) modulates ERalpha activity; wild type ERbeta (ERbeta1) and its splice variants may therefore impact on hormone responsiveness of breast cancer. ERbeta2/ERbetacx acts as a dominant negative inhibitor of ERalpha and expression of ERbeta2 mRNA has been proposed as a candidate marker for outcome in primary breast cancer following adjuvant endocrine therapy. We therefore now assess ERbeta2 protein by immunostaining and mRNA by quantitative RT-PCR in relation to treatment outcome. METHODS: ERbeta2-specific immunostaining was quantified in 141 primary breast cancer cases receiving adjuvant endocrine therapy, but no neoadjuvant therapy or adjuvant chemotherapy. The expression of mRNA for ERbeta2/ERbetacx was measured in 100 cases by quantitative RT-PCR. Statistical analysis of breast cancer relapse and breast cancer survival was performed using Kaplan Meier log-rank tests and Cox's univariate and multivariate survival analysis. RESULTS: High ERbeta2 immunostaining (Allred score >5) and high ERbeta2 mRNA levels were independently associated with significantly better outcome across the whole cohort, including both ERalpha positive and negative cases (Log-Rank P < 0.05). However, only ERbeta2 mRNA levels were significantly associated with better outcome in the ERalpha + subgroup (Log-Rank P = 0.01) and this was independent of grade, size, nodal status and progesterone receptor status (Cox hazard ratio 0.31 P = 0.02 for relapse; 0.17 P = 0.01 for survival). High ERbeta2 mRNA was also associated with better outcome in node negative cases (Log Rank P < 0.001).ERbeta2 protein levels were greater in ERalpha positive cases (T-test P = 0.00001), possibly explaining the association with better outcome. Levels of ERbeta2 protein did not correlate ERbeta2 mRNA levels, but 34% of cases had both high mRNA and protein and had a significantly better outcome (Log-Rank relapse P < 0.005). CONCLUSION: High ERbeta2 protein levels were associated with ERalpha expression. Although most cases with high ERbeta2 mRNA had strong ERbeta2 immunostaining, mRNA levels but not protein levels were independently predictive of outcome in tamoxifen-treated ERalpha + tumours. Post-transcriptional control needs to be considered when assessing the biological or clinical importance of ERbeta proteins. [Abstract/Link to Full Text]

Wong PS, Matsumura F
Promotion of breast cancer by beta-hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice.
BMC Cancer. 2007;7130.
BACKGROUND: Exposure to beta-Hexachlorocyclohexane (beta-HCH), a contaminant of the hexachlorohexane pesticide lindane, has been implicated as a risk factor in the development of breast cancers in epidemiological studies. Previous studies in our laboratory have demonstrated the ability of beta-HCH to elicit its actions via a ligand-independent activation of the estrogen receptor through increased c-Neu (= erbB2 or HER-2) expression and kinase activation in both the BG-1 and MCF-7 cell lines. In addition, long term exposure (33 passages) to beta-HCH was shown to promote the selection of MCF-7 cells which exhibit a more metastatic phenotype. METHODS: In this current study, we decided to investigate the long-term effects of beta-HCH in both the MCF10AT1 cell line which was derived from a normal epithelial cell line by stably transfecting a mutated c-Ha-ras and a MMTV-Neu mouse model for mammary cancer in vivo. MCF10AT1 cells were exposed for 20 passages with beta-HCH, 4-OH-Tamoxifen (Tam), or 17-beta-estradiol (E2) after which cells were analyzed for proliferation rates and mRNA expression by RT-PCR. In our in vivo studies, MMTV-Neu mice were injected with beta-HCH and observed for tumor formation over a 70 week period. RESULTS: beta-HCH and Tam selected MCF10AT1 cells demonstrated increased mRNA expression of MMP-13 (collagenase-3) a marker of increased invasiveness. beta-HCH treatment was also seen to increase the expression in a number of proto-oncogenes (c-Neu, Cyclin D1, p27), cell status markers (Met-1, CK19), and the inflammatory marker NFkappaB. Previous studies, have demonstrated the role of these markers as evidence of malignant transformations, and further illustrate the ability of beta-HCH to be carcinogenic. To demonstrate beta-HCH's tumorigenic properties in an in vivo system, we used an MMTV-Neu mouse model.MMTV-Neu is a c-Neu overexpressing strain which has been shown to spontaneously develop mammary tumors at later stages of aging. In this experiment, beta-HCH exposure was shown to both accelerate the appearance (~8 weeks for median tumor-free period) and incidence (~25% increase at the end of the test period) of tumors when compared to control mice receiving only the corn-oil vehicle. CONCLUSION: Based upon these results, it was concluded that beta-HCH does act as a breast cancer promoter which exerts its tumorigenic activity via increased c-Neu expression. [Abstract/Link to Full Text]

Defossez G, Mathoulin-Pelissier S, Ingrand I, Gasquet I, Sifer-Riviere L, Ingrand P, Salamon R, Migeot V
Satisfaction with care among patients with non-metastatic breast cancer: development and first steps of validation of the REPERES-60 questionnaire.
BMC Cancer. 2007;7129.
BACKGROUND: The care itinerary for cancer involves difficulties that occur in several different areas, whether in the diagnostic procedures, in surgery, or in adjuvant treatment. The aim of this work was to obtain a valid instrument measuring satisfaction among patients with breast cancer and exploring their care itinerary overall. METHODS: Development phase: Patient focus groups were implemented in two French regions in order to identify areas of satisfaction in relation to the different phases of care provision in breast cancer. On the basis of the literature and the themes and wordings derived from the focus groups, the patients identified several areas of satisfaction, which they found to be partially covered in an American satisfaction measure that has been validated in the French general population (the Consumer Satisfaction Survey in its French version, CSS-VF, 39 items). The patient focus groups suggested adaptation of certain dimensions of this instrument to the potential care providers (37 items) and produced 45 new items in six areas.Validation phase: Using a large sample of patients (cohort of 820 women with invasive non-metastatic breast cancer) approached one month after treatment, this phase selected items that were comprehensible (non-response rate < 10%), non-redundant (r < 0.80) and reproducible (test-retest conducted on a sub-sample of 166 patients). The dimensions were identified by factor analysis on the selected items. Divergent and discriminant validity were assessed (relationships with quality of life questionnaire, comparisons between extreme groups). RESULTS: Results were in favour of not inserting additional broken-down items into the CSS-VF and retaining 21 new items. The factor analysis found the initial structure of the CSS-VF (39 items in 9 dimensions) and the 21 new items divide up into four dimensions (listening abilities and information provided by doctors, organisation and follow-up of medical care provision, psychological support, material environment). No redundancy was observed between new items and CSS-VF items. Internal consistency was high. Divergent and discriminant validity were satisfactory. CONCLUSION: Adding four new dimensions to the CSS-VF yielded a valid 60-item instrument for assessment of care provided in breast cancer. These promising results now require further investigations of its responsiveness and its robustness in other linguistic, cultural and healthcare settings. [Abstract/Link to Full Text]

Pugh TJ, Bebb G, Barclay L, Sutcliffe M, Fee J, Salski C, O'Connor R, Ho C, Murray N, Melosky B, English J, Vielkind J, Horsman D, Laskin JJ, Marra MA
Correlations of EGFR mutations and increases in EGFR and HER2 copy number to gefitinib response in a retrospective analysis of lung cancer patients.
BMC Cancer. 2007;7128.
BACKGROUND: Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (EGFR), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, EGFR and HER2, in 39 patients treated with gefitinib at the BC Cancer Agency. METHODS: Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18-24, coding for the tyrosine kinase domain of EGFR, were amplified by PCR and sequenced. EGFR and HER2 copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test. RESULTS: Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with EGFR amplification, three with HER2 amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and EGFR mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in EGFR or HER2 copy number (p = 0.552 and 0.437, respectively). CONCLUSION: Neither mutation of EGFR nor increased copy number of EGFR or HER2 was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond EGFR status may be necessary to accurately predict treatment outcome. [Abstract/Link to Full Text]

Castellino RC, De Bortoli M, Lin LL, Skapura DG, Rajan JA, Adesina AM, Perlaky L, Irwin MS, Kim JY
Overexpressed TP73 induces apoptosis in medulloblastoma.
BMC Cancer. 2007;7127.
BACKGROUND: Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated DeltaNp73 to assess their effects on growth. METHODS: We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the DeltaNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and DeltaNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and DeltaNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. RESULTS: Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated DeltaNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or DeltaNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to chemotherapeutic agents. CONCLUSION: These results indicate that primary medulloblastomas express significant levels of TP73 isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells. [Abstract/Link to Full Text]

Huang J, Zhang YL, Teng XM, Lin Y, Zheng DL, Yang PY, Han ZG
Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma.
BMC Cancer. 2007;7126.
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. SFRP1 (the secreted frizzled-related protein 1), a putative tumor suppressor gene mapped onto chromosome 8p12-p11.1, the frequent loss of heterozygosity (LOH) region in human HCC, encodes a Wingless-type (Wnt) signaling antagonist and is frequently inactivated by promoter methylation in many human cancers. However, whether the down-regulation of SFRP1 can contribute to hepatocarcinogenesis still remains unclear. METHODS: We investigated the expression of SFRP1 through real time RT-PCR and immunohistochemistry staining. The cell growth and colony formation were observed as the overexpression and knockdown of SFRP1. The DNA methylation status within SFRP1 promoter was analyzed through methylation-specific PCR or bisulphate-treated DNA sequencing assays. Loss of heterozygosity was here detected with microsatellite markers. RESULTS: SFRP1 was significantly down-regulated in 76.1% (35/46) HCC specimens at mRNA level and in 30% (30/100) HCCs indicated by immunohistochemistry staining, as compared to adjacent non-cancerous livers. The overexpression of SFRP1 can significantly inhibit the cell growth and colony formation of YY-8103, SMMC7721, and Hep3B cells. The RNA interference against the constitutional SFRP1 in the offspring SMMC7721 cells, which were stably transfected by ectopic SFRP1, can markedly promote cell growth of these cells. LOH of both microsatellite markers D8S532 and D8SAC016868 flanking the gene locus was found in 13% (6 of 46 HCCs) and 6.5% (3 of 46 HCCs) of the informative cases, respectively, where 5 of 8 HCC specimens with LOH showed the down-regulation of SFRP1. DNA hypermethylation within SFRP1 promoter was identified in two of three HCC specimens without SFRP1 expression. Moreover, the DNA methylation of SFRP1 promoter was significantly reduced, along with the re-expression of the gene, in those HCC cell lines, Bel7404, QGY7701, and MHCC-H, as treated by DAC. CONCLUSION: Our data suggested that the down-regulation of SFRP1 as a candidate tumor suppressor gene, triggered by the epigenetic and/or genetic events, could contribute to the oncogenesis of HCC. [Abstract/Link to Full Text]

Li JY, Quan ZW, Zhang Q, Liu JW
The synergistic inhibitory effect of somatostatin-doxorubicin co-treatment on gallbladder carcinoma.
BMC Cancer. 2007;7125.
BACKGROUND: Gallbladder cancer is the most common billiary tract malignancy and carries a very poor prognosis. Somatostatin was recently shown to play an important role in the development of various tumors. In the current study, we evaluated the effect of doxorubicin on the chemosensitivity of gallbladder cancer cells and xenograft growth after treatment with somatostatin. METHODS: Twenty-four hours after somatostatin treatment, doxorubicin was gradually added and the growth curve of gallbladder cancer cells was determined. Exponential-phase gallbladder cancer cells were treated with doxorubicine or co-treated with doxorubicine and somastatine and the respective IC50 values were determined. In addition, the inhibitory effect on the growth of gallbladder cancer xenograft on nude mice was evaluated using the same treatments as those described above. RESULTS: Treatment of gallbladder cancer cells with somatostatin led to a block in the cell cycle at the S phase. Growth inhibition of gallbladder cancer cells by doxorubicin was concentration-dependent (P < 0.05). However, upon co-treatment with doxorubicin and somatostatin, the IC50 value significantly decreased as compared to that of cells treated with doxorubicine alone (P < 0.05). Interestingly, treatment with either doxorubicin or somatostatin did not significantly inhibit xenograft growth on nude mice, in contrast to a co-treatment with both drugs (P < 0.05). CONCLUSION: Somatostatin most likely sensitizes the chemotherapeutic effect and diminishes the cytotoxicity of doxorubicin in a gallbladder cancer cell line and in mouse gallbladder cancer xenografts. [Abstract/Link to Full Text]

Pinho SS, Matos AJ, Lopes C, Marcos NT, Carvalheira J, Reis CA, Gärtner F
Sialyl Lewis x expression in canine malignant mammary tumours: correlation with clinicopathological features and E-Cadherin expression.
BMC Cancer. 2007;7124.
BACKGROUND: Sialyl Lewis x (sLex) antigen is a carbohydrate antigen that is considered not only a marker for cancer but also implicated functionally in the malignant behaviour of cancer cells. Overexpression of sLex is associated with enhanced progression and metastases of many types of cancer including those of the mammary gland. Canine mammary tumours can invade and give rise to metastases via either lymphatic or blood vessels.E-Cadherin is specifically involved in epithelial cell-to-cell adhesion. In cancer, E-Cadherin underexpression is one of the alterations that characterizes the invasive phenotype and is considered an invasion/tumour suppressor gene. Partial or complete loss of E-Cadherin expression correlates with poor prognosis in canine malignant mammary cancer.The aim of this study was to analyse the sLex expression in canine malignant mammary tumours and to evaluate if the presence of sLex correlates with the expression of E-Cadherin and with clinicopathological features. METHODS: Fifty-three cases of canine mammary carcinomas were analysed immunohistochemically using monoclonal antibodies against sLex (IgM) and E-Cadherin (IgG). The clinicopathological data were then assessed to determine whether there was a correlation with sLex tumour expression. Double labelled immunofluorescence staining was performed to analyse the combined expression of sLex and E-Cadherin. RESULTS: sLex expression was consistently demonstrated in all cases of canine mammary carcinomas with different levels of expression. We found a significant relationship between the levels of sLex expression and the presence of lymph node metastases. We also demonstrated that when E-Cadherin expression was increased sLex was reduced and vice-versa. The combined analysis of both adhesion molecules revealed an inverse relationship. CONCLUSION: In the present study we demonstrate the importance of sLex in the malignant phenotype of canine malignant mammary tumours. Our results support the use of sLex as a prognostic tumour marker in canine mammary carcinomas. Furthermore, we showed that sLex and E-Cadherin expression were inversely correlated. Future studies are warranted to clarify the molecular mechanism underlying the relation between sLex and E-Cadherin in canine mammary carcinoma cells which represents an important comparative model to woman breast cancer. [Abstract/Link to Full Text]

Bethke L, Webb E, Sellick G, Rudd M, Penegar S, Withey L, Qureshi M, Houlston R
Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk.
BMC Cancer. 2007;7123.
BACKGROUND: Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. METHODS: To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. RESULTS: There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.80 and OR = 1.34, 95% CI: 1.00-1.79 respectively). CONCLUSION: This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility. [Abstract/Link to Full Text]

Yu D, Zhuang L, Sun X, Chen J, Yao Y, Meng K, Ding Y
Particular distribution and expression pattern of endoglin (CD105) in the liver of patients with hepatocellular carcinoma.
BMC Cancer. 2007;7122.
BACKGROUND: Endoglin (CD105) has been considered a prognostic marker for hepatocellular carcinoma (HCC), and widely used as an appropriate targeting for antiangenesis therapy in some cancers. Our aim was to evaluate the distribution and expression of CD105 in the liver of patients with HCC, and to discuss whether CD105 may be used as an appropriate targeting for antiangenesis therapy in HCC. METHODS: Three parts of liver tissues from each of 64 patients with HCC were collected: tumor tissues (TT), adjacent non-tumor (AT) liver tissues within 2 cm, and tumor free tissues (TF) 5 cm far from the tumor edge. Liver samples from 8 patients without liver diseases served as healthy controls (HC). The distribution and expression of CD105 in tissues were evaluated by immunohistochemistry, Western blotting analysis, and real-time PCR. HIF-1alpha and VEGF165 protein levels in tissues were analyzed by Immunohistochemistry and Western blotting analysis or ELISA. RESULTS: CD105 was positively stained mostly in a subset of microvessels 'endothelial sprouts' in TT of all patients while CD105 showed diffuse positive staining, predominantly on hepatic sinus endothelial cells in the surrounding of draining veins in TF and AT. The mean score of MVD-CD105 (mean +/- SD/0.74 mm2) was 19.00 +/- 9.08 in HC, 153.12 +/- 53.26 in TF, 191.12 +/- 59.17 in AT, and 85.43 +/- 44.71 in TT, respectively. Using a paired t test, the expression of CD105 in AT and TF was higher than in TT at protein (MVD, p = 0.012 and p = 0.007, respectively) and mRNA levels (p < 0.001 and p = 0.009, respectively). Moreover, distribution and expression of CD105 protein were consistent with those of HIF-1alpha and VEGF165 protein in liver of patients with HCC. The level of CD105 mRNA correlated with VEGF165 level in TF (r = 0.790, p = 0.002), AT (r = 0.723, p < 0.001), and TT (r = 0.473, p = 0.048), respectively. CONCLUSION: It is demonstrated that CD105 was not only present in neovessels in tumor tissues, but also more abundant in hepatic sinus endothelium in non-tumor tissues with cirrhosis. Therefore, CD105 may not be an appropriate targeting for antiangenesis therapy in HCC, especially with cirrhosis. [Abstract/Link to Full Text]

Damaraju VL, Bouffard DY, Wong CK, Clarke ML, Mackey JR, Leblond L, Cass CE, Grey M, Gourdeau H
Synergistic activity of troxacitabine (Troxatyl) and gemcitabine in pancreatic cancer.
BMC Cancer. 2007;7121.
BACKGROUND: Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials. METHODS: The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software. RESULTS: Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine. CONCLUSION: These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients. [Abstract/Link to Full Text]

Ye M, Xia B, Guo Q, Zhou F, Zhang X
Association of diminished expression of RASSF1A with promoter methylation in primary gastric cancer from patients of central China.
BMC Cancer. 2007;7120.
BACKGROUND: Although methylation-mediated inactivation of expression of RASSF1A, a candidate tumor suppressor gene, has been observed in several human cancers, the data concerning alteration of RASSF1A expression and methylation in Chinese primary gastric cancer are scarce. Moreover, direct evidence showing the association between protein expression of RASSF1A and primary human cancers is lacking. The aim of this study was to investigate RASSF1A expression in tissue of primary gastric cancer (GC) at mRNA and protein levels, and to establish the possible relationship between DNA methylation status and protein expression of RASSF1A in Chinese. METHODS: Fifty-four patients with primary gastric cancers were included in the study of RASSF1A mRNA expression and methylation status between the cancer tissue and the corresponding adjacent normal tissue. 20 out of 54 patients were included for study of RASSF1A protein expression. The expression of RASSF1A at mRNA and protein levels was determined by RT-PCR and Western-blotting, respectively. The RASSF1A promoter methylation was detected by methylation-specific PCR. RESULTS: RASSF1A mRNA and protein expressions in GC were reduced significantly with comparison to the corresponding normal tissues (OD value: 0.2589 +/- 0.2407 vs 0.5448 +/- 0.2971, P < 0.0001; 0.1874 +/- 0.0737 vs 0.6654 +/- 0.2201, P < 0.0001, respectively). Methylation frequency of RASSF1A in primary GC is higher than that in the corresponding normal tissues (66.7% vs. 14.8%, P < 0.0001). Furthermore, RASSF1A mRNA expression in methylation group of GC was further reduced when compared to the unmethylation group of GC (0.1384 +/- 0.1142 vs. 0.5018 +/- 0.2463, P < 0.0001). CONCLUSION: Expression of RASSF1A was reduced in tissue of GC at mRNA and protein levels. Diminished expression of RASSF1A was associated with the promoter methylation. [Abstract/Link to Full Text]

Jarnjak-Jankovic S, Hammerstad H, Saebře-Larssen S, Kvalheim G, Gaudernack G
A full scale comparative study of methods for generation of functional Dendritic cells for use as cancer vaccines.
BMC Cancer. 2007;7119.
BACKGROUND: Dendritic cells (DCs) are professional antigen-presenting cells with the ability to induce primary T-cell responses and are commonly produced by culturing monocytes in the presence of IL-4 and GM-CSF for 5-7 days (Standard DC). Recently, Dauer and co-workers presented a modified protocol for differentiation of human monocytes into mature DCs within 48 hours (Fast DC). Here we report a functional comparison of the two strategies for generation of DCs from human monocytes with adaptions for large-scale clinical use. METHODS: The Elutra Cell Selection System was used to isolate monocytes after collection of leukapheresis product. The enriched monocytes were cultured in gas permeable Teflon bags with IL-4 and GM-CSF for 24 hours (Fast DC) or 5 days (Standard DC) to obtain immature DCs. The cells were then transfected with mRNA from the leukemia cell line Jurkat E6 by electroporation and incubated for additional 24 h or 2 days in the presence of pro-inflammatory cytokines (TNFalpha, IL-1beta, IL-6 and PGE2) to obtain mature DCs. RESULTS: Mature Fast DC and Standard DC displayed comparable levels of many markers expressed on DC, including HLA-DR, CD83, CD86, CD208 and CCR7. However, compared to Standard DC, mature Fast DC was CD14high CD209low. Fast DC and Standard DC transfected with Jurkat E6-cell mRNA were equally able to elicit T cell specifically recognizing transfected DCs in vitro. IFNgamma-secreting T cells were observed in both the CD4+ and CD8+ subsets. CONCLUSION: Our results indicate that mature Fast DC are functional antigen presenting cells (APCs) capable of inducing primary T-cell responses, and suggest that these cells may be valuable for generation of anti-tumor vaccines. [Abstract/Link to Full Text]

Gervasini G, García-Martín E, Ladero JM, Pizarro R, Sastre J, Martínez C, García M, Diaz-Rubio M, Agúndez JA
Genetic variability in CYP3A4 and CYP3A5 in primary liver, gastric and colorectal cancer patients.
BMC Cancer. 2007;7118.
BACKGROUND: Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk. METHODS: CYP3A4 and CYP3A5 genotypes were determined in 574 individuals including 178 patients with primary liver cancer, 82 patients with gastric cancer, 151 patients with colorectal cancer, and 163 healthy individuals. RESULTS: The variant allele frequencies for patients with liver cancer, gastric cancer, colorectal cancer and healthy controls, respectively, were: CYP3A4*1B, 4.8 % (95% C.I. 2.6-7.0), 3.7 % (0.8-6.6) 4.3% (2.0-6.6) and 4.3% (2.1-6.5); CYP3A5*3, 91.8 % (93.0-97.4), 95.7% (92.6-98.8), 91.7% (88.6-94.8) and 90.8% (87.7-93.9). The association between CYP3A4*1B and CYP3A5*3 variant alleles did not significantly differ among patients and controls. No differences in genotypes, allele frequencies, or association between variant alleles were observed with regard to gender, age at diagnosis, tumour site or stage. CONCLUSION: Common polymorphisms on CYP3A4 and CYP3A5 genes do not modify the risk of developing digestive cancers in Western Europe. [Abstract/Link to Full Text]

de Kok M, Frotscher CN, van der Weijden T, Kessels AG, Dirksen CD, van de Velde CJ, Roukema JA, Bell AV, van der Ent FW, von Meyenfeldt MF
Introduction of a breast cancer care programme including ultra short hospital stay in 4 early adopter centres: framework for an implementation study.
BMC Cancer. 2007;7117.
BACKGROUND: Whereas ultra-short stay (day care or 24 hour hospitalisation) following breast cancer surgery was introduced in the US and Canada in the 1990s, it is not yet common practice in Europe. This paper describes the design of the MaDO study, which involves the implementation of ultra short stay admission for patients after breast cancer surgery, and evaluates whether the targets of the implementation strategy are reached. The ultra short stay programme and the applied implementation strategy will be evaluated from the economic perspective. METHODS/DESIGN: The MaDO study is a pre-post-controlled multi-centre study, that is performed in four hospitals in the Netherlands. It includes a pre and post measuring period of six months each with six months of implementation in between in at least 40 patients per hospital per measurement period.Primary outcome measure is the percentage of patients treated in ultra short stay. Secondary endpoints are the percentage of patients treated according to protocol, degree of involvement of home care nursing, quality of care from the patient's perspective, cost-effectiveness of the ultra short stay programme and cost-effectiveness of the implementation strategy. Quality of care will be measured by the QUOTE-breast cancer instrument, cost-effectiveness of the ultra short stay programme will be measured by means of the EuroQol (administered at four time-points) and a cost book for patients. Cost-effectiveness analysis will be performed from a societal perspective. Cost-effectiveness of the implementation strategy will be measured by determination of the costs of implementation activities. DISCUSSION: This study will reveal barriers and facilitators for implementation of the ultra short stay programme. Moreover, the results of the study will provide information about the cost-effectiveness of the ultra short stay programme and the implementation strategy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN77253391. [Abstract/Link to Full Text]

Flatmark K, Reed W, Halvorsen T, Sřrensen O, Wiig JN, Larsen SG, Fodstad Ř, Giercksky KE
Pseudomyxoma peritonei--two novel orthotopic mouse models portray the PMCA-I histopathologic subtype.
BMC Cancer. 2007;7116.
BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant in vitro and in vivo PMP models. METHODS: Human tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development. RESULTS: Xenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category. CONCLUSION: In conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment. [Abstract/Link to Full Text]

Fan C, Jin M, Chen K, Zhang Y, Zhang S, Liu B
Case-only study of interactions between metabolic enzymes and smoking in colorectal cancer.
BMC Cancer. 2007;7115.
BACKGROUND: Gene-gene and gene-environment interactions involved in the metabolism of carcinogens may increase the risk of cancer. Our objective was to measure the interactions between common polymorphisms of P450 (CYP1A2, CYP1B1, CYP2E1), GSTM1 and T1, SULT1A1 and cigarette smoking in colorectal cancer (CRC). METHODS: A case-only design was conducted in a Chinese population including 207 patients with sporadic CRC. Unconditional logistic regression analysis was performed adjusting for age, gender, alcohol consumption, and cigarette smoking. RESULTS: The interaction odds ratio (COR) for the gene-gene interaction between CYP1B1 1294G and SULT1A1 638A allele was 2.68 (95% CI: 1.16-6.26). The results of the gene-environment analyses revealed that an interaction existed between cigarette smoking and the CYP1B1 1294G allele for CRC (COR = 2.62, 95%CI: 1.01-6.72), the COR for the interaction of CYP1B1 1294G and smoking history > 35 pack-years was 3.47 (95%CI: 1.12-10.80). No other significant gene-gene and gene-environment interactions were observed. CONCLUSION: Our results showed that the interaction between polymorphisms in CYP1B1 1294G and SULT1A1*2 may play a significant role on CRC in the Chinese population. Also, it is suggested that the association between cigarette smoking and CRC could be differentiated by the CYP1B1 1294G allele. [Abstract/Link to Full Text]

Gockel I, Sultanov FS, Domeyer M, Goenner U, Junginger T
Developments in esophageal surgery for adenocarcinoma: a comparison of two decades.
BMC Cancer. 2007;7114.
BACKGROUND: The objective of this study was to examine outcomes in patients undergoing esophageal resection for adenocarcinoma at our institution during a 20-year period and, in particular, to address temporal trends in long-term survival. METHODS: Out of 470 patients who underwent esophagectomy for malignancy between September 1985 and September 2005, a total number of 175 patients presented with esophageal adenocarcinoma. Patients enrolled in this study included AEG (adenocarcinoma of the esophagogastric junction) type I tumors only. Time trends were studied comparing two decades, 9/1985 to 9/1995 (DI) and 10/1995 to 9/2005 (DII). RESULTS: The overall survival was significantly more favourable in patients undergoing esophageal resection for adenocarcinoma in the recent time period (DII, 10/1995 to 9/2005) as compared to the early time period (DI, 9/1985 to 9/1995) (log rank test: p = 0.0329). Significant differences in the recent decade were seen based on lower ASA-classifications, earlier tumor stages, and the operative procedure with a higher frequency of transhiatal resections (p < 0.05). 30-day mortality improved from 8.3% to 3.1% during the 20-year time-interval, thus without statistical significance. CONCLUSION: Based on our experience, overall survival is improving over time for adenocarcinoma of the esophagus. Factors that may play an important role in this trend include early diagnosis and improved patient selection through better preoperative staging, improved surgical technique with a tailored approach carefully evaluated by physiologic patient status, comorbidity and tumor extent. [Abstract/Link to Full Text]

Gagel B, Piroth M, Pinkawa M, Reinartz P, Zimny M, Kaiser HJ, Stanzel S, Asadpour B, Demirel C, Hamacher K, Coenen HH, Scholbach T, Maneschi P, DiMartino E, Eble MJ
pO polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the puzzle of tumor hypoxia?
BMC Cancer. 2007;7113.
BACKGROUND: The present study was conducted to analyze the value of ([18F] fluoromisonidazole (FMISO) and [18F]-2-fluoro-2'-deoxyglucose (FDG) PET as well as color pixel density (CPD) and tumor perfusion (TP) assessed by color duplex sonography (CDS) for determination of therapeutic relevant hypoxia. As a standard for measuring tissue oxygenation in human tumors, the invasive, computerized polarographic needle electrode system (pO2 histography) was used for comparing the different non invasive measurements. METHODS: Until now a total of 38 Patients with malignancies of the head and neck were examined. Tumor tissue pO2 was measured using a pO2-histograph. The needle electrode was placed CT-controlled in the tumor without general or local anesthesia. To assess the biological and clinical relevance of oxygenation measurement, the relative frequency of pO2 readings, with values < or = 2.5, < or = 5.0 and < or = 10.0 mmHg, as well as mean and median pO2 were stated. FMISO PET consisted of one static scan of the relevant region, performed 120 min after intravenous administration. FMISO tumor to muscle ratios (FMISOT/M) and tumor to blood ratios (FMISOT/B) were calculated. FDG PET of the lymph node metastases was performed 71 +/- 17 min after intravenous administration. To visualize as many vessels as possible by CDS, a contrast enhancer (Levovist, Schering Corp., Germany) was administered. Color pixel density (CPD) was defined as the ratio of colored to grey pixels in a region of interest. From CDS signals two parameters were extracted: color hue--defining velocity (v) and color area--defining perfused area (A). Signal intensity as a measure of tissue perfusion (TP) was quantified as follows: TP = vmean x Amean. RESULTS: In order to investigate the degree of linear association, we calculated the Pearson correlation coefficient. Slight (|r| > 0.4) to moderate (|r| > 0.6) correlation was found between the parameters of pO2 polarography (pO2 readings with values < or = 2.5, < or = 5.0 and < or = 10.0 mmHg, as well as median pO2), CPD and FMISOT/M. Only a slight correlation between TP and the fraction of pO2 values < or = 10.0 mmHg, median and mean pO2 could be detected. After exclusion of four outliers the absolute values of the Pearson correlation coefficients increased clearly. There was no relevant association between mean or maximum FDG uptake and the different polarographic- as well as the CDS parameters. CONCLUSION: CDS and FMISO PET represent different approaches for estimation of therapy relevant tumor hypoxia. Each of these approaches is methodologically limited, making evaluation of clinical potential in prospective studies necessary. [Abstract/Link to Full Text]

Gagel B, Piroth M, Pinkawa M, Reinartz P, Krohn T, Kaiser HJ, Stanzel S, Breuer C, Asadpour B, Schmachtenberg A, Eble MJ
Sequential (gemcitabine/vinorelbine) and concurrent (gemcitabine) radiochemotherapy with FDG-PET-based target volume definition in locally advanced non-small cell lung cancer: first results of a phase I/II study.
BMC Cancer. 2007;7112.
BACKGROUND: The aim of the study was to determine the maximal tolerated dose (MTD) of gemcitabine every two weeks concurrent to radiotherapy, administered during an aggressive program of sequential and simultaneous radiochemotherapy for locally advanced, unresectable non-small cell lung cancer (NSCLC) and to evaluate the efficacy of this regime in a phase II study. METHODS: 33 patients with histologically confirmed NSCLC were enrolled in a combined radiochemotherapy protocol. 29 patients were assessable for evaluation of toxicity and tumor response. Treatment included two cycles of induction chemotherapy with gemcitabine (1200 mg/m2) and vinorelbine (30 mg/m2) at day 1, 8 and 22, 29 followed by concurrent radiotherapy (2.0 Gy/d; total dose 66.0 Gy) and chemotherapy with gemcitabine every two weeks at day 43, 57 and 71. Radiotherapy planning included [18F] fluorodeoxyglucose positron emission tomography (FDG PET) based target volume definition. 10 patients were included in the phase I study with an initial gemcitabine dose of 300 mg/m2. The dose of gemcitabine was increased in steps of 100 mg/m2 until the MTD was realized. RESULTS: MTD was defined for the patient group receiving gemcitabine 500 mg/m2 due to grade 2 (next to grade 3) esophagitis in all patients resulting in a mean body weight loss of 5 kg (SD = 1.4 kg), representing 8% of the initial weight. These patients showed persisting dysphagia 3 to 4 weeks after completing radiotherapy. In accordance with expected complications as esophagitis, dysphagia and odynophagia, we defined the MTD at this dose level, although no dose limiting toxicity (DLT) grade 3 was reached.In the phase I/II median follow-up was 15.7 months (4.1 to 42.6 months). The overall response rate after completion of therapy was 64%. The median overall survival was 19.9 (95% CI: [10.1; 29.7]) months for all eligible patients. The median disease-free survival for all patients was 8.7 (95% CI: [2.7; 14.6]) months. CONCLUSION: After induction chemotherapy, the maximum tolerated dose and frequency of gemcitabine was defined at 500 mg/m2 every two weeks in three cycles during a maximum of 7 weeks of thoracic radiotherapy for the phase II study. This regimen represents an effective and tolerable therapy in the treatment of NSCLC. [Abstract/Link to Full Text]

Chen CL, Loy A, Cen L, Chan C, Hsieh FC, Cheng G, Wu B, Qualman SJ, Kunisada K, Yamauchi-Takihara K, Lin J
Signal transducer and activator of transcription 3 is involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells.
BMC Cancer. 2007;7111.
BACKGROUND: Stat3 has been classified as a proto-oncogene and constitutive Stat3 signaling appears to be involved in oncogenesis of human cancers. However, whether constitutive Stat3 signaling plays a role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and soft-tissue sarcomas is still unclear. METHODS: To examine whether Stat3 is activated in osteosarcomas, rhabdomyosarcomas and other soft-tissue sarcomas we analyzed sarcoma tissue microarray slides and sarcoma cell lines using immunohistochemistry and Western blot analysis, respectively, with a phospho-specific Stat3 antibody. To examine whether the activated Stat3 pathway is important for sarcoma cell growth and survival, adenovirus-mediated expression of a dominant-negative Stat3 (Y705F) and a small molecule inhibitor (termed STA-21) were used to inhibit constitutive Stat3 signaling in human sarcoma cell lines expressing elevated levels of Stat3 phosphorylation. Cell viability was determined by MTT assays and induction of apoptosis was analyzed by western blotting using antibodies that specifically recognize cleaved caspases-3, 8, and 9. RESULTS: Stat3 phosphorylation is elevated in 19% (21/113) of osteosarcoma, 27% (17/64) of rhabdomyosarcoma, and 15% (22/151) of other soft-tissue sarcoma tissues as well as in sarcoma cell lines. Expression of the dominant-negative Stat3 and treatment of STA-21 inhibited cell viability and growth and induced apoptosis through caspases 3, 8 and 9 pathways in human sarcoma cell lines expressing elevated levels of phosphorylated Stat3. CONCLUSION: This study demonstrates that Stat3 phosphorylation is elevated in human rhabdomyosarcoma, osteosarcomas and soft-tissue sarcomas. Furthermore, the activated Stat3 pathway is important for cell growth and survival of human sarcoma cells. [Abstract/Link to Full Text]

Booth CM, Dranitsaris G, Gainford MC, Berry S, Fralick M, Fralick J, Sue J, Clemons M
External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer.
BMC Cancer. 2007;7110.
BACKGROUND: Setting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer. METHODS: A comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario. RESULTS: During the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast), the median time to funding approval was 31 months (range 14-46). Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each) than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56). CONCLUSION: Priority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all) of these external factors may play in the debate over priority-setting. [Abstract/Link to Full Text]

Chiu KP, Ariyaratne P, Xu H, Tan A, Ng P, Liu ET, Ruan Y, Wei CL, Sung WK
Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes.
BMC Cancer. 2007;7109.
BACKGROUND: Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations. METHODS: GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes. RESULTS: Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg++, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-Myc and Trp53 were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in Ras and genes encoding adhesion or cytoskeleton proteins such as integrin, beta-catenin, alpha-catenin, and actin. CONCLUSION: The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis. [Abstract/Link to Full Text]

Vigneswaran N, Baucum DC, Wu J, Lou Y, Bouquot J, Muller S, Zacharias W
Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not its receptors during oral cancer progression.
BMC Cancer. 2007;7108.
BACKGROUND: TRAIL plays an important role in host immunosurveillance against tumor progression, as it induces apoptosis of tumor cells but not normal cells, and thus has great therapeutic potential for cancer treatment. TRAIL binds to two cell-death-inducing (DR4 and DR5) and two decoy (DcR1, and DcR2) receptors. Here, we compare the expression levels of TRAIL and its receptors in normal oral mucosa (NOM), oral premalignancies (OPM), and primary and metastatic oral squamous cell carcinomas (OSCC) in order to characterize the changes in their expression patterns during OSCC initiation and progression. METHODS: DNA microarray, immunoblotting and immunohistochemical analyses were used to examine the expression levels of TRAIL and its receptors in oral epithelial cell lines and in archival tissues of NOM, OPM, primary and metastatic OSCC. Apoptotic rates of tumor cells and tumor-infiltrating lymphocytes (TIL) in OSCC specimens were determined by cleaved caspase 3 immunohistochemistry. RESULTS: Normal oral epithelia constitutively expressed TRAIL, but expression was progressively lost in OPM and OSCC. Reduction in DcR2 expression levels was noted frequently in OPM and OSCC compared to respective patient-matched uninvolved oral mucosa. OSCC frequently expressed DR4, DR5 and DcR1 but less frequently DcR2. Expression levels of DR4, DR5 and DcR1 receptors were not significantly altered in OPM, primary OSCC and metastatic OSCC compared to patient-matched normal oral mucosa. Expression of proapoptotic TRAIL-receptors DR4 and DR5 in OSCC seemed to depend, at least in part, on whether or not these receptors were expressed in their parental oral epithelia. High DR5 expression in primary OSCC correlated significantly with larger tumor size. There was no significant association between TRAIL-R expression and OSSC histology grade, nodal status or apoptosis rates of tumor cells and TIL. CONCLUSION: Loss of TRAIL expression is an early event during oral carcinogenesis and may be involved in dysregulation of apoptosis and contribute to the molecular carcinogenesis of OSCC. Differential expressions of TRAIL receptors in OSCC do not appear to play a crucial role in their apoptotic rate or metastatic progression. [Abstract/Link to Full Text]

Balasubramanian SP, Cross SS, Globe J, Cox A, Brown NJ, Reed MW
Endostatin gene variation and protein levels in breast cancer susceptibility and severity.
BMC Cancer. 2007;7107.
BACKGROUND: Endostatin is a potent endogenous anti-angiogenic agent which inhibits tumour growth. A non-synonymous coding polymorphism in the Endostatin gene is thought to affect Endostatin activity. We aimed to determine the role of this Endostatin polymorphism in breast cancer pathogenesis and any influence on serum Endostatin levels in healthy volunteers. Endostatin protein expression on a breast cancer micro array was also studied to determine any relationship to genotype and to breast cancer prognosis. METHODS: The 4349G > A (coding non-synonymous) polymorphism in exon 42 of the Endostatin gene was genotyped in approximately 846 breast cancer cases and 707 appropriate controls. In a separate healthy cohort of 57 individuals, in addition to genotyping, serum Endostatin levels were measured using enzyme linked immunosorbant assay (ELISA). A semi-quantitative assessment of Endostatin protein expression on immunostained tissue micro arrays (TMA) constructed from breast cancer samples of patients with genotype data was performed. RESULTS: The rare allele (A) was significantly associated with invasive breast cancers compared to non-invasive tumours (p = 0.03), but there was no association with tumour grade, nodal status, vascular invasion or overall survival. There was no association with breast cancer susceptibility. Serum Endostatin levels and Endostatin protein expression on the tissue micro array were not associated with genotype. CONCLUSION: The Endostatin 4349A allele is associated with invasive breast cancer. The Endostatin 4349G > A polymorphism however does not appear to be associated with breast cancer susceptibility or severity in invasive disease. By studying circulating levels and tumour Endostatin protein expression, we have shown that any influence of this polymorphism is unlikely to be through an effect on the levels of protein produced. [Abstract/Link to Full Text]

Levin VA, Ictech S, Hess KR
Impact of phase II trials with progression-free survival as end-points on survival-based phase III studies in patients with anaplastic gliomas.
BMC Cancer. 2007;7106.
BACKGROUND: To assess progression-free survival (PFS) as the appropriate end-point for phase II trials for anaplastic gliomas (AGs) and to determine the impact of PFS on survival-based phase III trials. METHODS: Combined data from 16 phase II studies (N = 529 patients) were analyzed to determine progression-free survival (PFS) at 6, 9, and 12 months and the impact of age, Karnofsky performance score (KPS), number of prior chemotherapies, and response to treatment on PFS. RESULTS: The specific chemotherapy used was the major effector of PFS at 6, 9, and 12 months. Age, KPS, treatment response rate, and number of prior chemotherapies did not affect PFS to the same extent. Hierarchical cluster analyses and linear least squares fitting of PFS9 v PFS12 demonstrated the existence of three therapeutic efficacy groups with PFS rates at 6, 9, and 12 months ranging from lowest (A) to highest (C). The PFS6 was 15% in group A and 41% in group C (p < .0001); the PFS12 was 9% in group A and 33% in group C (p < .0001). Further, 80% of patients at recurrence had a 23% likelihood that each chemotherapy would provide > 1 year of additional life. CONCLUSION: Based on PFS rates at 6, 9, and 12 months for AG patients, a differential of 1.5 to 2 years is the norm and could invalidate overall survival as an end-point for phase III studies in patients with AG. PFS is a more reliable end-point because it reflects the true antitumor benefit of the chemotherapy. [Abstract/Link to Full Text]

Norgall S, Papoutsi M, Rössler J, Schweigerer L, Wilting J, Weich HA
Elevated expression of VEGFR-3 in lymphatic endothelial cells from lymphangiomas.
BMC Cancer. 2007;7105.
BACKGROUND: Lymphangiomas are neoplasias of childhood. Their etiology is unknown and a causal therapy does not exist. The recent discovery of highly specific markers for lymphatic endothelial cells (LECs) has permitted their isolation and characterization, but expression levels and stability of molecular markers on LECs from healthy and lymphangioma tissues have not been studied yet. We addressed this problem by profiling LECs from normal dermis and two children suffering from lymphangioma, and also compared them with blood endothelial cells (BECs) from umbilical vein, aorta and myometrial microvessels. METHODS: Lymphangioma tissue samples were obtained from two young patients suffering from lymphangioma in the axillary and upper arm region. Initially isolated with anti-CD31 (PECAM-1) antibodies, the cells were separated by FACS sorting and magnetic beads using anti-podoplanin and/or LYVE-1 antibodies. Characterization was performed by FACS analysis, immunofluorescence staining, ELISA and micro-array gene analysis. RESULTS: LECs from foreskin and lymphangioma had an almost identical pattern of lymphendothelial markers such as podoplanin, Prox1, reelin, cMaf and integrin-alpha1 and -alpha9. However, LYVE-1 was down-regulated and VEGFR-2 and R-3 were up-regulated in lymphangiomas. Prox1 was constantly expressed in LECs but not in any of the BECs. CONCLUSION: LECs from different sources express slightly variable molecular markers, but can always be distinguished from BECs by their Prox1 expression. High levels of VEGFR-3 and -2 seem to contribute to the etiology of lymphangiomas. [Abstract/Link to Full Text]

Recent Articles in Molecular Cancer

Komatsu K, Buchanan FG, Otaka M, Jin M, Odashima M, Horikawa Y, Watanabe S, Dubois RN
Gene expression profiling following constitutive activation of MEK1 and transformation of rat intestinal epithelial cells.
Mol Cancer. 2006;563.
BACKGROUND: Constitutive activation of MEK1 (caMEK) can induce the oncogenic transformation of normal intestinal epithelial cells. To define the genetic changes that occur during this process, we used oligonucleotide microarrays to determine which genes are regulated following the constitutive activation of MEK in normal intestinal epithelial cells. RESULTS: Microarray analysis was performed using Affymetrix GeneChip and total RNA from doxycycline inducible RIEtiCAMEK cells in the presence or absence of doxycycline. MEK-activation induced at least a three-fold difference in 115 gene transcripts (75 transcripts were up-regulated, and 40 transcripts were down-regulated). To verify whether these mRNAs are indeed regulated by the constitutive activation of MEK, RT-PCR analysis was performed using the samples from caMEK expressing RIE cells (RIEcCAMEK cells) as well as RIEtiCAMEK cells. The altered expression level of 69 gene transcripts was confirmed. Sixty-one of the differentially expressed genes have previously been implicated in cellular transformation or tumorogenesis. For the remaining 8 genes (or their human homolog), RT-PCR analysis was performed on RNA from human colon cancer cell lines and matched normal and tumor colon cancer tissues from human patients, revealing three novel targets (rat brain serine protease2, AMP deaminase 3, and cartilage link protein 1). CONCLUSION: Following MEK-activation, many tumor-associated genes were found to have significantly altered expression levels. However, we identified three genes that were differentially expressed in caMEK cells and human colorectal cancers, which have not been previously linked to cellular transformation or tumorogenesis. [Abstract/Link to Full Text]

Rask K, Zhu Y, Wang W, Hedin L, Sundfeldt K
Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression.
Mol Cancer. 2006;562.
BACKGROUND: The involvement of the cyclooxygenases (COX), in particular COX-2, is well documented for many tumours, e.g. colon, breast and prostate cancer, by both experimental and clinical studies. There are epidemiological data from subjects using NSAIDs, and experimental evidence supporting the hypothesis of prostaglandins (PGs) as regulators of tumourigenesis in the ovary. One of the end products of PG-synthesis, PGE2, regulates several key-processes, which are characteristic for tumour growth, e.g. angiogenesis, proliferation and apoptosisis. The present study investigated the pathway for PGE2-synthesis and signalling in ovarian tumourigenesis by analysing specimen from normal ovaries (n = 18), benign (B) (n = 8), borderline type (BL) (n = 6) and malignant tumours (AC) (n = 22). The expression and cell-specific localization of COX-1, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and two of the receptors for PGE2, EP1 and EP2, were examined by immunoblotting (IB) and immunohistochemistry (IHC). RESULTS: The results are in line with earlier studies demonstrating an increase of COX-2 in AC compared to the normal ovary, B and BL tumours. Increased expressions were also observed for COX-1, mPGES-1 and EP-1 which all were significantly (p < 0.05) augmented in less differentiated AC (grades: moderately-, poorly- and undifferentiated). The increase of COX-2 was also correlated to stage (FIGO classification) with significant elevations in stages II and III. EP1 was increased in stage III while no significant alterations were demonstrated for COX-1, mPGES-1 or EP2 for stage. IHC revealed staining of the tumour cells, but also increase of COX-1, COX-2, mPGES-1 and EP1-2 in the stromal compartment of AC (grades: moderately-, poorly- and undifferentiated). This observation suggests interactions between tumour cells and stromal cells (fibroblasts, immune cells), e.g. paracrine signalling mediated by growth factors, cytokines and possibly PGs. CONCLUSION: The increases of COX-1, COX-2, mPGES-1 and EP1-2 in epithelial ovarian cancer, supports the hypothesis that PGE2-synthesis and signalling are of importance for malignant transformation and progression. The observed augmentations of COX-1, COX-2 and mPGES-1 have implications for future therapeutic strategies. [Abstract/Link to Full Text]

Malik MT, Kakar SS
Regulation of angiogenesis and invasion by human Pituitary tumor transforming gene (PTTG) through increased expression and secretion of matrix metalloproteinase-2 (MMP-2).
Mol Cancer. 2006;561.
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. Existence of a relationship between PTTG levels and tumor angiogenesis and metastasis has been reported. However, the mechanisms by which PTTG achieve these functions remain unknown. In the present study, we investigated the effect of overexpression of PTTG on secretion and expression of metastasis-related metalloproteinase-2 (MMP-2) in HEK293 cells, cell migration, invasion and tubule formation. RESULTS: Transient or stable transfection of HEK293 cells with PTTG cDNA showed a significant increase in secretion and expression of MMP-2 measured by zymography, reverse transcriptase (RT/PCR), ELISA, and MMP-2 gene promoter activity. Furthermore, in our studies, we showed that tumor developed in nude mice on injection of HEK293 cells that constitutively express PTTG expressed high levels of both MMP-2 mRNA and protein, and MMP-2 activity. Conditioned medium collected from the HEK293 cells overexpressing PTTG showed a significant increase in cell migration, invasion and tubule formation of human umbilical vein endothelial cells (HUVEC). Pretreatment of conditioned medium with MMP-2-specific antibody significantly decreased these effects, suggesting that PTTG may contribute to tumor angiogenesis and metastasis via activation of proteolysis and increase in invasion through modulation of MMP-2 activity and expression. CONCLUSION: Our results provide novel information that PTTG contributes to cell migration, invasion and angiogenesis by induction of MMP-2 secretion and expression. Furthermore, we showed that tumors developed in nude mice on injection of HEK293 cells that constitutively express PTTG induce expression of MMP-2 and significantly increase its functional activity, suggesting a relationship between PTTG levels and MMP-2 which may play a critical role in regulation of tumor growth, angiogenesis and metastasis. Blocking of function of PTTG or down regulation of its expression in tumors may result in suppression of tumor growth and metastasis, through the down regulation of MMP-2 expression and activity. To our knowledge, this study is the first study demonstrating the modulation of MMP-2 expression and biological activity by PTTG. [Abstract/Link to Full Text]

Ducasse M, Brown MA
Epigenetic aberrations and cancer.
Mol Cancer. 2006;560.
The correlation between epigenetic aberrations and disease underscores the importance of epigenetic mechanisms. Here, we review recent findings regarding chromatin modifications and their relevance to cancer. [Abstract/Link to Full Text]

Costello LC, Franklin RB
Tumor cell metabolism: the marriage of molecular genetics and proteomics with cellular intermediary metabolism; proceed with caution!
Mol Cancer. 2006;559.
Metabolic transformations of malignant cells are essential to the development and progression of all cancers. The understanding of the pathogenesis and progression of cancer requires the establishment of the altered genetic/metabolic factors that are essential to the development, growth, and proliferation of the malignant cells. Recognition of this important relationship has resulted in a resurgence of interest in the intermediary metabolism of tumor cells. The role of molecular genetics and proteomics and the application of molecular technology in assessing altered cellular metabolism has become a major area of biomedical research. The contemporary generation of biomedical scientists is exceptionally well trained in all areas of molecular biology and molecular technology, which are now important tools to be applied to the regulation of cellular intermediary metabolism. Simultaneously, the didactic and methodological training associated with the principles and operation of metabolic pathways, enzymology, cellular enzyme activity, and associated biochemical implications has been diminished and often eliminated from the pre- and post-doctoral programs. Interpretations and conclusions of alterations in cellular enzyme activity and associated metabolic pathways based on genetic/proteomic changes can and will result in misrepresentation of important metabolic implications in malignancy and other diseases. It is essential that the genetic/proteomic studies be coupled to biochemical/metabolic cellular events to satisfy the axiom: "genetic transformations and proteomic alterations will have little relevancy to disease processes if the genetic/proteomic alterations are not manifested in altered and impaired cellular and metabolic function". The appropriate marriage of molecular genetics/proteomics with the regulation of cellular intermediary metabolism will provide new revelations and understanding of malignancy that could not be achieved in earlier generations. [Abstract/Link to Full Text]

Sperr EV
Libraries and the future of scholarly communication.
Mol Cancer. 2006;558.
Changes in the structure of commercial scholarly publishing have led to spiraling subscription prices. This has resulted in a "serials crisis" that has eroded library budgets and threatened the system of scientific communication. Open access represents one possible solution, and librarians are working to help make it a reality. [Abstract/Link to Full Text]

Zaretsky JZ, Barnea I, Aylon Y, Gorivodsky M, Wreschner DH, Keydar I
MUC1 gene overexpressed in breast cancer: structure and transcriptional activity of the MUC1 promoter and role of estrogen receptor alpha (ERalpha) in regulation of the MUC1 gene expression.
Mol Cancer. 2006;557.
BACKGROUND: The MUC1 gene encodes a mucin glycoprotein(s) which is basally expressed in most epithelial cells. In breast adenocarcinoma and a variety of epithelial tumors its transcription is dramatically upregulated. Of particular relevance to breast cancer, steroid hormones also stimulate the expression of the MUC1 gene. The MUC1 gene directs expression of several protein isoforms, which participate in many crucial cell processes. Although the MUC1 gene plays a critical role in cell physiology and pathology, little is known about its promoter organization and transcriptional regulation. The goal of this study was to provide insight into the structure and transcriptional activity of the MUC1 promoter. RESULTS: Using TRANSFAC and TSSG soft-ware programs the transcription factor binding sites of the MUC1 promoter were analyzed and a map of transcription cis-elements was constructed. The effect of different MUC1 promoter regions on MUC1 gene expression was monitored. Different regions of the MUC1 promoter were analyzed for their ability to control expression of specific MUC1 isoforms. Differences in the expression of human MUC1 gene transfected into mouse cells (heterologous artificial system) compared to human cells (homologous natural system) were observed. The role of estrogen on MUC1 isoform expression in human breast cancer cells, MCF-7 and T47D, was also analyzed. It was shown for the first time that synthesis of MUC1/SEC is dependent on estrogen whereas expression of MUC1/TM did not demonstrate such dependence. Moreover, the estrogen receptor alpha, ERalpha, could bind in vitro estrogen responsive cis-elements, EREs, that are present in the MUC1 promoter. The potential roles of different regions of the MUC1 promoter and ER in regulation of MUC1 gene expression are discussed. CONCLUSION: Analysis of the structure and transcriptional activity of the MUC1 promoter performed in this study helps to better understand the mechanisms controlling transcription of the MUC1 gene. The role of different regions of the MUC1 promoter in expression of the MUC1 isoforms and possible function of ERalpha in this process has been established. The data obtained in this study may help in development of molecular modalities for controlled regulation of the MUC1 gene thus contributing to progress in breast cancer gene therapy. [Abstract/Link to Full Text]

Pan J, Mestas J, Burdick MD, Phillips RJ, Thomas GV, Reckamp K, Belperio JA, Strieter RM
Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis.
Mol Cancer. 2006;556.
Renal cell carcinoma (RCC) is characterized by organ-specific metastases. The chemokine stromal derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 have been suggested to regulate organ-specific metastasis in various other cancers. On this basis, we hypothesized that the biological axis of CXCL12 via interaction with its receptor, CXCR4, is a major mechanism for RCC metastasis. We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC. We detected up-regulation of CXCR4 mRNA and protein levels on a human RCC cell line by either knockdown of the von Hippel-Lindau (VHL) tumor suppressor protein, or incubating the cells under hypoxic conditions. The enhanced CXCR4 expression was mediated through the interaction of the Hypoxia Inducible Factor-1alpha (HIF-1alpha) with the promoter region of the CXCR4 gene. Furthermore, the expression of CXCR4 on human RCC directly correlated with their metastatic ability in vivo in both heterotopic and orthotopic SCID mouse models of human RCC. Neutralization of CXCL12 in SCID mice abrogated metastasis of RCC to target organs expressing high levels of CXCL12; without altering tumor cell proliferation, apoptosis, or tumor-associated angiogenesis. Therefore, our data suggest that the CXCL12/CXCR4 biological axis plays an important role in regulating the organ-specific metastasis of RCC. [Abstract/Link to Full Text]

Ertel A, Verghese A, Byers SW, Ochs M, Tozeren A
Pathway-specific differences between tumor cell lines and normal and tumor tissue cells.
Mol Cancer. 2006;5(1):55.
BACKGROUND: Cell lines are used in experimental investigation of cancer but their capacity to represent tumor cells has yet to be quantified. The aim of the study was to identify significant alterations in pathway usage in cell lines in comparison with normal and tumor tissue. METHODS: This study utilized a pathway-specific enrichment analysis of publicly accessible microarray data and quantified the gene expression differences between cell lines, tumor, and normal tissue cells for six different tissue types. KEGG pathways that are significantly different between cell lines and tumors, cell lines and normal tissues and tumor and normal tissue were identified through enrichment tests on gene lists obtained using Significance Analysis of Microarrays (SAM). RESULTS: Cellular pathways that were significantly upregulated in cell lines compared to tumor cells and normal cells of the same tissue type included ATP synthesis, cell communication, cell cycle, oxidative phosphorylation, purine, pyrimidine and pyruvate metabolism, and proteasome. Results on metabolic pathways suggested an increase in the velocity nucleotide metabolism and RNA production. Pathways that were downregulated in cell lines compared to tumor and normal tissue included cell communication, cell adhesion molecules (CAMs), and ECM-receptor interaction. Only a fraction of the significantly altered genes in tumor-to-normal comparison had similar expressions in cancer cell lines and tumor cells. These genes were tissue-specific and were distributed sparsely among multiple pathways. CONCLUSION: Significantly altered genes in tumors compared to normal tissue were largely tissue specific. Among these genes downregulation was a major trend. In contrast, cell lines contained large sets of significantly upregulated genes that were common to multiple tissue types. Pathway upregulation in cell lines was most pronounced over metabolic pathways including cell nucleotide metabolism and oxidative phosphorylation. Signaling pathways involved in adhesion and communication of cultured cancer cells were downregulated. The three way pathways comparison presented in this study brings light into the differences in the use of cellular pathways by tumor cells and cancer cell lines. [Abstract/Link to Full Text]

Fu SL, Ganter B, Lipsick JS
Myb proteins inhibit fibroblast transformation by v-Rel.
Mol Cancer. 2006;554.
Genes that cause cancer have been divided into two general classes--oncogenes that act in a dominant fashion to transform normal cells into a malignant state, and tumor suppressor genes that act in a dominant fashion to prevent such transformation. In this report, we demonstrate that both the v-myb retroviral oncogene, which causes leukemic transformation of hematopoietic cells, and the c-myb proto-oncogene can also function as inhibitors of fibroblast transformation by the v-rel oncogene. These results imply that the myb genes can function either as oncogenes or as tumor suppressors in different cellular contexts. [Abstract/Link to Full Text]

Taylor AC, Schuster K, McKenzie PP, Harris LC
Differential cooperation of oncogenes with p53 and Bax to induce apoptosis in rhabdomyosarcoma.
Mol Cancer. 2006;553.
BACKGROUND: Deregulated expression of oncogenes such as MYC and PAX3-FKHR often occurs in rhabdomyosarcomas. MYC can enhance cell proliferation and apoptosis under specific conditions, whereas PAX3-FKHR has only been described as anti-apoptotic. RESULTS: In order to evaluate how MYC and PAX3-FKHR oncogenes influenced p53-mediated apoptosis, rhabdomyosarcoma cells were developed to independently express MYC and PAX3-FKHR cDNAs. Exogenous wild-type p53 expression in MYC transfected cells resulted in apoptosis, whereas there was only a slight effect in those transfected with PAX3-FKHR. Both oncoproteins induced BAX, but BAX induction alone without expression of wild-type p53 was insufficient to induce apoptosis. Data generated from genetically modified MEFs suggested that expression of all three proteins; MYC, BAX and p53, was required for maximal cell death to occur. CONCLUSION: We conclude that cooperation between p53 and oncoproteins to induce apoptosis is dependent upon the specific oncoprotein expressed and that oncogene-mediated induction of BAX is necessary but insufficient to enhance p53-mediated apoptosis. These data demonstrate a novel relationship between MYC and p53-dependent apoptosis, independent of the ability of MYC to induce p53 that may be important in transformed cells other than rhabdomyosarcoma. [Abstract/Link to Full Text]

Ghiselli G
SMC3 knockdown triggers genomic instability and p53-dependent apoptosis in human and zebrafish cells.
Mol Cancer. 2006;552.
BACKGROUND: The structural maintenance of chromosome 3 (SMC3) protein is a constituent of a number of nuclear multimeric protein complexes that are involved in DNA recombination and repair in addition to chromosomal segregation. Overexpression of SMC3 activates a tumorigenic cascade through which mammalian cells acquire a transformed phenotype. This has led us to examine in depth how SMC3 level affects cell growth and genomic stability. In this paper the effect of SMC3 knockdown has been investigated. RESULTS: Mammalian cells that are SMC3 deficient fail to expand in a clonal population. In order to shed light on the underlying mechanism, experiments were conducted in zebrafish embryos in which cell competence to undergo apoptosis is acquired at specific stages of development and affects tissue morphogenesis. Zebrafish Smc3 is 95% identical to the human protein, is maternally contributed, and is expressed ubiquitously at all developmental stages. Antisense-mediated loss of Smc3 function leads to increased apoptosis in Smc3 expressing cells of the developing tail and notocord causing morphological malformations. The apoptosis and the ensuing phenotype can be suppressed by injection of a p53-specific MO that blocks the generation of endogenous p53 protein. Results in human cells constitutively lacking p53 or BAX, confirmed that a p53-dependent pathway mediates apoptosis in SMC3-deficient cells. A population of aneuploid cells accumulated in zebrafish embryos following Smc3-knockdown whereas in human cells the transient downregulation of SMC3 level lead to the generation of cells with amplified centrosome number. CONCLUSION: Smc3 is required for normal embryonic development. Its deficiency affects the morphogenesis of tissues with high mitotic index by triggering an apoptotic cascade involving p53 and the downstream p53 target gene bax. Cells with low SMC3 level display centrosome abnormalities that can lead to or are the consequence of dysfunctional mitosis and/or aneuploidy. Collectively the data support the view that SMC3 deficiency affects chromosomal stability leading to the activation of p53-dependent mitotic checkpoint. [Abstract/Link to Full Text]

Morgan R, Fairfax B, Pandha HS
Calcium insensitivity of FA-6, a cell line derived from a pancreatic cancer associated with humoral hypercalcemia, is mediated by the significantly reduced expression of the Calcium Sensitive Receptor transduction component p38 MAPK.
Mol Cancer. 2006;551.
The Calcium-Sensing Receptor is a key component of Calcium/Parathyroid hormone homeostatic system that helps maintain appropriate plasma Ca2+ concentrations. It also has a number of non-homeostatic functions, including cell cycle regulation through the p38 MAPK pathway, and recent studies have indicated that it is required for Ca2+ mediated growth arrest in pancreatic carcinoma cells. Some pancreatic cancers produce pathogenic amounts of parathyroid like hormones, however, which significantly increase Ca2+ plasma concentrations and might be expected to block further cell growth. In this study we have investigated the expression and function of the p38 MAPK signaling pathway in Ca2+ sensitive (T3M-4) and insensitive (FA6) pancreatic cancer cell lines. FA-6 cells, which are derived from a pancreatic adenocarcinoma that secretes a parathyroid hormone related peptide, exhibit only very low levels of p38 MAPK expression, relative to T3M-4 cells. Transfecting FA-6 cells with a p38 MAPK expression construct greatly increases their sensitivity to Ca2+. Furthermore, the reduction of p38 MAPK in T3M-4 cells significantly reduces the extent to which high levels of Ca2+ inhibit proliferation. These results suggest that the low levels of p38 MAPK expression in FA-6 cells may serve to reduce their sensitivity to high concentrations of external Ca2+ that would otherwise block proliferation. [Abstract/Link to Full Text]

Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I, Patankar MS
Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors.
Mol Cancer. 2006;5(1):50.
BACKGROUND: The mucin MUC16 and the glycosylphosphatidylinositol anchored glycoprotein mesothelin likely facilitate the peritoneal metastasis of ovarian tumors. The biochemical basis and the kinetics of the binding between these two glycoproteins are not clearly understood. Here we have addressed this deficit and provide further evidence supporting the role of the MUC16-mesothelin interaction in facilitating cell-cell binding under conditions that mimic the peritoneal environment. RESULTS: In this study we utilize recombinant-Fc tagged human mesothelin to measure the binding kinetics of this glycoprotein to MUC16 expressed on the ovarian tumor cell line OVCAR-3. OVCAR-3 derived sublines that did not express MUC16 showed no affinity for mesothelin. In a flow cytometry-based assay mesothelin binds with very high affinity to the MUC16 on the OVCAR-3 cells with an apparent Kd of 5-10 nM. Maximum interaction occurs within 5 mins of incubation of the recombinant mesothelin with the OVCAR-3 cells and significant binding is observed even after 10 sec. A five-fold molar excess of soluble MUC16 was unable to completely inhibit the binding of mesothelin to the OVCAR-3 cells. Oxidation of the MUC16 glycans, removal of its N-linked oligosaccharides, and treatment of the mucin with wheat germ agglutinin and erythroagglutinating phytohemagglutinin abrogates its binding to mesothelin. These observations suggest that at least a subset of the MUC16-asscociated N-glycans is required for binding to mesothelin. We also demonstrate that MUC16 positive ovarian tumor cells exhibit increased adherence to A431 cells transfected with mesothelin (A431-Meso+). Only minimal adhesion is observed between MUC16 knockdown cells and A431-Meso+ cells. The binding between the MUC16 expressing ovarian tumor cells and the A431-Meso+ cells occurs even in the presence of ascites from patients with ovarian cancer. CONCLUSION: The strong binding kinetics of the mesothelin-MUC16 interaction and the cell adhesion between ovarian tumor cells and A431-Meso+ even in the presence of peritoneal fluid strongly support the importance of these two glycoproteins in the peritoneal metastasis of ovarian tumors. The demonstration that N-linked glycans are essential for mediating mesothlein-MUC16 binding may lead to novel therapeutic targets to control the spread of ovarian carcinoma. [Abstract/Link to Full Text]

Cools N, Ponsaerts P, Lenjou M, Nijs G, Van Bockstaele DR, Van Tendeloo VF, Berneman ZN
Sensitive detection of human papillomavirus type 16 E7-specific T cells by ELISPOT after multiple in vitro stimulations of CD8+ T cells with peptide-pulsed autologous dendritic cells.
Mol Cancer. 2006;549.
BACKGROUND: Cervical cancer is the second most common gynecological cancer amongst women world-wide. Despite optimized protocols, standard treatments still face several disadvantages. Therefore, research aims at the development of immune-based strategies using tumor antigen-loaded dendritic cells for the induction of cellular anti-tumor immunity. RESULTS: In this study, we used dendritic cells loaded with the HLA-A2-restricted HPV type 16 E711-20 peptide in order to induce an in vitro CD8+ T cell response. For this purpose, peptide-pulsed dendritic cells were co-cultured with autologous CD8+ T cells. After 5 weekly stimulations with peptide-pulsed mature dendritic cells, cultured T cells were analyzed for antigen specificity by an IFN-gamma ELISPOT assay. Using this ELISPOT assay, we were able to detect E7-specific IFN-gamma-secreting CD8+ T cells in 5/5 healthy donors. CONCLUSION: We show that peptide-pulsed mature dendritic cells are able to stimulate a HPV type 16 E7 peptide-specific immune response in vitro. These experiments describe an efficient culture protocol for antigen-specific T cells for use in pre-clinical vaccination research and confirm the need for sensitive T cell assays for detection of tumor-specific immune responses in vitro. [Abstract/Link to Full Text]

De Gottardi A, Dumonceau JM, Bruttin F, Vonlaufen A, Morard I, Spahr L, Rubbia-Brandt L, Frossard JL, Dinjens WN, Rabinovitch PS, Hadengue A
Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro.
Mol Cancer. 2006;548.
BACKGROUND: Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function. RESULTS: the expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group) and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity.The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity. CONCLUSION: the bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis. [Abstract/Link to Full Text]

Baumbusch LO, Myhre S, Langerřd A, Bergamaschi A, Geisler SB, Lřnning PE, Deppert W, Dornreiter I, Břrresen-Dale AL
Expression of full-length p53 and its isoform Deltap53 in breast carcinomas in relation to mutation status and clinical parameters.
Mol Cancer. 2006;547.
BACKGROUND: The tumor suppressor gene p53 (TP53) controls numerous signaling pathways and is frequently mutated in human cancers. Novel p53 isoforms suggest alternative splicing as a regulatory feature of p53 activity. RESULTS: In this study we have analyzed mRNA expression of both wild-type and mutated p53 and its respective Deltap53 isoform in 88 tumor samples from breast cancer in relation to clinical parameters and molecular subgroups. Three-dimensional structure differences for the novel internally deleted p53 isoform Deltap53 have been predicted. We confirmed the expression of Deltap53 mRNA in tumors using quantitative real-time PCR technique. The mRNA expression levels of the two isoforms were strongly correlated in both wild-type and p53-mutated tumors, with the level of the Deltap53 isoform being approximately 1/3 of that of the full-length p53 mRNA. Patients expressing mutated full-length p53 and non-mutated (wild-type) Deltap53, "mutational hybrids", showed a slightly higher frequency of patients with distant metastasis at time of diagnosis compared to other patients with p53 mutations, but otherwise did not differ significantly in any other clinical parameter. Interestingly, the p53 wild-type tumors showed a wide range of mRNA expression of both p53 isoforms. Tumors with mRNA expression levels in the upper or lower quartile were significantly associated with grade and molecular subtypes. In tumors with missense or in frame mutations the mRNA expression levels of both isoforms were significantly elevated, and in tumors with nonsense, frame shift or splice mutations the mRNA levels were significantly reduced compared to those expressing wild-type p53. CONCLUSION: Expression of p53 is accompanied by the functionally different isoform Deltap53 at the mRNA level in cell lines and human breast tumors. Investigations of "mutational hybrid" patients highlighted that wild-type Deltap53 does not compensates for mutated p53, but rather may be associated with a worse prognosis. In tumors, both isoforms show strong correlations in different mutation-dependent mRNA expression patterns. [Abstract/Link to Full Text]

Yasuda A, Sawai H, Takahashi H, Ochi N, Matsuo Y, Funahashi H, Sato M, Okada Y, Takeyama H, Manabe T
The stem cell factor/c-kit receptor pathway enhances proliferation and invasion of pancreatic cancer cells.
Mol Cancer. 2006;546.
BACKGROUND: The transmembrane protein c-kit is a receptor tyrosine kinase (KIT) and KIT is expressed in solid tumors and hematological malignancies such as gastrointestinal stromal tumor (GIST), small-cell lung cancer and chronic myelogenous leukemia (CML). KIT plays a critical role in cell proliferation and differentiation and represents a logical therapeutic target in GIST and CML. In pancreatic cancer, c-kit expression has been observed by immunohistochemical techniques. In this study, we examined the influence of c-kit expression on proliferation and invasion using five pancreatic cancer cell lines. In addition, the inhibitory effect of imatinib mesylate on stem cell factor (SCF)-induced proliferation and invasion was evaluated. Finally, we also analyzed KIT and SCF expression in pancreatic cancer tissues using immunohistochemistry and correlated the results with clinical features. RESULTS: RT-PCR revealed that two pancreatic cancer cell lines, PANC-1 and SW1990, expressed c-kit mRNA. By Western blot analysis, c-kit protein was also present in those lines. In KIT-positive pancreatic cancer cell lines, proliferation and invasion were significantly enhanced by addition of SCF. In contrast, SCF did not enhance proliferation and invasion in the three KIT-negative lines (BxPC-3, Capan-2 and MIA PaCa-2). 5 muM imatinib mesylate significantly inhibited SCF-enhanced proliferation to the same extent compared with the control. Similarly, SCF-enhanced invasive ability was significantly inhibited by 5 muM imatinib mesylate. KIT was expressed in 16 of 42 clinical specimens by immunohistochemistry, and KIT expression was significantly related to venous system invasion. Furthermore, patients expressing both KIT and SCF had a somewhat lower survival. CONCLUSION: Our results demonstrated that the SCF-KIT pathway enhanced the proliferation and invasiveness in KIT-positive pancreatic cancer cell lines and that the enhanced proliferation and invasion were inhibited by imatinib mesylate. We propose that inhibitors of c-kit tyrosine kinase receptor have the potential to slow the progression of KIT-positive pancreatic cancers. [Abstract/Link to Full Text]

Sexton E, Van Themsche C, LeBlanc K, Parent S, Lemoine P, Asselin E
Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells.
Mol Cancer. 2006;545.
BACKGROUND: Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. At the molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Six different human uterine cancer cell lines were used as a model (HeLa, Hec-1A, KLE, RL95-2, Ishikawa and EN-1078D). RESULTS AND DISCUSSION: High-dose of resveratrol triggered apoptosis in five out of six uterine cancer cell lines, as judged from Hoechst nuclear staining and effector caspase cleavage. In accordance, uterine cancer cell proliferation was decreased. Resveratrol also reduced cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT. Endogenous COX-2 protein levels were decreased, concomitant with a decrease in production of COX metabolites PGE2 and PGF2alpha, in each uterine cancer cell line expressing detectable levels of COX-1 and/or COX-2 in presence of resveratrol. Although COX expression was identified as a target of resveratrol in uterine cancer cells, inhibition of COX activity or exogenously added PGE2 did not modulate the effect of resveratrol on cellular proliferation. CONCLUSION: High-dose of resveratrol exerts tumoricidal activity over uterine cancer cells and regulates COX expression. In these cells, resveratrol would not directly target COX activity, but possibly other enzymes involved in prostaglandin synthesis that act downstream of the COXs. [Abstract/Link to Full Text]

Hayslip J, Montero A
Tumor suppressor gene methylation in follicular lymphoma: a comprehensive review.
Mol Cancer. 2006;544.
Transcriptional silencing of tumor suppressor genes, associated with DNA methylation, is a common epigenetic event in hematologic malignancies. Although DNA hypermethylation of CpG islands is well described in acute leukemias and myelodysplastic syndromes, much less is known of the specific methylation changes that commonly occur in follicular B cell lymphomas. Earlier methylation studies of follicular lymphoma involved only cell lines; however there is a growing literature of methylation changes in primary human FL samples. Published studies of primary follicular lymphoma specimens have demonstrated that: androgen receptor, SHP1, and death-associated protein kinase genes are commonly methylated. By contrast, the cyclin dependent kinase inhibitors p15, p16, and p57 are uncommon epigenetic events in follicular lymphoma. Methylation of cyclin dependent kinase inhibitors is more common in high grade lymphomas, and may be an important step in the progression and transformation of follicular lymphoma. Further methylation studies in follicular lymphoma should investigate the prognostic and therapeutic significance of these epigenetic changes and investigate methylation of other genes. Finally, reactivation of methylated tumor suppressor genes through the use of hypomethylating agents is a promising and novel approach to the treatment of indolent and transformed follicular lymphomas. [Abstract/Link to Full Text]

Sun XF, Zhang H
Clinicopathological significance of stromal variables: angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas.
Mol Cancer. 2006;543.
Cancer research has mainly focused on alterations of genes and proteins in cancer cells themselves that result in either gain-of-function in oncogenes or loss-of-function in tumour-suppressor genes. However, stromal variables within or around tumours, including blood and lymph vessels, stromal cells and various proteins, have also important impacts on tumour development and progression. It has been shown that disruption of stromal-epithelial interactions influences cellular proliferation, differentiation, death, motility, genomic integrity, angiogenesis, and other phenotypes in various tissues. Moreover, stromal variables are also critical to therapy in cancer patients. In this review, we mainly focus on the clinicopathological significance of stromal variables including angiogenesis, lymphangiogenesis, inflammatory infiltration, matrix metalloproteinase (MMP), and the particularly interesting new cysteine-histidine rich protein (PINCH) in colorectal cancer (CRC). [Abstract/Link to Full Text]

Mello de Queiroz F, Suarez-Kurtz G, Stühmer W, Pardo LA
Ether ŕ go-go potassium channel expression in soft tissue sarcoma patients.
Mol Cancer. 2006;542.
BACKGROUND: The expression of the human Eag1 potassium channel (Kv10.1) is normally restricted to the adult brain, but it has been detected in both tumour cell lines and primary tumours. Our purpose was to determine the frequency of expression of Eag1 in soft tissue sarcoma and its potential clinical implications. RESULTS: We used specific monoclonal antibodies to determine the expression levels of Eag1 in soft tissue sarcomas from 210 patients by immunohistochemistry. Eag1 was expressed in 71% of all tumours, with frequencies ranging from 56% (liposarcoma) to 82% (rhabdomyosarcoma). We detected differences in expression levels depending on the histological type, but no association was seen between expression of this protein and sex, age, grade or tumour size. Four cell lines derived from relevant sarcoma histological types (fibrosarcoma and rhabdomyosarcoma) were tested for Eag1 expression by real-time RT-PCR. We found all four lines to be positive for Eag1. In these cell lines, blockage of Eag1 by RNA interference led to a decrease in proliferation. CONCLUSION: Eag1 is aberrantly expressed in over 70% sarcomas. In sarcoma cell lines, inhibition of Eag1 expression and/or function leads to reduced proliferation. The high frequency of expression of Eag1 in primary tumours and the restriction of normal expression of the channel to the brain, suggests the application of this protein for diagnostic or therapeutic purposes. [Abstract/Link to Full Text]

Hemmerlein B, Weseloh RM, Mello de Queiroz F, Knötgen H, Sánchez A, Rubio ME, Martin S, Schliephacke T, Jenke M, Heinz-Joachim-Radzun W, Pardo LA
Overexpression of Eag1 potassium channels in clinical tumours.
Mol Cancer. 2006;541.
BACKGROUND: Certain types of potassium channels (known as Eag1, KCNH1, Kv10.1) are associated with the production of tumours in patients and in animals. We have now studied the expression pattern of the Eag1 channel in a large range of normal and tumour tissues from different collections utilising molecular biological and immunohistochemical techniques. RESULTS: The use of reverse transcription real-time PCR and specifically generated monoclonal anti-Eag1 antibodies showed that expression of the channel is normally limited to specific areas of the brain and to restricted cell populations throughout the body. Tumour samples, however, showed a significant overexpression of the channel with high frequency (up to 80% depending on the tissue source) regardless of the detection method (staining with either one of the antibodies, or detection of Eag1 RNA). CONCLUSION: Inhibition of Eag1 expression in tumour cell lines reduced cell proliferation. Eag1 may therefore represent a promising target for the tailored treatment of human tumours. Furthermore, as normal cells expressing Eag1 are either protected by the blood-brain barrier or represent the terminal stage of normal differentiation, Eag1 based therapies could produce only minor side effects. [Abstract/Link to Full Text]

Alao JP, Stavropoulou AV, Lam EW, Coombes RC
Role of glycogen synthase kinase 3 beta (GSK3beta) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells.
Mol Cancer. 2006;540.
Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death in vitro and in vivo. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Recently, HDACIs were shown to induce Akt dephosphorylation by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This disruption results in the increased association of PP1 with Akt, resulting in the dephosphorylation and consequent inactivation of the kinase. Akt enhances cellular survival through the phosphorylation-dependent inhibition of several pro-apoptotic proteins. Akt is an important negative regulator of GSK3beta, a kinase that has been shown to regulate apoptosis in response to various stimuli. In the present study, we investigated the role of GSK3beta in mediating the cytotoxic effects in MCF-7 breast cancer cells treated with trichostatin A (TSA), a prototype HDACI. We show that TSA induces Akt dephosphorylation in a PP1-dependent manner, resulting in activation of GSK3beta in MCF-7 cells. Similarly, knockdown of HDAC1 and-2 by small interfering RNA (siRNA) resulted in the dephosphorylation of Akt and GSK3beta. Selective inhibition of GSK3beta attenuated TSA induced cytotoxicity and resulted in enhanced proliferation following drug removal. Our findings identify GSK3beta as an important mediator of TSA-induced cytotoxicity in MCF-7 breast cancer cells. [Abstract/Link to Full Text]

Ruano Y, Mollejo M, Ribalta T, Fiańo C, Camacho FI, Gómez E, de Lope AR, Hernández-Moneo JL, Martínez P, Meléndez B
Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling.
Mol Cancer. 2006;539.
BACKGROUND: Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations. RESULTS: We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containing well-known oncogenes in GBMs were also detected at 7p12 (EGFR), 7q21 (CDK6), 4q12 (PDGFRA), and 12q13-15 (MDM2 and CDK4). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes SLA/LP and STIM2 (4p15), and TNFSF13B and COL4A2 (13q32-34). Some of the candidate target genes of amplification (EGFR, CDK6, MDM2, CDK4, and TNFSF13B) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target TNFSF13B was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs. CONCLUSION: This high-resolution analysis allowed us to propose novel candidate target genes such as STIM2 at 4p15, and TNFSF13B or COL4A2 at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight the important influence in GBM of signaling pathways such as the PI3K/AKT, consistent with the invasive features of this tumor. [Abstract/Link to Full Text]

Iovino F, Lentini L, Amato A, Di Leonardo A
RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts.
Mol Cancer. 2006;538.
BACKGROUND: Incorrect segregation of whole chromosomes or parts of chromosome leads to aneuploidy commonly observed in cancer. The correct centrosome duplication, assuring assembly of a bipolar mitotic spindle, is essential for chromosome segregation fidelity and preventing aneuploidy. Alteration of p53 and pRb functions by expression of HPV16-E6 and E7 oncoproteins has been associated with centrosome amplification. However, these last findings could be the result of targeting cellular proteins in addition to pRb by HPV16-E7 oncoprotein. To get a more detailed picture on the role of pRb in chromosomal instability and centrosome amplification, we analyzed the effects of the acute loss of retinoblastoma gene function in primary conditional Rb deficient mouse embryonic fibroblasts (MEFs). Moreover, since pRb is a transcriptional repressor, microarray analysis was done on pRb-competent and pRb-deficient MEFs to evaluate changes in expression of genes for centrosome homeostasis and for correct mitosis. RESULTS: Acute loss of pRb induces centrosome amplification and aneuploidy in the vast majority of cells analyzed. A time course analysis shows a decrease of cells with amplified centrosomes after 40 days from the adenoviral infection. At this time only 12% of cells still show amplified centrosomes. Interestingly, cells with pRb constitutive loss show a similar percentage of cells with amplified centrosomes. DNA-Chip analyses in MEFs wt (mock infected) and pRb depleted (Ad-Cre infected) cells reveal differential expression of genes controlling both centrosome duplication and mitotic progression. CONCLUSION: Our findings suggest a direct link between pRb status, centrosome amplification and chromosomal instability, and define specific mitotic genes as targets whose gene expression has to be altered to achieve or maintain aneuploidy. [Abstract/Link to Full Text]

Staub E, Gröne J, Mennerich D, Röpcke S, Klamann I, Hinzmann B, Castanos-Velez E, Mann B, Pilarsky C, Brümmendorf T, Weber B, Buhr HJ, Rosenthal A
A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer.
Mol Cancer. 2006;537.
BACKGROUND: Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. RESULTS: We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes) are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. CONCLUSION: An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin) also have a substantial impact on the formation of co-expression islands in colorectal carcinoma. [Abstract/Link to Full Text]

Rübben A, Bausch B, Nikkels A
Somatic deletion of the NF1 gene in a neurofibromatosis type 1-associated malignant melanoma demonstrated by digital PCR.
Mol Cancer. 2006;536.
BACKGROUND: Neurofibromatosis type 1 (NF1) is the most common hereditary neurocutaneous disorder and it is associated with an elevated risk for malignant tumors of tissues derived from neural crest cells. The NF1 gene is considered a tumor suppressor gene and inactivation of both copies can be found in NF1-associated benign and malignant tumors. Melanocytes also derive from neural crest cells but melanoma incidence is not markedly elevated in NF1. In this study we could analyze a typical superficial spreading melanoma of a 15-year-old boy with NF1 for loss of heterozygosity (LOH) within the NF1 gene. Neurofibromatosis in this patient was transmitted by the boy's farther who carried the mutation NF1 c. 5546 G/A. RESULTS: Melanoma cells were isolated from formalin-fixed tissue by liquid coverslip laser microdissection. In order to obtain statistically significant LOH data, digital PCR was performed at the intragenic microsatellite IVS27AC28 with DNA of approx. 3500 melanoma cells. Digital PCR detected 23 paternal alleles and one maternal allele. Statistical analysis by SPRT confirmed significance of the maternal allele loss. CONCLUSION: To our knowledge, this is the first molecular evidence of inactivation of both copies of the NF1 gene in a typical superficial spreading melanoma of a patient with NF1. The classical double-hit inactivation of the NF1 gene suggests that the NF1 genetic background promoted melanoma genesis in this patient. [Abstract/Link to Full Text]

Mathur S, Schmidt C, Das C, Tucker PW
Open Access and beyond.
Mol Cancer. 2006;535.
Uncensored exchange of scientific results hastens progress. Open Access does not stop at the removal of price and permission barriers; still, censorship and reading disabilities, to name a few, hamper access to information. Here, we invite the scientific community and the public to discuss new methods to distribute, store and manage literature in order to achieve unfettered access to literature. [Abstract/Link to Full Text]

Spee B, Jonkers MD, Arends B, Rutteman GR, Rothuizen J, Penning LC
Specific down-regulation of XIAP with RNA interference enhances the sensitivity of canine tumor cell-lines to TRAIL and doxorubicin.
Mol Cancer. 2006;534.
BACKGROUND: Apoptosis resistance occurs in various tumors. The anti-apoptotic XIAP protein is responsible for inhibiting apoptosis by reducing caspase-3 activation. Our aim is to evaluate whether RNA inhibition against XIAP increases the sensitivity of canine cell-lines for chemotherapeutics such as TRAIL and doxorubicin. We used small interfering RNA's (siRNA) directed against XIAP in three cell-lines derived from bile-duct epithelia (BDE), mammary carcinoma (P114), and osteosarcoma (D17). These cell-lines represent frequently occurring canine cancers and are highly comparable to their human counterparts. XIAP down-regulation was measured by means of quantitative PCR (Q-PCR) and Western blotting. The XIAP depleted cells were treated with a serial dilution of TRAIL or doxorubicin and compared to mock- and nonsense-treated controls. Viability was measured with a MTT assay. RESULTS: All XIAP siRNA treated cell-lines showed a mRNA down-regulation over 80 percent. Western blot analysis confirmed mRNA measurements. No compensatory effect of IAP family members was seen in XIAP depleted cells. The sensitivity of XIAP depleted cells for TRAIL was highest in BDE cells with an increase in the ED50 of 14-fold, compared to mock- and nonsense-treated controls. The sensitivity of P114 and D17 cell-lines increased six- and five-fold, respectively. Doxorubicin treatment in XIAP depleted cells increased sensitivity in BDE cells more than eight-fold, whereas P114 and D17 cell-lines showed an increase in sensitivity of three- and five-fold, respectively. CONCLUSION: XIAP directed siRNA's have a strong sensitizing effect on TRAIL-reduced cell-viability and a smaller but significant effect with the DNA damaging drug doxorubicin. The increase in efficacy of chemotherapeutics with XIAP depletion provides the rationale for the use of XIAP siRNA's in insensitive canine tumors. [Abstract/Link to Full Text]

Recent Articles in Cancer Cell International

Planque N, Perbal B
A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis.
Cancer Cell Int. 2003 Aug 22;3(1):15.
The CCN (CYR61 [Cystein-rich61]/CTGF [connective tissue growth factor]/NOV [Nephroblastoma overexpressed]) proteins constitute a family of regulatory factors involved in many aspects of cell proliferation and differentiation. An increasing body of evidence indicates that abnormal expression of the CCN proteins is associated to tumourgenesis. The multimodular architecture of the CCN proteins, and the production of truncated isoforms in tumours, raise interesting questions regarding the participation of each individual module to the various biological properties of these proteins. In this article, we review the current data regarding the involvement of CCN proteins in tumourigenesis. We also attempt to provide structural basis for the stimulatory and inhibitory functions of the full length and truncated CCN proteins that are expressed in various tumour tissues. [Abstract/Link to Full Text]

Jones LJ, Veale RB
Redistribution of beta-catenin in response to EGF and lithium signalling in human oesophageal squamous carcinoma cell lines.
Cancer Cell Int. 2003 Aug 15;3(1):13.
BACKGROUND: The beta-catenin link between membrane-bound cadherins and the actin cytoskeleton regulates cell adhesion and consequently metastasis. Abnormal stabilisation of beta-catenin enhances its transcriptional activities. Factors affecting beta-catenin's functions are important in understanding metastatic diseases such as oesophageal squamous cell carcinoma (SCC). RESULTS: In human oesophageal SCCs beta-catenin localises predominantly to the plasma membrane. The presence of free beta-catenin in the cytoplasm/nucleus was low. This indicates that beta-catenin's activities are skewed towards cell-cell adhesion in these oesophageal SCCs. Exposure to EGF or Li alone, produced a slight increase in membrane concentrations but only Li induced beta-catenin stabilisation in the cytoplasm. In combination, EGF and Li decreased membrane-associated beta-catenin, concomitantly increasing cytoplasmic concentrations. Convergence of these signalling pathways appears to induce a beta-catenin shift from the membrane into the cytoplasm. CONCLUSION: Therefore, although the adhesive role of beta-catenin appears to be intact, exogenous signals increase the stability of free beta-catenin thereby reducing cell-cell adhesion in these tumours. [Abstract/Link to Full Text]

Hollander C, Nyström M, Janciauskiene S, Westin U
Human mast cells decrease SLPI levels in type II - like alveolar cell model, in vitro.
Cancer Cell Int. 2003 Aug 20;3(1):14.
BACKGROUND: Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. RESULT: We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p < 0.01) in a SLPI-producing, type II-like alveolar cell line, (A549) when co-cultured with HMC-1 cells, but not in an HMC-1-conditioned medium, for 96 hours. By contrast, increased SLPI mRNA expression (by 1.58-fold, p < 0.05) was found under the same experimental conditions. Immunohistochemical analysis revealed mast cell transmigration in co-culture with SLPI-producing A549 cells for 72 and 96 hours. CONCLUSION: These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response. [Abstract/Link to Full Text]

Reeder JE, Sowden MP, Messing EM, Klover P, Villa-Moruzzi E, Ludlow JW
Inducible expression of catalytically active type 1 serine/threonine protein phosphatase in a human carcinoma cell line.
Cancer Cell Int. 2003 Jul 23;3(1):12.
BACKGROUND: One of the major cellular serine/threonine protein phosphatases is protein phosphatase type 1 (PP1). Studies employing many eukaryotic systems all point to a crucial role for PP1 activity in controlling cell cycle progression. One physiological substrate for PP1 appears to be the product of the retinoblastoma susceptibility gene (pRB), a demonstrated tumor suppressor. The growth suppressive activity of pRB is regulated by its phosphorylation state. Of critical importance is the question of the in vivo effect of PP1 activity on pRB and growth regulation. As a first step towards addressing this question, we developed an inducible PP1 expression system to investigate the regulation of PP1 activity. RESULTS: We have established a cell line for inducing protein expression of the type 1, alpha-isotype, serine/threonine protein phosphatase (PP1alpha). A plasmid encoding a fusion protein of the catalytic subunit of PP1alpha with a 6-histidine peptide (6His) and a peptide from hemagluttinin (HA) was transfected into the UMUC3 transitional cell carcinoma cell line, previously transfected with the reverse tetracycline transactivator plasmid pUHD172-1neo. A stable cell line designated LLWO2F was established by selection with hygromycin B. 6His-HA-PP1alpha protein appeared in cell lysates within two hours following addition of doxycycline to the culture medium. This protein localizes to the nucleus as does endogenous PP1alpha, and was shown to associate with PNUTS, a PP1-nuclear targeting subunit. Like endogenous PP1alpha, immunocomplexed 6His-HA-PP1alpha is active toward phosphorylase a and the product of the retinoblastoma susceptibility gene, pRB. When forcibly overexpressing 6His-HA-PP1alpha, there is a concomitant decrease in endogenous PP1alpha levels. CONCLUSIONS: These data suggest the existence of an autoregulatory mechanism by which PP1alpha protein levels and activity remain relatively constant. RT-PCR analyses of isolated polysome fractions support the notion that this putative autoregulatory mechanism is exerted, at least in part, at the translational level. Implications of these findings for the study of PP1alpha function in vivo are discussed. [Abstract/Link to Full Text]

Nocentini S
Apoptotic response of malignant rhabdoid tumor cells.
Cancer Cell Int. 2003 Jul 15;3(1):11.
BACKGROUND: Malignant rhabdoid tumors (MRTs) are extremely aggressive and resist current radio- and chemotherapic treatments. To gain insight into the dysfunctions of MRT cells, the apoptotic response of a model cell line, MON, was analyzed after exposure to several genotoxic and non-genotoxic agents employed separately or in association. RESULTS: Fluorescence microscopy of chromatin morphology and electrophoretic analysis of internucleosomal DNA fragmentation revealed that MON cells were, comparatively to HeLa cells, resistant to apoptosis after treatment with etoposide, cisplatin (CisPt) or X-rays, but underwent some degree of apoptosis after ultraviolet (UV) C irradiation. Concomitant treatment of MON cells with X-rays or vinblastine and the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin resulted in synergistic induction of apoptosis. Western blot analysis showed that the p53 protein was upregulated in MON cells after exposure to all the different agents tested, singly or in combination. In treated cells, the p53 downstream effectors p21WAF1/CIP1, Mdm2 and Bax were induced with some inconsistency with regard to the accumulation of p53. Poly ADP-ribose polymerase (PARP) cleavage, indicative of ongoing apoptosis, occurred in UVC-irradiated cells and, especially, in cells treated with combinations of X-rays or vinblastine with wortmannin. However, there was moderate or no PARP cleavage in cells treated with CisPt, X-rays, vinblastine or wortmannin singly or with the combinations X-rays plus CisPt or vinblastine and CisPt plus vinblastine or wortmannin. The synergistic effect on the induction of apoptosis exerted by some agent combinations corresponded with synergy in respect of MON cell growth inhibition. CONCLUSION: These results suggest abnormalities in the p53 pathway and apoptosis control in MRT cells. The Ras/PI3-K/AKT signaling pathway might also be deregulated in these cells by generating an excess of survival factors. These dysfunctions might contribute to the resistance of MRTs to current antineoplastic treatments and could warrant consideration in the search of new therapeutic approaches. [Abstract/Link to Full Text]

Hamelers IH, Van Schaik RF, Sussenbach JS, Steenbergh PH
17beta-Estradiol responsiveness of MCF-7 laboratory strains is dependent on an autocrine signal activating the IGF type I receptor.
Cancer Cell Int. 2003 Jul 11;3(1):10.
BACKGROUND: Human MCF-7 cells have been studied extensively as a model for breast cancer cell growth. Many reports have established that serum-starved MCF-7 cells can be induced to proliferate upon the sole addition of 17beta-estradiol (E2). However, the extent of the mitogenic response to E2 varies in different MCF-7 strains and may even be absent. In this study we compared the E2-sensitivity of three MCF-7 laboratory strains. RESULTS: The MCF-7S line is non-responsive to E2, the MCF-7 ATCC has an intermediate response to E2, while the MCF-7 NKI is highly E2-sensitive, although the levels and activities of the estrogen receptor (ER) are not significantly different. Both suramin and IGF type I receptor blocking antibodies are able to inhibit the mitogenic response to E2-treatment in MCF-7 ATCC and MCF-7 NKI cells. From this we conclude that E2-induced proliferation is dependent on IGF type I receptor activation in all three MCF-7 strains. CONCLUSIONS: The results presented in this article suggest that E2-responsiveness of MCF-7 cells is dependent on the secretion of an autocrine factor activating the IGF-IR. All three strains of MCF-7 breast cancer cells investigated do not respond to E2 if the IGF-RI-pathway is blocked. Generally, breast cancer therapy is targeted at inhibiting estrogen action. This study suggests that inhibition of IGF-action in combination with anti-estrogen-treatment may provide a more effective way in treatment or even prevention of breast cancer. [Abstract/Link to Full Text]

Elkak AE, Newbold RF, Thomas V, Mokbel K
Is telomerase reactivation associated with the down-regulation of TGF beta receptor-II expression in human breast cancer?
Cancer Cell Int. 2003 Jul 6;3(1):9.
BACKGROUND: Telomerase is a ribonucleoprotein that synthesizes telomeres and plays an important role in chromosomal stability and cellular immortalisation. Telomerase activity is detectable in most human cancers but not in normal somatic cells. TGF beta (transforming growth factor beta) is a member of a family of cytokines that are essential for cell survival and seems to be down-regulated in human cancer. Recent in vitro work using human breast cancer cell lines has suggested that TGF beta down-regulates the expression of hTERT (human telomerase reverse transcriptase) : the catalytic subunit of telomerase. We have therefore hypothesised that telomerase reactivation is associated with reduced immunohisto-chemical expression of TGF beta type II receptor (RII) in human breast cancer. METHODS: TGF beta RII immunohistochemical expression was determined in 24 infiltrating breast carcinomas with known telomerase activity (17 telomerase-positive and 7 telomerase-negative). Immunohistochemical expression of TGF beta RII was determined by a breast pathologist who was blinded to telomerase data. RESULTS: TGF beta RII was detected in all lesions. The percentage of stained cells ranged from 1-100%. The difference in TGF beta RII expression between telomerase positive and negative tumours was not statistically significant (p = 1.0). CONCLUSION: The results of this pilot study suggest that there is no significant association between telomerase reactivation and TGF-beta RII down-regulation in human breast cancer. [Abstract/Link to Full Text]

Mobasheri A, Fox R, Evans I, Cullingham F, Martín-Vasallo P, Foster CS
Epithelial Na, K-ATPase expression is down-regulated in canine prostate cancer; a possible consequence of metabolic transformation in the process of prostate malignancy.
Cancer Cell Int. 2003 Jun 13;3(1):8.
BACKGROUND: An important physiological function of the normal prostate gland is the synthesis and secretion of a citrate rich prostatic fluid. In prostate cancer, citrate production levels are reduced as a result of altered cellular metabolism and bioenergetics. Na, K-ATPase is essential for citrate production since the inward Na+ gradients it generates are utilized for the Na+ dependent uptake of aspartate, a major substrate for citrate synthesis. The objective of this study was to compare the expression of previously identified Na, K-ATPase isoforms in normal canine prostate, benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma (PCa) using immunohistochemistry in order to determine whether reduced citrate levels in PCa are also accompanied by changes in Na, K-ATPase expression. RESULTS: Expression of Na, K-ATPase alpha1 and beta1 isoforms was observed in the lateral and basolateral plasma membrane domains of prostatic epithelial cells in normal and BPH prostates. Canine kidney was used as positive control for expression of Na, K-ATPase alpha1 and gamma isoforms. The alpha1 isoform was detected in abundance in prostatic epithelial cells but there was no evidence of alpha2, alpha3 or gamma subunit expression. In advanced PCa, Na, K-ATPase alpha1 isoform expression was significantly lower compared to normal and BPH glands. The abundant basolateral immunostaining observed in normal and BPH tissue was significantly attenuated in PCa. CONCLUSION: The loss of epithelial structure and function and the transformation of normal epithelial cells to malignant cells in the canine prostate have important implications for cellular metabolism and are accompanied by a down regulation of Na, K-ATPase. [Abstract/Link to Full Text]

Dominici S, Pieri L, Comporti M, Pompella A
Possible role of membrane gamma-glutamyltransferase activity in the facilitation of transferrin-dependent and -independent iron uptake by cancer cells.
Cancer Cell Int. 2003 May 14;3(1):7.
BACKGROUND: The molecular mechanisms by which iron is physiologically transported trough the cellular membranes are still only partially understood. Several studies indicate that a reduction step of ferric iron to ferrous is necessary, both in the case of transferrin-mediated and transferrin-independent iron uptake. Recent studies from our laboratory described gamma-glutamyltransferase activity (GGT) as a factor capable to effect iron reduction in the cell microenvironment. GGT is located on the outer aspect of plasma membrane of most cell types, and is often expressed at high levels in malignant tumors and their metastases. The present study was aimed at verifying the possibility that GGT-mediated iron reduction may participate in the process of cellular iron uptake. RESULTS: Four distinct human tumor cell lines, exhibiting different levels of GGT activity, were studied. The uptake of transferrin-bound iron was investigated by using 55Fe-loaded transferrin, as well as by monitoring fluorimetrically the intracellular iron levels in calcein-preloaded cells. Transferrin-independent iron uptake was investigated using 55Fe complexed by nitrilotriacetic acid (55Fe-NTA complex).The stimulation of GGT activity, by administration to cells of the substrates glutathione and glycyl-glycine, was generally reflected in a facilitation of transferrin-bound iron uptake. The extent of such facilitation was correlated with the intrinsic levels of the enzyme present in each cell line. Accordingly, inhibition of GGT activity by means of two independent inhibitors, acivicin and serine/boric acid complex, resulted in a decreased uptake of transferrin-bound iron. With Fe-NTA complex, the inhibitory effect - but not the stimulatory one - was also observed. CONCLUSION: It is concluded that membrane GGT can represent a facilitating factor in iron uptake by GGT-expressing cancer cells, thus providing them with a selective growth advantage over clones that do not possess the enzyme. [Abstract/Link to Full Text]

Kudinov Y, Wiseman CL, Kharazi AI
Phorbol myristate acetate and Bryostatin 1 rescue IFN-gamma inducibility of MHC class II molecules in LS1034 colorectal carcinoma cell line.
Cancer Cell Int. 2003 Mar 25;3(1):4.
BACKGROUND: The expression of major histocompatibility complex class II (MHCII) antigens in both mouse and human tumors is rare, and these antigens are not easily inducible by IFN-gamma (IFNg). Since MHCII may play an important role in the development of host antitumor immune response, we explored the possibility of restoring MHCII inducibility in several IFNg-resistant tumor cell lines using protein kinase C (PKC) agonists phorbol myristate acetate (PMA) or Bryostatin. RESULTS: Tumor cells were co-cultured with various concentrations of PMA and IFNg for 48 hr. The expression of MHCII antigens and receptors IFNgR1 and IFNgR2 was determined by flow cytometry. We showed that the presence of as little as 0.1 ng/ml of PMA in tissue culture restored the ability of weakly inducible LS1034 colon carcinoma cells to express MHCII in response to IFNg (100 - 10,000 IU/ml) in a dose-dependent manner. Likewise, Bryostatin 1, as low as 10 ng/ml produced a 5-6 fold upregulation of MHCII. The effect of PMA was not observed in two other poorly responding cell lines, MSTO-211H mesothelioma and HepG2 hepatocellular carcinoma, and was abrogated by relatively high concentrations of PKC inhibitors staurosporine (100 nM) and GF 109203X (1,000 nM). Both surface and intracellular staining of all cell lines with antibodies against IFNgR1 and IFNgR2 failed to detect any increase in IFNg receptor expression following incubation with PMA. CONCLUSION: In this study we showed that IFNg-inducibility of MHCII antigens in weakly inducible LS1034 colorectal carcinoma cell line can be rescued by concomitant incubation with PKC agonists. Bryostatin 1 may be considered for further investigation of IFNg-dependent MHCII induction in resistant tumors in vivo. [Abstract/Link to Full Text]

Mould R, Pondel MD
Calcitonin receptor gene expression in K562 chronic myelogenous leukemic cells.
Cancer Cell Int. 2003 Apr 25;3(1):6.
BACKGROUND: The peptide hormone calcitonin (CT) can significantly effect the proliferation rate of CT receptor (CTR) positive human cancer cells. We wish to identify additional human cancers expressing CTRs and assay the effects of CT on their growth rates and signal transduction pathways. RESULTS: The expression of the human calcitonin receptor (hCTR) gene in the chronic myelogenous leukemia cell line K562 was examined. RT-PCR on total RNA extracted from K562 cells detected the presence of hCTR mRNA. Further analysis demonstrated that multiple hCTR isoforms were present. Incubation of K562 cells with salmon calcitonin (sCT), but not amylin, caused an increase in intracellular levels of cAMP similar to that induced by forskolin treatment. We further demonstrated that butyrate induced erythroid differentiation of K562 cells caused a significant decrease in hCTR mRNA levels. However, phorbol myristate acetate (PMA) induced megakaryocytic differentiation of these cells had no significant effect on hCTR mRNA levels. We demonstrated that exposure to various concentrations of sCT had no effect on the cellular proliferation of K562 cells in vitro. CONCLUSION: Chronic myelogenous k562 cells express multiple CTR isoforms. However, CT does not effect K562 proliferation rates. It is likely that the small increase in intracellular levels of cAMP following CT treatment is not sufficient to interfere with cellular growth. [Abstract/Link to Full Text]

Huang Z, Tong Y, Wang J, Huang Y
NMR studies of the relationship between the changes of membrane lipids and the cisplatin-resistance of A549/DDP cells.
Cancer Cell Int. 2003 Apr 8;3(1):5.
Changes of membrane lipids in cisplatin-sensitive A549 and cisplatin-resistant A549/DDP cells during the apoptotic process induced by a clinical dose of cisplatin (30 &mgr;M) were detected by 1H and 31P-NMR spectroscopy and by membrane fluidity measurement. The apoptotic phenotypes of the two cell lines were monitored with flow cytometry. The assays of apoptosis showed that significant apoptotic characteristics of the A549 cells were induced when the cells were cultured for 24 hours after treatment with cisplatin, while no apoptotic characteristic could be detected for the resistant A549/DDP cells even after 48 hours. The results of 1H-NMR spectroscopy demonstrated that the CH2/CH3 and Glu/Ct ratios of the membrane of A549 cells increased significantly, but those in A549/DDP cell membranes decreased. In addition, the Chol/CH3 and Eth/Ct ratios decreased for the former but increased for the latter cells under the same conditions. 31P-NMR spectroscopy indicated levels of phosphomonoesters (PME) and ATP decreased in A549 but increased in A549/DDP cells after being treated with cisplatin. These results were supported with the data obtained from 1H-NMR measurements. The results clearly indicated that components and properties of membrane phospholipids of the two cell lines were significantly different during the apoptotic process when they were treated with a clinical dose of cisplatin. Plasma membrane fluidity changes during cisplatin treatment as detected with the fluorescence probe TMA-DPH also indicate marked difference between the two cell lines. We provided evidence that there are significant differences in plasma membrane changes during treatment of cisplatin sensitive A549 and resistant A549/DDP cells. [Abstract/Link to Full Text]

Cameron IL, Munoz J, Barnes CJ, Hardman WE
High dietary level of synthetic vitamin E on lipid peroxidation, membrane fatty acid composition and cytotoxicity in breast cancer xenograft and in mouse host tissue.
Cancer Cell Int. 2003 Mar 12;3(1):3.
BACKGROUND: d-alpha-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-alpha-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-alpha-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice were killed at either 2 or 6 weeks after the start of dietary intervention. During necropsy, tumor and host tissues were excised for histology and for biochemical analyses. RESULTS: Tumor growth was significantly reduced by 6 weeks of sE supplementation. Thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were suppressed in tumor and in host tissues in sE supplemented mice. In the sE treated mice, the fatty acid composition of microsomal and mitochondrial membranes of tumor and host tissues had proportionately less linoleic acid (n-6 C 18-2), similar levels of arachidonic acid (n-6 C 20-4), but more docosahexanoic acid (n-3 C 22-6). The sE supplementation had no significant effect on blood counts or on intestinal histology but gave some evidence of cardiac toxicity as judged by myocyte vacuoles and by an indicator of oxidative stress (increased ratio of Mn SOD mRNA over GPX1 mRNA). CONCLUSIONS: At least one of the stereoisomers in sE has antitumor activity. Synthetic vitamin E appears to preferentially stabilize membrane fatty acids with more double bonds in the acyl chain. Although sE suppressed tumor growth and lipid peroxidation, it may have side-effects in the heart. [Abstract/Link to Full Text]

Zhang J, Li Y, Shen B
PI3-K/Akt pathway contributes to IL-6-dependent growth of 7TD1 cells.
Cancer Cell Int. 2003 Feb 17;3(1):1.
BACKGROUND: Recently, growing evidence suggests the involvement of PI 3-K/Akt in IL-6-dependent survival and proliferative responses in several types of cells. However, whether PI 3-K/Akt plays the same role in IL-6-dependent growth of 7TD1 mouse-mouse B cell hybridoma is not known. METHODS: We investigated the activation status of Akt in 7TD1 cells induced by IL-6. With PI 3-K specific inhibitor wortmannin, we also investigated the biological roles of Akt activation in 7TD1 cells. RESULTS: IL-6 stimulated phosphorylation of Akt in a dose- and time-dependent manner in 7TD1 cells. Wortmannin significantly reduced IL-6-induced phosphorylation of Akt and IL-6-dependent growth of 7TD1 cells. Furthermore, wortmannin blocked IL-6-induced up-regulation of XIAP, but not Bcl-2 in 7TD1 cells. CONCLUSION: The data suggest that IL-6-induced PI 3-K/Akt activation is essential for the optimal growth of 7TD1 cells through up-regulation of anti-apoptosis proteins such as XIAP. [Abstract/Link to Full Text]

Jiang H, Coleman J, Miskimins R, Miskimins WK
Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells.
Cancer Cell Int. 2003 Feb 18;3(1):2.
BACKGROUND: Eukaryotic initiation factor 4E (eIF4E) is essential for cap-dependent initiation of translation. Cell proliferation is associated with increased activity of eIF4E and elevated expression of eIF4E leads to tumorigenic transformation. Many tumors express very high levels of eIF4E and this may be a critical factor in progression of the disease. In contrast, overexpression of 4EBP, an inhibitor of eIF4E, leads to cell cycle arrest and phenotypic reversion of some transformed cells. RESULTS: A constitutively active form of 4EBP-1 was inducibly expressed in the human breast cancer cell line MCF7. Induction of constitutively active 4EBP-1 led to cell cycle arrest. This was not associated with a general inhibition of protein synthesis but rather with changes in specific cell cycle regulatory proteins. Cyclin D1 was downregulated while levels of the CDK inhibitor p27Kip1 were increased. The levels of cyclin E and CDK2 were unaffected but the activity of CDK2 was significantly reduced due to increased association with p27Kip1. The increase in p27Kip1 did not reflect changes in p27Kip1 mRNA or degradation rates. Rather, it was associated with enhanced synthesis of the protein, even though 4EBP-1 is expected to inhibit translation. This could be explained, at least in part, by the ability of the p27Kip1 5'-UTR to mediate cap-independent translation, which was also enhanced by expression of constitutively active 4EBP-1. CONCLUSIONS: Expression of active 4EBP-1 in MCF7 leads to cell cycle arrest which is associated with downregulation of cyclin D1 and upregulation of p27Kip1. Upregulation of p27Kip1reflects increased synthesis which corresponds to enhanced cap-independent translation through the 5'-UTR of the p27Kip1 mRNA. [Abstract/Link to Full Text]

Fujii Y, Tomita K, Sano H, Yamasaki A, Hitsuda Y, Adcock IM, Shimizu E
Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide in SV-40 transformed lung epithelial cells.
Cancer Cell Int. 2002 Nov 20;2(1):16.
BACKGROUND: Since lung epithelial cells are constantly being exposed to reactive oxygen intermediates (ROIs), the alveolar surface is a major site of oxidative stress, and each cell type may respond differently to oxidative stress. We compared the extent of oxidative DNA damage with that of mitochondrial injury in lung epithelial cells at the single cell level. RESULT: DNA damage and mitochondrial injury were measured after oxidative stress in the SV-40 transformed lung epithelial cell line challenged with hydrogen peroxide (H2O2). Single cell analysis of DNA damage was determined by assessing the number of 8-oxo-2-deoxyguanosine (8-oxo-dG) positive cells, a marker of DNA modification, and the length of a comet tail. Mitochondrial membrane potential, DeltaPsim, was determined using JC-1. A 1 h pulse of H2O2 induced small amounts of apoptosis (3%). 8-oxo-dG-positive cells and the length of the comet tail increased within 1 h of exposure to H2O2. The number of cells with reduced DeltaPsim increased after the addition of H2O2 in a concentration-dependent manner. In spite of a continual loss of DeltaPsim, DNA fragmentation was reduced 2 h after exposure to H2O2. CONCLUSION: The data suggest that SV-40 transformed lung epithelial cells are resistant to oxidative stress, showing that DNA damage can be dissociated from mitochondrial injury. [Abstract/Link to Full Text]

Sawada T, Yamada O, Yoshimura N, Hatori K, Fuchinoue S, Teraoka S
Xenoantigen, an alphaGal epitope-expression construct driven by the hTERT-promoter, specifically kills human pancreatic cancer cell line.
Cancer Cell Int. 2002 Oct 3;2(1):14.
BACKGROUND: We previously reported the usefulness of the alphaGal epitope as a target molecule for gene therapy against cancer. To induce cancer cell specific transcription of the alphaGal epitope, an expression vector which synthesizes the alphaGal epitope under the control of a promoter region of the human telomerase reverse transcriptase (hTERT), NK7, was constructed. METHODS: NK7 was transfected into a human pancreatic carcinoma cell line, MIA cells, and telomerase-negative SUSM-1 cells served controls. Expression of the alphaGal epitope was confirmed by flow cytometry using IB4 lectin. The susceptibility of transfected MIA cells to human natural antibodies, was examined using a complement-dependent cytotoxic cross-match test (CDC) and a flow cytometry using annexin V. RESULTS: The alphaGal epitope expression was detected only on the cell surfaces of NK7-transfected MIA cells, i.e., not on naive MIA cells or telomerase negative SUSM-1 cells. The CDC results indicated that MIA cells transfected with NK7 are susceptible to human natural antibody-mediated cell killing, and the differences, as compared to NK-7 transfected telomerase negative SUSM-1 cells or telomerase positive naďve MIA cells, were statistically significant. The flow cytometry using annexin V showed a higher number of the apoptotic cells in NK-7 transfected MIA cells than in naďve MIA cells. CONCLUSIONS: The results suggest that alphaGal epitope-expression, under the control of the hTERT-promoter, may be useful in cancer specific gene therapy. [Abstract/Link to Full Text]

Crowe DL, Kim R
A phosphorylation defective retinoic acid receptor mutant mimics the effects of retinoic acid on EGFR mediated AP-1 expression and cancer cell proliferation.
Cancer Cell Int. 2002 Oct 8;2(1):15.
BACKGROUND: The effects of the vitamin A metabolite retinoic acid (RA) are mediated at the transcriptional level by retinoic acid receptors (RAR). These proteins are part of a superfamily of transcription factors which activate target gene expression when bound to their respective ligands. In addition to ligand binding, heterodimerization with transcriptional cofactors and posttranslational modification such as phosphorylation are also critical for transactivation function. Previous studies have shown that phosphorylation of a serine residue at amino acid 77 in the RARalpha amino terminus was required for basal activation function of the transcription factor. RESULTS: We have determined that RA inhibits cyclin H and cdk7 expression thereby decreasing levels of phosphorylated RARalpha in human cancer cell lines. To determine the effects of decreased RARalpha phosphorylation in human cancer cells, we stably transfected a phosphorylation defective mutant RARalpha expression construct into SCC25 cultures. Cells expressing the mutant RARalpha proliferated more slowly than control clones. This decreased proliferation was associated with increased cyclin dependent kinase inhibitor expression and decreased S phase entry. In the absence of ligand, the RARalpha mutant inhibited AP-1 activity to an extent similar to that of RA treated control clones. Levels of some AP-1 proteins were inhibited due to decreased EGFR expression upstream in the signaling pathway. CONCLUSIONS: These results indicate that hypophosphorylated RARalpha can mimic the anti-AP-1 effects of RA in the absence of ligand. [Abstract/Link to Full Text]

Rothbarth K, Stammer H, Werner D
Proteasome-mediated degradation antagonizes critical levels of the apoptosis-inducing C1D protein.
Cancer Cell Int. 2002 Sep 2;2(1):12.
The C1D gene is expressed in a broad spectrum of mammalian cells and tissues but its product induces apoptotic cell death when exceeding a critical level. Critical levels are achieved in a fraction of cells by transient transfection with EGFP-tagged C1D expression constructs. However, transfected cells expressing sub-critical levels of C1D(EGFP) escape apoptotic cell death by activation of a proteasome-mediated rescue mechanism. Inhibition of the proteasome-dependent degradation of the C1D(EGFP) protein results in a parallel increase of the intracellular C1D level and in the fraction of apoptotic cells. [Abstract/Link to Full Text]

Jain S
Kinetic model for designing a cancer therapy.
Cancer Cell Int. 2002 Sep 24;2(1):13.
A kinetic model has been developed to study cancer growth. Cancer growth has been considered as interaction between various independent but interacting compartments. The model considers cell growth and metastasis resulting in the formation of new tumor masses. Using certain representative parameter values, cell growth has been modeled in the absence and the presence of various cancer therapies. Based on this analysis, the critical parameters involved in cancer development have been identified. This model may thus be useful in studying and designing a cancer therapy using the data obtained from specific in vitro experiments. [Abstract/Link to Full Text]

Hardman WE, Munoz J, Cameron IL
Role of lipid peroxidation and antioxidant enzymes in omega 3 fatty acids induced suppression of breast cancer xenograft growth in mice.
Cancer Cell Int. 2002 Jul 17;2(1):10.
BACKGROUND: Supplementing mice with high levels of dietary n-3 polyunsaturated fatty acids (PUFAs) increases the n-3 PUFAs in cell membranes, increases the susceptibility of the cells for lipid peroxidation (LPO) and decreases the growth rate of mammary and other tumors. However, the results of an earlier study indicated that a factor in addition to LPO was involved in the reduction in tumor growth in n-3 PUFAs fed mice. Athymic mice bearing MDA-MB-231 human breast carcinoma xenografts, were fed fish oil concentrate (FOC) or control diets, with and without supplemental Vitamin E (2000 IU /kg diet) and were sacrificed both before and after doxorubicin (DOX) treatment to evaluate factors involved in tumor growth suppression. RESULTS: Prior to DOX, basal LPO in the tumor of 3% FOC fed mice was slightly higher than in the control fed mice and was decreased in mice consuming FOC with vitamin E. Vitamin E suppressed the DOX induced increase in LPO in the tumors of control mice, however, vitamin E was not sufficient to suppress a DOX induced increase in LPO in the tumors of FOC fed mice. The mean growth rate of tumors of FOC fed mice was significantly less than the mean growth rate of the tumors of control mice. Multiple regression analyses indicated that suppression of glutathione peroxidase (GPX) activity by FOC prior to DOX therapy was more important than increased LPO as an explanation of tumor growth suppression. Tumor induced cachexia was decreased in mice consuming FOC. CONCLUSIONS: It appears that the increased sensitivity to DOX was related to an FOC induced reduction in GPX activity. FOC reduced tumor induced cachexia. [Abstract/Link to Full Text]

Rahman MU, Mazumder A
Primary Research: Short Communication: Evidence Supporting Rare AIDS-Kaposi's Sarcoma Metastasis In Keeping With Their Vascular Endothelial Evolution.
Cancer Cell Int. 2002 Jul 24;2(1):11.
BACKGROUND: It is postulated that the unusual manifestations of Kaposis's sarcoma cells in nonendothelial brain tissues and on eyeballs in advanced acquired immune deficiency syndrome (AIDS) cases are metastasized AIDS-Kaposi's sarcoma cells arising from vascular endothelial cells. METHODS: Experiments were performed to explore the above hypothesis by testing for intercellular adhesion molecule-1 (CD54 antigens) on cutaneous AIDS-Kaposi's sarcoma cells as well as on AIDS-Kaposi's sarcoma cells isolated from eyeballs as studies have illustrated that, unlike localized Kaposi's sarcoma cells of primary lesions, proliferating Kaposi's sarcoma cells in proximity to primary lesions express a negative or diminished phenotype when evaluated for identical surface antigens. Parallel CD54 antigen tests were done on vascular endothelial cells and monocytes/macrophages as endothelial cells are considered evolutionarily related to Kaposi's sarcoma cells and monocytes/macrophages are ideal CD54 antigen positive controls. RESULTS: Our data showed that only AIDS-Kaposi's sarcoma cells of the eyes did not express CD54 antigens. CONCLUSIONS: We therefore report that our findings support the postulation suggesting AIDS-Kaposi's sarcoma dissemination in advanced AIDS patients in keeping with their vascular endothelial heredity. [Abstract/Link to Full Text]

Przybylo M, Hoja-Lukowicz D, Litynska A, Laidler P
Different glycosylation of cadherins from human bladder non-malignant and cancer cell lines.
Cancer Cell Int. 2002 Jun 18;26.
BACKGROUND: The aim of the present study was to determine whether stage of invasiveness of bladder cancer cell lines contributes to alterations in glycan pattern of their cadherins. RESULTS: Human non-malignant epithelial cell of ureter HCV29, v-raf transfected HCV29 line (BC3726) and transitional cell cancers of urine bladder Hu456 and T24 were grown in cell culture. Equal amounts of protein from each cell extracts were separated by SDS-PAGE electrophoresis and were blotted on an Immobilon P membrane. Cadherins were immunodetected using anti-pan cadherin mAb and lectin blotting assays were performed, in parallel. N-oligosaccharides were analysed by specific reaction with Galanthus nivalis agglutinin (GNA), Sambucus nigra agglutinin (SNA), Maackia amurensis agglutinin (MAA), Datura stramonium agglutinin (DSA), Aleuria aurantia agglutinin (AAA), Phaseolus vulgaris agglutinin (PHA-L) and wheat germ agglutinin (WGA). The cadherin from HCV29 cell line possessed bi- and/or 2,4-branched triantennary complex type glycans, some of which were alpha2,6-sialylated. The cadherin from BC3726 cell line exhibited exclusively high mannose type glycans. Cadherins from Hu456 and T24 cell lines expressed high mannose type glycans as well as beta1,6-branched oligosaccharides with poly-N-acetyllactosamine structures and alpha2,3-linked sialic acid residues. Additionally, the presence of fucose and alpha2,6-sialic acid residues on the cadherin from T24 cell line was detected. CONCLUSIONS: These results indicate that N-glycosylation pattern of cadherin from bladder cancer cell line undergoes modification during carcinogenesis. [Abstract/Link to Full Text]

Johnson NC, Kruk PA
BRCA1 Zinc RING Finger Domain Disruption Alters Caspase Response in Ovarian Surface Epithelial Cells.
Cancer Cell Int. 2002 Jul 5;2(1):7.
BACKGROUND: The frequently occurring 185delAG mutation occurs in the amino-terminal zinc RING domain of the breast and ovarian cancer susceptibility gene, BRCA1. We sought to determine differential cell viability and apoptotic response of human ovarian surface epithelial cells with and without the 185delAG mutation. RESULTS: BRCA1wt and BRCA1+ cells were treated with staurosporine. Cell proliferation assays showed BRCA1wt cells grew to a greater extent compared to BRCA1+ cells. Trypan blue exclusion assays confirmed this observation. Western immunoblot analysis revealed that caspase 3 levels were higher after staurosporine treatment in BRCA1+ cells than in wild type cells, while full length DNA Fragmentation Factor 45 levels were lower in BRCA1+ cells. While there was no significant difference in levels of excision repair cross complementing protein1 (ERCC1) with BRCA1 status, BRCA1+ cells demonstrated cleavage of polyribose ADP polymerase (PARP) before wild type cells. CONCLUSIONS: Disruption of the BRCA1 RING domain caused altered cell viability and caspase-dependent apoptotic response after chemotoxic stress. [Abstract/Link to Full Text]

Song L, Li Y, Shen B
Protein kinase ERK contributes to differential responsiveness of human myeloma cell lines to IFNalpha.
Cancer Cell Int. 2002 Jul 8;2(1):9.
BACKGROUND: Despite IFNalpha has been used extensively in the treatment of multiple myeloma (MM), there are also several reports suggesting that IFNalpha may aggravate isease in some MM patients. That means the effect of IFNalpha on the growth of myeloma cells in vivo may be different. In this study, we selected two human myeloma cell lines that vary remarkably in response to IFNalpha and focused on elucidating the mechanism of differential IFNalpha responsiveness. RESULTS: Sko-007 is a myeloma cell line whose growth is arrested by IFNalpha; however, IFNalpha promoted the proliferation of the other myeloma cell line U266. We observed that the growth-stimulation effect of IFNalpha on U266 cells did not result from up-regulation of the IL-6 receptors on cell surface; while IFNalpha treatment on Sko-007 cells significantly reduced gp130 expression. Moreover, the transcription factors STAT3 and STAT1, which are involved in the JAK/STAT signal transduction pathway, can be activated in both IFNalpha-stimulated and -inhibited myeloma cell lines; while the activation of the protein kinase ERK, which is involved in the Ras/MAPK signal transduction pathway, can be down-regulated in IFNalpha-arrested Sko-007 cells and up-regulated in IFNalpha-stimulated U266 cells. In addition, both IFNalpha-induced growth-stimulation effect and the up-regulated activation of ERK in U266 cells were efficiently inhibited by PD98059, the specific inhibitor of MAPK/ERK kinase (MEK). CONCLUSION: Myeloma cells responsiveness to IFNalpha is heterogeneous and the activation state of ERK in the Ras/MAPK signalling pathway mainly contributed to this difference. [Abstract/Link to Full Text]

Talyshinsky MM, Souprun YY, Huleihel MM
Anti-viral activity of red microalgal polysaccharides against retroviruses.
Cancer Cell Int. 2002 Jul 5;2(1):8.
Red microalgal polysaccharides significantly inhibited the production of retroviruses (murine leukemia virus- MuLV) and cell transformation by murine sarcoma virus(MuSV-124) in cell culture. The most effective inhibitory effect of these polysaccharides against both cell transformation and virus production was obtained when the polysaccharide was added 2 h before or at the time of infection. Although, addition of the polysaccharide post-infection significantly reduced the number of transformed cells, but its effect was less marked than that obtained when the polysaccharide was added before or at the time of infection.The finding that the inhibition of cell transformation by MuSV-124 was reversible after removal of the polysaccharide suggested that microalgal polysaccharides inhibited a late step after provirus integration into the host genome. In conclusion, our findings could support the possibility that the polysaccharide may affect early steps in the virus replication cycle, such as virus absorption into the host cells, in addition to its effect on a late step after provirus integration. [Abstract/Link to Full Text]

Szende B, Szökán G, Tyihá E, Pál K, Gáborjányi R, Almás M, Khlafulla AR
Antitumor effect of lysine-isopeptides.
Cancer Cell Int. 2002 May 17;2(1):4.
Isopeptides (&straightepsilon;-peptides) of lysine, with a given Mw and low polydispersity (10-400 units), were synthesized to study the relationship between their chemical structure and biological effect. The designed compounds were of high purity, low polydispersity and high stereochemical purity. The effect of the compounds was tested on a human erythroleukemia cell line (K-562) and on four transplantable mouse tumors (L1210 lymphoid leukemia, P38 macrophage derived tumor, Ehrlich ascites carcinoma, Lewis lung tumor /LLT/). In case of the L1210 and P388 tumors and the Ehrlich carcinoma, survival of the animals was used as an indicator of the effect. In case of the Lewis lung tumor, the number and size of metastases in the lung and/or liver of treated and untreated mice were used as indicators. The polymers of polymerisation degree 80-120 (Mw 10.2-15.4 KD) showed the strongest antiproliferative effect both on K562 cells and the tumors growing in vivo. This effect was manifest with a significantly higher survival rate as compared to the control (L1210, P38, Ehrlich ascites), furthermore, by a decrease in the number and size of liver and lung metastases (LLT). [Abstract/Link to Full Text]

Wheatley D, Grynszpan D
Can we speed up the online publishing process? And who will pay for it, anyway?
Cancer Cell Int. 2002 May 27;2(1):5. [Abstract/Link to Full Text]

Harris PA, Lamb J, Heaton B, Wheatley DN
Possible attenuation of the G2 DNA damage cell cycle checkpoint in HeLa cells by extremely low frequency (ELF) electromagnetic fields.
Cancer Cell Int. 2002 May 7;2(1):3.
BACKGROUND: The issue remains unresolved as to whether low frequency magnetic fields can affect cell behaviour, with the possibility that they may be in part responsible for the increased incidence of leukaemia in parts of the population exposed to them. METHODS: Combined treatment of HeLa cells with gamma-irradiation (1, 3 and 5 Grays) and extra low frequency magnetic fields of ~50 Hz was carried out under rigorously controlled conditions. RESULTS: Synchronised cells progressing from S-phase arrived at mitosis on average marginally ahead of irradiation controls not exposed to ELF. In no instance out of a total of twenty separate experiments did this "double-insult" further delay entry of cells into mitosis, as had been anticipated. CONCLUSION: This apparently "non-genotoxic" agent (ELF) appears to be capable of affecting cells that would normally arrest for longer in G2, suggesting a weakening of the stringency of the late cycle (G2) checkpoint. [Abstract/Link to Full Text]

Leclerc GJ, Leclerc GM, Barredo JC
Real-time RT-PCR analysis of mRNA decay: half-life of Beta-actin mRNA in human leukemia CCRF-CEM and Nalm-6 cell lines.
Cancer Cell Int. 2002 Mar 7;2(1):1.
BACKGROUND: We describe an alternative method to determine mRNA half-life (t1/2) based on the Real-Time RT-PCR procedure. This approach was evaluated by using the beta-actin gene as a reference molecule for measuring of mRNA stability. RESULTS: Human leukemia Nalm-6 and CCRF-CEM cells were treated with various concentrations of Actinomycin D to block transcription and aliquots were removed periodically. Total RNA was isolated and quantified using the RiboGree&ncircledR; fluorescent dye with the VersaFluor Fluorometer System. One &mgr;g of total RNA was reverse transcribed and used as template for the amplification of a region of the beta-actin gene (231 bp). To generate the standard curve, serial ten-fold dilutions of the pBactin-231 vector containing the cDNA amplified fragment were employed, beta-actin mRNAs were quantified by Real-Time RT-PCR using the SYB&RcircledR; Green I fluorogenic dye and data analyzed using the iCycle iQ system software. Using this method, the beta-actin mRNA exhibited a half-life of 6.6 h and 13.5 h in Nalm-6 and CCRF-CEM cells, respectively. The t1/2 value obtained for Nalm-6 is comparable to those estimated from Northern blot studies, using normal human leukocytes (5.5 h). CONCLUSIONS: We have developed a rapid, sensitive, and reliable method based on Real-Time RT-PCR for measuring mRNA half-life. Our results confirm that beta-actin mRNA half-life can be affected by the cellular growth rate. [Abstract/Link to Full Text]

Recent Articles in Breast Cancer Research

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]

Habel LA, Shak S, Jacobs MK, Capra A, Alexander C, Pho M, Baker J, Walker M, Watson D, Hackett J, Blick NT, Greenberg D, Fehrenbacher L, Langholz B, Quesenberry CP
A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.
Breast Cancer Res. 2006;8(3):R25.
INTRODUCTION: The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting. METHODS: A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score. RESULTS: After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7-3.9%), 10.7% (95% CI 6.3-14.9%), and 15.5% (95% CI 7.6-22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5-7.9%), 17.8% (95% CI 11.8-23.3%), and 19.9% (95% CI 14.2-25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values. CONCLUSION: In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients. [Abstract/Link to Full Text]

Hawes D, Downey S, Pearce CL, Bartow S, Wan P, Pike MC, Wu AH
Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity.
Breast Cancer Res. 2006;8(2):R24.
INTRODUCTION: Increased mammographic density is a strong risk factor for breast cancer. The reasons for this are not clear; two obvious possibilities are increased epithelial cell proliferation in mammographically dense areas and increased breast epithelium in women with mammographically dense breasts. We addressed this question by studying the number of epithelial cells in terminal duct lobular units (TDLUs) and in ducts, and their proliferation rates, as they related to local breast densities defined histologically within individual women. METHOD: We studied deep breast tissue away from subcutaneous fat obtained from 12 healthy women undergoing reduction mammoplasty. A slide from each specimen was stained with the cell-proliferation marker MIB1. Each slide was divided into (sets of) areas of low, medium and high density of connective tissue (CT; highly correlated with mammographic densities). Within each of the areas, the numbers of epithelial cells in TDLUs and ducts, and the numbers MIB1 positive, were counted. RESULTS: The relative concentration (RC) of epithelial cells in high compared with low CT density areas was 12.3 (95% confidence interval (CI) 10.9 to 13.8) in TDLUs and 34.1 (95% CI 26.9 to 43.2) in ducts. There was a much smaller difference between medium and low CT density areas: RC = 1.4 (95% CI 1.2 to 1.6) in TDLUs and 1.9 (95% CI 1.5 to 2.3) in ducts. The relative mitotic rate (RMR; MIB1 positive) of epithelial cells in high compared with low CT density areas was 0.59 (95% CI 0.53 to 0.66) in TDLUs and 0.65 (95% CI 0.53 to 0.79) in ducts; the figures for the comparison of medium with low CT density areas were 0.58 (95% CI 0.48 to 0.70) in TDLUs and 0.66 (95% CI 0.44 to 0.97) in ducts. CONCLUSION: Breast epithelial cells are overwhelmingly concentrated in high CT density areas. Their proliferation rate in areas of high and medium CT density is lower than that in low CT density areas. The increased breast cancer risk associated with increased mammographic densities may simply be a reflection of increased epithelial cell numbers. Why epithelium is concentrated in high CT density areas remains to be explained. [Abstract/Link to Full Text]

Perreard L, Fan C, Quackenbush JF, Mullins M, Gauthier NP, Nelson E, Mone M, Hansen H, Buys SS, Rasmussen K, Orrico AR, Dreher D, Walters R, Parker J, Hu Z, He X, Palazzo JP, Olopade OI, Szabo A, Perou CM, Bernard PS
Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay.
Breast Cancer Res. 2006;8(2):R23.
INTRODUCTION: Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation. METHODS: Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype. RESULTS: We found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 x 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation. CONCLUSION: A real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes. [Abstract/Link to Full Text]

Jacobs EJ, Feigelson HS, Bain EB, Brady KA, Rodriguez C, Stevens VL, Patel AV, Thun MJ, Calle EE
Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort.
Breast Cancer Res. 2006;8(2):R22.
INTRODUCTION: Vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis and is over-expressed in breast cancer. At least four polymorphisms in the VEGF gene have been associated with changes in VEGF expression levels: -2578C/A, -1154G/A and -634G/C are all located in the promoter region; and +936C/T is located in the 3'-untranslated region. METHOD: We examined the association between these four VEGF polymorphisms and risk for breast cancer among postmenopausal women in CPS-II (Cancer Prevention Study II) Nutrition Cohort. This cohort was established in 1992 and participants were invited to provide a blood sample between 1998 and 2001. Included in this analysis were 501 postmenopausal women who provided a blood sample and were diagnosed with breast cancer between 1992 and 2001 (cases). Control individuals were 504 cancer-free postmenopausal women matched to the cases with respect to age, race/ethnicity, and date of blood collection (controls). RESULTS: We found no association between any of the polymorphisms examined and overall breast cancer risk. However, associations were markedly different in separate analyses of invasive cancer (n = 380) and in situ cancer (n = 107). The -2578C and -1154G alleles, which are both hypothesized to increase expression of VEGF, were associated with increased risk for invasive breast cancer (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.00-2.14 for -2578 CC versus AA; OR 1.64, 95% CI 1.02-2.64 for -1154 GG versus AA) but they were not associated with risk for in situ cancer. The +936C allele, which is also hypothesized to increase VEGF expression, was not clearly associated with invasive breast cancer (OR 1.21, 95% CI 0.88-1.67 for +936 CC versus TT/CT), but it was associated with reduced risk for in situ cancer (OR 0.59, 95% CI 0.37-0.93 for CC versus TT/CT). The -634 C/G polymorphism was not associated with either invasive or in situ cancer. CONCLUSION: Our findings provide limited support for the hypothesis that the -2578C and -1154G VEGF alleles are associated with increased risk for invasive but not in situ breast cancer in postmenopausal women. [Abstract/Link to Full Text]

Wärnberg F, White D, Anderson E, Knox F, Clarke RB, Morris J, Bundred NJ
Effect of a farnesyl transferase inhibitor (R115777) on ductal carcinoma in situ of the breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo.
Breast Cancer Res. 2006;8(2):R21.
INTRODUCTION: The ras pathway is essential for cell growth and proliferation. The effects of R115777, a farnesyl transferase inhibitor, were investigated in cancer cell lines expressing varying levels of growth factor receptors and with differing ras status. Effects on tumour xenografts and human ductal carcinoma in situ (DCIS) of the breast in a xenograft mouse model were also tested. METHOD: In vitro, the concentrations required to reduce cell numbers by 50% (50% inhibitory concentration) were established (MDA-MB231, MCF-7, MCF-7/HER2-18, BT-474, SK-BR3 and SKOV3). Human DCIS was implanted in nude mice or, in separate experiments, cultured cells were injected (MDA-MB231, MCF-7/HER2-18, SKOV3) and allowed to form tumours. Proliferation and apoptosis were determined by immunohistochemistry in xenografts and cell tumours. RESULTS: The 50% inhibitory concentrations varied a hundred-fold, from 39 nmol/l (+/- 26 nmol/l) for SKBR3 to 5.9 micromol/l(+/- 0.8 micromol/l) for MDA-MB231. In MCF-7/HER2-18 and SKOV3 cells the levels of tumour growth inhibition were approximately 85% and 40%, respectively. There was a significant decrease in the cell turnover index (CTI; proliferation/apoptosis). In MDA-MB 231 with activated k-ras no inhibition was observed. In treated DCIS xenografts proliferation decreased and apoptosis increased. The CTI ratio between the start and 1 and 2 weeks of treatment were 1.99 and 1.50, respectively, for controls and 0.85 (P = 0.005) and 0.75 (P = 0.08) for treated xenografts. CONCLUSION : Treatment with the farnesyl transferase inhibitor reduced cell growth in vitro and cell tumour growth in vivo. In DCIS treatment resulted in a reduced CTI. R115777 is a promising treatment for breast cancer but the relation between effect and growth factor receptor and ras status has to be established. [Abstract/Link to Full Text]

Sloan EK, Pouliot N, Stanley KL, Chia J, Moseley JM, Hards DK, Anderson RL
Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone.
Breast Cancer Res. 2006;8(2):R20.
INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several beta3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific alphavbeta3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of alphavbeta3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of alphavbeta3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. alphavbeta3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, alphavbeta3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, alphavbeta3 increased 66cl4 tumor cell adhesion and alphavbeta3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific alphavbeta3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors. [Abstract/Link to Full Text]

Tovey SM, Dunne B, Witton CJ, Cooke TG, Bartlett JM
HER4 in breast cancer: comparison of antibodies against intra- and extra-cellular domains of HER4.
Breast Cancer Res. 2006;8(2):R19.
INTRODUCTION: We have previously linked HER4 expression with increased survival in breast cancer. However, other reports have associated HER4 with adverse prognostic significance. One possible explanation for the conflicting reports may be that these results are antibody dependent. The HER4 protein is enzymatically cleaved, which may alter the function of its intracellular domain (ICD). We have therefore compared the staining patterns of antibodies against its intracellular and extracellular domains using tissue microarray technology. METHODS: Immunohistochemistry was performed and evaluated on tumours from 402 tamoxifen treated oestrogen receptor positive patients. The HFR1 antibody recognises the ICD of HER4 and thus recognises both the intact receptor and the cleaved ICD. The H4.77.16 clone recognises an extracellular domain of HER4 and thus detects the full length receptor only. RESULTS: Both antibodies demonstrated nuclear, cytoplasmic and membranous staining. Concordance between the membrane staining patterns was high (88.44%, kappa 0.426). The HFR1 antibody, however, demonstrated generally higher levels of cytoplasmic staining (concordance 74.77%, kappa 0.351). The antibodies demonstrated very different patterns of nuclear staining. Over 60% of patients stained with the H4.77.16 had no nuclear staining whereas the vast majority showed staining with the HFR1 antibody (concordance 40.12%, kappa 0.051). Neither antibody demonstrated relationships between membranous or cytoplasmic HER4 staining and survival, although associations were seen with known poor prognostic markers. Cases with H4.77.16-determined nuclear staining had significantly poorer survival outcomes. CONCLUSION: The difference in antigen site may explain the different staining patterns we have seen with respect to location; with each antibody appearing to select for distinct compartments. Thus, HFR1 may select for cytoplasmic and nuclear HER4 ICD, whilst H4.77.16 selects for membranous HER4 and/or HER4 being recycled in cytoplasm or nucleus. This ability to distinguish between site and function of HER4 and its fragments is particularly important, with recent evidence highlighting the different functions of nuclear and mitochondrial HER4. [Abstract/Link to Full Text]

Yanochko GM, Eckhart W
Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells.
Breast Cancer Res. 2006;8(2):R18.
INTRODUCTION: Activation of the type I insulin-like growth factor receptor (IGFIR) promotes proliferation and inhibits apoptosis in a variety of cell types. Transgenic mice expressing a constitutively active IGFIR or IGF-I develop mammary tumors and increased levels of IGFIR have been detected in primary breast cancers. However, the contribution of IGFIR activation in promoting breast cancer progression remains unknown. Mammary epithelial cell lines grown in three-dimensional cultures form acinar structures that mimic the round, polarized, hollow and growth-arrested features of mammary alveoli. We used this system to determine how proliferation and survival signaling by IGFIR activation affects breast epithelial cell biology and contributes to breast cancer progression. METHODS: Pooled, stable MCF-10A breast epithelial cells expressing wild-type IGFIR or kinase-dead IGFIR (K1003A) were generated using retroviral-mediated gene transfer. The effects of over-expression of wild-type or kinase-dead IGFIR on breast epithelial cell biology were analyzed by confocal microscopy of three-dimensional cultures. The contribution of signaling pathways downstream of IGFIR activation to proliferation and apoptosis were determined by pharmacological inhibition of phosphatidylinositol 3' kinase (PI3K) with LY294002, MAP kinase kinase (MEK) with UO126 and mammalian target of rapamycin (mTOR) with rapamycin. RESULTS: We found that MCF-10A cells over-expressing the IGFIR formed large, misshapen acinar structures with filled lumina and disrupted apico-basal polarization. This phenotype was ligand-dependent, occurring with IGF-I or supraphysiological doses of insulin, and did not occur in cells over-expressing the kinase-dead receptor. We observed increased proliferation, decreased apoptosis and increased phosphorylation of Ser473 of Akt and Ser2448 of mTOR throughout IGFIR structures. Inhibition of PI3K with LY294002 or MEK with UO126 prevented the development of acinar structures from IGFIR-expressing but not control cells. The mTOR inhibitor rapamycin failed to prevent IGFIR-induced hyperproliferation and survival signaling. CONCLUSION: Increased proliferation and survival signaling as well as loss of apico-basal polarity by IGFIR activation in mammary epithelial cells may promote early lesions of breast cancer. Three-dimensional cultures of MCF-10A cells over-expressing the IGFIR are a useful model with which to study the role of IGFIR signaling in breast cancer progression and for characterizing the effects of chemotherapeutics targeted to IGFIR signaling. [Abstract/Link to Full Text]

Murray TJ, Yang X, Sherr DH
Growth of a human mammary tumor cell line is blocked by galangin, a naturally occurring bioflavonoid, and is accompanied by down-regulation of cyclins D3, E, and A.
Breast Cancer Res. 2006;8(2):R17.
INTRODUCTION: This study was designed to determine if and how a non-toxic, naturally occurring bioflavonoid, galangin, affects proliferation of human mammary tumor cells. Our previous studies demonstrated that, in other cell types, galangin is a potent inhibitor of the aryl hydrocarbon receptor (AhR), an environmental carcinogen-responsive transcription factor implicated in mammary tumor initiation and growth control. Because some current breast cancer therapeutics are ineffective in estrogen receptor (ER) negative tumors and since the AhR may be involved in breast cancer proliferation, the effects of galangin on the proliferation of an ER-, AhRhigh line, Hs578T, were studied. METHODS: AhR expression and function in the presence or absence of galangin, a second AhR inhibitor, alpha-naphthoflavone (alpha-NF), an AhR agonist, indole-3-carbinol, and a transfected AhR repressor-encoding plasmid (FhAhRR) were studied in Hs578T cells by western blotting for nuclear (for instance, constitutively activated) AhR and by transfection of an AhR-driven reporter construct, pGudLuc. The effects of these agents on cell proliferation were studied by 3H-thymidine incorporation and by flow cytometry. The effects on cyclins implicated in mammary tumorigenesis were evaluated by western blotting. RESULTS: Hs578T cells were shown to express high levels of constitutively active AhR. Constitutive and environmental chemical-induced AhR activity was profoundly suppressed by galangin as was cell proliferation. However, the failure of alpha-NF or FhAhRR transfection to block proliferation indicated that galangin-mediated AhR inhibition was either insufficient or unrelated to its ability to significantly block cell proliferation at therapeutically relevant doses (IC50 = 11 microM). Galangin inhibited transition of cells from the G0/G1 to the S phases of cell growth, likely through the nearly total elimination of cyclin D3. Expression of cyclins A and E was also suppressed. CONCLUSION: Galangin is a strong inhibitor of Hs578T cell proliferation that likely mediates this effect through a relatively unique mechanism, suppression of cyclin D3, and not through the AhR. The results suggest that this non-toxic bioflavonoid may be useful as a chemotherapeutic, particularly in combination with agents that target other components of the tumor cell cycle and in situations where estrogen receptor-specific therapeutics are ineffective. [Abstract/Link to Full Text]

Crawford NP, Ziogas A, Peel DJ, Hess J, Anton-Culver H, Hunter KW
Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer.
Breast Cancer Res. 2006;8(2):R16.
INTRODUCTION: There is growing evidence that heritable genetic variation modulates metastatic efficiency. Our previous work using a mouse mammary tumor model has shown that metastatic efficiency is modulated by the GTPase-activating protein encoded by Sipa1 ('signal-induced proliferation-associated gene 1'). The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) within the human SIPA1 gene are associated with metastasis and other disease characteristics in breast cancer. METHOD: The study population (n = 300) consisted of randomly selected non-Hispanic Caucasian breast cancer patients identified from a larger population-based series. Genomic DNA was extracted from peripheral leukocytes. Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR. RESULTS: The variant 2760G>A and the -313G>A allele were associated with lymph node involvement (P = 0.0062 and P = 0.0083, respectively), and the variant 545C>T was associated with estrogen receptor negative tumors (P = 0.0012) and with progesterone negative tumors (P = 0.0339). Associations were identified between haplotypes defined by the three SNPs and disease progression. Haplotype 3 defined by variants -313G>A and 2760G>A was associated with positive lymph node involvement (P = 0.0051), and haplotype 4 defined by variant 545C>T was associated with estrogen receptor and progesterone receptor negative status (P = 0.0053 and P = 0.0199, respectively). CONCLUSION: Our findings imply that SIPA1 germline polymorphisms are associated with aggressive disease behavior in the cohort examined. If these results hold true in other populations, then knowledge of SIPA1 SNP genotypes could potentially enhance current staging protocols. [Abstract/Link to Full Text]

Friedman E, Kotsopoulos J, Lubinski J, Lynch HT, Ghadirian P, Neuhausen SL, Isaacs C, Weber B, Foulkes WD, Moller P, Rosen B, Kim-Sing C, Gershoni-Baruch R, Ainsworth P, Daly M, Tung N, Eisen A, Olopade OI, Karlan B, Saal HM, Garber JE, Rennert G, Gilchrist D, Eng C, Offit K, Osborne M, Sun P, Narod SA
Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.
Breast Cancer Res. 2006;8(2):R15.
INTRODUCTION: BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. METHODS: In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. RESULTS: There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16-0.83; p = 0.02). CONCLUSION: Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers. [Abstract/Link to Full Text]

Scutt D, Lancaster GA, Manning JT
Breast asymmetry and predisposition to breast cancer.
Breast Cancer Res. 2006;8(2):R14.
INTRODUCTION: It has been shown in our previous work that breast asymmetry is related to several of the known risk factors for breast cancer, and that patients with diagnosed breast cancer have more breast volume asymmetry, as measured from mammograms, than age-matched healthy women. METHODS: In the present study, we compared the breast asymmetry of women who were free of breast disease at time of mammography, but who had subsequently developed breast cancer, with that of age-matched healthy controls who had remained disease-free to time of the present study. The study group consisted of 252 asymptomatic women who had normal mammography, but went on to develop breast cancer. The control group were 252 age-matched healthy controls whose mammograms were also normal and who remained free of cancer during the study period. Breast volume was calculated from the cranio-caudal mammograms for each group, and the relationships between asymmetry, established risk factors and the presence or absence of breast cancer were explored. RESULTS: The group who went on to develop breast cancer had higher breast asymmetry than controls (absolute asymmetry odds ratio 1.50 per 100 ml, confidence interval (CI) 1.10, 2.04; relative asymmetry 1.09, CI 1.01, 1.18), increased incidence of family history of breast cancer, lower age at menarche, later menopause, later first pregnancies and a higher frequency of high risk breast parenchyma types. Conditional logistic regression analysis showed that breast asymmetry, height, family history of breast cancer, age at menarche, parenchyma type and menopausal status were significant independent predictors of breast cancer. When age at menopause was included in the model for the subgroup of post-menopausal women, absolute breast fluctuating asymmetry (FA) and relative breast FA remained significant effects. CONCLUSION: Breast asymmetry was greater in healthy women who later developed breast cancer than in women who did not. [Abstract/Link to Full Text]

Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, Ashley S, Smith I, Ottestad L, Kanis J
Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026].
Breast Cancer Res. 2006;8(2):R13.
INTRODUCTION: Experimental and clinical data show that the oral bisphosphonate clodronate (Bonefos) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival. METHODS: 1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated. RESULTS: Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event. CONCLUSION: These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer. [Abstract/Link to Full Text]

Sternlicht MD
Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis.
Breast Cancer Res. 2006;8(1):201.
Part of how the mammary gland fulfills its function of producing and delivering adequate amounts of milk is by forming an extensive tree-like network of branched ducts from a rudimentary epithelial bud. This process, termed branching morphogenesis, begins in fetal development, pauses after birth, resumes in response to estrogens at puberty, and is refined in response to cyclic ovarian stimulation once the margins of the mammary fat pad are met. Thus it is driven by systemic hormonal stimuli that elicit local paracrine interactions between the developing epithelial ducts and their adjacent embryonic mesenchyme or postnatal stroma. This local cellular cross-talk, in turn, orchestrates the tissue remodeling that ultimately produces a mature ductal tree. Although the precise mechanisms are still unclear, our understanding of branching in the mammary gland and elsewhere is rapidly improving. Moreover, many of these mechanisms are hijacked, bypassed, or corrupted during the development and progression of cancer. Thus a clearer understanding of the underlying endocrine and paracrine pathways that regulate mammary branching may shed light on how they contribute to cancer and how their ill effects might be overcome or entirely avoided. [Abstract/Link to Full Text]


Symposium Mammographicum 2000, Meeting Abstracts, York, United Kingdom, 4 - 6 October 2000.
Breast Cancer Res. 2000;2 Suppl 2A1-70. [Abstract/Link to Full Text]

Rosenberg LU, Magnusson C, Lindström E, Wedrén S, Hall P, Dickman PW
Menopausal hormone therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study.
Breast Cancer Res. 2006;8(1):R11.
INTRODUCTION: Breast cancers of different histology have different clinical and prognostic features. There are also indications of differences in aetiology. We therefore evaluated the risk of the three most common histological subtypes in relation to menopausal hormone therapy and other breast cancer risk factors. METHODS: We used a population-based case-control study of breast cancer to evaluate menopausal hormone therapy and other breast cancer risk factors for risk by histological subtype. Women aged 50 to 74 years, diagnosed with invasive ductal (n = 1,888), lobular (n = 308) or tubular (n = 93) breast cancer in Sweden in 1993 to 1995 were compared with 3,065 age-frequency matched controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ductal, lobular, and tubular cancer. RESULTS: Women who had used medium potency estrogen alone were at increased risks of both ductal and lobular cancer. Medium potency estrogen-progestin was associated with increased risks for all subtypes, but the estimates for lobular and tubular cancer were higher compared with ductal cancer. We found OR 5.6 (95% CI 3.2-9.7) for lobular cancer, OR 6.5 (95% CI 2.8-14.9) for tubular cancer and OR 2.3 (95% CI 1.6-3.3) for ductal cancer with > or =5 years use of medium potency estrogen-progestin therapy. Low potency oral estrogen (mainly estriol) appeared to be associated with an increased risk for lobular cancer, but the association was strongest for short-term use. Reproductive and anthropometric factors, smoking, and past use of oral contraceptives were mostly similarly related to the risks of the three breast cancer subtypes. Recent alcohol consumption of > 10 g alcohol/day was associated with increased risk only for tubular cancer (OR 3.1, 95% CI 1.4-6.8). CONCLUSION: Menopausal hormone therapy was associated with increased risks for breast cancer of both ductal and lobular subtype, and medium potency estrogen-progestin therapy was more strongly associated with lobular compared with ductal cancer. We also found medium potency estrogen-progestin therapy and alcohol to be strongly associated with tubular cancer. With some exceptions, most other risk factors seemed to be similarly associated with the three subtypes of breast cancer. [Abstract/Link to Full Text]

Mann GJ, Thorne H, Balleine RL, Butow PN, Clarke CL, Edkins E, Evans GM, Fereday S, Haan E, Gattas M, Giles GG, Goldblatt J, Hopper JL, Kirk J, Leary JA, Lindeman G, Niedermayr E, Phillips KA, Picken S, Pupo GM, Saunders C, Scott CL, Spurdle AB, Suthers G, Tucker K, Chenevix-Trench G
Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource.
Breast Cancer Res. 2006;8(1):R12.
INTRODUCTION: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives. METHODS: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study. RESULTS: Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue--both normal and malignant--including 126 from carriers of BRCA1 or BRCA2 mutations. CONCLUSION: These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected. [Abstract/Link to Full Text]

Tromberg BJ, Cerussi A, Shah N, Compton M, Durkin A, Hsiang D, Butler J, Mehta R
Imaging in breast cancer: diffuse optics in breast cancer: detecting tumors in pre-menopausal women and monitoring neoadjuvant chemotherapy.
Breast Cancer Res. 2005;7(6):279-85.
Diffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) are non-invasive diagnostic techniques that employ near-infrared (NIR) light to quantitatively characterize the optical properties of centimeter-thick, multiple-scattering tissues. Although NIR was first applied to breast diaphanography more than 70 years ago, quantitative optical methods employing time- or frequency-domain 'photon migration' technologies have only recently been used for breast imaging. Because their performance is not limited by mammographic density, optical methods can provide new insight regarding tissue functional changes associated with the appearance, progression, and treatment of breast cancer, particularly for younger women and high-risk subjects who may not benefit from conventional imaging methods. This paper reviews the principles of diffuse optics and describes the development of broadband DOS for quantitatively measuring the optical and physiological properties of thick tissues. Clinical results are shown highlighting the sensitivity of diffuse optics to malignant breast tumors in 12 pre-menopausal subjects ranging in age from 30 to 39 years and a patient undergoing neoadjuvant chemotherapy for locally advanced breast cancer. Significant contrast was observed between normal and tumor regions of tissue for deoxy-hemoglobin (p = 0.005), oxy-hemoglobin (p = 0.002), water (p = 0.014), and lipids (p = 0.0003). Tissue hemoglobin saturation was not found to be a reliable parameter for distinguishing between tumor and normal tissues. Optical data were converted into a tissue optical index that decreased 50% within 1 week in response to neoadjuvant chemotherapy. These results suggest a potential role for diffuse optics as a bedside monitoring tool that could aid the development of new strategies for individualized patient care. [Abstract/Link to Full Text]

Mankoff D
Imaging in breast cancer - breast cancer imaging revisited.
Breast Cancer Res. 2005;7(6):276-8. [Abstract/Link to Full Text]

Kumar AS, Bhatia V, Henderson IC
Overdiagnosis and overtreatment of breast cancer: rates of ductal carcinoma in situ: a US perspective.
Breast Cancer Res. 2005;7(6):271-5.
The incidence of breast ductal carcinoma in situ (DCIS) in the USA exceeds that of other countries. This cannot be explained entirely by the frequency of mammographic screening in the USA and may result from differences in the interpretation of mammograms and/or the frequency with which biopsies are obtained. Although the percentage of DCIS patients treated with mastectomy has decreased, the absolute number is unchanged and the use of lumpectomy with whole-breast radiotherapy has increased in inverse proportion to the decrease in mastectomy. Treatment of DCIS with tamoxifen is still limited. [Abstract/Link to Full Text]

Paci E, Duffy S
Overdiagnosis and overtreatment of breast cancer: overdiagnosis and overtreatment in service screening.
Breast Cancer Res. 2005;7(6):266-70.
Screening mammography has been shown to be effective for reducing breast cancer mortality. According to screening theory, the first expected consequence of mammography screening is the detection of the disease at earlier stages and this diagnostic anticipation changes the population incidence curve, with an observed increase in incidence rates at earlier ages. It is unreasonable to expect that the age-specific incidence will ever return to pre-screening levels or to anticipate a significant reduction of incidence at older ages immediately after the first screening round. The interpretation of incidence trends, especially in the short term, is difficult. Methodology for quantification of overdiagnosis and statistical modelling based on service screening data is not well developed and few population-based studies are available. The overtreatment issue is discussed in terms of appropriateness of effective treatment considering the question of chemotherapy in very early stages and the use of breast conserving surgery. [Abstract/Link to Full Text]

Duffy SW, Agbaje O, Tabar L, Vitak B, Bjurstam N, Björneld L, Myles JP, Warwick J
Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer.
Breast Cancer Res. 2005;7(6):258-65.
Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1% of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1% of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation. [Abstract/Link to Full Text]

Ligibel JA, Winer EP
Aromatase inhibitors as adjuvant therapy for postmenopausal women: a therapeutic advance but many unresolved questions.
Breast Cancer Res. 2005;7(6):255-7.
Adjuvant hormonal therapy for postmenopausal women with early stage breast cancer has become far more complex over the past several years. This commentary reviews the current status of the five major trials evaluating the use of the aromatase inhibitors in the adjuvant setting. The data currently available suggest that the aromatase inhibitors are efficacious either as upfront therapy or after a course of tamoxifen. Ongoing trials will compare these approaches and guide the use of these agents in the years to come. [Abstract/Link to Full Text]

Naylor TL, Greshock J, Wang Y, Colligon T, Yu QC, Clemmer V, Zaks TZ, Weber BL
High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization.
Breast Cancer Res. 2005;7(6):R1186-98.
INTRODUCTION: Genomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution. METHODS: We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines. RESULTS: Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses. CONCLUSION: High resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets. [Abstract/Link to Full Text]

Schindlbeck C, Kampik T, Janni W, Rack B, Jeschke U, Krajewski S, Sommer H, Friese K
Prognostic relevance of disseminated tumor cells in the bone marrow and biological factors of 265 primary breast carcinomas.
Breast Cancer Res. 2005;7(6):R1174-85.
INTRODUCTION: The prognostic significance of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has been demonstrated in many studies. Yet, it is not clear which of the primary tumors' biological factors predict hematogenous dissemination. We therefore examined 'tissue micro arrays' (TMAs) of 265 primary breast carcinomas from patients with known bone marrow (BM) status for HER2, Topoisomerase IIalpha (Top IIa), Ki 67, and p53. METHODS: BM analysis was performed by cytospin preparation and immunocytochemical staining for cytokeratin (CK). TMAs were examined by immunohistochemistry (IHC) for HER2, Top IIa, Ki 67 and p53, and fluorescence in situ hybridization (FISH) for HER2. RESULTS: HER2 (2+/3+) was positive in 35/167 (21%) cases (FISH 24.3%), Top IIa (>10%) in 87/187 (46%), Ki 67 in 52/184 (28%) and p53 (>5%) in 61/174 cases (34%). Of 265 patients, 68 (25.7%) showed DTC-BM with a median of 2/2 x 106 cells (1 to 1,500). None of the examined factors significantly predicted BM positivity. Significant correlation was seen between HER2 IHC and Top IIa (p = 0.06), Ki 67 (p = 0.031), and p53 (p < .001). Top IIa correlated with Ki 67 and p53, and Ki 67 also with p53 (p = 0.004). After a median follow-up of 60.5 months (7 to 255), the presence of DTC-BM showed prognostic relevance for overall survival (p = 0.03), whereas HER2 (IHC, p = 0.04; FISH, p = 0.03) and Ki 67 (p = 0.04) correlated with disease free survival, and HER2 with distant disease free survival (IHC, p = 0.06; FISH, p = 0.05). DISCUSSION: The congruence of the examined factors' expression rates indicates a causal line of suppressor, proliferation, and mitosis markers, and growth factor receptors. Hematogenous tumor cell spread seems to be an independent process. The examination of these factors on DTC-BM is the aim of ongoing research. [Abstract/Link to Full Text]

Patel AV, Calle EE, Pavluck AL, Feigelson HS, Thun MJ, Rodriguez C
A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk.
Breast Cancer Res. 2005;7(6):R1168-73.
INTRODUCTION: The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA. METHODS: Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer. RESULTS: We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk. CONCLUSION: Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes. [Abstract/Link to Full Text]

Dalenc F, Giamarchi C, Petit M, Poirot M, Favre G, Faye JC
Farnesyl-transferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways.
Breast Cancer Res. 2005;7(6):R1159-67.
INTRODUCTION: We have previously shown that FTI-277, a farnesyl transferase inhibitor (FTI), enhances the efficacy of tamoxifen (Tam) in inhibiting the proliferation of the estrogen dependent MCF-7 cell line. As the cellular response to Tam is the result of an inhibition of both estrogen receptor-dependent and -independent pathways, we have used the estrogen receptor selective anti-estrogen ICI182,780 and N-pyrrolidine(-phenylmethyl-phenoxy)-ethanamine-HCl (PBPE), a selective ligand of anti-estrogen binding site (AEBS), to dissect out the mechanism(s) associated with the observed additivity resulting from combination treatment with FTI-277 and Tam. Moreover, for these studies, FTI-277 has been replaced by R115,777, a FTI currently in phase III clinical trials. METHODS: The quantitative sulphorhodamine B (SRB) colorimetric assay was used to determine the growth inhibitory effect of agents on MCF-7 cells. Dose response interactions between R115,777-Tam, R115,777-ICI182,780 and R115,777-PBPE were evaluated, at the IC50 point, using the isobologram method. Apoptotic cell death (DNA fragmentation, nucleus condensation and cytokeratin 18 cleavage) and inhibition of the mevalonate pathway (western blot) were also determined. RESULTS: Combinations of the specific FTI R115,777 with either ICI182,780 or PBPE exhibit a synergistic effect on MCF-7 cell growth inhibition, while its combination with Tam is additive, as previously reported for FTI-277. Apoptosis is detected after treatment with combinations of R115,777 with either Tam or PBPE but not with ICI182,780, suggesting that each combination inhibits cell proliferation by different mechanisms. Even though the ER pathway has not yet been deciphered, it is shown here that the AEBS pathway is able to interfere with the mevalonate pathway at the level of protein farnesylation. CONCLUSION: Overall, this work reveals that combinations of R115,777 with either selective ER ligands or a selective AEBS ligand are able to induce large increases in their anti-proliferative activities on MCF-7 cells. Moreover, these results suggest that it may be of definite interest to evaluate combinations of R115,777 with different anti-estrogens in the treatment of ER positive breast tumours. Based on these experimental data, such combinations may prove beneficial in different clinical scenarios or when used in specific sequences; studying the combination of R115,777 with ICI182,780 for early treatment and reserving combinations with either Tam or a selective AEBS ligand, such as BMS-217380-01, for more resistant disease. [Abstract/Link to Full Text]

Esserman LJ, Ozanne EM, Dowsett M, Slingerland JM
Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis.
Breast Cancer Res. 2005;7(6):R1153-8.
INTRODUCTION: Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers. METHODS: BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate. RESULTS: If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%. CONCLUSION: Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection. [Abstract/Link to Full Text]

Stoff-Khalili MA, Stoff A, Rivera AA, Banerjee NS, Everts M, Young S, Siegal GP, Richter DF, Wang M, Dall P, Mathis JM, Zhu ZB, Curiel DT
Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system.
Breast Cancer Res. 2005;7(6):R1141-52.
INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin. METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver. RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells. CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast. [Abstract/Link to Full Text]

Shilkaitis A, Green A, Punj V, Steele V, Lubet R, Christov K
Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism.
Breast Cancer Res. 2005;7(6):R1132-40.
INTRODUCTION: Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17beta-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved. METHODS: Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined. RESULTS: Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action. CONCLUSION: We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects. [Abstract/Link to Full Text]

Recent Articles in International Seminars in Surgical Oncology

Harmon RL, Sugarbaker PH
Prognostic indicators in peritoneal carcinomatosis from gastrointestinal cancer.
Int Semin Surg Oncol. 2005 Feb 8;2(1):3.
Peritoneal carcinomatosis from gastrointestinal cancer has new treatment options for surgical management. The approach uses cytoreductive surgery which combines peritonectomy and visceral resection in an effort to remove all visible cancer within the abdomen and pelvis. Then the peritoneal cavity is flooded with chemotherapy solution in an attempt to eradicate residual disease. In order to select patients for this approach the quantitative prognostic indicators for carcinomatosis were reviewed, compared and contrasted. Prognostic indicators to be used to select patients for this aggressive approach at the initiation of surgery and after completion of cytoreduction were studied. Four quantitative assessments to be used at the time of abdominal exploration were the Gilly staging, Japanese gastric cancer P score, peritoneal cancer index (PCI), and the simplified peritoneal cancer index (SPCI). All have value with the PCI being the most validated and most precise. Preoperative assessments include the tumor histopathology and the prior surgical score. The completeness of cytoreduction score is an assessment of residual disease after a maximal surgical effort. An opportunity for long-term survival following treatment for carcinomatosis requires a complete cytoreduction in all reports for gastrointestinal cancer. Quantitative prognostic indicators need to be knowledgeably employed when patients with carcinomatosis are being treated. Improved patient selection with greater benefit and reduced morbidity and mortality should result. [Abstract/Link to Full Text]

Quan GM, Carr D, Schlicht S, Powell G, Choong PF
Lessons learnt from the painful shoulder; a case series of malignant shoulder girdle tumours misdiagnosed as frozen shoulder.
Int Semin Surg Oncol. 2005 Jan 12;2(1):2.
Adhesive capsulitis or frozen shoulder is a common condition characterized by shoulder pain and stiffness. In patients in whom conservative measures have failed, more invasive interventions such as arthrographic or arthroscopic distension can be very effective in relieving symptoms and improving range of movement. However, absolute contraindications to these procedures include the presence of neoplasia around the shoulder girdle. We present five cases referred to our institution where the diagnosis of shoulder joint malignancy was delayed, following prolonged, ineffective treatment for frozen shoulder. These cases highlight the importance of careful review of the radiology and the need for reconsideration of the diagnosis in refractory "frozen shoulder". [Abstract/Link to Full Text]

Copcu E, Aktas A
Simultaneous two organ metastases of the giant basal cell carcinoma of the skin.
Int Semin Surg Oncol. 2005 Jan 4;2(1):1.
BACKGROUND: Basal Cell Carcinoma (BCC) is the most common carcinoma in humans. It accounts for 20% of carcinomas in men and 10-15% of carcinomas in women. Despite its high incidence, metastatic events are exceedingly rare. The reported frequency of metastatic dissemination is estimated at 0.0028-0.5 percent. Once metastasis is detected, there is a high mortality rate of 50% within 8 months. METHODS: In this study, we present a case of simultaneous lung and parotid metastases of giant BCC primary located on the right medial canthus of a 62 year old female. RESULTS: Examination of the tumor located on the medial canthus obtained showed "adenoid BCC". Computed tomography (CT) was performed to evaluate parotid region for evaluation of parotid gland and chest. Parotid and lung metastasis were detected in CT. Routine labarotory tests and radiological investigations were done. There was no abnormal finding. We also investigated this patient with a bone scan (normal), abdominal and cranial CT scans (also normal). CONCLUSION: Although metastasis of BCC is a very rare condition, this study reports a case of simultaneous parotid gland and lung metastasis originating from a giant BCC primary that was located on the right inner canthus of a 62 year old female. [Abstract/Link to Full Text]

Fadare O, Hart HJ
Anti-Ri antibodies associated with short-term memory deficits and a mature cystic teratoma of the ovary.
Int Semin Surg Oncol. 2004 11 10;1(1):11.
BACKGROUND: The IgG autoantibody ANNA-2 (anti-Ri) is a type 2 antineuronal antibody that has been found to bind to highly conserved and widely distributed adult brain proteins encoded by the Nova-1 and Nova-2 genes. Anti-Ri antibodies are typically detected in the serum and cerebrospinal fluids of patients with neurological disorders such as opsoclonus/myoclonus and cerebellar ataxia and in association with gynecologic and breast malignancies. CASE PRESENTATION: This report describes an unusual example of a 33-year-old female patient who developed short-term memory deficits over a 3-month period. An extensive neurological work-up, including a panel of paraneoplastic markers was negative with the exception of a high titer serum Anti-Ri (1:15,3600). A large left ovarian mass was palpated, surgically resected and eventually diagnosed as a mature cystic teratoma. Post-operatively, memory deficits had disappeared within 1 month and serum Anti-Ri titers had decreased significantly to 1:256. An extensive diagnostic work-up for other malignancies was negative. CONCLUSION: Although, Anti-Ri antibodies are typically associated with malignancies, this case illustrates the potential association between benign tumors and this autoantibody. [Abstract/Link to Full Text]

Jatoi A, Martenson J, Mahoney MR, Lair BS, Brindle JS, Nichols F, Caron N, Rowland K, Tschetter L, Alberts S
Results of a planned interim toxicity analysis with trimodality therapy, including carboplatin AUC = 4, paclitaxel, 5-fluorouracil, amifostine, and radiation for locally advanced esophageal cancer: preliminary analyses and treatment recommendations from the North Central Cancer Treatment Group.
Int Semin Surg Oncol. 2004 11 8;1(1):9.
PURPOSE: An aggressive trimodality approach from the Minnie Pearl Cancer Research Network [carboplatin AUC = 6, days 1 and 22; 5-fluorouracil 225 mg/m2 continuous infusion, days 1-42, paclitaxel 200 mg/m2, days 1 and 22; 45 Gy] has resulted in remarkable pathologic response rates but notable toxicity. This trial was designed to mitigate this toxicity by starting with a lower carboplatin dose, AUC = 4, and by adding subcutaneous amifostine. METHODS: This phase II trial included patients with locally advanced, potentially resectable esophageal cancer. All were to receive the above regimen with modifications of carboplatin AUC = 4 and amifostine 500 mg subcutaneously before radiation. All were then to undergo an esophagectomy. A planned interim toxicity analysis after the first 10 patients was to determine whether the carboplatin dose should escalate to AUC = 6. RESULTS: Ten patients were enrolled, and all required dose reductions/omissions during neoadjuvant therapy. One patient died from paclitaxel anaphylaxis. Six patients manifested a complete pathologic response. CONCLUSION: With this regimen, carboplatin AUC = 4 for patients with locally advanced esophageal cancer is appropriate. [Abstract/Link to Full Text]

Choong PF, Kunisada T, Slavin J, Schlicht S, Hicks R
The role of thallium-201 and pentavalent dimercaptosuccinic acid for staging cartilaginous tumours.
Int Semin Surg Oncol. 2004 11 8;1(1):10.
INTRODUCTION: Heterogeneity of cartilage tumours may confound accurate diagnosis and grading resulting in under and over treatment. Improved preoperative assessment of malignancy and grade would be invaluable for developing a rational plan for treatment. We examined correlations between nuclear tracer avidity and malignancy grade in cartilage tumours. METHODS: Between 1996 and 2000, 92 consecutive patients with cartilaginous tumours (50 benign, 42 non-metastatic malignant) underwent nuclear scanning. Thallium-201 (TL-201) and pentavalent dimercaptosuccinic acid (DMSAV) were used as nuclear isotopes. Scanning with these agents was performed on separate days 48 hours apart. Static and SPECT images were obtained at 30 m and 4 h after injection of nuclear tracer. Pathology review was undertaken blinded to the results of the nuclear scans and correlations between histologic results and trace uptake at 4 hours examined. RESULTS: 25 patients with negative DMSAV had benign tumours. 15/17 tumours with positive TL-201 had malignant tumours. 11/13 patients with both positive DMSAV and TL-201 scans had intermediate or high grade tumours and 4 of these developed metastases. We have developed an algorithm for the management of patients with tumours that aims to avoid over treatment of low grade tumours and under treatment of high grade tumours. CONCLUSION: Functional nuclear scanning with TL-201 and DMSAV complements other imaging modalities in the management of cartilaginous tumours. [Abstract/Link to Full Text]

Harish K, Narayanaswamy Y, Nirmala S
Treatment outcomes in locally advanced colorectal carcinoma.
Int Semin Surg Oncol. 2004 11 4;1(1):8.
BACKGROUND: Locally advanced colorectal cancers form a distinct subgroup where contiguous organs could be involved without distant metastases and so may be amenable to curative surgical resection. It was our objective to report our experience in treating six such patients with operable locally advanced colorectal carcinomas. METHODS: We retrospectively reviewed the case notes of 47 patients who were diagnosed with colorectal cancers at M S Ramaiah Medical Teaching Hospital between the years 1996 - 2001. Six patients were identified with T4 lesions, adjacent organ involvement and with no nodal involvement. The treatments and outcomes for these patients were then reviewed. RESULTS: Two of three patients with rectal malignancies who underwent pelvic exenteration succumbed to disease recurrence within the first 18 months. One of the three patients with colonic cancers died of non malignant causes. The other two are disease free till date. CONCLUSIONS: Aggressive multivisceral resections for locally advanced colonic cancers might be appropriate. Rectal cancers when locally advanced may be considered for pelvic exenteration, but a more guarded prognosis may apply. [Abstract/Link to Full Text]

Morsi H, Yong KL, Jewell AP
Evaluation of the Taguchi methods for the simultaneous assessment of the effects of multiple variables in the tumour microenvironment.
Int Semin Surg Oncol. 2004 9 20;1(1):7.
BACKGROUND: The control of proliferation, differentiation and survival of normal and malignant cells in the tumour microenvironment is under the control of a wide range of different factors, including cell:cell interactions, cytokines, growth factors and hormonal influences. However, the ways in which these factors interact are poorly understood. In order to compare the effects of multiple variables, experimental design becomes complex and difficult to manage. We have therefore evaluated the use of a novel approach to multifactorial experimental design, the Taguchi methods, to approach this problem. METHOD: The Taguchi methods are widely used by quality engineering scientists to compare the effects of multiple variables, together with their interactions, with a simple and manageable experimental design. In order to evaluate these methods, we have used a simple and robust system to compare a traditional experimental design with the Taguchi Methods. The effect of G-CSF, GM-CSF, IL3 and M-CSF on daunorubicin mediated cytotoxicity in K562 cells was measured using the MTT assay. RESULTS: Both methods demonstrated that the same combination of growth factors at the same concentrations minimised daunorubicin cytotoxicity in this assay. CONCLUSIONS: These findings demonstrate that Taguchi methods may be a valuable tool for the investigation of the interactions of multiple variables in the tumour microenvironment. [Abstract/Link to Full Text]

Gupta T, Agarwal JP
Planned neck dissection following chemo-radiotherapy in advanced HNSCC.
Int Semin Surg Oncol. 2004 Sep 17;1(1):6.
BACKGROUND: Neck dissection has traditionally played an important role in the management of patients with regionally advanced head and neck squamous cell carcinoma (HNSCC) treated with radical radiotherapy alone. However, with the incorporation of chemotherapy in the therapeutic strategy for advanced HNSCC and resultant improvement in outcome the routine use of post chemo-radiotherapy neck dissection is being questioned. METHODS: Published data for this review was identified by systematically searching MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language. RESULTS: There is lack of high quality evidence on the role of planned neck dissection in advanced HNSCC treated with chemo-radiotherapy. A systematic literature search could identify only one small randomized controlled trial (Level I evidence) addressing this issue, albeit with major limitations. Upfront neck dissection followed by chemo-radiotherapy resulted in better disease-specific survival as compared to chemoradiation only. Several single arm prospective and retrospective reports were also identified with significant heterogeneity and often-contradictory conclusions. CONCLUSIONS: Planned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. Unless there are better non-invasive ways to identify residual viable disease, the role of such neck dissection shall remain debatable. A large randomized controlled trial addressing this issue is needed to clarify its role and provide evidence-based answers. [Abstract/Link to Full Text]

Copcu E, Sivrioglu N
The new reconstruction technique in the treatment of the skin cancers located on the eyelid: Posterior temporalis fascia composite graft.
Int Semin Surg Oncol. 2004 Aug 11;1(1):5.
BACKGROUND: Difficulty of reconstruction of the eyelids arises from the need to reconstruct different supporting and covering structures in a single operation. Defects in the anterior lamella of the eyelids can be readily repaired with skin grafts or flaps but posterior lamellar reconstruction needs more complex applications. METHODS: We performed posterior lamellar eyelid reconstruction with posterior parts of the temporalis fascia, since their anatomical and histological features are very similar to the defects. Nine patients with skin tumors located on the periorbital region were treated with local skin flaps and deep layer of the temporalis fascia. RESULTS: Grafts were harvested very easily. There was no complication related with graft or donor site. Biopsy was performed in three cases and normal conjunctival elements were seen. Functional and acceptable aesthetically results were achieved in all patients. CONCLUSION: Ideal reconstructive material for replacement of the posterior lamina is still lacking. Tarsal reconstruction can be made with deep temporalis fascia with success since the thickness of the both tissues are very similar and also since the loose areolar layer of the temporalis fascia is very thin and highly vascularized, this layer can be used in reconstruction of the conjunctiva. According to our knowledge this is the first report of using of the posterior part of temporalis fascia as a composite graft in the literature. [Abstract/Link to Full Text]

Singh-Ranger G, Hussein M
Welcome To International Seminars In Surgical Oncology.
Int Semin Surg Oncol. 2004 Apr 23;1(1):1.
This editorial marks the launch of a new online journal for surgical and medical oncology. The internet has produced a profound shift in the way in which clinicians, researchers and patients seek, interpret and utilise medical information and research. The launch of our journal comes at a time when these changes are in a rapid phase of development and consolidation. [Abstract/Link to Full Text]

Kirkpatrick KL, Newbold RF, Mokbel K
There is no correlation between c-Myc mRNA expression and telomerase activity in human breast cancer.
Int Semin Surg Oncol. 2004 May 6;1(1):2.
BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. The hTERT (human telomerase reverse transcriptase) subunit seems to be the rate-limiting determinant of telomerase and knowledge of factors controlling hTERT transcription may be useful in therapeutic strategies. The hTERT promoter contains binding sites for c-Myc and there is experimental and in vitro evidence that c-Myc may increase hTERT expression. MATERIALS AND METHODS: RNA was extracted from 18 breast carcinomas and c-Myc mRNA expression was estimated by quantitative reverse transcriptase-PCR (RT-PCR) with Taqman methodology. These tumours had already been analysed for ER and PgR status using ligand-binding assays and had had their DNA ploidy and S-phase fractions measured by flow cytometry. Telomerase activity had already been determined by using a modified telomeric repeat and amplification protocol (TRAP) assay. RESULTS: Telomerase activity ranged from 0 to 246 units of Total Protein Generated (TPG), where one unit of TPG was equal to 600 molecules of telomerase substrate primers extended by at least three telomeric repeats. Median levels of TPG were 60 and mean levels 81. There was no significant correlation between levels of c-Myc mRNA expression, telomerase activity, S phase fraction or PgR. There was a significant negative correlation with ER status. CONCLUSION: Although the hTERT promoter contains potential binding sites for c-Myc oncoprotein, we have found no correlation between c-Myc mRNA levels and telomerase activity. [Abstract/Link to Full Text]

Singh-Ranger G, Mokbel K
Capsular contraction following immediate reconstructive surgery for breast cancer - An association with methylene blue dye.
Int Semin Surg Oncol. 2004 May 11;1(1):3.
Capsular contraction following implantation of breast prostheses occurs in 2-33% of patients undergoing breast augmentation. This condition can be debilitating for patients, and often requires revisional surgery. The aetiology of capsular contraction is unclear, but may be due to infection, haematoma or foreign body-type reactions.Methylene blue dye is a substance known to cause localised tissue inflammation, and is often used during breast cancer surgery to allow identification of the sentinel lymph node. We report a case of Baker Grade 4 capsular contraction necessitating revisional surgery, occurring in a patient who underwent immediate breast reconstruction during surgery for breast cancer. Methylene blue dye was used to locate the sentinel nodes during the original surgery, and was found to have heavily discoloured the prosthesis at subsequent revisional surgery. Capsular contraction may have been caused in part by a localised tissue reaction initiated by, or involving the dye. [Abstract/Link to Full Text]

Singh-Ranger G, Sharp A, Crinnion JN
Recurrence of granulosa cell tumour after thirty years with small bowel obstruction.
Int Semin Surg Oncol. 2004 May 11;1(1):4.
Granulosa cell tumours of the ovary are rare, comprising around 3% of ovarian tumours. These tumours have preponderance for local spread and extremely late recurrence. Although previous cases of recurrence have been described, it is extremely unusual for these tumours to recur after thirty years. We describe a case of recurrence of granulosa cell tumour after 30 years, presenting as small bowel obstruction. The patient had not been followed up after the original surgery, and on histological analysis, recurrence of the original tumour was confirmed. This case report emphasises the necessity for lifelong follow-up of patients who have had these tumours excised, and also the unusual way in which these tumours can recur. [Abstract/Link to Full Text]

Recent Articles in World Journal of Surgical Oncology

Lohsiriwat V, Lohsiriwat D, Chinswangwatanakul V, Akaraviputh T, Lert-Akyamanee N
Comparison of short-term outcomes between laparoscopically-assisted vs. transverse-incision open right hemicolectomy for right-sided colon cancer: a retrospective study.
World J Surg Oncol. 2007;549.
BACKGROUND: Laparoscopically-assisted right hemicolectomy (LRH) is an acceptable alternative to open surgery for right-sided colon cancer which offers patients less pain and faster recovery. However, special equipment and substantial surgical experience are required. The aim of the study is to compare the short-term surgical outcomes of LRH and open right hemicolectomy through right transverse skin crease incision (ORHT) for right-sided colon cancer. PATIENTS AND METHODS: This retrospective study included 33 patients with right-sided colon cancer who underwent elective right hemicolectomy by laparoscopic or open approaches through right transverse skin crease incision between March 2004 and September 2006 at the Department of Surgery, Faculty of Medicine Siriraj Hospital. Operative details, postoperative requirement of narcotics, recovery of bowel function, and oncological parameters were analyzed. RESULTS: Thirteen patients underwent LRH and 20 patients underwent ORHT. Both approaches achieved adequate oncological resection of the tumor. The laparoscopic group were characterized by shorter average incision lengths (7.7 vs 10.3 cm; p < 0.001), but longer average operating times (208 vs 105 min; p < 0.001). There was no significant difference in the time to first bowel movement, time to defecation, and time to resumption of normal diet between both groups (59 vs 64 hr; p = 0.64, 3.2 vs 3.7 d; p = 0.25 and 3.9 vs 4.3 d; p = 0.39). There was no statistically significant difference in the time to discontinuation of intravenous nacrotics and the length of hospital stay (1.0 vs 1.4 d; p = 0.25 and 6.2 vs 7.1 d; p = 0.3). CONCLUSION: LRH and ORHT for right-sided colon cancer resulted in the same short-term surgical outcomes including postoperative bowel function, narcotics consumption and length of hospital stay. However, LRH required a significantly longer operating time. [Abstract/Link to Full Text]

Parkins GE, Armah G, Ampofo P
Tumours and tumour-like lesions of the lower face at Korle Bu Teaching Hospital, Ghana--an eight year study.
World J Surg Oncol. 2007;548.
BACKGROUND: The oro-facial region including the jawbones, the maxilla and mandible and related tissues can be the site of a multitude of neoplastic conditions. These tumours have a predilection for the entire facial region; however, odontogenic tumours tend to affect the mandible more than the maxilla, especially, in West African children. We report results from a retrospective study spanning eight years on the frequency, clinical presentation, sites and character of lower face tumours seen in the main referral hospital in Ghana. PATIENTS AND METHODS: Records of consecutive patients of all age and sex seen by the first author's team at the Department of Oral and Maxillofacial Surgery, Korle-Bu Teaching Hospital with tumours affecting the lower part of the face from January 1996 to December 2003 were retrieved, coded and entered into a database. The data were then analyzed by age, sex, presenting signs and symptoms, site of lesion, and their histology. RESULTS: A total of 394 patients with oro-facial swellings were retrieved from the registry out of which 210 had lower face tumour and tumour-like lesions. The complete data set was obtained for 171 patients, comprising 99 (58%) males and 72 (42%) females. The most common clinical presenting features were mandibular facial swelling (63%), intra-oral swelling (55%), pain (41%) and ulceration (29%). The tumours were predominantly found in the right (43%), anterior (19%) and left (18%) aspects of the lower face. The remainder making up 20% were found in the floor of the mouth, tongue and lips. Seventy eight (45.6%) of the patients presented with lesions that were classified as malignant of which 54 (62%) were diagnosed as squamous cell carcinoma (SCC). Sixty-two (36.3%) had benign odontogenic tumours and thirty-one (18.1%) had non-odontogenic tumour-like lesions. Fifty-four (62%) of malignant tumours were squamous cell carcinoma; 58 (93.6%) of the benign odontogenic tumours were classified as ameloblastoma. The mean age at presentation of all lesions was 40.4 years with over 50% of benign lesions in patients aged between 11 and 30 years. Malignant tumours were more commonly detected in patients between 41 and 70 years (63%). CONCLUSION: Tumours and tumour-like lesions of the lower face comprising the mandible, tongue and adjacent structures are a diverse group of neoplasm and are seen commonly in practice of Maxillofacial surgery. Both malignant and benign tumours are seen in the Ghanaian population. In the present study, SCC and ameloblastoma were the commonest malignant and benign odontogenic tumours seen respectively; the two representing more than 65% of all tumours. [Abstract/Link to Full Text]

Gupta V, Nahak B, Sakhuja P, Agarwal AK, Kumar N, Mishra PK
Primary isolated extramedullary plasmacytoma of colon.
World J Surg Oncol. 2007;547.
BACKGROUND: Extramedullary plasmacytoma is an uncommon entity that most commonly involves nasopharynx or upper respiratory tract. Involvement of the gastrointestinal tract occurs in approximated 10% of cases. Isolated primary plasmacytoma of colon is rare and only 7 well documented cases have been reported in the literature. CASE PRESENTATION: We present a case of 42 year male who presented with diarrhea. Multiple colonic strictures were found on investigation. Colonoscopic biopsy was not helpful in making any specific diagnosis. Patient underwent subtotal colectomy. Isolated primary colonic plasmacytoma was found on histopathological examination. CONCLUSION: Plasmacytoma is known to occur in extra osseous sites. Primary colonic plasmacytoma, however, is a rare clinical entity. Primary colonic plasmacytoma may have varying clinical presentations including multiple colonic strictures that may mimic colonic tuberculosis or inflammatory bowel disease. Although these cases are rare, treating physician as well as radiologist, and pathologist should be aware of this entity. [Abstract/Link to Full Text]

Vankalakunti M, Saikia UN, Mathew M, Kang M
Xanthogranulomatous osteomyelitis of ulna mimicking neoplasm.
World J Surg Oncol. 2007;546.
BACKGROUND: Xanthogranulomatous osteomyelitis often presents as a severe chronic inflammation associated with pain, fever, and leukocytosis. It may mimic carcinoma in the involved organs. CASE PRESENTATION: A 50-year-old post-menopausal woman presented with a 2 year history of increasing swelling in the extensor aspect of her right forearm. Plain X-ray revealed an ill-defined expansile osteolytic lesion in the diaphysis of ulna. The gross, microscopic and ultrastructure findings of the curettage specimen was consistent with xanthogranulomatous osteomyelitis. CONCLUSION: This case highlights the rare occurrence of xanthogranulomatous osteomyelitis involving ulna, which can mimic as a primary or secondary bone tumors. A correct diagnosis can only be made on histopathological examination. [Abstract/Link to Full Text]

Menenakos C, Braumann C, Hartmann J, Jacobi CA
Retroperitoneal Castleman's tumor and paraneoplastic pemphigus: report of a case and review of the literature.
World J Surg Oncol. 2007;545.
BACKGROUND: Castleman's disease is a rare lymphoproliferative syndrome. Its etiology and pathogenesis are unclear. The disease can be occasionally associated with a paraneoplastic pemphigus (PNP), an autoimmune mucocutaneous disorder commonly seen in neoplasms of lymphocytic origin. CASE PRESENTATION: We present a case of a 63-year old male patient who was referred for surgical treatment of a lately diagnosed retroperitoneal pelvic mass. The patient had been already treated for two years due to progressive diffuse cutaneous lesions histologically consistent with lichen ruber verucosus and pemphigus vulgaris. Intraoperatively a highly vascularized solid mass occupying the small pelvis was resected after meticulous vascular ligation and hemostasis. After surgery and following immunosuppressive treatment a clear remission of the skin lesions was observed. CONCLUSION: Castleman's tumor should be always suspected when a retroperitoneal mass is combined with PNP. In a review of the literature we found 37 additional cases. Complete surgical resection of the tumor can be curative in most of the cases. [Abstract/Link to Full Text]

Gockel I, Domeyer M, Wolloscheck T, Konerding MA, Junginger T
Resection of the mesopancreas (RMP): a new surgical classification of a known anatomical space.
World J Surg Oncol. 2007;544.
BACKGROUND: Prognosis after surgical therapy for pancreatic cancer is poor and has been attributed to early lymph node involvement as well as to a strong tendency of cancer cells to infiltrate into the retropancreatic tissue and to spread along the peripancreatic neural plexuses. The objective of our study was to classify the anatomical-surgical layer of the mesopancreas and to describe the surgical principles relevant for resection of the mesopancreas (RMP). Immunohistochemical investigation of the mesopancreatic-perineural lymphogenic structures was carried out with the purpose of identifying possible routes of metastatic spread. METHODS: Resection of the mesopancreas (RMP) was performed in fresh corpses. Pancreas and mesopancreas were separated from each other and the mesopancreas was immunohistochemically investigated. RESULTS: The mesopancreas strains itself dorsally of the mesenteric vessels as a whitish-firm, fatty tissue-like layer. Macroscopically, in the dissected en-bloc specimens of pancreas and mesopancreas nerve plexuses were found running from the dorsal site of the pancreatic head to the mesopancreas to establish a perineural plane. Immunohistochemical examinations revealed the lymphatic vessels localized in direct vicinity of the neuronal plexuses between pancreas and mesopancreas. CONCLUSION: The mesopancreas as a perineural lymphatic layer located dorsally to the pancreas and reaching beyond the mesenteric vessels has not been classified in the anatomical or surgical literature before. The aim to ensure the greatest possible distance from the retropancreatic lymphatic tissue which drains the carcinomatous focus can be achieved in patients with pancreatic cancer only by complete resection of the mesopancreas (RMP). [Abstract/Link to Full Text]

Gulec SA, Hoenie E, Rheinheimer K
A multimodality localization technique for radio-guided surgery.
World J Surg Oncol. 2007;543.
BACKGROUND: Intraoperative localization of image or endoscopy-detected lesions occasionally pose surgical challenges due to the small lesion size and/or difficult anatomic exposure. Identification of such lesions can be facilitated using a hand-held gamma probe with utilization of Tc-99m macroaggregate albumen (MAA) localization technique. The radiopharmaceutical injection can be performed using ultrasound (US) or endoscopy guidance. CASE PRESENTATIONS: The clinical use of the Tc-99m MAA protocol gamma probe-guided surgery was discussed in three representative cases. Surgical indication was diagnostic exploration in two patients with suspicious lymphadenopathy, and determination of extent of surgical resection in a patient with polyposis. Lesion localization with 100 microcurie (3.7 MBq) Tc-99m MAA prior to surgical exploration resulted in definitive localization of lesions intraoperatively. CONCLUSION: The use Tc-99m MAA deposition technique at the site of surgical target is a highly efficient radio-guided surgery technique with definitive impact on the success of surgical exploration in selected indications. [Abstract/Link to Full Text]

Orditura M, Lieto E, Ferraraccio F, De Cataldis G, Troiani T, Castellano P, Catalano G, Ciardiello F, Galizia G, De Vita F
Hepatoid carcinoma colliding with a liposarcoma of the left colon serosa presenting as an abdominal mass.
World J Surg Oncol. 2007;542.
BACKGROUND: Hepatoid adenocarcinoma (HAC) is a peculiar type of extrahepatic adenocarcinoma generally characterized by adenocarcinomatous and hepatocellular carcinoma (HCC)-like foci. Stomach is the most frequent site where hepatoid adenocarcinoma occurs, although it has been described in many other organs. On the other side, liposarcoma is a rare, malignant tumor that develops from fat cells. CASE PRESENTATION: We describe here a case of hepatoid carcinoma in collision with a liposarcoma of the left colon serosa in a 71-year-old man. It presented as an abdominal mass involving several organs, falsely mimicking metastatic colonic adenocarcinoma. Recognition of this entity was evident on microscopic evaluation following surgery. The patient had an objective response following liposomal antracycline chemotherapy, with a 3-year overall survival. CONCLUSION: To our knowledge, this is the first case of a hepatoid tumor colliding with a liposarcoma of the left colon serosa reported to date. [Abstract/Link to Full Text]

Denzinger S, Luebke L, Burger M, Kessler S, Wieland WF, Otto W
Vacuum-assisted closure therapy in ureteroileal anastomotic leakage after surgical therapy of bladder cancer.
World J Surg Oncol. 2007;541.
BACKGROUND: Vacuum-assisted closure (VAC) is an acknowledged method of treating wound healing disorders, but has been viewed as a contraindication in therapy of intraabdominal fistulas. CASE PRESENTATION: We present the case of an 83-year old patient with ureteroileal anastomotic insufficiency following cystectomy and urinary diversion by Bricker ileal conduit due to urothelial bladder cancer. After developing an open abdomen on the 16th postoperative day a leakage of the ureteroileal anastomosis appeared that cannot be managed by surgical means. To stop the continued leakage we tried a modified VAC therapy with a silicon covered polyurethane foam under a suction of 125 mmHg. After 32 days with regularly changes of the VAC foam under general anesthesia the fistula resolved without further problems of ureteroileal leakage. CONCLUSION: We present the first report of VAC therapy successfully performed in urinary tract leakage after surgical treatment of bladder cancer. VAC therapy of such disorders requires greater care than of superficial application to avoid mechanical alterations of internal organs but opens new opportunities in cases without surgical alternatives. [Abstract/Link to Full Text]

Fotou M, Oikonomou V, Zagouri F, Sergentanis TN, Nonni A, Athanassiadou P, Drouveli T, Atsouris E, Kotzia E, Zografos GC
Imprint cytology on microcalcifications excised by Vacuum-Assisted Breast Biopsy: A rapid preliminary diagnosis.
World J Surg Oncol. 2007;540.
BACKGROUND: To evaluate imprint cytology in the context of specimens with microcalcifications derived from Vacuum-Assisted Breast Biopsy (VABB). PATIENTS AND METHODS: A total of 93 women with microcalcifications BI-RADS 3 and 4 underwent VABB and imprint samples were examined. VABB was performed on Fischer's table using 11-gauge Mammotome vacuum probes. A mammogram of the cores after the procedure confirmed the excision of microcalcifications. For the application of imprint cytology, the cores with microcalcifications confirmed by mammogram were gently rolled against glass microscope slides and thus imprint smears were made. For rapid preliminary diagnosis Diff-Quick stain, modified Papanicolaou stain and May Grunwald Giemsa were used. Afterwards, the core was dipped into a CytoRich Red Collection fluid for a few seconds in order to obtain samples with the use of the specimen wash. After the completion of cytological procedures, the core was prepared for routine histological study. The pathologist was blind to the preliminary cytological results. The cytological and pathological diagnoses were comparatively evaluated. RESULTS: According to the pathological examination, 73 lesions were benign, 15 lesions were carcinomas (12 ductal carcinomas in situ, 3 invasive ductal carcinomas), and 5 lesions were precursor: 3 cases of atypical ductal hyperplasia (ADH) and 2 cases of lobular neoplasia (LN). The observed sensitivity and specificity of the cytological imprints for cancer were 100% (one-sided, 97.5% CI: 78.2%-100%). Only one case of ADH could be detected by imprint cytology. Neither of the two LN cases was detected by the imprints. The imprints were uninformative in 11 out of 93 cases (11.8%). There was no uninformative case among women with malignancy. CONCLUSION: Imprint cytology provides a rapid, accurate preliminary diagnosis in a few minutes. This method might contribute to the diagnosis of early breast cancer and possibly attenuates patients' anxiety. [Abstract/Link to Full Text]

Hafez RF
Stereotaxic gamma knife surgery in treatment of critically located pilocytic astrocytoma: preliminary result.
World J Surg Oncol. 2007;539.
BACKGROUND: Low-grade gliomas are uncommon primary brain tumors, located more often in the posterior fossa, optic pathway, and brain stem and less commonly in the cerebral hemispheres. CASE PRESENTATIONS: Two patients with diagnosed recurrent cystic pilocytic astrocytoma critically located within the brain (thalamic and brain stem) were treated with gamma knife surgery. Gamma knife surgery (GKS) did improve the patient's clinical condition very much which remained stable later on. Progressive reduction on the magnetic resonance imaging (MRI) studies of the solid part of the tumor and almost disappearance of the cystic component was achieved within the follow-up period of 36 months in the first case with the (thalamic located lesion) and 22 months in the second case with the (brain stem located lesion). CONCLUSION: Gamma knife surgery represents an alternate tool in the treatment of recurrent and/or small postoperative residual pilocytic astrocytoma especially if they are critically located. [Abstract/Link to Full Text]

Wuntakal R, Bharathan R, Rockall A, Jeyarajah A
Interesting case of ovarian sarcoidosis: The value of multi disciplinary team working.
World J Surg Oncol. 2007;538.
BACKGROUND: Sarcoidosis of the genital tract is a rare condition. Ovarian manifestation of this disease is rarer still. CASE PRESENTATION: The case presented here represents ovarian manifestation of sarcoidosis. At the point of referral to our hospital, based on computerised tomography (CT) ovarian carcinoma was a differential diagnosis. Further magnetic resonance imaging along with CT guided biopsy aided by laboratory study supported a diagnosis of sarcoidosis. Patient responded to medical management by a multidisciplinary team. CONCLUSION: The case shows the importance of FNAC and biopsy in case or ovarian masses and multi disciplinary team approach to management. [Abstract/Link to Full Text]

Fukunaga S, Futani H, Yoshiya S
Endoscopically assisted resection of a scapular osteochondroma causing snapping scapula syndrome.
World J Surg Oncol. 2007;537.
BACKGROUND: Osteochondroma is the most common benign bone tumor in the scapula. This condition might lead to snapping scapula syndrome, which is characterized by painful, audible, and/or palpable abnormal scapulothoracic motion. In the present case, this syndrome was successfully treated by use of endoscopically assisted resection of the osteochondroma. CASE PRESENTATION: A 41-year-old man had a tolerable pain in his scapular region over a 10 years' period. The pain developed gradually with shoulder motion, in particular with golf swing since he was aiming a professional golf player career. On physical examination, "clunking" was noted once from 90 degrees of abduction to 180 degrees of shoulder motion. A trans-scapular roentgenogram and computed tomography images revealed an osteochondroma located at the anterior and inferior aspect of the scapula. Removal of the tumor was performed by the use of endoscopically assisted resection. One portal was made at the lateral border of the scapula to introduce a 2.7-mm-diameter, 30 degrees Hopkins telescope. The tumor was resected in a piece-by-piece manner by the use of graspers through the same portal. Immediately after the operation pain relief was obtained, and the "clunking" disappeared. CT images showed complete tumor resection. The patient could start playing golf one week after the surgery. CONCLUSION: Endoscopically assisted resection of osteochondroma of the scapula provides a feasible technique to treat snapping scapula syndrome and obtain early functional recovery with a short hospital stay and cosmetic advantage. [Abstract/Link to Full Text]

Slupski MW, Szczylik C, Jasinski MK
Unexpected response to systemic chemotherapy in case of primarily nonresectable advanced disseminated intrahepatic cholangiocarcinoma.
World J Surg Oncol. 2007;536.
BACKGROUND: Cholangiocellular cancers account for about 10-15% of primary liver cancers. Prognosis is poor, with expected survival of less than 5% at five-year. CASE PRESENTATION: The case described shows remission of a disseminated cholangiocellular carcinoma (focal changes in liver, metastases to lungs) after neoadjuvant chemotherapy. The initial diagnosis was based on ultrasound examination and confirmed with computer tomography. Tumour biopsy and histopathological examination revealed cholangiocellular carcinoma. The patient underwent chemotherapy. After remission of lesions in lungs and reduction/regression of tumours in liver to one focal change, right lobe liver resection was performed. The histopathological examination did not reveal any viable carcinoma cells, only necrotic tissues in place of the primary tumour as well as in local portal vein branches was seen. Thirty months after the operation the patient is in a good overall condition and no recurrence has been observed. CONCLUSION: Appropriate neoadjuvant chemotherapy may allow radical resection in a previously unresectable cholangiocellular cancer. [Abstract/Link to Full Text]

Shrikhande SV, Saoji RR, Barreto SG, Kakade AC, Waterford SD, Ahire SB, Goliwale FM, Shukla PJ
Outcomes of resection for rectal cancer in India: the impact of the double stapling technique.
World J Surg Oncol. 2007;535.
BACKGROUND: The introduction of circular staplers into colorectal surgery has revolutionized anastomotic techniques stretching the limits of sphincter preservation. Data on the double-stapling technique (DST) has been widely published in the West where the incidence of colorectal cancer is high. However studies using this technique and their results, in the Indian scenario, as well as the rest of Asia, have been few and far between. AIM: To evaluate the feasibility of the DST in Indian patients with low rectal cancers and assess its impact on anastomotic leak rates, covering colostomy rates, level of resection and morbidity in patients undergoing low anterior resection (LAR). METHODS: A comparative analysis was performed between retrospectively acquired data on 78 patients (mean age 53.2 +/- 13.5 years) undergoing LAR with the single-stapling technique (SST) (between January 1999 and December 2001) and prospective data acquired on 138 LARs (mean age 50.3 +/- 13.9 years) performed using the DST (between January 2003 - December 2005). RESULTS: A total of 77 out of 78 patients in the SST group had Astler Coller B and C disease while the number was 132/138 in the DST group. The mean distance of the tumor from anal verge was 7.6 cm (2.5-15 cm) and 8.0 cm (4-15 cm) in the DST and SST groups, respectively. In the DST group, there were 5 (3.6%) anastomotic failures and 62 (45%) covering stomas compared to 7 (8.9%) anastomotic failures and 51 (65.4%) covering stomas in the SST group. The anastomotic leak rate, though objectively lower in the DST group, did not attain statistical significance (p = 0.12). Covering stoma rates were significantly lower in DST group (p = 0.006). There was 1 death in the DST group due to cardiac causes (unrelated to the anastomosis) and no mortality in the SST group. The LAR and abdominoperineal resection (APR) rates were 40% and 60%, respectively, during 1999-2001. In 2005, these rates were 55% and 45%, respectively. CONCLUSION: This study, perhaps the first from India, demonstrates the feasibility of the DST in a country where the incidence of colorectal cancer is increasing. Since the age at presentation is at least a decade younger than the Western world, consideration of sphincter preservation assumes greater significance. The observed improvement of surgical outcomes with DST needs further studies to significantly prove these findings in a population where the tumors at presentation are predominantly Astler Coller Stage B and C. [Abstract/Link to Full Text]

Cash BD, Johnston LR, Johnston MH
Cryospray ablation (CSA) in the palliative treatment of squamous cell carcinoma of the esophagus.
World J Surg Oncol. 2007;534.
BACKGROUND: Esophageal carcinoma is the ninth most prevalent cancer worldwide with squamous cell carcinoma (SCCA) and adenocarcinoma accounting for the vast majority of new cases (13,900 in 2003). Cure rates in the U.S. are less than 10%, similar to lung cancer. More than 50% of patients with esophageal carcinoma present with unresectable or metastatic disease, are not surgical candidates, or display disease progression despite the addition of neoadjuvant chemoradiotherapy to surgery. Need for improved palliation exits. CASE PRESENTATION: This case describes a 73-year-old African American male who presented with recurrent squamous cell carcinoma (SCCA) of the esophagus who has a achieved complete remission for 24 months via endoscopic cryospray ablation. CONCLUSION: Endoscopic cryo spray ablation warrants further investigation as a palliative treatment modality for esophageal cancer. This is the first reported case in the medical literature. [Abstract/Link to Full Text]

Abbas F, Memon A, Siddiqui T, Kayani N, Ahmad NA
Granular cell tumors of the urinary bladder.
World J Surg Oncol. 2007;533.
BACKGROUND: Granular cell tumors (GCTs) are extremely rare lesions of the urinary bladder with only nine cases being reported in world literature of which one was malignant. Generally believed to be of neural origin based on histochemical, immunohistochemical, and ultrastructural studies; they mostly follow a clinically benign course but are commonly mistaken for malignant tumors since they are solid looking, ulcerated tumors with ill-defined margins. MATERIALS AND METHODS: We herein report two cases of GCTs, one benign and one malignant, presenting with gross hematuria in a 14- and a 47-year-old female, respectively. RESULTS: Histopathology revealed characteristic GCTs with positive immunostaining for neural marker (S-100) and negative immunostaining for epithelial (cytokeratin, Cam 5.2, AE/A13), neuroendocrine (neuron specific enolase, chromogranin A, and synaptophysin) and sarcoma (desmin, vimentin) markers. The benign tumor was successfully managed conservatively with transurethral resection alone while for the malignant tumor, radical cystectomy, hysterectomy with bilateral salpingo-oophorectomy, anterior vaginectomy, plus lymph node dissection was done. Both cases show long-term disease free survival. CONCLUSION: We recommend careful pathologic assessment for establishing the appropriate diagnosis and either a conservative or aggressive surgical treatment for benign or localized malignant GCT of the urinary bladder, respectively. [Abstract/Link to Full Text]

Schwarz RE
Factors influencing change of preoperative treatment intent in a gastrointestinal cancer practice.
World J Surg Oncol. 2007;532.
BACKGROUND: Postoperative assessment of indications for cancer directed surgical procedures frequently differs from preoperative plans. METHODS: Specifically defined preoperative indications and postoperative results were followed prospectively over 48 months in a single surgeon academic practice, and relationships to postoperative outcomes evaluated. RESULTS: Operations were performed on 406 patients with a median age of 61 (range: 18-90). Major operations (n = 303, 75%) involved 270 abdominal resections including pancreatectomies (37%), liver resections (23%), gastrectomies (19%), and others (21%). Preoperative curative (70%), diagnostic (38%), palliative (12%), access (9%), and non-cancer related therapy (21%) goals were in part combined in 176 patients (43%). Postoperative assessment differed from preoperative goals in 118 patients (29%). Predominant reasons were proof of benign disease (n = 35), incomplete resection (R1 or R2, n = 23), unresectability by laparoscopy (n = 21) or laparotomy (n = 21), or others (n = 18). Potential preoperative cure or palliation goals were not achieved in 37% or 15% of cases, respectively. Circumstances of changed treatment intent were specific for disease site. CONCLUSION: Preoperative therapeutic intent frequently differs from postoperative assessments in gastrointestinal cancer, based on shortcomings in diagnosis or therapy. Formulations of precise operative indications are recommended to optimize individual outcomes and avoid unnecessary or ineffective procedures. [Abstract/Link to Full Text]

Duncan TJ, Watson NF, Al-Attar AH, Scholefield JH, Durrant LG
The role of MUC1 and MUC3 in the biology and prognosis of colorectal cancer.
World J Surg Oncol. 2007;531.
BACKGROUND: MUC1 and MUC3 are from a large family of glycoproteins with an aberrant expression profile in various malignancies. Much interest has been focused on the role of these proteins in the development and progression of colorectal cancer; however, no previous studies have included the highly confounding variable of vascular invasion in their survival analysis. Using high throughput tissue microarray technology we assessed the prognostic value of MUC1 and MUC3 expression in the largest cohort of colorectal cancer patients to date. We propose that tumours lacking expression of MUC1 and MUC3 will be more likely to metastasise, due to previously observed loss of cell-cell adhesion, and this will therefore lead to more aggressive cancers with poorer prognosis. METHODS: A tissue micro-array was prepared from tumour samples of 462 consecutive patients undergoing resection of a primary colorectal cancer. A comprehensive prospectively recorded data base with mean follow up of 75 months was collected and included common clinicopathological variables and disease specific survival. Immunohistochemical analysis of MUC1 and MUC3 expression was performed using antibodies NCL-MUC1 and 1143/B7 respectively, results were correlated with the variables within the database. RESULTS: Positive expression of MUC1 and MUC3 was seen in 32% and 74% of tumours respectively. On univariate analysis no correlation was seen with either MUC1 or MUC3 and any of the clinicopathological variables including tumour grade and stage, vascular invasion and tumour type. Kaplan-Meier analysis demonstrated a significant reduction in disease specific survival with MUC1 positive tumours (p = 0.038), this was not seen with MUC3 (p = 0.552). On multivariate analysis, using Cox proportional hazards model, MUC1 expression was shown to be an independent marker of prognosis (HR 1.339, 95%CI 1.002-1.790, p = 0.048). CONCLUSION: MUC1 expression in colorectal cancer is an independent marker of poor prognosis, even when vascular invasion is included in the analysis. These results support previous studies suggesting a role for MUC1 in colorectal cancer development possibly through its effects on cell adhesion. [Abstract/Link to Full Text]

Pandey M, Prakash O, Mathews A, Nayak N, Ramachandran K
Choroidal melanoma metastasizing to maxillofacial bones.
World J Surg Oncol. 2007;530.
BACKGROUND: Melanomas are malignant neoplasm of melanocytic origin, commonly seen on skin and various mucous membranes. Melanomas are the commonest intraocular malignant tumour in the adults. CASE PRESENTATION: A 50-year-old female presented with complains of painless progressive swelling in right cheek region of two months duration. Examination revealed a 6 x 4 cm bony hard swelling in right zygomatic region near and below lateral canthus of right eye with loss of vision. Investigations revealed it to be a choroidal melanoma metastasizing to the zygomatic bone. Patient was successfully treated by surgery. CONCLUSION: Choroidal melanoma, which commonly metastasizes to liver and lungs, never involves the lymph nodes and metastasis to facial bones is rare. Here we report a case of choroidal melanoma metastasizing to maxillofacial bones. [Abstract/Link to Full Text]

Ahn JY, Chang JH, Kim SH, Lee KS
Pleomorphic adenocarcinoma of the lacrimal gland with multiple intracranial and spinal metastases.
World J Surg Oncol. 2007;529.
BACKGROUND: Pleomorphic adenoma of the lacrimal gland is known to undergo malignant transformation when incompletely excised. Even if such a malignant change occurs, intracranial direct invasion and leptomeningeal seeding are seldom encountered. CASE PRESENTATION: A 50-year-old woman presented with malignant transformation associated with both intracranial invasion and multiple intracranial and spinal disseminations in the third recurrence of pleomorphic adenoma of the lacrimal gland, 6 years after initial treatment. MRI demonstrated increased extent of orbital mass, extending to the cavernous sinus. The patient underwent intensity-modulated radiation therapy (IMRT) and Gamma Knife radiosurgery. Follow-up MRI showed multiple leptomeningeal disseminations to the intracranium and spine. CONCLUSION: It is important to recognize that leptomeningeal intracranial and spinal disseminations of pleomorphic adenocarcinoma can occur, although it is extremely rare. To our knowledge, we report the first case of pleomorphic adenocarcinoma of the lacrimal gland presumably metastasizing to the intracranium and spine. [Abstract/Link to Full Text]

Rekhi B, Gorad BD, Chinoy RF
Proximal-type epithelioid sarcoma--a rare, aggressive subtype of epithelioid sarcoma presenting as a recurrent perineal mass in a middle-aged male.
World J Surg Oncol. 2007;528.
BACKGROUND: Epithelioid sarcoma (ES) is an uncommon soft tissue sarcoma. Lately, subtypes of ES, including proximal-type ES have been recognized, with relatively few reports on such cases. CASE PRESENTATION: A 47-year-old male presented with a perineal soft tissue mass that was excised elsewhere and the biopsy was submitted for a review diagnosis. On histology, a multi nodular tumor was seen comprising sheets of oval to polygonal cells with moderate amount of cytoplasm. Interspersed were larger, rhabdoid cells with abundant eosinophilic cytoplasm and prominent nucleoli. Focal necrosis was noted. A wide panel of immunohistochemical (IHC) markers was performed to rule out a range of differential diagnoses, including a poorly differentiated carcinoma, a melanoma and a variety of sarcomas with epithelioid differentiation. On IHC, the tumor cells showed a polyphenotypic expression, including positivity for epithelial markers i.e cytokeratin (CK), CK7, EMA and mesenchymal markers like vimentin and CD 34. Desmin was focally positive. CK20, CEA, S-100, HMB-45, SMA, LCA and CD31 were negative. A diagnosis of a proximal-type ES was formed. Six moths later, despite adjuvant chemo and radiotherapy (CT and RT), the patient continued to have the lesion and was referred again. In addition to the earlier histological features, sections from the persistent tumor mass showed an increased number of larger cells along with multinucleated tumor giant cells. CONCLUSION: The value of identifying this uncommon tumor from a list of differential diagnoses is in view of its aggressive behavior, as seen in our case. A wide excision with clear margins is imperative with options of post-operative CT/RT in individual cases during a close follow-up. [Abstract/Link to Full Text]

Naka N, Takenaka S, Nanno K, Moriguchi Y, Chun BM, Sonoda S, Hashimoto N, Tsukamoto Y, Araki N
Acute adrenal crisis after orthopedic surgery for pathologic fracture.
World J Surg Oncol. 2007;527.
BACKGROUND: Adrenal crisis after surgical procedure is a rare but potentially catastrophic life-threatening event. Its manifestations, such as hypotension, tachycardia, hypoxia, and fever mimic the other more common postoperative complications. Clinical outcome is dependent upon early recognition of the condition and proper management with exogenous steroid administration. CASE PRESENTATION: We report a 75-year-old man who presented with shock immediately after surgery for a femoral fracture from lung cancer metastasis. Anemia and severe hyponatremia were detected. Despite adequate fluid resuscitation, nonspecific symptoms including hypotension, tachycardia, hypoxia, fever and confusion occurred. Emergent CT revealed enlarged bilateral adrenal glands. Under the diagnosis of adrenal crisis due to metastatic infiltration of adrenal glands, the patient was treated with appropriate steroid replacement resulting in rapid improvement and recovery. CONCLUSION: We describe a case of adrenal crisis caused by the lack of adrenal reserve based on metastatic involvement and surgical stress, the first published case of adrenal crisis after surgery for a pathologic fracture from lung cancer metastasis. Surgeons treating pathologic fractures should be aware of this complication and familiar with its appropriate therapy because of increasing opportunity to care patients with metastatic bone tumors due to recent advances in cancer treatment. [Abstract/Link to Full Text]

Stern JR, Frankel WL, Ellison EC, Bloomston M
Solid serous microcystic adenoma of the pancreas.
World J Surg Oncol. 2007;526.
BACKGROUND: Cystic neoplasms of the pancreas are less common than solid tumors, and portend a better prognosis. They can be divided into serous and mucinous subtypes, with the former behaving less aggressively and generally considered benign. Of the serous neoplasms, serous microcystic adenoma is the most common. An extremely rare solid variant of serous microcystic adenoma lacking secretory capability has been described. Herein, we present the fourth described case of this solid variant and review the literature. CASE PRESENTATION: We present a case of a 62 year-old man with a history of abdominal pain, who on CT scan was found to have a solid mass at the junction of the head and body of the pancreas. The patient was offered resection for diagnosis and treatment, and subsequently underwent distal pancreatectomy and splenectomy. Based on gross pathology, histology and immunohistochemistry, the mass was determined to be a solid serous microcystic adenoma. CONCLUSION: Solid serous microcystic adenoma shows similar histologic and immunohistologic features to its classic cystic counterpart, but lacks any secretory functionality. It appears to behave in a benign manner, and as such, surgical resection is curative for patients with this tumor. Furthermore, until more cases of solid SMA are identified to further elucidate its natural history and improve the reliability of preoperative diagnosis, surgical resection of this solid pancreatic tumor should be considered standard therapy in order to exclude malignancy. [Abstract/Link to Full Text]

Alzaraa A, Vodovnik A, Montgomery H, Saeed M, Sharma N
Breast metastasis from a renal cell cancer.
World J Surg Oncol. 2007;525.
BACKGROUND: Metastases to the breast from extramammary tumours are uncommon, and metastatic renal cell carcinoma to the breast is extremely rare. We report a metastasis to the breast from a renal primary with the radiological and histopathological features. CASE PRESENTATION: An 81-year-old lady was seen in the breast clinic for a right breast mass after sustaining a fall. Clinical examination and investigations revealed a metastatic cancer from a renal primary. She received surgical treatment only and is under regular follow-up in the oncology clinic. CONCLUSION: The treatment strategy for metastatic breast diseases is based on a proper assessment of such cases by surgeons, radiologists and histopathologists. [Abstract/Link to Full Text]

Rekhi B, Shet TM, Badwe RA, Chinoy RF
Fibromatosis-like carcinoma-an unusual phenotype of a metaplastic breast tumor associated with a micropapilloma.
World J Surg Oncol. 2007;524.
BACKGROUND: Fibromatosis-like metaplastic carcinoma is a newly described metaplastic breast tumor, literature on which is still evolving. CASE PRESENTATION: A 77-year-old lady presented with a 2 x 2 cm mass with irregular margins in the upper and outer quadrant of left breast. Fine needle aspiration cytology (FNAC) from the lump was inconclusive. A lumpectomy was performed and sent for frozen section, which revealed presence of spindle cells showing mild atypia in a sclerotic stroma. The tumor cells revealed prominent infiltration into the adjacent fat. A differential diagnosis of a low-grade sarcoma vs. a metaplastic carcinoma, favoring the former, was offered. Final histology sections revealed an infiltrating tumor with predominant spindle cells in a collagenous background, simulating a fibromatosis. Adjacent to the tumor were foci of benign ductal hyperplasia and a micropapilloma. Immunohistochemistry (IHC) showed diffuse co-expression of epithelial markers i.e. cytokeratins (CK, HMWCK, CK7) and EMA along with a mesenchymal marker i.e. vimentin in the tumor cells. Myoepithelial markers (SMA and p63) showed focal positivity. A diagnosis of a low-grade fibromatosis-like carcinoma breast associated with a micropapilloma was formed. CONCLUSION: Fibromatosis-like carcinoma is a rare form of a metaplastic breast tumor. This diagnosis requires an index of suspicion while dealing with spindle cell breast tumors. The importance of making this diagnosis to facilitate an intra operative surgical planning is marred by diagnostic difficulties. In such cases, IHC is imperative in forming an objective diagnosis. [Abstract/Link to Full Text]

Jeyaretna DS, Oriolowo A, Smith ME, Watkins RM
Solitary neurofibroma in the male breast.
World J Surg Oncol. 2007;523.
BACKGROUND: Neurofibroma of the male breast outside of neurofibromatosis is extremely rare with only one previous case having been reported. CASE PRESENTATION: A 48 year old male patient with a neurofibroma in the breast presenting with gynaecomastia is reported. Clinical and mammogram findings with fine needle aspiration cytology and full histology are presented. CONCLUSION: To our knowledge this is only the second case of a neurofibroma in a male breast in the English literature and the first report to include the mammographic findings. [Abstract/Link to Full Text]

Cicenas S, Vencevicius V
Lung cancer in patients with tuberculosis.
World J Surg Oncol. 2007;522.
BACKGROUND: Coexistent lung cancer and pulmonary tuberculosis is an urgent problem of thoracic surgery presenting a challenging task for diagnosis and surgical treatment. MATERIALS AND METHODS: From 1990 to 2005, 2218 patients with lung cancer underwent surgical treatment in Department of Thoracic Surgery and Oncology, Institute of Oncology, Vilnius University. In 46 (2.1%) patients coexistence of lung cancer and tuberculosis was found. Central lung cancer was diagnosed in 37 (80.4%) and peripheral--in 9 (19.6%) patients. Epidermoid cancer was diagnosed in 24 (52.2%) patients, adenocarcinoma--in 10 (21.7%) and adenoepidermoid carcinoma--in 12 (26.1%) patients. Stage I cancer was diagnosed in 12 (26.1%), stage II--in 11 (23.9%), and stage IIIA--in 23 (50%) patients. RESULTS: Pneumonectomy was performed in 18 (39.2%), lobectomy in 10 (21.7%), bilobectomy in 10 (21.7%), segmentectomy in 8 (17.4%) patients. Postoperative surgical complications were observed in 9 (19.5%) patients, non-surgical complications occurred in 19 patients (41.3%). Six patients (13.04%) died. Combined treatment was applied to 23 (50%) patients. CONCLUSION: Coexistence of tuberculosis and lung cancer in thoracic surgery is fairly rare. This combination was diagnosed only in 46 cases (2.1%) out of 2218 operated lung cancer patients. Epidermoid carcinoma and stage IIIA disease was diagnosed in 50% of patients. Postoperative surgical complications occurred in 9 patients (19.5%) with lung cancer and tuberculosis. Six patients (13%) died in postoperative period. Surgery is the method of choice in treatment of combination of tuberculosis and lung cancer. Median survival of these patients was 28 +/- 2 months. [Abstract/Link to Full Text]

Kudo J, Nishiwaki T, Haruki N, Ishiguro H, Shibata Y, Terashita Y, Sugiura H, Shinoda N, Kimura M, Kuwabara Y, Fujii Y
Aberrant nuclear localization of beta-catenin without genetic alterations in beta-catenin or Axin genes in esophageal cancer.
World J Surg Oncol. 2007;521.
BACKGROUND: beta-catenin is a multifunctional protein involved in two apparently independent processes: cell-cell adhesion and signal transduction. beta-catenin is involved in Wnt signaling pathway that regulates cellular differentiation and proliferation. In this study, we investigated the expression pattern of beta-catenin and cyclin D1 using immunohistochemistry and searched for mutations in exon 3 of the beta-catenin gene and Axin gene in esophageal squamous cell carcinoma. MATERIALS AND METHODS: Samples were obtained from 50 esophageal cancer patients. Immunohistochemical staining for beta-catenin and cyclin D1 was done. Mutational analyses of the exon3 of the beta-catenin gene and Axin gene were performed on tumors with nuclear beta-catenin expression. RESULTS: Four (8%) esophageal cancer tissues showed high nuclear beta-catenin staining. Overexpression of cyclin D1 was observed in 27 out of 50 (54%) patients. All four cases that showed nuclear beta-catenin staining overexpressed cyclin D1. No relationship was observed between the expression pattern of beta-catenin and cyclin D1 and age, sex, tumor size, stage, differentiation grade, lymph node metastasis, response to chemotherapy, or survival. No mutational change was found in beta-catenin exon 3 in the four cases with nuclear beta-catenin staining. Sequencing analysis of the Axin cDNA revealed only a splicing variant (108 bp deletion, position 2302-2409) which was present in the paired normal mucosa. CONCLUSION: A fraction of esophageal squamous cell carcinomas have abnormal nuclear accumulation of beta-catenin accompanied with increased cyclin D1 expression. Mutations in beta-catenin or axin genes are not responsible for this abnormal localization of beta-catenin. [Abstract/Link to Full Text]

Nigri GR, Dente M, Valabrega S, Aurello P, D'Angelo F, Montrone G, Ercolani G, Ramacciato G
Gastrointestinal stromal tumor of the anal canal: an unusual presentation.
World J Surg Oncol. 2007;520.
BACKGROUND: Gastrointestinal stromal tumors (GIST) of the stomach are the most frequent followed by those of the intestinal tract, while colon and rectum represent rare sites. GIST of the anal canal are extremely rare. They have been studied along with GIST of the rectum, as a single entity, and along with them they represent 5% of GIST. GIST arising from the anal canal account for only 2%-8% of the anorectal GIST. Thus anal GIST must be considered an exceptional case. CASE PRESENTATION: A 78-year-old man was referred to our Institution for an anal mass, in absence of any symptom. The patient was treated by local excision. An histological diagnosis of a low grade GIST was made. No further treatment was necessary. No local recurrence of distant metastases were found at follow-up. CONCLUSION: At the moment, only ten cases of c-kit positive anal GIST are reported in the literature. These few data are not sufficient to establish a widely accepted approach for this neoplasia.We recommend to perform an initial local excision, to define the risk of aggressive behavior and the resection margins and proceed to a more aggressive treatment, if the GIST belongs to high or very high risk group. The role of adjuvant therapy is still uncertain. Although inhibitors of tyrosine-kinase receptor needs further studies before their routine use, their role in case of distant or local recurrence has been accepted. Patients' close follow up is mandatory to disclose as soon as possible local recurrences or metastases. [Abstract/Link to Full Text]

Recent Articles in Journal of Carcinogenesis

Govan VA, Carrara HR, Sachs JA, Hoffman M, Stanczuk GA, Williamson AL
Ethnic differences in allelic distribution of IFN-g in South African women but no link with cervical cancer.
J Carcinog. 2003 May 16;2(1):3.
BACKGROUND: The failure of specific types of human papillomaviruses (HPV) to raise effective immune responses may be important in the pathogenesis of cervical cancer, the second most common cancer in South African women. Polymorphisms of a number of cytokine genes have been implicated in inducing susceptibility or resistance to cancers caused by infectious agents owing to their role in determining host immune response. Polymorphisms of IL-10 and IFN-gamma genes are believed to influence the expression and/or secretion levels of their respective cytokines. METHODS AND RESULTS: In this study, women with histologically proven cancer of the cervix (n = 458) and hospital-based controls (n = 587) were investigated for bi-allelic -1082 (A/G) polymorphisms of IL-10 and the bi-allelic +874(A/T) polymorphisms of IFN-gamma. In addition, the distributions of the allelic frequencies were stratified in both the African and mixed race population groups of South Africa. We found striking differences in the allele distribution of IFN-gamma (X2 = 0.02) among the two ethnic groups. A significant increase in the allele distribution of the IFN-gamma AA genotype was found in the African group compared to the mixed population group (OR, 0.5; 95% CI, 0.2-1.0). For IL-10 there were no significant allelic differences between the two South African ethnic groups. Furthermore, when the ethnic groups were combined the IL-10 allelic frequencies in the combined South African data were similar to those observed in an Oriental population from Southern China and in an Italian population. However, the allele frequencies of the IFN-gamma genotype among the two South African ethnic groups were different when compared to an Italian Caucasoid group. While crude analysis of these data showed both statistically significantly increased and diminished risks of cervical cancer among high producers of INF-gamma and low producers of IL-10 respectively, these associations were no longer significant when the data were adjusted for confounding factors. CONCLUSION: These findings demonstrate a clear correlation between ethnicity and IFN-gamma polymorphism across different population groups. However, these differences in ethnicity and gene polymorphisms in the aforementioned cytokines are suggested not to influence the development of invasive cervical cancer but may represent an important susceptibility biomarker for other diseases and should be explored further. [Abstract/Link to Full Text]

Youssef J, Elbi C, Warren B, Yourtee D, Nagarur R, Molteni A, Cunningham ML, Badr M
Glucocorticoid-like effects of antihepatocarcinogen Rotenone are mediated via enhanced serum corticosterone levels: Molecular Fitting and Receptor Activation Studies.
J Carcinog. 2003 Feb 14;2(1):2.
BACKGROUND: Recent studies suggest that rotenone alters cell signal transduction pathways in a manner similar to glucocorticoids. Histological and biochemical markers of glucocorticoid effects in vivo, evaluated in our laboratories, provide further evidence for similarities in the activity of glucocorticoids and rotenone. The purpose of this study was to investigate the mechanism by which rotenone produces glucocorticoid-like effects. METHODS: Male B6C3F1 mice were treated for 7 days with rotenone (600 ppm in diet), the glucocorticoid antagonist RU486 (2 mg/kg/day, ip), corticosterone (2 mg/kg/day, ip), or both rotenone and RU 486. Control mice received drug-free diet and the vehicle (corn oil, ip). Following preservation in 10% neutral buffered formalin, tissues were embedded in paraffin. Sections were stained with hematoxylin, eosin, and were examined by light microscopy. Tissue sections were processed for in situ enzymatic end labeling of 3'-hydroxy-DNA strand breaks, a measure of apoptosis. Corticosterone was quantified in sera, using a solid phase radioimmunoassay kit. Cells (cell line 1470.2 derived from C127 mouse mammary adenocarcinoma cells) were transiently transfected with 5 &mgr;g of pLTRLuc and 1 &mgr;g of beta-Galactosidase expression vectors using a BTX square-wave pulser at 155 V, 4 pulses (40 ms each). Cells were then treated with dexamethasone, rotenone, or a mixture of both for 6 hr, harvested and assayed for luciferase and beta-Galactosidase activity. Using Root Mean Square (RMS) fit analysis (Alchemy trade mark, Tripose, Inc., St Louis, MO), we assessed possible structural similarities between rotenone and corticosterone, dehydrocorticosterone, glucocorticoid antagonists ZK 98.299, and RU 486. RMS fit was calculated by selecting three atoms in each of the molecules, followed by calculating the distance between these atoms. An RMS value of zero between two molecules indicates identical molecular characteristics. A positive value suggests diminished similarity with a value of 1 or higher excluding any such similarities. RESULTS: Although the stimulatory effect exerted by rotenone on hepatocellular apoptosis was in the opposite direction of that produced by the glucocorticoid antagonist RU 486, data suggested that rotenone does not directly activate the glucocorticoid receptor. Molecular fitting of rotenone to glucocorticoid receptor agonists and antagonists as well as examination of the transcriptional activation of a glucocorticoid-responsive reporter gene (Mouse MammaryTumorVirus) in response to rotenone indicated that it is highly unlikely that rotenone interacts directly with the glucocorticoid receptor. However, feeding male B6C3F1 mice a diet containing rotenone (600 ppm for 7 days) resulted in a 3-fold increase in serum levels of corticosterone relative to control animals. Corticosterone is the major glucocorticoid in rodents. CONCLUSION: Rotenone does not interact directly with the glucocorticoid receptor. Elevation of serum corticosterone levels in response to rotenone may explain the glucocorticoid-like effects of this compound, and may play a role in its anti-hepatocarcinogenic effect. [Abstract/Link to Full Text]

Kovvali G
Carcinogenesis and cancer prevention: the process and the disease deserve a better understanding.
J Carcinog. 2002 Nov 15;1(1):1. [Abstract/Link to Full Text]

Kovvali G, Shiff S, Telang N, Das K, Kohgo Y, Narayan S, Li H
Carcinogenesis: The more we seek to know the more we need to know - Challenges in the post Genomic Era.
J Carcinog. 2003 Jan 31;2(1):1. [Abstract/Link to Full Text]

Recent Articles in The Oncologist

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]

Boccia R, Lillie T, Tomita D, Balducci L
The effectiveness of darbepoetin alfa administered every 3 weeks on hematologic outcomes and quality of life in older patients with chemotherapy-induced anemia.
Oncologist. 2007 May;12(5):584-93.
Chemotherapy-induced anemia (CIA) may substantially impact the health-related quality of life (HRQoL) of older cancer patients. This exploratory analysis evaluated the effect of darbepoetin alfa administered as a fixed dose (300 microg) every 3 weeks (Q3W) on hematologic outcomes, HRQoL, and safety in older (> or =65 years old) versus younger (<65 years old) patients with CIA (hemoglobin <11 g/dl). Patients were categorized by age at screening: <65, > or =65 to <70, > or =70 to <75, > or =75 to <80, and > or =80 years old. Patients who received at least one dose of darbepoetin alfa were included in the analysis; of 1,493 patients, 724 were > or =65 years old. Age did not appear to influence hematologic outcomes after treatment with darbepoetin alfa; in all age categories, similar percentages of patients (78%-80%) achieved the target hemoglobin in approximately the same time (4-5 weeks). Also, the percentage of patients in each age category who received RBC transfusions was reduced from 10%-13% in month 1 to 2%-4% in month 4. Although younger patients reported the greatest improvement in HRQoL scores, approximately one half in each older age category reported clinically significant improvement in fatigue, and improvement in the Energy and Overall Health Assessment and Work Productivity and Activity Impairment scales. There were no treatment-related deaths. Treatment-related thromboembolic events were reported by <1% of patients <65 years old and <1% of patients > or =65 to <70 and > or =70 to <75 years old. Darbepoetin alfa Q3W appeared well tolerated and effective for treating older patients with CIA. [Abstract/Link to Full Text]

Giusti RM, Shastri KA, Cohen MH, Keegan P, Pazdur R
FDA drug approval summary: panitumumab (Vectibix).
Oncologist. 2007 May;12(5):577-83.
On September 27, 2006, the U.S. Food and Drug Administration granted approval to panitumumab (Vectibix, Amgen, Inc., Thousand Oaks, CA) for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Panitumumab approval is based on the results of a single, open-label, randomized, multinational study that enrolled 463 patients with EGFR-expressing (at least 1+ membrane staining in > or =1% of tumor cells) metastatic colorectal cancer. Patients were randomized to either best supportive care (BSC) alone or BSC plus panitumumab, 6 mg/kg i.v., every other week. The primary study endpoint was progression-free survival (PFS), determined by an independent review committee that was blinded as to treatment assignment. BSC patients who progressed were eligible to receive panitumumab. The study patients' median age was 62 years, with 40% aged > or =65; 63% were male, 99% were white, 86% had a baseline Eastern Cooperative Oncology Group performance status score of 0 or 1, and 67% had colon cancer. The median time from diagnosis of metastases was approximately 19 months and the median number of prior therapies was 2.4. The PFS duration was significantly longer among patients randomized to receive panitumumab in addition to BSC (n = 231) compared with BSC alone (n = 232). The median and mean PFS times were 56 and 96.4 days, respectively, for patients receiving panitumumab and 51 and 59.7 days, respectively, for patients receiving BSC alone. Nineteen partial responses (8%, 95% confidence interval [CI], 5.3%-12.5%) were observed in panitumumab treated patients. The median duration of response was 17 weeks (95% CI, 16-25 weeks). Approximately 75% of patients in the BSC alone arm crossed over to receive panitumumab after disease progression. There was no difference in overall survival between the two study arms. The most common adverse events were skin rash, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea. The most serious adverse events were pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, diarrhea, and constipation. [Abstract/Link to Full Text]

Chen YB, Rahemtullah A, Hochberg E
Primary effusion lymphoma.
Oncologist. 2007 May;12(5):569-76.
Primary effusion lymphoma (PEL) is a rare HIV-associated non-Hodgkin's lymphoma (NHL) that accounts for approximately 4% of all HIV-associated NHL. PEL has a unique clinical presentation in having a predilection for arising in body cavities such as the pleural space, pericardium, and peritoneum. PEL cells are morphologically variable with a null lymphocyte immunophenotype and evidence of human herpesvirus (HHV)-8 infection. The exact oncogenic mechanisms of HHV-8 have not been clearly defined. Treatment is usually with combination CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy and antiretroviral therapy (if HIV positive). The prognosis for PEL is poor, with a median survival time of around 6 months. As the exact molecular steps in HHV-8-driven oncogenesis are unraveled, it is hoped that more specific therapeutic targets will be revealed. [Abstract/Link to Full Text]

Allen AM, Tishler RB
Commentary: IMRT for head and neck cancer: many chapters left to write.
Oncologist. 2007 May;12(5):565-8. [Abstract/Link to Full Text]

Grégoire V, De Neve W, Eisbruch A, Lee N, Van den Weyngaert D, Van Gestel D
Intensity-modulated radiation therapy for head and neck carcinoma.
Oncologist. 2007 May;12(5):555-64.
Intensity-modulated radiation therapy (IMRT) for head and neck tumors refers to a new approach that aims at increasing the radiation dose gradient between the target tissues and the surrounding normal tissues at risk, thus offering the prospect of increasing the locoregional control probability while decreasing the complication rate. As a prerequisite, IMRT requires a proper selection and delineation of target volumes. For the latter, recent data indicate the potential of functional imaging to complement anatomic imaging modalities. Nonrandomized clinical series in paranasal sinuses and pharyngolaryngeal carcinoma have shown that IMRT was able to achieve a very high rate of locoregional control with less morbidity, such as dry-eye syndrome, xerostomia, and swallowing dysfunction. The promising results of IMRT are likely to be achieved when many treatment conditions are met, for example, optimal selection and delineation of the target volumes and organs at risk, appropriate physical quality control of the irradiation, and accurate patient setup with the use of onboard imaging. Because of the complexity of the various tasks, it is thus likely that these conditions will only be met in institutions having large patient throughput and experience with IMRT. Therefore, patient referral to those institutions is recommended. [Abstract/Link to Full Text]

Jeung HC, Rha SY, Kim HK, Lim HY, Kim S, Kim SY, Gong SJ, Park CH, Ahn JB, Noh SH, Chung HC
Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations.
Oncologist. 2007 May;12(5):543-54.
This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarray-based comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m(2) twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m(2) bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m(2) bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment. [Abstract/Link to Full Text]

Kunnimalaiyaan M, Chen H
Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors.
Oncologist. 2007 May;12(5):535-42.
A growing body of literature is demonstrating that Notch signaling is a more complex process than originally thought. Contradictory findings of notch-1 acting as an oncogene or a tumor suppressor revealed that its role is very specific to the cellular context. In this review we focus on the tumor suppressor role of Notch-1 signaling in neuroendocrine tumors (NETs) such as carcinoid and medullary thyroid cancers. NETs secrete various bioactive hormones that can cause debilitating symptoms. Surgery is the only potential curative treatment for the patients with NETs. Notch-1 signaling is absent in these tumors and activation of Notch-1 significantly reduces tumor growth in vitro. Therefore, identification of compound(s) that activate the Notch-1 pathway in NETs could be a potential strategy to treat patients with NETs. [Abstract/Link to Full Text]

Uronis HE, Bendell JC
Anal cancer: an overview.
Oncologist. 2007 May;12(5):524-34.
Anal cancer is a rare tumor with an incidence that has been rising over the last 25 years. The disease was once thought to develop as a result of chronic irritation, but it is now known that this is not the case. Multiple risk factors, including human papillomavirus (HPV) infection, anoreceptive intercourse, cigarette smoking, and immunosuppression, have been identified. HIV infection is also associated with anal cancer; there is a higher incidence in HIV-positive patients but the direct relationship between HIV and anal cancer has been difficult to separate from the prevalence of HPV in this population. HIV infection is also associated with anal cancer; there are increasing numbers of HIV-positive patients being diagnosed with the disease. Treatment of anal cancer prior to the 1970s involved abdominoperineal resection, but the standard of care is now concurrent chemoradiation therapy, with surgery reserved for those patients with residual disease. We present a case of anal cancer followed by a general discussion of both risk factors and treatment. [Abstract/Link to Full Text]

el-Shami K, Griffiths E, Streiff M
Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment.
Oncologist. 2007 May;12(5):518-23.
Thrombophilia is a well-described consequence of cancer and its treatment. The pathogenesis of this phenomenon is complex and multifactorial. Nonbacterial thrombotic endocarditis (NBTE) is a serious and potentially underdiagnosed manifestation of this prothrombotic state that can cause substantial morbidity in affected patients, most notably recurrent or multiple ischemic cerebrovascular strokes. Diagnosis of NBTE requires a high degree of clinical suspicion as well as the judicious use of two-dimensional echocardiography to document the presence of valvular thrombi. In the absence of contraindications to therapy, treatment consists of systemic anticoagulation, which may ameliorate symptoms and prevent further thromboembolic episodes, as well as control of the underlying malignancy whenever possible. [Abstract/Link to Full Text]

Goodsell DS
The molecular perspective: hepatitis B virus.
Oncologist. 2007 May;12(5):516-7. [Abstract/Link to Full Text]

Gentilini O, Chagas E, Zurrida S, Intra M, De Cicco C, Gatti G, Silva L, Renne G, Cassano E, Veronesi U
Sentinel lymph node biopsy in male patients with early breast cancer.
Oncologist. 2007 May;12(5):512-5.
Mastectomy with axillary dissection is still the most commonly recommended procedure for male breast cancer. The aim of this study was to retrospectively evaluate our experience in 32 male patients with early breast cancer who underwent sentinel lymph node biopsy (SLNB) and axillary dissection only in cases of metastases in the sentinel lymph node (SLN). The median age was 58 years (range, 33-80). Lymphoscintigraphy was successful in all patients, with a mean number of visualized SLNs per patient of 1.3 (range, 1-2). At surgery, the identification rate of the SLN was 100%, with a mean number of removed SLNs per patient of 1.5 (range, 1-3). Twenty-six patients had negative SLNs, six patients had positive SLNs. Two patients with metastatic SLNs had additional positive nodes. After a median follow-up of 30 months (range, 1-63) no axillary reappearance of the disease occurred. As with women, we recommend SLNB in male patients with breast cancer and clinically negative axilla. [Abstract/Link to Full Text]

Berry D
Commentary: the hazards of survival comparisons.
Oncologist. 2007 May;12(5):510-1. [Abstract/Link to Full Text]

Lewis JP
An interpretation of the EBCTCG data.
Oncologist. 2007 May;12(5):505-9.
Published data and figures from the Early Breast Cancer Clinical Trialists' Collaborative Group are explored and interpreted as supporting a concept that the prime impact of adjuvant hormonal and polychemotherapy therapy is on soon-to-emerge tumors, with the timing of benefit accrual being mostly limited to the time of drug administration. Nevertheless, once benefit in reducing recurrence occurs, the benefit is maintained for years. Depending on how this is viewed, there may or may not be a carryover effect of these therapies in the setting of adjuvant breast cancer. [Abstract/Link to Full Text]

Shun SC, Beck SL, Pett MA, Richardson SJ
Assessing responsiveness of cancer-related fatigue instruments: distribution-based and individual anchor-based methods.
Oncologist. 2007 Apr;12(4):495-504.
BACKGROUND: The aims of the study were to examine the responsiveness of Chinese versions of the Cancer Fatigue Scale (C-CFS), the Schwartz Cancer Fatigue Scale-revised (C-SCFS-r), and the Fatigue Symptom Inventory (C-FSI) based on effect sizes and patient perceptions of change. METHOD: Convenience sampling was used to recruit subjects at a chemotherapy treatment center for outpatients in Taiwan. Data were collected twice: on the day cancer patients were receiving chemotherapy treatment (T1) and 2 days post-treatment (T2). RESULTS: Questionnaires were complete at T2 by 148 subjects (60.9%). The differences between T1 and T2 were statistically significant for all three scales. The effect sizes, ranging from a medium to a large change for the C-CFS, C-SCFS-r, and C-FSI were reported based on four groups (self-reported no increase, small increase, moderate increase, and large increase). Generalized estimating equations were used to compare the fatigue scores based on the four groups by controlling for the fatigue level at baseline and the time effect. The results indicate that the fatigue scores after 2 days of treatment in the three "change" groups were statistically significantly larger than in the "no increase" group. In addition, the pretreatment fatigue level in the "large increase" group was significantly higher than in the other three groups. CONCLUSION: Results indicate that the three scales are sensitive to change over 2 days. However, the three scales may not effectively discriminate between a moderate and large change. Therefore, further testing on cancer patients with severe fatigue to examine responsiveness to detect minimal important differences for the three scales is recommended. [Abstract/Link to Full Text]

Ozer H, Mirtsching B, Rader M, Luedke S, Noga SJ, Ding B, Dreiling L
Neutropenic events in community practices reduced by first and subsequent cycle pegfilgrastim use.
Oncologist. 2007 Apr;12(4):484-94.
The impact of first- and subsequent-cycle growth factor use in the community setting has not been studied extensively. We conducted this large, prospective, noncomparative study to assess neutropenia and related complications in patients receiving myelotoxic chemotherapy with pegfilgrastim support in community practices. Patients > or = 18 years old with cancers other than leukemia or myelodysplastic syndrome, including those with major comorbidities, were eligible. Pegfilgrastim (6 mg) was to be administered approximately 24 hours after chemotherapy in all cycles (minimum, four cycles). A total of 2,112 patients was included in the analyses. The most common tumor types were breast cancer (46%), non-Hodgkin's lymphoma (15%), and non-small cell lung cancer (13%). Chemotherapies administered most often were a platinum plus a taxane (18%), and anthracycline plus an alkylating agent (18%), and a taxane plus an anthracycline plus an alkylating agent (16%). The percentage of patients with neutropenia-related hospitalization was 2.9% in cycle 1 and 5.6% across all cycles. Chemotherapy dose reductions and delays were attributed to neutropenia in 1.8% and 0.9% of patients, respectively, in cycle 2 and 2.9% and 2.1% of patients, respectively, across all cycles. Febrile neutropenia (absolute neutrophil count <1.0 x 10(9)/l with temperature > or = 38.2 degrees C) occurred in 3.6% of patients in cycle 1 and in 6.3% of patients across all cycles. The most frequently reported serious adverse events were febrile neutropenia (3.4%), neutropenia (2.6%), and dehydration (2.6%). Bone pain (0.1%) was the only related serious adverse event reported in more than one patient. Data from this community-based study suggest that patients undergoing chemotherapy benefit from pegfilgrastim support beginning in the first cycle of chemotherapy. [Abstract/Link to Full Text]

Bennett CL, Calhoun EA
Evaluating the total costs of chemotherapy-induced febrile neutropenia: results from a pilot study with community oncology cancer patients.
Oncologist. 2007 Apr;12(4):478-83.
PURPOSE: While cancer chemotherapy-related febrile neutropenia affects patients' activities and medical expenditures, few studies have reported on the total costs of this condition. Here, we evaluate the feasibility of obtaining detailed and comprehensive cost information on patients who experience febrile neutropenia during cancer chemotherapy treatment. METHODS: Community oncology cancer patients who experienced chemotherapy-associated febrile neutropenia recorded information about use of medical care, tests, devices, medications, and lost productivity. Direct cost estimates were derived from Medicare Physician Fee Schedules and cost-to-charge ratios. Indirect cost estimates were based on modified Labor Force, Employment, and Earnings data for employed patients and wages earned by paid caregivers. Multivariate regression models evaluated predictors of higher direct, indirect, and total costs. RESULTS: Outpatients' mean direct and indirect costs were 5,704 dollars and 1,201 dollars (lymphoma), 1,094 dollars and 1,530 dollars (breast cancer), and 1,329 dollars and 1,325 dollars (lung cancer and myeloma), respectively. The mean direct and indirect costs were three- to tenfold and 1.5- to threefold greater for inpatients, respectively. Factors associated with higher direct costs of care included diagnosis of lymphoma and inpatient care; higher indirect costs, male versus female gender; higher total costs, lymphoma diagnosis and inpatient care. CONCLUSION: Estimation of the total costs of cancer-related neutropenia is feasible. Indirect costs appear to account for as much as half of the total supportive care costs when febrile neutropenia is managed in the outpatient setting and about one fifth of the total supportive care costs in the inpatient setting. [Abstract/Link to Full Text]

Senan S, Smit EF
Design of clinical trials of radiation combined with antiangiogenic therapy.
Oncologist. 2007 Apr;12(4):465-77.
Clinical trials showing longer survival when chemotherapy is combined with antiangiogenic agents (AAs) have led to growing interest in designing combined modality protocols that exploit abnormalities in tumor vasculature. Approved agents include bevacizumab, a recombinant monoclonal antibody that binds to vascular endothelial growth factor, and two small molecule multitargeted tyrosine kinase inhibitors of angiogenesis (SU11248 and BAY-43-9006) that have been approved for therapy of renal cancer. Targeting tumor vasculature has a strong biological rationale in radiation therapy, and preclinical studies consistently show an increase in radiosensitization with combined treatment. Preclinical studies indicate that excessive damage to tumor vasculature can result in radioresistance in some situations, and early clinical data suggest that treatment sequencing may be important when combining AAs with radiation. Radiation itself appears to antagonize any hypoxia that can be induced by long-term administration of AAs. The optimal biological doses of AAs with radiotherapy are unknown, and surrogate markers of efficacy remain to be validated. Early clinical trials should therefore include studies designed to identify mechanisms of interaction and increases in tumor hypoxia. This review highlights preclinical and early clinical data that are relevant for clinical trial design. Optimal radiation planning and delivery is required to minimize the volume of irradiated normal organs and to establish safe dose-volume parameters for phase II-III clinical trials. [Abstract/Link to Full Text]

Grossi F, Aita M, Follador A, Defferrari C, Brianti A, Sinaccio G, Belvedere O
Sequential, alternating, and maintenance/consolidation chemotherapy in advanced non-small cell lung cancer: a review of the literature.
Oncologist. 2007 Apr;12(4):451-64.
A platinum-based doublet with a third-generation agent (paclitaxel, vinorelbine, gemcitabine, docetaxel) represents the standard first-line treatment for advanced non-small cell lung cancer patients with good performance status (PS). Traditional chemotherapy provides response rates of 20%-40% and a median survival of 8-10 months. In an attempt to improve its outcome, alternative schedules have been proposed, namely sequential, alternating, and maintenance/consolidation therapy. Sequential chemotherapy with a platinum-based doublet followed by a single agent is feasible in patients with good PS; preliminary results from randomized phase III trials with combination chemotherapy as a comparator are promising, suggesting similar efficacy and a better toxicity profile for the sequential arm. The use of sequential single agents is an option for elderly and frail patients unsuitable for a platinum-based combination. Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will be proven superior to standard chemotherapy in patients with good PS. However, sufficient evidence exists that it could be appropriate in the elderly or in unfit individuals. Consolidation/maintenance chemotherapy may provide additional benefit for patients achieving disease control after standard first-line chemotherapy. Better results are seen when maintenance consists of an agent that has proven active in the induction phase. Further evaluation of this strategy, as well as of consolidation/maintenance therapy with targeted agents, is warranted. In conclusion, these approaches may improve the outcome in selected patients with advanced non-small cell lung cancer, but further results from randomized trials are needed. In the meantime, sequential, alternating, and maintenance/consolidation therapy should still be considered investigational. [Abstract/Link to Full Text]

Los M, Roodhart JM, Voest EE
Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer.
Oncologist. 2007 Apr;12(4):443-50.
Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. In 2004, this approach was validated in a randomized, controlled phase III clinical trial. It was shown that the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A, to conventional chemotherapy prolonged survival over chemotherapy alone in patients with metastatic colorectal cancer. In this review, we discuss the results of the clinical trials that have led to the incorporation of antiangiogenic agents into the treatment of patients with advanced colorectal cancer. We limit ourselves to the two agents that have been tested extensively in phase III trials: bevacizumab and vatalanib, a small molecule tyrosine kinase inhibitor against VEGF receptors. In addition, we discuss the adverse effects of bevacizumab and vatalanib and the clinical management of the side effects. [Abstract/Link to Full Text]

Jamali FR, Darwiche SS, El-Kinge N, Tawil A, Soweid AM
Disease progression following imatinib failure in gastrointestinal stromal tumors: role of surgical therapy.
Oncologist. 2007 Apr;12(4):438-42.
Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal neoplasms of the GI tract. The optimal management of GISTs has been evolving rapidly over the past 5 years and depends on proper histopathologic and radiologic diagnosis as well as appropriate multidisciplinary medical and surgical treatments. Complete surgical resection of primary localized GIST with negative margins remains the best therapeutic option today. In the setting of locally advanced or metastatic disease, imatinib mesylate has emerged as the initial treatment of choice, administered either as cytoreductive or as definitive treatment. Surgery or ablative modalities in this setting are becoming increasingly employed, particularly when all disease becomes amenable to gross resection or destruction, or to manage complications arising from the disease following imatinib failure. We report on the surgical management of an unusual and clinically significant complication following progression of disease secondary to imatinib resistance. The role of surgical therapy in the management of GIST complications following resistance to imatinib and the integration of surgical and molecular therapy of locally advanced or metastatic GISTs are discussed. [Abstract/Link to Full Text]

Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, Hirte HW, Eder JP, Lenz HJ, Schwartz B
Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.
Oncologist. 2007 Apr;12(4):426-37.
Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer. [Abstract/Link to Full Text]

Pentheroudakis G, Briasoulis E, Pavlidis N
Cancer of unknown primary site: missing primary or missing biology?
Oncologist. 2007 Apr;12(4):418-25.
Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths and represents both a diagnostic and a management challenge. In CUP, the regression or dormancy of the primary tumor, the development of early, uncommon, systemic metastases, and the resistance to therapy are hallmarks of this heterogeneous clinical entity. Still, no consensus exists on whether CUP is simply a group of metastatic tumors with unidentified primaries or a distinct entity with specific genetic/phenotypic aberrations that define it as "primary metastatic disease." In this review, we present karyotypic analyses as well as the single-gene, single-protein studies done on the expression of oncogenes, tumor- or metastasis-suppressor genes, as well as angiogenesis effectors. These studies show frequent expression of oncoproteins, lack of activating epidermal growth factor receptor/c-Kit mutations or amplification, uncommon presence of tumor- or metastasis-suppressor gene mutations and highly active angiogenesis in CUP. Informative as they may be, these data have been observed in several solid tumors of known primary and failed to identify a CUP-specific molecular signature. The latter, if it exists, probably consists of a multigene expression pattern not captured by single-gene studies. Gene and protein microarray technologies offer promise for the unraveling of complex genetic programs that would either identify each CUP's primary tissue of origin or instead define the CUP-specific molecular signature. Confirmation of one of the two hypotheses would either improve primary disease-oriented therapy or develop CUP-oriented treatments targeting molecular aberrations that drive neoplastic growth/dissemination. [Abstract/Link to Full Text]

Hirasaki S, Noguchi T, Mimori K, Onuki J, Morita K, Inoue H, Sugihara K, Mori M, Hirano T
BAC clones related to prognosis in patients with esophageal squamous carcinoma: an array comparative genomic hybridization study.
Oncologist. 2007 Apr;12(4):406-17.
PURPOSE: The prognosis of patients with esophageal carcinoma is poor. To identify genomic alterations associated with poor patient prognosis, we analyzed whole DNA copy number profiles of esophageal squamous carcinomas (ESCs) using array-based comparative genomic hybridization (aCGH). MATERIALS AND METHODS: Twenty-one operated and two biopsied cases of esophageal squamous cancer were examined for study. Each sample was laser microdissected to obtain pure cancer cell populations. The extracted DNA was analyzed using aCGH. RESULTS: One of the most representative alterations was a previously reported amplification at 11q13.3. In addition, some novel alterations, such as deletion of 16p13.3, were identified. Of the 19 patients who were reassessed more than 5 years after the operation, nine were still living and 10 had died from disease recurrence. When aCGH profiles from the surviving group and the deceased group were compared, significant differences were recognized in 68 of 4,030 bacterial artificial chromosome (BAC) clones. Almost half of these clones were present at nine limiting regions in 4q, 13q, 20q, and Xq. For 22 of these 68 BAC clones, there also was a significant difference in the Kaplan-Meier survival curve, using the log-rank test, when comparing patients who had an alteration in a particular clone with those who did not. CONCLUSIONS: aCGH study of esophageal squamous cancer clearly identified BAC clones that are related to the prognosis of patients. These clones give us the opportunity to determine specific genes that are associated with cancer progression. [Abstract/Link to Full Text]

Jřrgensen JT, Nielsen KV, Ejlertsen B
Pharmacodiagnostics and targeted therapies - a rational approach for individualizing medical anticancer therapy in breast cancer.
Oncologist. 2007 Apr;12(4):397-405.
The selection of therapy for a particular breast cancer patient is traditionally based on average results from randomized clinical trials. Rational pharmacotherapy is in essence about selecting the right drug(s) for the right patient, and in order to guide this selection process pharmacodiagnostic tests are indispensable. A number of tests have been developed or are under development for targeted therapies, such as antiestrogens, human epidermal growth factor receptor 2 inhibitors, and topoisomerase inhibitors. Based on a biopsy from the tumor, the tests are able to identify patients with a high probability to benefit from these therapies. The detection of the predictive biomarkers is based on different technologies, such as immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization. Pharmacodiagnostic tests will play an important role in the further development of targeted therapies and may be seen as a prerequisite for the introduction of individualized medicine in oncology. [Abstract/Link to Full Text]

Penault-Llorca F, Abrial C, Mouret-Reynier MA, Raoelfils I, Durando X, Leheurteur M, Gimbergues P, Tortochaux J, Curé H, Chollet P
Achieving higher pathological complete response rates in HER-2-positive patients with induction chemotherapy without trastuzumab in operable breast cancer.
Oncologist. 2007 Apr;12(4):390-6.
Recent trials of induction chemotherapy in bulky operable breast cancer have shown much higher pathological complete response (pCR) rates with trastuzumab-driven combinations. However, it is useful to take into account the specific chemosensitivity of HER-2-positive tumors. The aim of this study was to assess the pCR rate according to HER-2 status in response to chemotherapy, without an anti-HER-2 specific biological agent, in 710 operable breast cancer patients. Since 1982, these patients have been treated with several different neoadjuvant chemotherapy combinations. During this period, HER-2 overexpression was most often not assessed. Subsequently, we assessed HER-2 expression using archival paraffin-embedded tissue. A technically usable specimen was available for 413 of the 710 patients. Before treatment, 51 patients were HER-2 positive, 287 patients were HER-2 negative, and the results were inconclusive for 75 patients. Of these patients, a pCR in breast and nodes was obtained in 94 patients (14.3%), but this event was threefold more frequent for HER-2-positive patients (23.5%) than for HER-2-negative patients (7%). The overall survival (OS) and disease-free survival (DFS) rates at 10 years were 66.6% and 57.4%, respectively. The DFS rate was, as expected, better for HER-2-negative patients, with HER-2 status assessed before as well as after chemotherapy. A significant difference was found for OS in favor of HER-2-negative patients only with postchemotherapy assessment of HER-2, a fact similar to our previous findings. Finally, there was a tendency toward a higher DFS rate for HER-2-positive patients who achieved a pCR compared with HER-2-positive patients who did not. [Abstract/Link to Full Text]

Tripathy D
Capecitabine in combination with novel targeted agents in the management of metastatic breast cancer: underlying rationale and results of clinical trials.
Oncologist. 2007 Apr;12(4):375-89.
At present there is no established standard of care for metastatic breast cancer and prognosis remains poor, although the use of newer chemotherapeutic regimens has led to modest improvements in survival. Capecitabine, an oral prodrug of 5-fluorouracil, is a promising addition to these approaches, having already shown single-agent activity against metastatic breast cancer. Following a pivotal trial demonstrating that capecitabine confers increased survival when used in combination with docetaxel, it is being investigated intensively in combined regimens using other standard chemotherapeutic agents, as well as with novel molecularly targeted therapies. Among the novel agents, the most intensively studied in combination with capecitabine is trastuzumab. Despite preclinical data suggesting that these two agents might not show additive effects, clinical trials have been very encouraging for both heavily pretreated patients and for patients receiving first-line therapy in the metastatic setting. This work is being further extended in an ongoing trial in the neoadjuvant setting. An initial trial in combination with bevacizumab, enrolling heavily pretreated patients, was less successful, but following the example of the E2100 trial, this combination is being re-examined in less heavily treated patients. In addition, this review discusses ongoing trials with an array of newer molecularly targeted agents. Significant improvement in time to progression has already been demonstrated in the combination of lapatinib and capecitabine compared with capecitabine monotherapy; for the most part, however, these trials are still in early stages. [Abstract/Link to Full Text]

Stanway SJ, Delavault P, Purohit A, Woo LW, Thurieau C, Potter BV, Reed MJ
Steroid sulfatase: a new target for the endocrine therapy of breast cancer.
Oncologist. 2007 Apr;12(4):370-4.
Inhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mRNA expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women. [Abstract/Link to Full Text]

Koop CE
Health and health care for the 21st century: for all the people.
Oncologist. 2007 Apr;12(4):366-9. [Abstract/Link to Full Text]

Koop CE
Health and health care for the 21st century: for all the people.
Am J Public Health. 2006 Dec;96(12):2090-2. [Abstract/Link to Full Text]

Lappin TR, Maxwell AP, Johnston PG
Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia.
Oncologist. 2007 Apr;12(4):362-5. [Abstract/Link to Full Text]

Littlewood TJ
Response to "Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia".
Oncologist. 2007 Aug;12(8):1031-2; author reply 1032-4. [Abstract/Link to Full Text]

Cohen MH, Gootenberg J, Keegan P, Pazdur R
FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer.
Oncologist. 2007 Mar;12(3):356-61.
On June 20, 2006, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), administered in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) for the second-line treatment of metastatic carcinoma of the colon or rectum. Efficacy and safety were demonstrated in one Eastern Cooperative Oncology Group (ECOG) open-label, multicenter, randomized, three-arm, active-controlled trial enrolling 829 adult patients. Patients had received a fluoropyrimidine- and irinotecan-based regimen as initial therapy for metastatic disease; or they had received prior adjuvant irinotecan-based chemotherapy and had recurred within 6 months of completing therapy. Treatments included bevacizumab, 10 mg/kg, as a 90-minute i.v. infusion on day 1, every 2 weeks, either alone or in combination with FOLFOX4, or FOLFOX4 alone. The bevacizumab monotherapy arm was closed to accrual after an interim efficacy analysis suggested a possibly shorter survival in that arm. Overall survival (OS), the primary study endpoint, was significantly longer for patients receiving bevacizumab in combination with FOLFOX4 than for those receiving FOLFOX4 alone. The objective response rate was significantly higher in the FOLFOX4 plus bevacizumab arm than in the FOLFOX4 alone arm. The duration of response was approximately 6 months for both treatment arms. Patients treated with the bevacizumab combination were also reported, based on investigator assessment, to have significantly longer progression-free survival. There were no new bevacizumab safety signals. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, and congestive heart failure. [Abstract/Link to Full Text]

Recent Articles in CA: A Cancer Journal for Clinicians

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]

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]


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]

Tsao AS, Kim ES, Hong WK
Chemoprevention of cancer.
CA Cancer J Clin. 2004 May-Jun;54(3):150-80.
Cancer chemoprevention is defined as the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The success of several recent clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational and appealing strategy. This review will highlight current clinical research in chemoprevention, the biologic effects of chemopreventive agents on epithelial carcinogenesis, and the usefulness of intermediate biomarkers as markers of premalignancy. Selected chemoprevention trials are discussed with a focus on strategies of trial design and clinical outcome. Future directions in the field of chemoprevention will be proposed that are based on recently acquired mechanistic insight into carcinogenesis. [Abstract/Link to Full Text]

Balch CM, Soong SJ, Atkins MB, Buzaid AC, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF
An evidence-based staging system for cutaneous melanoma.
CA Cancer J Clin. 2004 May-Jun;54(3):131-49; quiz 182-4.
A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy. [Abstract/Link to Full Text]

Greene FL
TNM: our language of cancer.
CA Cancer J Clin. 2004 May-Jun;54(3):129-30. [Abstract/Link to Full Text]

Vickers A
Alternative cancer cures: "unproven" or "disproven"?
CA Cancer J Clin. 2004 Mar-Apr;54(2):110-8.
Oncology has always coexisted with therapies offered outside of conventional cancer treatment centers and based on theories not found in biomedicine. These alternative cancer cures have often been described as "unproven," suggesting that appropriate clinical trials have not been conducted and that the therapeutic value of the treatment is unknown. Contrary to much popular and scientific writing, many alternative cancer treatments have been investigated in good quality clinical trials, and they have been shown to be ineffective. In this article, clinical trial data on a number of alternative cancer cures including Livingston-Wheeler, Di Bella Multitherapy, antineoplastons, vitamin C, hydrazine sulfate, Laetrile, and psychotherapy are reviewed. The label "unproven" is inappropriate for such therapies; it is time to assert that many alternative cancer therapies have been "disproven." [Abstract/Link to Full Text]

Cormier JN, Pollock RE
Soft tissue sarcomas.
CA Cancer J Clin. 2004 Mar-Apr;54(2):94-109.
Sarcomas are a heterogeneous group of rare tumors that arise predominantly from the embryonic mesoderm. They present most commonly as an asymptomatic mass originating in an extremity but can occur anywhere in the body, particularly the trunk, retroperitoneum, or the head and neck. Pretreatment radiologic imaging is critical for defining the local extent of a tumor, staging the disease, guiding biopsies, and aiding in diagnosis. Core-needle biopsy is the preferred biopsy technique for diagnosing soft tissue sarcomas. The American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcomas is based on histologic grade, the tumor size and depth, and the presence of distant or nodal metastases. Despite improvements in local control rates with wide local resections and radiation therapy, metastasis and death remain a significant problem in 50% of patients who present with high-risk soft tissue sarcomas. The most common site of metastasis is the lungs, and metastasis generally occurs within two to three years after the completion of therapy. Progress in the molecular characteristics of these tumors should in the near future translate into molecularly based therapies that can be incorporated into standard treatment strategies. [Abstract/Link to Full Text]

Ward E, Jemal A, Cokkinides V, Singh GK, Cardinez C, Ghafoor A, Thun M
Cancer disparities by race/ethnicity and socioeconomic status.
CA Cancer J Clin. 2004 Mar-Apr;54(2):78-93.
This article highlights disparities in cancer incidence, mortality, and survival in relation to race/ethnicity, and census data on poverty in the county or census tract of residence. The incidence and survival data derive from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program; mortality data are from the National Center for Health Statistics (NCHS); data on the prevalence of major cancer risk factors and cancer screening are from the National Health Interview Survey (NHIS) conducted by NCHS. For all cancer sites combined, residents of poorer counties (those with greater than or equal to 20% of the population below the poverty line) have 13% higher death rates from cancer in men and 3% higher rates in women compared with more affluent counties (less than 10% below the poverty line). Differences in cancer survival account for part of this disparity. Among both men and women, five-year survival for all cancers combined is 10 percentage points lower among persons who live in poorer than in more affluent census tracts. Even when census tract poverty rate is accounted for, however, African American, American Indian/Alaskan Native, and Asian/Pacific Islander men and African American and American Indian/Alaskan Native women have lower five-year survival than non-Hispanic Whites. More detailed analyses of selected cancers show large variations in cancer survival by race and ethnicity. Opportunities to reduce cancer disparities exist in prevention (reductions in tobacco use, physical inactivity, and obesity), early detection (mammography, colorectal screening, Pap tests), treatment, and palliative care. [Abstract/Link to Full Text]

Freeman HP
Poverty, culture, and social injustice: determinants of cancer disparities.
CA Cancer J Clin. 2004 Mar-Apr;54(2):72-7. [Abstract/Link to Full Text]


Patient pages. Finding cancer early.
CA Cancer J Clin. 2004 Jan-Feb;54(1):53-6; quiz 57-9. [Abstract/Link to Full Text]

Smith RA, Cokkinides V, Eyre HJ
American Cancer Society guidelines for the early detection of cancer, 2004.
CA Cancer J Clin. 2004 Jan-Feb;54(1):41-52.
Each January, the American Cancer Society (ACS) publishes a summary of its recommendations for early cancer detection, including updates, emerging issues that are relevant to screening for cancer, or both. In the spring of 2003, the ACS announced updated guidelines for breast cancer screening, and several other organizations released updated guidelines that we compare with recent ACS updates. Finally, the most recent data pertaining to participation rates in cancer screening are presented by age and sex from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System, as are U.S. maps profiling states based on the proportion of the age-eligible population not recently screened for breast cancer or colorectal cancer. [Abstract/Link to Full Text]

Tiwari RC, Ghosh K, Jemal A, Hachey M, Ward E, Thun MJ, Feuer EJ
A new method of predicting US and state-level cancer mortality counts for the current calendar year.
CA Cancer J Clin. 2004 Jan-Feb;54(1):30-40.
Every January for more than 40 years, the American Cancer Society (ACS) has estimated the total number of cancer deaths that are expected to occur in the United States and individual states in the upcoming year. In a collaborative effort to improve the accuracy of the predictions, investigators from the National Cancer Institute and the ACS have developed and tested a new prediction method. The new method was used to create the mortality predictions for the first time in Cancer Statistics, 2004 and Cancer Facts & Figures 2004. The authors present a conceptual overview of the previous ACS method and the new state-space method (SSM), and they review the results of rigorous testing to determine which method provides more accurate predictions of the observed number of cancer deaths from the years 1997 to 1999. The accuracy of the methods was compared using squared deviations (the square of the predicted minus observed values) for each of the cancer sites for which predictions are published as well as for all cancer sites combined. At the national level, the squared deviations were not consistently lower for every cancer site for either method, but the average squared deviations (averaged across cancer sites, years, and sex) was substantially lower for the SSM than for the ACS method. During the period 1997 to 1999, the ACS estimates of deaths were usually greater than the observed numbers for all cancer sites combined and for several major individual cancer sites, probably because the ACS method was less sensitive to recent changes in cancer mortality rates (and associated counts) that occurred for several major cancer sites in the early and mid 1990s. The improved accuracy of the new method was particularly evident for prostate cancer, for which mortality rates changed dramatically in the late 1980s and early 1990s. At the state level, the accuracy of the two methods was comparable. Based on these results, the ACS has elected to use the new method for the annual prediction of the number of cancer deaths at the national and state levels. [Abstract/Link to Full Text]

Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ
Cancer statistics, 2004.
CA Cancer J Clin. 2004 Jan-Feb;54(1):8-29.
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 rates based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and mortality rates are age standardized to the 2000 US standard million population. A total of 1,368,030 new cancer cases and 563,700 deaths are expected in the United States in 2004. Incidence rates stabilized among men from 1995 through 2000 but continued to increase among females by 0.4% per year from 1987 through 2000. Mortality rates have decreased by 1.5% per year since 1992 among men, but have stabilized from 1998 through 2000 among women. Cancer death rates continued to decrease from the three major cancer sites in men (lung and bronchus, colon and rectum, and prostate) and from female breast and colorectal cancers in women. In analyses by race and ethnicity, African-American men and women have 40% and 20% higher death rates from all cancers combined compared with White men and women, respectively. Cancer incidence and mortality 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 do Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden from cancer can be accelerated by applying existing cancer control knowledge into practice among all segments of the population. [Abstract/Link to Full Text]

Vance RB
The marriage of cancer control and advocacy.
CA Cancer J Clin. 2004 Jan-Feb;54(1):6-7. [Abstract/Link to Full Text]


Patient Pages. Answers to questions often asked by cancer survivors about nutrition and physical activity.
CA Cancer J Clin. 2003 Sep-Oct;53(5):303-9. [Abstract/Link to Full Text]

Albert MR, Weinstock MA
Keratinocyte carcinoma.
CA Cancer J Clin. 2003 Sep-Oct;53(5):292-302.
Keratinocyte carcinoma is by far the most common cancer in the United States. Basal cell carcinomas and squamous cell carcinomas account for approximately 80% and 20% of cases of KC, respectively. The term nonmelanoma skin cancer is commonly used to refer to squamous cell carcinomas and basal cell carcinomas; however, other types of nonmelanoma skin cancer, such as adnexal tumors and sarcomas, are less common and differ in their cell type, behavior, and epidemiologic features from KC. Primary care clinicians are well positioned to diagnose KC and to educate patients about preventive measures such as sun protection and self-examination. Here we review epidemiologic data and strategies for prevention, diagnosis, and clinical management of KC. [Abstract/Link to Full Text]

Brown JK, Byers T, Doyle C, Coumeya KS, Demark-Wahnefried W, Kushi LH, McTieman A, Rock CL, Aziz N, Bloch AS, Eldridge B, Hamilton K, Katzin C, Koonce A, Main J, Mobley C, Morra ME, Pierce MS, Sawyer KA
Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices.
CA Cancer J Clin. 2003 Sep-Oct;53(5):268-91.
Cancer survivors are often highly motivated to seek information about food choices, physical activity, dietary supplement use, and complementary nutritional therapies to improve their treatment outcomes, quality of life, and survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information on which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity issues during the phases of cancer treatment and recovery, living after recovery from treatment, and living with advanced cancer; selected nutritional and physical activity issues such as body weight, food choices, and complementary and alternative nutritional options; and selected issues related to breast, colorectal, lung, prostate, head and neck, and upper gastrointestinal cancers. In addition, handouts containing commonly asked questions and answers and a resource list are provided for survivors and families. Tables that grade the scientific evidence for benefit versus harm related to nutrition and physical activity for breast, colorectal, lung, and prostate cancers are also included for this growing body of knowledge to provide guidance for informed decision making and to identify areas for future research. [Abstract/Link to Full Text]

Chlebowski RT
The American Cancer Society guide for nutrition and physical activity for cancer survivors: a call to action for clinical investigators.
CA Cancer J Clin. 2003 Sep-Oct;53(5):266-7. [Abstract/Link to Full Text]

Frumkin H
Agent Orange and cancer: an overview for clinicians.
CA Cancer J Clin. 2003 Jul-Aug;53(4):245-55. [Abstract/Link to Full Text]

Holmes CE, Muss HB
Diagnosis and treatment of breast cancer in the elderly.
CA Cancer J Clin. 2003 Jul-Aug;53(4):227-44.
As the population of the United States ages, women over the age of 65 have become a prominent cohort in the breast cancer population, with approximately 50% of all new breast cancers occurring in women aged 65 years and older. Early studies in breast cancer often excluded women based on age or comorbidity, leaving physicians and patients with a growing number of diagnostic and treatment options, each of which often carry short-term morbidity risks for potential long-term gain. We review the current data available for diagnosis and treatment of elderly women with breast cancer in both the adjuvant and metastatic disease setting. In addition, the role of screening and new concepts in prevention are discussed with emphasis on the older patient. [Abstract/Link to Full Text]

O'Brien K, Cokkinides V, Jemal A, Cardinez CJ, Murray T, Samuels A, Ward E, Thun MJ
Cancer statistics for Hispanics, 2003.
CA Cancer J Clin. 2003 Jul-Aug;53(4):208-26.
In this article, the American Cancer Society (ACS) provides estimates on the number of new cancer cases and deaths, and compiles health statistics on the US Hispanic population. The compiled statistics include cancer incidence, mortality, and behaviors relevant to cancer using the most recent data on incidence from the National Cancer Institute's (NCI) Surveillance, Epidemiolgy, and End Results (SEER) Program, mortality data from the National Center for Health Statistics, and behavioral information from the Behavior Risk Factor Surveillance System (Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System [BRFSS], Youth Risk Behavior Surveillance System [YRBSS], and National Health Interview Survey [NHIS].) An estimated 67,400 new cases of cancer and 22,100 cancer deaths will occur among Hispanics in 2003. Hispanics have lower incidence and death rates from all cancers combined and from the four most common cancers (breast, prostate, lung and bronchus, and colon and rectum) than non-Hispanic whites. However, Hispanics have higher incidence and mortality rates from cancers of the stomach, liver, uterine cervix, and gallbladder, reflecting in part greater exposure to specific infectious agents and lower rates of screening for cervical cancer, as well as dietary patterns and possible genetic factors. Strategies for reducing cancer risk among Hispanics include further development of effective interventions to increase screening and physical activity, reductions in tobacco use and obesity, and the development and application of effective vaccines. [Abstract/Link to Full Text]

Huerta EE
Cancer statistics for Hispanics, 2003: good news, bad news, and the need for a health system paradigm change.
CA Cancer J Clin. 2003 Jul-Aug;53(4):205-7. [Abstract/Link to Full Text]


Excess weight linked to 90,000 US cancer deaths annually.
CA Cancer J Clin. 2003 Jul-Aug;53(4):203-4. [Abstract/Link to Full Text]


Medicare managed care patients more likely to use hospice.
CA Cancer J Clin. 2003 Jul-Aug;53(4):202-3. [Abstract/Link to Full Text]


Two studies find high-fiber diet lowers colon cancer risk.
CA Cancer J Clin. 2003 Jul-Aug;53(4):201-2. [Abstract/Link to Full Text]


Invasive lobular carcinoma incidence increasing.
CA Cancer J Clin. 2003 May-Jun;53(3):137. [Abstract/Link to Full Text]

Kattlove H, Winn RJ
Ongoing care of patients after primary treatment for their cancer.
CA Cancer J Clin. 2003 May-Jun;53(3):172-96.
Nearly nine million people living in the United States have had a diagnosis of cancer. As the population ages, this number will increase. Most of these people will need follow-up care to deal with problems related to their cancer. Depending on the cancer, they may or may not benefit from surveillance to detect recurrence. Most will be more likely than average to develop a second primary cancer. Some will be genetically susceptible to another type of cancer. Many will have complications from their treatment that need attention. Also, their treatment may have altered certain physiologic functions. Finally, many will have suffered psychosocial difficulties either as a result of their cancer or its treatment. This article deals with these issues for the most commonly encountered cancers. Its major goal is to alert physicians to be aware of and help them to deal with these issues. Clearly, such an ambitious goal can only be partly achieved in a single journal article. Hopefully, the references included will allow physicians to proceed further if they wish. [Abstract/Link to Full Text]


Finding breast cancer early.
CA Cancer J Clin. 2003 May-Jun;53(3):170-1. [Abstract/Link to Full Text]

Smith RA, Saslow D, Sawyer KA, Burke W, Costanza ME, Evans WP, Foster RS, Hendrick E, Eyre HJ, Sener S
American Cancer Society guidelines for breast cancer screening: update 2003.
CA Cancer J Clin. 2003 May-Jun;53(3):141-69.
In 2003, the American Cancer Society updated its guidelines for early detection of breast cancer based on recommendations from a formal review of evidence and a recent workshop. The new screening recommendations address screening mammography, physical examination, screening older women and women with comorbid conditions, screening women at high risk, and new screening technologies. [Abstract/Link to Full Text]

Garber JE
Breast cancer screening: a final analysis?
CA Cancer J Clin. 2003 May-Jun;53(3):138-40. [Abstract/Link to Full Text]


Oncologists disagree on impact of patient internet use.
CA Cancer J Clin. 2003 May-Jun;53(3):135-7. [Abstract/Link to Full Text]

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

Irvin Vidrine J, Anderson CB, Pollak KI, Wetter DW
Race/ethnicity, smoking status, and self-generated expected outcomes from smoking among adolescents.
Cancer Control. 2005 Nov;12 Suppl 251-7.
Racial/ethnic differences in adolescent smoking suggest that different factors may motivate smoking among various racial/ethnic groups. This study examined relations among race/ethnicity, self-generated smoking outcome expectancies, and smoking status. Our findings noted that current smoking was highest among Hispanics, whereas African Americans and Asians were least likely to ever smoke. African Americans were most likely to experiment but least likely to smoke currently. Five expectancies differed significantly by race/ethnicity: reduce tension, image, negative aesthetics, addiction, and cost. However, none were significant mediators or moderators. Racial/ethnic groups most susceptible to smoking initiation and with the highest rates of current smoking should be targeted for prevention and cessation. Research is needed to examine more thoroughly racial/ethnic differences in expectancies. [Abstract/Link to Full Text]

Hunter JL
Cervical cancer educational pamphlets: Do they miss the mark for Mexican immigrant women's needs?
Cancer Control. 2005 Nov;12 Suppl 242-50.
The rate of invasive cervical cancer in US Hispanic women is nearly doubled that of non-Hispanics. Using in-depth interviews and content/grade level analysis of educational materials, this study explores the relevance of cervical cancer education materials to the needs of Mexican immigrant women. It also addresses health literacy issues that create barriers to learning. Findings show aspects of language, content, reading level, structure, and visual images in 22 cervical cancer pamphlets from 11 health care sites in a Midwest city were not relevant to the learning needs or health literacy levels of local Mexican immigrant women. Further research is recommended to establish an evidence base regarding optimal presentation of key elements of the cervical cancer educational message for Mexican immigrant women. [Abstract/Link to Full Text]

Garza MA, Luan J, Blinka M, Farabee-Lewis RI, Neuhaus CE, Zabora JR, Ford JG
A culturally targeted intervention to promote breast cancer screening among low-income women in East Baltimore, Maryland.
Cancer Control. 2005 Nov;12 Suppl 234-41.
In Maryland, outreach initiatives have been unsuccessful in engaging low-income African American women in mammography screening. This study aimed to identify factors influencing screening rates for low-income African American women. Based on the Health Belief Model, a modified time series design was used to implement a culturally targeted intervention to promote a no-cost mammography-screening program. Data were collected from women 40 years of age and older on their history of mammography use and their knowledge and beliefs about breast cancer. A 50% screening rate was achieved among 119 eligible participants. Significant predictors of screening behaviors were perceived barriers, lack of insurance, and limited knowledge. This culturally targeted intervention resulted in an unprecedented screening rate among low-income African American women in Baltimore, Maryland. [Abstract/Link to Full Text]

Dignan MB, Burhansstipanov L, Hariton J, Harjo L, Rattler T, Lee R, Mason M
A comparison of two Native American Navigator formats: face-to-face and telephone.
Cancer Control. 2005 Nov;12 Suppl 228-33.
The study was designed to test the relative effectiveness of a Navigator intervention delivered face-to-face or by telephone to urban Native American women. The effectiveness of the intervention was evaluated using a design that included a pretest, random assignment to face-to-face or telephone group, and posttest. The Social Cognitive Theory-based intervention was a tailored education program developed to address individual risk factors for breast cancer. At posttest, self-reported mammograms in the past year increased from 29% to 41.3% in the telephone group and from 34.4% to 45.2% in the face-to-face group. There was no difference in change from pretest to posttest between the telephone and face-to-face groups. Navigators can be effective in increasing adherence to recommendations for screening mammography among urban American Indian women. [Abstract/Link to Full Text]

Palmer RC, Fernandez ME, Tortolero-Luna G, Gonzales A, Dolan Mullen P
Acculturation and mammography screening among Hispanic women living in farmworker communities.
Cancer Control. 2005 Nov;12 Suppl 221-7.
The relationship between acculturation and mammography screening practices among Hispanic women is unclear due to inconsistent study findings. The purpose of this research was to further investigate the effect of acculturation on mammography screening practices among Hispanic women and to explore the effect of biculturalism on mammography screening. Hispanic female farmworkers (N = 716) who were 50 years of age and older living in communities in Texas, New Mexico, and California were interviewed at their homes. Data collection was conducted from November 2001 to February 2002. Logistic regression models showed no significant effect for acculturation for the entire sample. Post hoc stratified analysis found that bicultural study participants in California were 3 times more likely to be adherent to screening compared to those with low acculturation. Study findings suggest that distinct differences might exist for Hispanic women living in farmworker communities in California, and perhaps other communities not on the United States-Mexico border. Women in such communities with low levels of acculturation can be targeted for interventions to increase mammography adherence. [Abstract/Link to Full Text]

Goytia EJ, Rapkin B, Weiss ES, Golub D, Guzman V, O'Connor M
Readiness and capacity of librarians in public libraries to implement a breast cancer outreach and screening campaign in medically underserved communities.
Cancer Control. 2005 Nov;12 Suppl 213-20.
Community-based partnerships are an important means of addressing cancer health disparities in medically underserved communities. Public libraries may be ideal partners in this effort. To assess the readiness and capacity of a public library system to implement cancer recruitment and outreach campaigns, 58 librarians in the Queens Borough Public Library System in New York completed self-administered questionnaires before and after a training on breast health, cancer, and screening. Results indicate that they are interested in participating in a cancer outreach campaign and feel it is a critical need in their community. Many librarians lacked the knowledge about cancer and cancer information resources needed to participate optimally. Nevertheless, librarians provide a cultural bridge to medically underserved communities. Partnering with a public library system to improve access to care has great potential, yet a number of challenges need to be overcome. [Abstract/Link to Full Text]

Wong-Kim E, Sun A, Merighi JR, Chow EA
Understanding quality-of-life issues in Chinese women with breast cancer: a qualitative investigation.
Cancer Control. 2005 Nov;12 Suppl 26-12.
Little is known about the cultural beliefs and quality of life (QOL) of US-born and foreign-born Chinese women with breast cancer. We conducted individual semistructured qualitative interviews to explore the meaning of QOL, identify beliefs about cancer, and make comparison between US-born and foreign-born survivors. Women in this study identified the stigma of breast cancer that exists in the Asian community. They also described interpersonal support as central to a good QOL. However, when describing QOL, foreign-born Chinese women referred to wealth more frequently, while US-born Chinese women indicated friendship more frequently. The study findings support the need for culturally appropriate interventions that take into consideration the cancer-related beliefs and QOL of breast cancer survivors in the Chinese community. [Abstract/Link to Full Text]

Meade CD
Cancer, culture and literacy: critical next steps in improving care for diverse populations.
Cancer Control. 2005 Nov;12 Suppl 24-5. [Abstract/Link to Full Text]

Khan N, Oriuchi N, Higuchi T, Endo K
Review of fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the follow-up of medullary and anaplastic thyroid carcinomas.
Cancer Control. 2005 Oct;12(4):254-60.
BACKGROUND: The goal of posttreatment follow-up for medullary and anaplastic thyroid cancer (MTC and ATC) is the early diagnosis of recurrence or metastases. However, routine follow-up protocols, including physical examination and clinically oriented investigations, are not standardized, and their sensitivity in accurately detecting recurrent or metastatic disease is often suboptimal. A valuable addition to posttreatment follow-up of oncology patients is positron emission tomography using fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG-PET). METHODS: We review the role of FDG-PET imaging in the follow-up of patients previously treated for MTC and ATC. RESULTS: Based on the encouraging literature data, FDG-PET appears to be useful in detecting recurrent or metastatic disease in patients with MTC and ATC, providing a higher sensitivity (66% to 100%) and specificity (79% to 90%) than conventional imaging methods. However, the PET technique is limited by less accurate spatial assignment of small lesions, especially in the lung and liver. CONCLUSIONS: Supporting evidence indicates that FDG-PET has a significant role in the follow-up of patients with MTC and ATC. [Abstract/Link to Full Text]

el-Houseini ME, Mohammed MS, Elshemey WM, Hussein TD, Desouky OS, Elsayed AA
Enhanced detection of hepatocellular carcinoma.
Cancer Control. 2005 Oct;12(4):248-53.
BACKGROUND: Tumor markers in the early detection of tumors are promising tools that could improve the control and treatment of tumors. While alpha-fetoprotein (AFP) is a commonly used tumor marker in the detection of hepatocellular carcinoma (HCC), its sensitivity and specificity are insufficient to detect HCC in all patient samples. METHODS: We compared AFP with serum levels of vascular endothelial growth factors (VEGF and VEGF-A), insulin-like growth factor-2 (IGF-II), and the activity of the lysosomal enzyme alpha-L-fucosidase (AFU) in the sensitivity of detection of HCC and cirrhosis in Egyptian patients. RESULTS: The sensitivity of tumor detection using AFP was 68.2%. This level of detection was increased to 88.6% when AFP was evaluated in conjunction with AFU. The combined use of AFP and VEGF increased the sensitivity of detection to 95.5% in patients with HCC. The combination of the three markers yielded 100% detection sensitivity. VEGF-A showed a low specificity (20%), and IGF-II showed extremely low sensitivity (4.5%). CONCLUSIONS: We suggest that AFU or VEGF or both be measured with AFP to improve the detection sensitivity of HCC. [Abstract/Link to Full Text]

Kienstra MA, Padhya TA
Head and neck melanoma.
Cancer Control. 2005 Oct;12(4):242-7.
BACKGROUND: Melanoma of the head and neck and its treatment are complex issues. The behavior of head and neck melanoma is aggressive, and it has an overall poorer prognosis than that of other skin sites. METHODS: The authors review current data on the treatment of head and neck melanoma, including both cutaneous and mucosal melanoma. RESULTS: Current understanding of the behavior of head and neck melanoma is reviewed and treatment stratagems are presented. Controversies in treatment include lymphoscintigraphy with sentinel node biopsy, nodal dissection, margin size, role of radiation therapy, and reconstruction. The management goal is to treat melanoma aggressively while minimizing the effects of treatment on patient quality of life. CONCLUSIONS: Due to its aggressiveness, head and neck melanoma should be treated aggressively when morbidity is not significantly increased. Patient specific treatment is imperative. [Abstract/Link to Full Text]

Lawson DH
Choices in adjuvant therapy of melanoma.
Cancer Control. 2005 Oct;12(4):236-41.
BACKGROUND: High-dose interferon (IFN) is the approved agent for adjuvant treatment of melanoma in the United States. This approval is for high-risk, predominantly stage III patients with cutaneous primaries. There are still decisions to be made in the care of these patients. Also, there are questions about whether the IFN data can be extrapolated to patients with other stages of melanoma and whether adjuvant treatment should be offered to these individuals. Clearly there is room for improvement in this area. METHODS: The literature on this topic and ongoing national trials in the United States were reviewed. RESULTS: The data are insufficient to recommend other agents in the adjuvant treatment of melanoma outside a clinical trial. Extrapolation of the IFN data to patient populations other than those studied is problematic at best. National trials are available for most patient populations. CONCLUSIONS: The adjuvant treatment of choice for melanoma patients is participation in a clinical trial. [Abstract/Link to Full Text]

Puleo CA, Messina JL, Riker AI, Glass LF, Nelson C, Cruse CW, Johnson TM, Sondak VK
Sentinel node biopsy for thin melanomas: which patients should be considered?
Cancer Control. 2005 Oct;12(4):230-5.
BACKGROUND: As the incidence of melanoma increases, thin melanomas are being diagnosed at an increasingly frequent rate. Currently available prognostic factors are limited in their ability to reliably discriminate which patients will manifest regional nodal metastasis and would be identified early through sentinel node biopsy. METHODS: We summarized our experience with sentinel node biopsy for patients with cutaneous melanomas less than 1.00 mm in Breslow thickness, with evaluation of Clark level as a predictor of positive sentinel node metastasis. RESULTS: Among the 409 patients identified, micrometastases were found in the sentinel node in 20 patients, for an overall incidence of nodal progression of 4.9%. A total of 252 (62%) were Clark level II or III (11 of whom had a positive sentinel node) and 157 (38%) were Clark level IV (9 of whom had a positive sentinel node). We reviewed the literature to identify reliable indicators that might be helpful in determining which patients with "thin melanomas" would be likely to manifest regional progression to warrant routinely undergoing a preoperative lymphoscintigraphy followed by a sentinel node biopsy. CONCLUSIONS: Based on available data, patients with melanomas between 0.75 and 1.00 mm are appropriate candidates to be considered for sentinel node biopsy after discussing the likelihood of finding evidence of nodal progression, the risks of sentinel node biopsy (including the risk of a false-negative result), and the lack of proven survival benefit from any form of surgical nodal staging. [Abstract/Link to Full Text]

Homsi J, Kashani-Sabet M, Messina JL, Daud A
Cutaneous melanoma: prognostic factors.
Cancer Control. 2005 Oct;12(4):223-9.
BACKGROUND: Recent data have changed our views of prognostic factors in cutaneous melanoma. While some newer methods have yielded better prognostic information, some insights have evolved as a result of large-scale population-based analyses. METHODS: We review current data on several different prognostic factors and divide these factors according to their application in localized primary melanoma or metastatic melanoma. For each prognostic factor, the level of evidence supporting its use and its applicability to clinical practice are considered. RESULTS: For localized primary melanoma, the dominant predictors of survival include lesion thickness, ulceration, and lymph node involvement. Factors such as age, sex, anatomic location, and satellite/in-transit lesions are important in localized melanoma. Factors currently being investigated are tumor vascularity, vascular invasion, mitotic rate, tumor regression, and tumor-infiltrating lymphocytes. For metastatic melanoma, the most important prognostic factors are site of metastases and the presence of elevated serum lactic dehydrogenase. The value of these prognostic factors to clinicians caring for melanoma patients is discussed. CONCLUSIONS: A better understanding of prognostic factors in cutaneous melanoma has evolved over the last decade, allowing oncologists to provide appropriate treatment for their patients. Many of the prognostic factors are interrelated. In the near future, it is expected that several molecular genetic factors will provide more insight into the prognosis of patients with melanoma. [Abstract/Link to Full Text]

Demierre MF, Sondak VK
Chemoprevention of melanoma: theoretical and practical considerations.
Cancer Control. 2005 Oct;12(4):219-22.
BACKGROUND: Chemoprevention refers to the use of agents to reverse, suppress, or prevent carcinogenic progression of cancer. The use of chemoprevention is an unexplored strategy in melanoma prevention. METHODS: A retrospective review of the literature was undertaken regarding the important elements in evaluating chemoprevention as a strategy in melanoma. RESULTS: Several considerations need to be addressed before a chemoprevention agent can be moved to a large randomized trial. Statins have both experimental and epidemiologic evidence to support their further development as candidate chemopreventive agents, but the evidence is insufficient to justify large-scale phase III studies. A strong scientific rationale, a systematic approach to chemoprevention agent development with rigorous chemoprevention designs, and careful selection of surrogate endpoint biomarkers are critical issues in developing a chemoprevention strategy. CONCLUSIONS: Addressing these relevant considerations will allow for the development of chemoprevention in melanoma. [Abstract/Link to Full Text]

Horton J
Venous thrombotic events in cancer: the bottom line.
Cancer Control. 2005 Sep;12 Suppl 131-7. [Abstract/Link to Full Text]

Kakkar AK
Low-molecular-weight heparin and survival in patients with malignant disease.
Cancer Control. 2005 Sep;12 Suppl 122-30. [Abstract/Link to Full Text]

Lee A, Levine M
Treatment of venous thromboembolism in cancer patients.
Cancer Control. 2005 Sep;12 Suppl 117-21. [Abstract/Link to Full Text]

Liebman HA
Current perspectives on primary prophylaxis and patient risk factors for venous thromboembolism in the cancer patient.
Cancer Control. 2005 Sep;12 Suppl 111-6. [Abstract/Link to Full Text]

Heit JA
Cancer and venous thromboembolism: scope of the problem.
Cancer Control. 2005 Sep;12 Suppl 15-10. [Abstract/Link to Full Text]

Horton J
Venous thromboembolism and cancer: current issues and treatment updates.
Cancer Control. 2005 Sep;12 Suppl 13-4; quiz 38-40. [Abstract/Link to Full Text]

Vincent AL, Price R, Field T, Greene JN, Sandin RL
Addition of fluoroquinolone prophylaxis to a blood and marrow transplant unit reduces Gram-negative infections.
Cancer Control. 2005 Jul;12(3):203-6. [Abstract/Link to Full Text]

Minter A, Malik R, Ledbetter L, Winokur TS, Hawn MT, Saif MW
Colon cancer in pregnancy.
Cancer Control. 2005 Jul;12(3):196-202. [Abstract/Link to Full Text]

Kutner JS, Main DS, Westfall JM, Pace W
The practice-based research network as a model for end-of-life care research: challenges and opportunities.
Cancer Control. 2005 Jul;12(3):186-95. [Abstract/Link to Full Text]

Myers C, Stuber ML, Bonamer-Rheingans JI, Zeltzer LK
Complementary therapies and childhood cancer.
Cancer Control. 2005 Jul;12(3):172-80.
BACKGROUND: The use of complementary and alternative therapies by children with cancer is common. Up to 84% of children have used complementary therapies along with conventional medical treatment for cancer. METHODS: We reviewed the PubMed and CINAHL databases for studies published between 1994 and 2004 on the use of complementary and alternative therapies by children with cancer and reports from any publication year through 2004 of clinical trials involving complementary and alternative therapies for children with cancer. RESULTS: Fourteen studies were retrieved reporting the results of survey or interview data collected from parents on children's use of complementary and alternative therapies during or after childhood cancer. Across studies, the use of such therapies ranged from 31% to 84%. Common reasons for using complementary and alternative therapies were to do everything possible for their child, to help with symptom management, and to boost the immune system. Many parents indicated they also hoped to treat or cure the cancer. In most cases, the child's treating physician had not been informed of the child's use of complementary and alternative therapies. CONCLUSIONS: Use of complementary therapies by children with cancer is common, although methodological variations limit the ability to compare results across studies. Treating physicians often do not know the child is using complementary therapies in addition to medical treatments. The scientific evidence is limited regarding the effects and mechanisms of action of complementary or alternative therapies, but research is being conducted on these topics. [Abstract/Link to Full Text]

Bower JE, Woolery A, Sternlieb B, Garet D
Yoga for cancer patients and survivors.
Cancer Control. 2005 Jul;12(3):165-71.
BACKGROUND: Yoga has been practiced for thousands of years to improve physical and emotional well-being. Empirical research on yoga has been ongoing for several decades, including several recent studies conducted with cancer patients and survivors. METHODS: This review provides a general introduction to yoga and a detailed review of yoga research in cancer. RESULTS: Nine studies conducted with cancer patients and survivors yielded modest improvements in sleep quality, mood, stress, cancer-related distress, cancer-related symptoms, and overall quality of life. Studies conducted in other patient populations and healthy individuals have shown beneficial effects on psychological and somatic symptoms, as well as other aspects of physical function. CONCLUSIONS: Results from the emerging literature on yoga and cancer provide preliminary support for the feasibility and efficacy of yoga interventions for cancer patients, although controlled trials are lacking. Further research is required to determine the reliability of these effects and to identify their underlying mechanisms. [Abstract/Link to Full Text]

Corbin L
Safety and efficacy of massage therapy for patients with cancer.
Cancer Control. 2005 Jul;12(3):158-64.
BACKGROUND: As the popularity of complementary/alternative medicine (CAM) grows, patients are incorporating more CAM therapies into their conventional cancer care. Massage therapy, a CAM therapy known primarily for its use in relaxation, may also benefit patients with cancer in other ways. Massage can also be associated with risks in the oncology population. Risks can be minimized and benefits maximized when the clinician feels comfortable discussing CAM with his or her patients. This article reviews and summarizes the literature on massage and cancer to help provide the clinician with information to help facilitate discussions with patients. METHODS: MEDLINE and CINAHL databases were searched to identify relevant articles. These were reviewed for content and other pertinent references. RESULTS: Significant information was extracted from these resources to provide this overview of the use of massage for patients with cancer. CONCLUSIONS: Conventional care for patients with cancer can safely incorporate massage therapy, although cancer patients may be at higher risk of rare adverse events. The strongest evidence for benefits of massage is for stress and anxiety reduction, although research for pain control and management of other symptoms common to patients with cancer, including pain, is promising. The oncologist should feel comfortable discussing massage therapy with patients and be able to refer patients to a qualified massage therapist as appropriate. [Abstract/Link to Full Text]

Kumar NB, Allen K, Bell H
Perioperative herbal supplement use in cancer patients: potential implications and recommendations for presurgical screening.
Cancer Control. 2005 Jul;12(3):149-57.
BACKGROUND: Products made from botanicals that are used to maintain or improve health are known as herbal supplements, botanicals, or phytomedicines. Many herbs have a long history of use and claimed health benefits. However, many herbal supplements and botanicals have potent pharmacologic activity that can contribute to adverse effects and drug interactions. The use of herbal supplements by cancer patients in the perioperative period is common and consistent with the substantial increase in the use of alternative medical therapies. METHODS: We reviewed the literature to examine the constituents, safety, pharmacokinetics, and pharmacodynamics of those herbal supplements that are predominantly used by cancer patients. RESULTS: Different supplements possess antiplatelet activity, adversely interact with corticosteroids and central nervous system depressant drugs, have gastrointestinal manifestations, produce hepatotoxicity and nephrotoxicity, and produce additive effects when used with opioid analgesics. CONCLUSIONS: With the increasing use of herbal supplements by cancer patients, surgical staff need to screen patients pre-surgically for use of these supplements. Clinical practice guidelines are needed for screening and prevention of herbal supplement usage to prevent potential adverse events that may arise from herbal medications taken alone or combined with conventional therapies during the perioperative period. [Abstract/Link to Full Text]

Myers C, Jacobsen P
Integrative medicine and oncology: emerging evidence.
Cancer Control. 2005 Jul;12(3):146-7. [Abstract/Link to Full Text]

Coppage L, Sroufe A, Robinson L
Imaging in oncology: chest mass.
Cancer Control. 2005 Apr;12(2):126, 137-9. [Abstract/Link to Full Text]

Recent Articles in Pathology Oncology Research

Tarracciano L, Bouygue GR, Startatri R, Guerriero F, M R Bouygue C
A case of fulminant "talc pneumoconiosis": where is the smoking gun?
Pathol Oncol Res. 2005;11(3):184; author reply 185. [Abstract/Link to Full Text]

Dekel Y, Rath-Wolfson L, Rudniki C, Koren R
Talc inhalation is a life-threatening condition.
Pathol Oncol Res. 2004;10(4):231-3.
A case of rapidly progressive disease and pulmonary hypertension due to chronic cosmetic talc inhalation is presented. Although an uncommon cause of pulmonary hypertension, talc, especially through intravenous administration, should be included in the etiology of parenchymal pulmonary hypertension. In our case talc inhalation was inadvertent, causing fulminant disease leading to the patient's death. To our knowledge, this is the first case of inadvertent talc inhalation causing death in adult patient. [Abstract/Link to Full Text]

Aydin VM, Cekinmez M, Kizilkilic O, Kayaselcuk F, Sen O, Altinors N
Unusual case of skull metastasis secondary to pancreatic adenocarcinoma.
Pathol Oncol Res. 2005;11(3):182-3.
Skull metastasis must be kept in mind when considering the differential diagnosis of a skull tumor. Skull metastases cause local swelling that is usually painless, and rarely they lead to neurologic dysfunction. Despite the fact that hematogenous skull metastases can be caused by nearly all types of tumors (lung, prostate, thyroid carcinoma, malignant melanoma), breast cancer is associated with the highest rate of metastatic skull lesions. We report an extremely rare case of skull metastasis from a pancreatic adenocarcinoma, in a 65-year-old woman, presented with painless frontoparietal scalp swelling which developed within three months. To the best of our knowledge, this is the second case involving the skull secondary to a pancreatic adenocarcinoma, and the first case when skull metastasis was the first evidence of a pancreatic adenocarcinoma. [Abstract/Link to Full Text]

Venizelos I, Tamiolakis D, Lambropoulou M, Nikolaidou S, Bolioti S, Papadopoulos H, Papadopoulos N
An unusual case of posttransplant peritoneal primary effusion lymphoma with T-cell phenotype in a HIV-negative female, not associated with HHV-8.
Pathol Oncol Res. 2005;11(3):178-81.
Primary effusion lymphoma (PEL) is a recently individualized form of non-Hodgkin's lymphoma (WHO classification) that mainly develops in HIV infected males, more frequently in homosexuals and advanced stages of the disease (total CD4+ lymphocyte count below 100-200/microL). Occasionally, it appears in other immunodepressive states (such as solid organs transplant period) and even, although very rarely, in immunocompetent patients. From a pathogenetic point of view, PEL has been related to Kaposi's sarcoma associated herpes virus (also named human herpesvirus 8, HHV-8), an etiological factor of Kaposi's sarcoma. The relative infrequency of this disease, the absence of wide casuistics allowing a better characterization, and its unfavorable outcome support the need of a deeper knowledge. We present here the clinical-biological findings of a patient, HIV seronegative, who was diagnosed with peritoneal PEL of T-cell origin, and not HHV-8-associated, five years after renal transplantation. [Abstract/Link to Full Text]

Vári S, Cserneky M, Kádár A, Szende B
Development of present and future of telepathology in Hungary.
Pathol Oncol Res. 2005;11(3):174-7.
Pathologists in Hungary evaluate several hundred thousand histological specimens yearly, and a second opinion is requested in 5-10 percent of cases. Application of multimedia systems (i.e. telepathology) is convenient and efficient to establish a correct diagnosis in such cases. The first telepathology connection in Hungary has been established between the 1st Department of Pathology and Experimental Cancer Research, Semmelweis University and the Department of Pathology, Central Hospital of the Ministry of the Interior. Further development occurred in the course of various projects, supported by the EU (Inter-path, Re-transplant, Be Pro): new stations were established in three university institutes and six county hospitals. Electronic fixation of the images and their transmission by telephone line (ISDN) is easily available and an important feature of the multimedia system applied in telepathology. The system used by us is suited to evaluate frozen or paraffin-embedded histologic sections, as well as immunohistochemical and cytologic specimens, if necessary supplemented with transmission of macroscopic pictures. Our experience with bilateral consultations has proven the importance of telepathology. The telepathology system established in Hungary is now ready to join the telepathology network of the EU. [Abstract/Link to Full Text]

Dündar M, Koçak I, Culhaci N, Erol H
Determination of apoptosis through bax expression in cryptorchid testis: an experimental study.
Pathol Oncol Res. 2005;11(3):170-3.
The aim was to determine the expression of Bax in germ cells of rats with unilateral experimental cryptorchidism, and to evaluate the role of apoptosis in germ cell loss. Twenty-one prepubertal rats were randomly subdivided into three groups after the execution of the left cryptorchidism model. Group 1 (n=8), group 2 (n=6) and group 3 (n=7) rats were killed at the end of the first, second and third month, respectively. Bax expression was assessed in Sertoli cells, spermatogonia and spermatocytes by immunohistochemistry. Percentages of Bax expression in spermatocytes and spermatogonia were decreased in the left testicles in the 2nd and 3rd months compared to results obtained in the 1st month (p<0.05). Percentage of Bax expression in the left testicles of group 1, at the level of both spermatogonia and spermatocytes was higher than that in the right one (p<0.05). However, in groups 2 and 3, the higher Bax expression on the left side was only seen in the spermatocytes (p<0.05). In all groups, the mean weight of the left testicle was lower than that of the scrotal counterpart where the difference was significant only in groups 1 and 3 (p<0.05). The weight of the left and right testicles was increasing with time. In this model of cryptorchidism, the affected testis had a decreased weight compared to the normal one. Based on the increased Bax expression, we think that apoptosis may play a role in the germ cell loss. [Abstract/Link to Full Text]

Zalatnai A
P-glycoprotein expression is induced in human pancreatic cancer xenografts during treatment with a cell cycle regulator, mimosine.
Pathol Oncol Res. 2005;11(3):164-9.
Application of several cell cycle checkpoint regulators seem to be promising in various experimental models including pancreatic cancer, and they are being evaluated in Phase I-II clinical trials. Among these compounds, mimosine, a plant-derived amino acid has shown an antineoplastic effect on human lung or pancreatic cancer xenografts in addition to cell cycle arrest in the late G1 phase. In the present study, immunosuppressed CBA mice bearing subcutaneously growing human ductal pancreatic adenocarcinomas were treated with 30 mg/kg L-mimosine for 34 days. The treatment resulted in retardation of tumor growth, accompanied by a significantly diminished proliferative activity (22.6%+/-1.7% Ki-67 positivity vs. 29.9%+/-1.1% in controls, mean+/-SEM, P<0.007) and an increased apoptotic rate (14.5+/-1.1 apoptotic cells/mm2 vs. 3.8+/-0.4/mm2 in the controls, P<0.0001). The immunohistochemical expression of the multidrug resistance gene (MDR1)-encoded P glycoprotein (p 170) was studied. The parental and the untreated tumors did not express p 170 protein, but in the mimosine-treated samples 30 to 60% of the carcinoma cells displayed a linear, membrane bound positivity. The results indicate that P-glycoprotein is inducible by a cell cycle regulator, creating an acquired resistant phenotype. [Abstract/Link to Full Text]

Behjati F, Atri M, Najmabadi H, Nouri K, Zamani M, Mehdipour P
Prognostic value of chromosome 1 and 8 copy number in invasive ductal breast carcinoma among Iranian women: an interphase FISH analysis.
Pathol Oncol Res. 2005;11(3):157-63.
Breast cancer is amongst the leading causes of death in women worldwide and the most common cancer amongst Iranian women. Unfortunately, the current clinical and histological criteria can only help 60 percent of women with breast cancer in diagnosis and long-term treatment. Therefore, genetic markers both at single gene and chromosomal level can play an important role in improving the diagnosis and prognosis of breast cancer patients. The aim of this retrospective study was to investigate the role of chromosome 1 and 8 copy number assessed by interphase fluorescence in situ hybridization (FISH), as prognostic parameters in 50 Iranian women, aged 35 to 64 years, with sporadic invasive ductal breast carcinoma. Chromosome 1 and 8 copy numbers were evaluated in relation to established clinicopathological parameters, the immunohistochemical markers ER, PR, P53 and cathepsin D, DNA index by flow cytometry, age and survival status of the patients. FISH using centromeric probes for chromosomes 1 and 8 was applied to interphase cell suspensions prepared from archived, Carnoyfixed tumor cells and selected paraffin-embedded tumor sections. Aneusomy for chromosomes 1 and 8 was present in all 50 patients to different levels. The total abnormality rate for chromosome 1 was 33.92 percent (4.24 percent monosomy and 29.68 percent polysomy), whereas for chromosome 8 this rate was 28.30 percent (6.48 percent monosomy and 21.82 percent polysomy). Statistically significant association (p<0.05) was demonstrated between monosomy 1 and patients' age below 50 years, and between monosomy 1 and poor survival, respectively. Disomy 8 was significantly associated with P53 expression. A borderline significant correlation was demonstrated between polysomy 8 and diploid DNA content, as well as between disomy 1 and disease-free status of the patients. Chromosome 1 and 8 copy numbers may be considered as useful prognostic markers in invasive ductal carcinoma of the breast. [Abstract/Link to Full Text]

Elek G, Gyökeres T, Schäfer E, Burai M, Pintér F, Pap A
Early diagnosis of pancreatobiliary duct malignancies by brush cytology and biopsy.
Pathol Oncol Res. 2005;11(3):145-55.
Two hundred and five preoperative intraductal samplings (brushing and biopsy) were evaluated from 113 patients with biliary or Wirsung duct strictures. One hundred and three strictures could be specified by histology of the operative specimens, autopsy, or by the patients' clinical course. Preoperative diagnostic efficacy depended on the tumor location (it was the best for ampullary and para-papillary tumors), but the average quantitative indices for sensitivity, absolute sensitivity, specificity, positive and negative predictive values, diagnostic accuracy of cytology were 53%, 20%, 100%, 100%, 25%, 59%, respectively. The same values for biopsy were 43%, 34%, 100%, 100%, 36% and 56%. These figures improved after simultaneous cytology and biopsy. Close cooperation with the endoscopist was necessary in cases of negative, inconclusive and dysplastic (27%) samples. Repetition of sampling improved the results by 8%. Among the 26 preoperative false negative cases, sampling-, technical- and interpretative errors occurred in 84%, 4% and 12%, respectively. Revision of samples revealed 4 malignant cases among the false negative cytologic brushings. Reclassification of specimens considering the latest criteria - primary and secondary malignant features, pancreatic intraepithelial neoplasia (PanINs), etc. - resulted in improvement of the diagnostic efficiency. [Abstract/Link to Full Text]

Nicolson GL
Lipid replacement/antioxidant therapy as an adjunct supplement to reduce the adverse effects of cancer therapy and restore mitochondrial function.
Pathol Oncol Res. 2005;11(3):139-44.
The most common complaints of cancer patients undergoing chemo- or radiotherapy are fatigue, nausea, vomiting, malaise, diarrhea and headaches. These adverse effects are thought to be due to damage of normal tissues during the course of therapy. In addition, recent evidence indicates that fatigue is related to reduced mitochondrial function through loss of efficiency in the electron transport chain caused by membrane oxidation, and this occurs during aging, in fatiguing illnesses and in cancer patients during cytotoxic therapy. Lipid Replacement Therapy administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage to normal tissues, restore mitochondrial and other cellular membrane functions and reduce the adverse effects of cancer therapy. Recent clinical trials using patients with chronic fatigue have shown the benefit of Lipid Replacement Therapy plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue by protecting mitochondrial and other cellular membranes from oxidative and other damage. In cancer patients a placebo-controlled, cross-over clinical trial using Lipid Replacement Therapy plus antioxidants demonstrated that the adverse effects of chemotherapy can be reduced in 57-70% of patients. Dietary use of unoxidized membrane lipids plus antioxidants is recommended for patients undergoing cancer therapy to improve quality of life but should not be taken at the same time of day as the therapy. [Abstract/Link to Full Text]

Sápi Z, Pápai Z, Hruska A, Antal I, Bodó M, Orosz Z
Her-2 oncogene amplification, chromosome 17 and DNA ploidy status in synovial sarcoma.
Pathol Oncol Res. 2005;11(3):133-8.
The treatment options for synovial sarcoma (SS) are very limited, though this type of sarcoma seems to be more heterogeneous than it has been traditionally considered. The present study investigates the Her-2 oncogene status of 20 cases of SS, to determine whether Her-2 amplification can be considered as a prognostic factor. Her-2 oncogene amplification was determined on smears (frozen material was used from our tumor bank in each case), using fluorescence in situ hybridization technique (dual color FISH with centromeric probe for chromosome 17 and specific probe for Her-2 oncogene). Moreover, protein expression was assessed by immunohistochemistry, and DNA ploidy status was measured using image analysis. We had 5 biphasic and 15 monophasic SSs, patients' age ranged from 13 to 68 years (mean, 39.8 years). Tumor size was larger than 5 cm in each case. Follow-up time ranged from 6 to 78 months (mean, 38.5 months). For statistical analysis the chi-square test was used. Her-2 oncogene amplification was found in three cases (15.0%) of 20 SSs. These cases proved to be 2+ positive by immunohistochemistry, but massive amplification, characteristic of a subset of breast carcinomas, was not observed. Her-2 oncogene amplification was significantly associated with a lower risk of developing metastasis (P<0.05) (none of the 3 amplified cases had metastases), while no association was found with recurrence. Six cases proved to be aneuploid and 14 were diploid, but no association was found between Her-2 amplification status and ploidy, and between ploidy status and metastasis or recurrence. Our results emphasize and confirm that Her-2 oncogene amplification is a rare event in SS, but the small subset of SS with Her-2 amplification has a better overall prognosis. Furthermore, this may open a theoretically new treatment possibility with Trastuzumab for Her-2-amplified cases of SS. [Abstract/Link to Full Text]

Culhaci N, Meteoglu I, Dundar M, Kocak I
Histopathological evaluation of renal vascular changes in rats exposed to passive smoking.
Pathol Oncol Res. 2005;11(2):121-4.
Cigarette smoking is an important risk factor for renal damage due to its effects on small interlobular arteries. We investigated the effects of long-term passive smoking on renal vascular structures in healthy rats exposed to smoke soon after birth. Forty-two Sprague-Dawley rats (21 males and 21 females) exposed to passive smoking comprised the experimental group and 33 non-exposed rats (17 males and 16 females) comprised the control group. The number of renal vessels, as well as the level of glomerular capillary sclerosis, hyalinosis of arterioles, and myointimal hyperplasia of arteries was assessed in renal biopsy specimens. The mean number of renal vessels in male and female rats exposed to passive smoke (21.71 and 13.81, respectively) did not significantly differ from the mean number of renal vessels in male and female control rats (22.47 and 13.06, respectively) (p>0.05). Levels of glomerulosclerosis, hyalinosis, and myointimal hyperplasia also did not differ between the experimental and control groups (p>0.05). Histopathologic evidence of renal vascular damage was not found in young rats exposed to passive smoke for 4 months. A longer or higher degree of exposure to cigarette smoke components may be required before such changes manifest, and aging and primary renal disease may play a role. [Abstract/Link to Full Text]

Cambruzzi E, Zettler CG, Alexandre CO
Expression of Ki-67 and squamous intraepithelial lesions are related with HPV in endocervical adenocarcinoma.
Pathol Oncol Res. 2005;11(2):114-20.
To estimate the association between human papillomavirus (HPV) status and the expression of p53, Ki-67 and bcl-2 in cases of endocervical adenocarcinoma, and the relation with squamous intraepithelial lesions (SIL) and age, 229 cases were selected, treated between 1995 and 2003 in the Hospital Nossa Senhora da Conceiçao. All samples were evaluated by polymerase chain reaction to determine HPV status. Immunohistochemical technique was used to investigate the expression of p53, Ki-67 and bcl-2. The joint occurrence of endocervical adenocarcinoma and SIL were estimated too. In the 229 evaluated cases, 182 cases (79.48%) were associated with the presence of the HPV. The most common types were HPV18 (93 cases - 51.09%) and HPV16 (62 cases - 34.06%). Expression of Ki-67 (p=0.009) and the presence of SIL (p=0.018) were associated to HPV infection. Expression of p53 (p=0.647) and bcl-2 (p=0.671) were not related to HPV status. The mean age of the patients was 53.2 years, without clear correlation between age group and HPV (p=0.095). The presence of HPV, especially type 18 in endocervical adenocarcinoma suggests that this agent can be an important cofactor in the development and progression of glandular neoplasms of the uterine cervix. The joint occurrence of endocervical adenocarcinoma and SIL may support this hypothesis. HPV may promote an increased proliferation index in endocervical adenocarcinoma, shown by the expression of Ki-67. [Abstract/Link to Full Text]

Matusan K, Dordevic G, Mozetic V, Lucin K
Expression of osteopontin and CD44 molecule in papillary renal cell tumors.
Pathol Oncol Res. 2005;11(2):108-13.
The aim of the study was to analyze the expression of CD44 adhesion molecule and its ligand osteopontin in papillary renal cell tumors, and to assess the possible prognostic significance of CD44 and osteopontin expression in papillary renal cell carcinomas. The expression of the standard and v6 exon containing isoforms of CD44 molecule, as well as of its ligand osteopontin, was immunohistochemically evaluated in 43 papillary renal cell tumors, which included 5 adenomas and 38 carcinomas. In order to assess their prognostic significance, the results obtained in papillary renal cell carcinomas were compared to usual clinicopathological parameters such as tumor size, histological grade, pathological stage, and Ki-67 proliferation index. Normal renal tissue was negative for CD44s and v6 isoforms, while the expression of osteopontin was found in distal tubular epithelial cells in the form of cytoplasmic granular positivity. CD44s and v6 isoforms were upregulated in 22 (58%) and 12 (32%) out of 38 carcinomas, respectively. Among all clinicopathological parameters examined, we only found significant association of CD44s-positive carcinomas with lower pathological stage (p=0.026). Papillary renal cell adenomas were generally negative for CD44s, except for focal positivity found in one sample. The osteopontin protein was detected in all adenomas and all papillary renal cell carcinomas, except one. Our results show constitutive expression of osteopontin in papillary renal tumors, including papillary renal cell adenomas. The upregulation of CD44s and v6 isoforms, although found in a considerable number of papillary renal cell carcinomas, does not appear to have any prognostic value in this type of renal cancer. [Abstract/Link to Full Text]

Cavalcanti Fde B, Alves VA, Pereira J, Kanamura CT, Wakamatsu A, Saldanha LB
Proliferative lesions of prostate: a multivariate approach to differential diagnosis.
Pathol Oncol Res. 2005;11(2):103-7.
Prostatic needle biopsies from 142 patients were studied: 61 cases were "benign", 19 atypical small acinar proliferation, 31 high-grade prostatic intraepithelial neoplasia, and 31 adenocarcinoma. Using univariate analysis of 46 previously described morphological features, 16 variables were selected, which were followed by multivariate discriminant analysis. Of these parameters, seven (glandular fusion, crystalloids, nucleolomegaly, papillary architecture, visibility of basal cell layer, areas of normal luminal cell nucleus/cytoplasm ratio and areas of high luminal cell nucleus/cytoplasm ratio) remained significant in discriminating the groups. Multivariate analysis selected a small panel of histological features as those most helpful in the differential diagnosis of proliferative lesions in prostate biopsies. [Abstract/Link to Full Text]

Kamali-Sarvestani E, Gharesi-Fard B, Sarvari J, Talei AA
Association of TNF-alpha and TNF-beta gene polymorphism with steroid receptor expression in breast cancer patients.
Pathol Oncol Res. 2005;11(2):99-102.
The presence of estrogen and progesterone receptors is correlated with good prognosis in breast cancer. The effect of TNF-alpha on down-regulation of estrogen receptor and blocking the proliferative response of breast cancer cells to estradiol have been demonstrated. However, the effect of TNFA and TNFB gene polymorphisms on the expression of steroid receptors in breast cancer cells is not well documented. Therefore, 160 breast cancer patients were recruited to investigate the association of TNFA and TNFB gene polymorphism with the level of steroid receptor expression. This association was not found to be significant for TNFA polymorphism and estrogen receptor expression (p=0.07). However, when combined genotypes of TNFA and TNFB polymorphism was considered, homozygous patients for lower TNF-alpha producer genotypes (TNFA1/A1 and TNFB1/B1) showed significantly higher progesterone receptor expression (p=0.041). Our findings indicate that TNFA and TNFB polymorphisms may be associated with the levels of steroid receptor expression in breast cancer patients. Further studies on a larger group of breast cancer patients are recommended. [Abstract/Link to Full Text]

Simsa P, Teillaud JL, Stott DI, Tóth J, Kotlan B
Tumor-infiltrating B cell immunoglobulin variable region gene usage in invasive ductal breast carcinoma.
Pathol Oncol Res. 2005;11(2):92-7.
A major focus of tumor immunology is to reveal the potential role and capacity of immunocompetent cells found in different solid tumor tissues. The most abundant infiltrating cells (TIL), the T lymphocytes have been investigated in details concerning T-cell receptor usage and specificity. However, B cells have hardly been investigated in this respect, although high cellular B-cell infiltration has been correlated with improved patients' survival in some breast carcinomas. This led to our objectives to study variable region gene usage of the tumor-infiltrating B cells in different breast carcinoma types. By defining the immunoglobulin repertoire of the tumor-infiltrating B lymphocytes in the most common invasive ductal carcinoma (IDC) of the breast we compared it to the rare medullary breast carcinoma (MBC). After phenotyping infiltrating ductal carcinomas, B cells were obtained from tumor tissue by microdissection technique. Numerous rearranged TIL-B immunoglobulin heavy chain V genes (VH) were amplified, cloned, sequenced, and comparatively analyzed. Some characteristics were found for both breast carcinoma types. The immunoglobulins produced by TIL-B in ductal carcinoma are highly matured and oligoclonal. We conclude that Ig variable region gene usage reveals similar and distinguishable characteristics of TIL-B immunoglobulin repertoires, which are representative of the nature of the immune responses in invasive ductal and medullary breast carcinomas. [Abstract/Link to Full Text]

Bircan S, Candir O, Kapucuoglu N
The effect of tumor invasion patterns on pathologic stage of bladder urothelial carcinomas.
Pathol Oncol Res. 2005;11(2):87-91.
The aim of this study was to investigate tumor invasion pattern, its heterogeneity and association with histopathological features and stage in invasive urothelial carcinoma of the bladder. We studied 62 cases of invasive urothelial carcinoma of the bladder. World Health Organization (WHO) 1973, WHO/ISUP 1998 and WHO 1999 systems were used for tumor grading. Pathologic staging of each case was done according to 1997 TNM system. During evaluation of the slides three main tumor invasion patterns were detected: "nodular", "trabecular" and "infiltrative". In addition, homogeneity or heterogeneity of invasion patterns was also recorded for each case. Of sixty-two invasive cases, 17 (27%) had nodular, 36 (58%) trabecular, and 9 (15%) infiltrative invasion pattern. There was a statistically significant difference between invasion patterns in relation to pathologic stage (pT) (p=0.001), but not to grade. Of the 17 cases with nodular invasion pattern and 36 tumors with trabecular invasion pattern, 13 (77%) and 26 (72%) were pT1, respectively, whereas 8 of 9 infiltrative cases (89%) were advanced stage (pT2-3). According to heterogeneity, forty-two cases (68%) had homogeneous, while the remaining 20 (32%) had heterogeneous invasion pattern. Of the 42 homogeneous cases 34 (81%) were pT1, whereas 14 of 20 heterogeneous cases (70%) were advanced stage (p=0.000). The different invasion patterns seem to have a large impact on pathologic stage, especially the infiltrative pattern. In addition, invasion heterogeneity appears to be of value in determination of biologic aggressiveness in urothelial carcinoma. [Abstract/Link to Full Text]

Komlósi K, Kellermayer R, Maász A, Havasi V, Hollódy K, Vincze O, Merkli H, Pál E, Melegh B
Maternally inherited deafness and unusual phenotypic manifestations associated with A3243G mitochondrial DNA mutation.
Pathol Oncol Res. 2005;11(2):82-6.
The mitochondrial DNA A3243G transition is a fairly common mutation which often associates with a MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) phenotype, however, a broad variety in the associated clinical picture has also been described. The patient reported here developed a generalized seizure at age 12, which was followed by bilateral hearing loss and occasional fatigue. The maternal inheritance pattern of hearing loss pointed to a possible mitochondrial origin, which was confirmed by molecular analysis of the mitochondrial DNA, revealing a heteroplasmic A3243G transition. Interestingly, muscle biopsy showed ragged-red fibers in the proband, which is unusual in the deafness-associated forms of this mitochondrial disorder. In addition to hearing impairment in four generations of the family, fatal cerebral embolization in the mother and fatal heart attack in the maternal grandmother (both at age 33) also occurred. On the contrary, diabetes, which usually accompanies the hearing loss variant, was specifically absent in all generations. The unusual manifestations associated with this mutation somewhat differentiate this family from the already known variants. [Abstract/Link to Full Text]

Croce MV, Rabassa ME, Pereyra A, Segal-Eiras A
Influence of sialic acid removal on MUC1 antigenic reactivity in head and neck carcinoma.
Pathol Oncol Res. 2005;11(2):74-81.
To investigate the influence of sialic acid removal on MUC1 peptidic and carbohydrate epitope reactivity in head and neck squamous cell carcinoma (HNSCC), tumor samples belonging to 24 HNSCC patients were studied by standard immunohistochemistry (IHC) with and without desialylation with 0.1 U/ml neuraminidase. From each tumor sample, subcellular fractions were obtained and analyzed by SDS-PAGE and Western blotting (WB). Three monoclonal antibodies (MAbs) were used: C595 MAb directed to MUC1 protein core, an anti-Tn hapten MAb, and an anti-sTn hapten MAb; a comparative analysis between desialylated and sialylated samples was performed. By IHC without neuraminidase treatment, 19 of 24 samples reacted with anti-MUC1 peptidic epitope, while Tn hapten was not detected and sTn was found in 1 of 24 cases. Desialylation increased either the number of reacting cells or the intensity of the reaction with C595 and anti-Tn MAbs, and some negative samples became positive. On the other hand, sTn expression decreased with desialylation. By WB, several bands from >200 to 25 kDa were found; desialylation increased high-molecular-weight bands, diminishing the detection of low-molecular-weight ones. The use of desialylation is a suitable treatment that contributes to the exposure of MUC1-associated epitopes, which may be related to the spreading of HNSCC. [Abstract/Link to Full Text]

Kopper L, Zalatnai A, Tímár J
Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy?
Pathol Oncol Res. 2005;11(2):69-73.
Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well. [Abstract/Link to Full Text]

Bal N, Kayaselçuk F, Polat A, Bolat F, Yilmaz Z, Tuncer I
Familial cystic nephroma in two siblings with pleuropulmonary blastoma.
Pathol Oncol Res. 2005;11(1):53-6.
Cystic nephroma (CN) and pleuropulmonary blastoma (PPB) are rare tumors. In the cases presented here, a 13-month-old boy underwent right radical nephrectomy for CN. From the family history we learned that four years ago the patient's older sister underwent left radical nephrectomy for CN at a different center when she was 4 years old. A lung tumor was detected in the sister one year after nephrectomy. Biopsy from the lung tumor revealed PPB, and the sister died within one year after biopsy. To the knowledge of the authors, these cases represent the second reported familial occurrence of CN and the fourth of CN and PPB. [Abstract/Link to Full Text]

Rieker RJ, Aulmann S, Schnabel PA, Sack FU, Otto HF, Mechtersheimer G, Schirmacher P, Bläker H
Cystic thymoma.
Pathol Oncol Res. 2005;11(1):57-60.
Thymic cysts are rare lesions located along the anatomical course of the third pharyngeal pouch. While most of the cases represent congenital cysts, they may also be related to neoplasms. We report a case of a micronodular thymoma with lymphoid stroma, which was completely built of small cysts, discuss the pathologic features of this tumor type and review the etiology and other aspects of thymic cysts. [Abstract/Link to Full Text]

Koch HJ, Hau P
ROC analysis as an additional method to characterize time to event data.
Pathol Oncol Res. 2005;11(1):50-2.
The receiver operating characteristic (ROC) is predominantly used to assess the discriminant power of diagnostic tests. The present paper proposes this method as an additional alternative to compare survival data of in oncology or related fields. Survival data of brain tumors were analysed with conventional Kaplan-Meier method and ROC. The Area und the Curve (ROC-curve) gives additional illustrative information to distinguish between two therapeutic approaches and low or high grade brain tumors. [Abstract/Link to Full Text]

Hadar T, Shvero J, Yaniv E, Ram E, Shvili I, Koren R
Expression of p53, Ki-67 and Bcl-2 in parathyroid adenoma and residual normal tissue.
Pathol Oncol Res. 2005;11(1):45-9.
The aim of this study was to investigate the expression of Ki-67, bcl-2 and p53 in parathyroid adenomas and their residual rim of normal parathyroid tissue. Specimens from 26 parathyroid adenomas were studied by immunohistochemical analysis for Ki-67, bcl-2 and p53 expression. Positive findings were noted for p53 in 4 (15%) adenomas and none of the residual rims of normal parathyroid tissue (p = 0.055); for Ki-67 in 15 (56%) adenomas and none of the residual rims of normal parathyroid tissue (p = 0.00002); and for bcl-2 in 19 (73%) adenomas and 8 (31%) residual rims of normal parathyroid tissue (p < 0.01). The high rate of Ki-67 expression may indicate susceptibility of parathyroid adenomas to clonal proliferation. The weak immunoreactive expression of p53, combined with a relatively strong expression of bcl-2, may contribute to the characteristic slow progression of these tumors. [Abstract/Link to Full Text]

Brnic Z, Gasparov S, Lozo PV, Anic P, Patrlj L, Ramljak V
Is quadrant biopsy sufficient in men likely to have advanced prostate cancer? Comparison with extended biopsy.
Pathol Oncol Res. 2005;11(1):40-4.
We hypothesized that quadrant prostate biopsy (QPB) provides sufficient first-line pathological evaluation of patients with presumed advanced prostate cancer (PC). The aim of this study was to investigate whether the reduction of core number in first-line PB from 6-12 to 4 in patients with presumed advanced PC leads to loss of clinically relevant information. We retrospectively studied 113 men that underwent PB, classified in two groups: "H" (high) and "L" (low likelihood of having advanced PC), according to PSA, digital rectal and transrectal ultrasound findings. Pathological results of 6-12-core PB and QPB were retrospectively compared for the presence of malignancy, percentage of positive cores, Gleason score (GS), and the presence of high-grade prostatic intraepithelial neoplasia (HGPIN). PC detection rate was not impaired in group H but dropped significantly in group L, and the percentage of positive cores was not significantly changed in group H (p=0.39), but decreased in group L (p=0.04), due to sampling scheme reduction. No HGPIN was missed with QPB in group H, while 2 HGPINs were missed in group L. No significant change in GS in either group was observed (p=0.12, p=0.13) due to reduction to QPB. We conclude that in patients with presumed advanced PC, reduction of the number of cores in PB may be an acceptable diagnostic strategy, but further studies are needed to analyze the impact of PB scheme reduction on other relevant pathological information obtained from PB. [Abstract/Link to Full Text]

Bircan S, Ensari A, Ozturk S, Erdogan N, Dundar I, Ortac F
Immunohistochemical analysis of c-myc, c-jun and estrogen receptor in normal, hyperplastic and neoplastic endometrium.
Pathol Oncol Res. 2005;11(1):32-9.
To evaluate the role of c-jun and c-myc proto-oncogenes in normal, hyperplastic and neoplastic endometrium in relation to estrogen receptor (ER) status and to investigate whether these genes can be related to other histopathological features of endometrial carcinoma, 32 endometrial carcinomas, 38 endometrial hyperplasias and 22 cyclic endometria (10 proliferative and 12 secretory) were evaluated histologically. Endometrial hyperplasia cases were classified as simple and complex hyperplasia without atypia, and atypical hyperplasia. Endometrial carcinoma cases were subtyped according to the International Society of Gynecological Pathologists. Modified FIGO system was used for both grading and staging. Immunohistochemical examination was performed using antibodies to ER-alpha, c-myc and c-jun with streptavidin-biotin-peroxidase technique. The mean percentage of ER-alpha positive cells changed cyclically during the menstrual cycle, and it was the highest (96%) and the lowest (31.6%) in proliferative and carcinomatous endometrium, respectively. There was a statistically significant difference between proliferative and secretory phases and proliferative and carcinomatous endometrium in relation to ER-alpha staining (p<0.05). There was also a statistically significant difference with respect to ERalpha reactivity between secretory phase and each hyperplastic group, as well as between the carcinoma group and each hyperplastic group (p<0.05). Although not significant, the mean percentage of c-myc expressing cells in the carcinoma group was higher (15.3%) than that of proliferative phase and hyperplastic groups. The mean percentage of c-jun positive cells in proliferative endometrium was slightly higher than in secretory endometrium, and it was the highest in atypical hyperplastic endometrium (28.3%), but there was no statistically significant difference between the groups. In carcinoma cases, a positive correlation was observed between c-jun positivity and tumor grade (p=0.027, r=0.3908), but such a correlation with c-myc was not found. A positive correlation was detected between ER-alpha and c-myc expression (p=0.038, r=0.3686). A progressive loss of ER seems to be correlated with increasing malignant transformation. C-myc expression might play a role in the development of endometrial carcinoma via ER. The association between c-jun and ER appears to be lost in endometrial carcinoma. The relationship between c-myc, c-jun and ER appears to be altered in endometrial carcinoma compared to that of menstrual endometrium. [Abstract/Link to Full Text]

Sobel G, Szabó I, Páska C, Kiss A, Kovalszky I, Kádár A, Paulin F, Schaff Z
Changes of cell adhesion and extracellular matrix (ECM) components in cervical intraepithelial neoplasia.
Pathol Oncol Res. 2005;11(1):26-31.
Cell-cell and cell-extracellular matrix interaction is crucial in tumor progression. Tight junction (TJ) proteins as occludin and claudins (CLDNs) play important role in this process together with several extracellular matrix components, as syndecan. Our previous work suggested significant changes in the expression of claudins even in the early stages of cervical carcinogenesis. The aim of our present work was to study the expression of occludin and syndecan-1, as compared to CLDNs, in early phases of cervical carcinogenesis. Paraffin sections of 50 samples were studied by immunohistochemistry, including cervical intraepithelial neoplasias (CINI-II-III), in situ carcinomas (CIS) and normal cervical samples. Occludin and CLDN-2 were found colocalized in the basal layer, while syndecan-1 and CLDN-1, -4 and -7 were coexpressed in the parabasal and intermedier layers in normal epithelia. Intensity of occludin staining decreased in CIN/CIS lesions, although it was more extended towards the upper epithelial layers with inverse relation with grades, as seen in the case of CLDN-2 expression. CLDN-1, -2, -4 and -7 were detected in the entire epithelium in CIN, showing decrease in CIS. The progression of CIN was associated with reduced syndecan-1 expression, in contrast to CLDN-1, -4 and -7 which increased toward CIS. The obtained data suggest that significant changes occur in the composition of cell adhesion complexes even in early stages of cervical carcinogenesis. The pattern of expression is characteristic for the alteration, the changes in the different components, however, are not parallel with each other. [Abstract/Link to Full Text]

Demokan S, Demir D, Suoglu Y, Kiyak E, Akar U, Dalay N
Polymorphisms of the XRCC1 DNA repair gene in head and neck cancer.
Pathol Oncol Res. 2005;11(1):22-5.
Inherited polymorphisms in the genes controlling the cell cycle or functioning in the DNA repair mechanisms may impair their function and contribute to genetic susceptibility. Abnormalities in the DNA repair have been reported in head and neck cancer. The XRCC1 gene functions in singlestrand break and base excision repair processes. In this study, two polymorphisms of the XRCC1 gene, Arg194Trp and Arg399Gln were investigated in 95 patients with head and neck carcinoma. The polymorphic regions were amplified by PCR followed by digestion with methylation-specific restriction enzymes, and analyzed electrophoretically. Genotype and allele frequencies were calculated, and association with cancer risk or clinical parameters was investigated. No association was observed between the genotypes and head and neck cancer for either polymorphism. Distribution of the alleles did not significantly differ between the patients and the control group. A significant association was only found for the Trp194 allele among the smoking individuals. Our data indicate that the Arg194Trp and Arg399Gln polymorphisms do not confer a significant risk for head and neck carcinogenesis. [Abstract/Link to Full Text]

Orosz Z, Tornóczky T, Sápi Z
Gastrointestinal stromal tumors: a clinicopathologic and immunohistochemical study of 136 cases.
Pathol Oncol Res. 2005;11(1):11-21.
The clinicopathologic features of 136 gastrointestinal stromal tumors were analyzed. The tumors occurred in 60 women and 76 men, ranging in age from 19 to 88 years (median 59 years, mean 59.2 years). Sixty-one cases arose from stomach, 38 from small intestine and 11 from colon or rectum. Abdominal cavity was indicated as tumor site in 10 cases, but the extra-gastrointestinal origin using strict criteria was not proved. Four locally recurrent cases and 12 metastatic samples were also included. The primary and recurrent tumors ranged in size from 0.5 to 30 cm (mean 8.3 cm). The large number of high-grade cases (85 of 112 classifiable) is alarming and emphasize the importance of oncology care. Histologically, ninety-two cases were classified as spindle cell while 11 as epithelioid GIST. Mixed cellularity was seen in 33 cases. Skeinoid fibers were present in 14 and coagulation necrosis in 40 primary cases. Ulceration observed by microscopic examination was common (36 of 110 cases, 32.7%), explaining the clinically frequently observed gastrointestinal bleeding. Unusual histological features such as stromal hyalinization and nuclear palisading were present in 30 and 27 cases, respectively. Immunohistochemical CD117 (c-kit) positivity was documented in 133 cases. Three cases with CD117 negative results were included, because their morphology was most consistent with GIST and immunohistochemical reactions excluded the possibility of other neoplasms. CD34 positivity was seen in 70%, alpha-smooth muscle actin positivity in 39.6% of examined cases. Only one case showed desmin reactivity and seven had S100 positive tumor cells. For h-caldesmon 39 cases proved to be positive (60.9% of the tested cases). [Abstract/Link to Full Text]

Kopper L, Tímár J
Genomics of lung cancer may change diagnosis, prognosis and therapy.
Pathol Oncol Res. 2005;11(1):5-10.
Despite significant improvements in tumor management in general, the prognosis of lung cancer patients remains dismal. It is a hope that our increasing knowledge in molecular aspects of tumor development, growth and progression will open new targets for therapeutic interventions. In this review we discuss some of the more recent results of this field. This includes the susceptibility factors, an association between genetic changes in EGFR pathway and tyrosine kinase inhibitors, the role of gene hypermethylation and genetic profiling, as well as different molecular aspects of tumor progression. Available data all support that lung cancer is a group of diseases with not only distinct histological but with similarly different genetic characters. Accordingly, the diagnosis, prognosis and therapy must accommodate this heterogeneity. [Abstract/Link to Full Text]

Recent Articles in Acta Oncologica

No recent articles are currently available.
Recent Articles in Cancer Science

No recent articles are currently available.
Recent Articles in Indian Journal of Cancer

Puri T, Singh K, Sharma DN, Khurana N
Epithelial-myoepithelial carcinoma of the base of tongue: pathology and management.
Indian J Cancer. 2004 Jul-Sep;41(3):138-40.
Epithelial-myoepithelial carcinoma is a rare tumor which makes up about 0.2% of epithelial neoplasms of the salivary glands; parotid gland being the most common primary site of origin. The tumor may also very rarely originate in minor salivary glands of the base of the tongue. Due to rarity of its occurrence, histogenesis and clear cut therapeutic guidelines are not defined. The present report describes the case of a 48 year old male who was diagnosed to have a tubular variant of epithelial-myoepithelial carcinoma of the base of tongue, Stage T3 N0 M0 (Stage group III). The patient was treated with neoadjuvant chemotherapy followed by radical radiotherapy (Rt) and is alive with no evidence of disease 14 months following end of treatment. [Abstract/Link to Full Text]

Venizelos I, Tamiolakis D, Simopoulos C, Nikolaidou S, Barbagadaki S, Lambropoulou M, Alexiadis G, Boglou P, Papadopoulos N
Diffuse large B-cell lymphoma arising from a multicentric mixed variant of Castleman's disease.
Indian J Cancer. 2004 Jul-Sep;41(3):135-7.
This case report describes a patient with multicentric mixed type Castleman's disease and concomitant non-Hodgkin's lymphoma of diffuse large B cell type in the neck. Multicentric CD is a systemic illness with disseminated lymphadenopathy; its aggressive and usually fatal course is associated with infectious complications and risk for malignant tumors, such as lymphoma or Kaposi sarcoma. [Abstract/Link to Full Text]

Sharma LM, Biswas G, Rai SS, Nair R, Gupta S, Parikh PM
Retro-peritoneal plasmacytoma: a case report and review of literature.
Indian J Cancer. 2004 Jul-Sep;41(3):133-4.
Solitary Extramedullary Plasmacytoma (EMP) is an uncommon neoplasm. When diagnosed, head and neck region is its most likely location. Rarely, it may occur in the retro-peritoneum. We report a 44 year old man with solitary extramedullary plasmacytoma in the retro peritoneum (RPEMP). The patient did not show response to three cycles of VAD chemotherapy. Thereafter Surgical excision of the mass was performed successfully. This is probably the first case report from Indian subcontinent. [Abstract/Link to Full Text]

Bhat DM, Poflee SV, Kotwal MN, Pangarkar MA, Gadkari RU, Bobhate SK
Giant cystosarcoma phyllodes tumor of prostate: case report of a rare entity.
Indian J Cancer. 2004 Jul-Sep;41(3):129-32.
Although glandular and stromal proliferations of prostate are very common in adult men, neoplastic proliferations of prostatic stroma are distinctly uncommon. These tumors are now grouped as Prostatic Stromal Proliferations of Uncertain Malignant Potential (PSPUMP). Phyllodes tumor of the prostate is a rare neoplasm in this group with cellular, sarcomatoid stroma and benign hyperplastic glands. It is a locally expansile tumor with clinical course varying from benign to aggressive. We report a case of a 45-year-old man presented with retention of urine and abdominal lump. On laparotomy it was a huge tumor of 4 kg and was histologicaly characterized by cellular pleomorphic stroma and hyperplastic epithelium. Immunohistochemistry demonstrated prostate specific antigen in the glands. It was diagnosed as cystosarcoma phyllodes tumor of prostate. This is extremely uncommon tumor similar in histology to that of breast and it's clinical course varies with the grade. The patient was without recurrence one year after surgery. [Abstract/Link to Full Text]

Al Bahar S, Pandita R, Bavishi K, Kreze O
All-transretinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia.
Indian J Cancer. 2004 Jul-Sep;41(3):125-8.
BACKGROUND: All-transretinoic acid (ATRA) and chemotherapy has improved complete remission rates and disease free survival in acute promyelocytic leukemia (APL). There is scanty data from Middle East. AIM: To determine the efficacy of ATRA and multi-agent combination chemotherapy in treatment of APL in a single Centre in Kuwait. SET-UPS AND DESIGN: Tertiary cancer centre, retrospective study. METHODS AND MATERIAL: All newly diagnosed APL patients were treated with oral ATRA 45 mg/m2 daily until complete remission (CR), intravenous daunorubicin 50 mg/m2 on days 1,3 and 5, cytosine arabinoside 100 mg/m2 12 hrly on days 1 through 10 and etoposide 100 mg/m2 on days 1 through 5. Post remission three courses of intensive consolidation chemotherapy were administered. Since October 1999, maintenance chemotherapy consisting of oral 6 mercaptopurine 9 mg/m2 daily, methotrexate 15 mg/m2 weekly and ATRA 45 mg/m2 for 2 weeks every three months was added. Complete remission rates and duration, relapse rate and toxicity were studied. RESULTS: 22 of 24 evaluable patients (91.6%) achieved CR. The median duration of remission was 13 months (range 2-55 months). Three patients (12.5%) relapsed. Two patients (8.3%) developed retinoic acid syndrome and responded to dexamethasone. Five patients (20.8%) died one each of refractory disease, during remission induction and of relapse. Two patients died while in remission. CONCLUSION: ATRA and combination chemotherapy results in high complete remission rates and low relapse rate in newly diagnosed APL. Maintenance therapy may be useful in preventing relapses. [Abstract/Link to Full Text]

Deo S, Kumar S, Shukla NK, Kar M, Mohanti BK, Sharma A, Raina V, Rath GK
Patient profile and treatment outcome of rectal cancer patients treated with multimodality therapy at a regional cancer center.
Indian J Cancer. 2004 Jul-Sep;41(3):120-4.
BACKGROUND: Incidence of rectal cancer has wide geographical variation. Disease pattern in developing countries is different from developed countries as majority of the patients present in advanced stage because of delayed referral and lack of uniform treatment practices. AIMS: Present study describes the patient profile and treatment results from a tertiary care cancer center in India. SETTING AND DESIGN: Tertiary care Regional cancer center. Retrospective analysis 89 patients with rectal adenocarcinoma treated between 1995 and 2002 were analyzed. METHODS: Patients with adenocarcinoma rectum were evaluated in a G.I. Oncology clinic and were treated using multimodality protocols involving surgery, radiotherapy and adjuvant chemotherapy. STATISTICAL ANALYSIS: A descriptive analysis of patient and disease profile, treatment patterns and out come was performed. Survival analysis was performed using Kaplan-Meier method. RESULTS: Mean age of the patients was 45.4 years and majority of them had tumor in lower third of rectum with evidence of extrarectal spread. Seventy five percent of the patients underwent curative resection with abdominoperineal resection being the commonest procedure. Forty seven percent of patients were given short course preoperative radiotherapy and the remaining received postoperative radiotherapy. Sixty four percent of patients could complete planned adjuvant chemotherapy. Operative mortality was 2% and 23% had morbidity. Local recurrence rate was 8.9%. 5-year disease free and overall survival was 54% and 58% respectively. CONCLUSION: Majority of rectal cancer patients present with locally advanced and low rectal growths leading to low sphincter salvage rates. Despite the advanced stage of presentation optimal oncologic results can be obtained by using a good surgical techniques in combination with adjuvant radiotherapy and chemotherapy. Short course preoperative radiotherapy seems to be more feasible in Indian context. Timely referral and uniform treatment guidelines throughout the country are needed for optimal management of rectal cancer in India. [Abstract/Link to Full Text]

Mittal RD, Srivastava DS, Mandhani A, Kumar A, Mittal B
Polymorphism of GSTM1 and GSTT1 genes in prostate cancer: a study from North India.
Indian J Cancer. 2004 Jul-Sep;41(3):115-9.
BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. The genetic polymorphisms of GSTM1 and GSTT1 genes have been studied earlier to evaluate the relative risk of various cancers. AIM, SETTING AND DESIGN: In the present study, we examined the association of the GSTM1 and GSTT1 gene polymorphisms with sporadic prostate cancer patients in north Indian population. MATERIAL AND METHODS: This case control study was undertaken over a period of 24 months and included 103 prostate cancer patients and 117 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. STATISTICAL ANALYSIS: Difference in genotype prevalence and association between case and control group were assessed by the Chi square and Fisher Exact tests. RESULTS: Frequencies of null genotypes in GSTT1 and GSTM1, was 11% (13/117) and 30% (35/117) respectively in control individuals. The frequencies of GSTT1 and GSTM1 null genotypes in prostate cancer patients were 34% (35/103) and 53% (55/103) respectively. CONCLUSION: Our study demonstrates that the null genotypes of GSTT1 and GSTM1 are substantially at higher risk for prostate carcinoma as compared to the normal healthy controls. The GSTT1 and GSTM1 null genotypes did not show significant association with tobacco usage in prostate cancer patients. However, the null genotypes were significantly stratified in 50-60 year-old patients when incidence of prostate cancer is high. [Abstract/Link to Full Text]

Pandey D, Zaidi S, Mahajan V, Kannan R
Pelvic exenteration: a perspective from a regional cancer center in India.
Indian J Cancer. 2004 Jul-Sep;41(3):109-14.
BACKGROUND: Pelvic exenteration is an extensive surgical procedure performed for locally advanced cancers in the pelvis. AIMS: The twenty-year experience with this procedure at the Cancer Institute has been analyzed for morbidity, failure pattern and survival. SETTINGS AND DESIGN: The case records of all the patients who had undergone pelvic exenteration between 1981 and 2000 at Cancer Institute (WIA), Chennai were retrieved from Tumor Registry and were analyzed. METHODS AND MATERIAL: Forty-eight patients underwent Pelvic Exenteration from 1981 to 2000 at the institute. Twenty-nine of them had rectal cancer, 15 had cervical cancer, 3 had bladder cancer, and 1 had ovarian cancer. There were 43 women and 5 men with a median age of 45 years. STATISTICAL ANALYSIS: The survival rates were calculated by Kaplan-Meier method using EGRET statistical software package. RESULTS: The operative mortality and postoperative morbidity were 10.42% and 62.50% respectively. The 5-year overall survival for the patients with Ca rectum and Ca cervix were 54.2% and 77.6% respectively. All 4 patients with Ca bladder or Ca ovary survived for more than 5 years. On multivariate analysis, nodal involvement and number of positive nodes emerged as significant prognostic factors for patients with Ca rectum. Although no factor reached statistical significance for patients with Ca cervix, those with adjacent organ invasion had a trend towards poorer survival. CONCLUSIONS: For carefully selected locally advanced cancer in the pelvis, pelvic exenteration may provide the opportunity of long-term survival. [Abstract/Link to Full Text]

Gupta S, Sodhani P
Why is high grade squamous intraepithelial neoplasia under-diagnosed on cytology in a quarter of cases? Analysis of smear characteristics in discrepant cases.
Indian J Cancer. 2004 Jul-Sep;41(3):104-8.
BACKGROUND: The accuracy of cervical cytology has been questioned due to high false negative rate. In order to improve the sensitivity of cytology it is prudent to analyze the factors which hamper with the diagnosis of high grade lesions. AIMS: To study the cyto-histologic agreement in High grade squamous intraepithelial lesions (HSIL) of uterine cervix and to analyze the smear characteristics in discrepant cases. SETTINGS AND DESIGN: Cervical smears of 100 histology proven cases of Cervical intraepithelial neoplasia III (CIN III) were retrieved and reviewed to study cyto-histologic agreement in the diagnosis of high grade lesions. The discrepant smears, undercalled on cytology, were further analyzed to determine the reasons for misinterpretations. Statistical analysis was performed to find out any significant factors for discrepancies. RESULTS: Cytology was able to correctly identify 74 HSILs while in 26 cases a diagnosis of Low grade squamous intraepithelial lesions (LSIL) or below was given. On review, 16 of these non correlating cases could be reclassified as HSIL on cytology while in 10 the diagnosis of LSIL or less persisted. 12/16 (75%) discrepant cases, reclassified as HSIL represented interpretive errors. Sampling errors (7/10) and air drying (5/10) were more frequent in under diagnosed cases. The statistical analysis did not yield any significant differences in the two review groups. CONCLUSION: 26% of HSIL cases were underdiagnosed on cervical smears. The major confounding factors responsible for under interpretation on cytology included air drying artifacts and metaplastic maturation of abnormal cells. [Abstract/Link to Full Text]

Srivastava A, Mandhani A, Kapoor R, Jain M, Dubey D, Srivastava A, Raghavendra M, Kumar A
Prognosticfactors in patients with renal cell carcinoma: is TNM (1997) staging relevant in Indian subpopulation?
Indian J Cancer. 2004 Jul-Sep;41(3):99-103.
BACKGROUND: RCC (Renal Cell Carcinoma) is a common genitourinary malignancy, but its behavior has not been studied in the Indian Subpopulation. AIMS: The aim of this study was to assess the validity of 1997 AJCC TNM staging in Indian subpopulation and also to identify independent predictors for survival in patients having RCC. SETTING AND DESIGN: Retrospective uncontrolled analysis of patients with RCC was performed at our centre. MATERIAL AND METHODS: Medical records of patients of undergoing radical nephrectomy at our center between 1994 to August 2003 were identified retrospectively. Medical records of 178 patients were available for analysis. Patient characteristics, preoperative imaging and surgical details were reviewed. Each tumor was staged according to the 1997 AJCC TNM classification. Nuclear grade was assigned according to the Fuhrman's grading system. STATISTICAL METHODS: Statistical analysis was performed using statistical software and descriptive statistics and survival functions were obtained. Univariate and multivariate analysis of factors affecting outcome of the patient were performed. RESULTS: Mean follow up period was 42.3 months (range 3 to 108 months). Stage wise 5-year Cancer specific survival was 87.2% in stage 1 disease, 74.3% in stage 2, 36.4% in stage 3 and 3.1% in stage 4. Univariate analysis revealed that stage, grade and lymph node status were statistically significant (P=0.009, 0.007 and 0.003 respectively). Sub-classifying stage 1 tumors between tumor of less than 4 cm. and more than 4 cm. did not reveal any statistically significant difference in survival (P=0.32). Multivariate analysis model revealed that Fuhrman's grade and lymph node status were statistically significant (P=0.007 and 0.002 respectively). CONCLUSION: This study validates the TNM (1997) staging for RCC as having significant survival impact in the Indian subpopulation. Sub-classifying stage 1 tumors between tumor of less than 4 cm. and more than 4 cm is not of much importance. Nuclear grade and lymph node involvement are important independent predictors of survival. Organ confined tumors with high nuclear grades need to be followed up more rigorously. [Abstract/Link to Full Text]

Deshpande AH, Kotwal MN, Bobhate SK
Glassy cell carcinoma of the uterine cervix a rare histology. Report of three cases with a review of the literature.
Indian J Cancer. 2004 Apr-Jun;41(2):92-5.
Glassy cell carcinoma is a poorly differentiated variant of adenosquamous carcinoma of the cervix associated with an aggressive course and a poor prognosis. We present three cases of glassy cell carcinoma of the cervix. Patients presented with a cervical growth which was biopsied. Histology the tumours showed nests of cells with a granular or clear cytoplasm, displaying marked pleomorphism and mitoses. Stroma showed an eosinophilic infiltrate. Two tumours showed a pure glassy cell pattern and one showed glandular differentiation with intracellular and extracellular mucin. Patients were treated with a combination of surgery, radiotherapy and chemotherapy but showed a poor response. Two patients died of the disease of pelvic or distant metastases within two years of diagnosis and one was lost to follow up. Although glassy cell carcinoma runs an aggressive clinical course, an early diagnosis may help in a more effective management and offer a better prognosis. [Abstract/Link to Full Text]

Sarda AK, Pandey D, Bhalla SA, Goyal A
Isolated submandibular gland metastasis from an occult papillary thyroid cancer.
Indian J Cancer. 2004 Apr-Jun;41(2):89-91.
A case of an isolated submandibular gland metastasis from a clinically occult papillary thyroid carcinoma is described in a 46-year old lady. Initial surgery was done based on the fine needle aspiration cytology (FNAC) report of adenocarcinoma of the submandibular gland. Histopathologic examination of the specimen suggested a metastatic papillary carcinoma. Occult papillary carcinoma in the thyroid was found by multiple blind FNACs. Subsequently to near-total thyroidectomy, no other site of metastasis was found on radio-iodine scanning. [Abstract/Link to Full Text]

Ciocca L, Scotti R
Residual facial disfigurement after the ablative surgery of a lachrymal gland carcinoma: a clinical report of the prosthetic rehabilitation.
Indian J Cancer. 2004 Apr-Jun;41(2):85-8.
Facial disfigurement after ablative surgery of a massive adeno-carcinoma of the lachrymal gland is described. A rehabilitation with a maxillofacial prosthesis was proposed to restore the aesthetic appearance of the patient without inserting craniofacial implants. Retention of a maxillofacial prosthesis, that is not anchored to implants, depends on the use of adhesives or on mechanical devices like glasses. This clinic report describes a residual anatomic defect which allowed for the double choice of wearing the facial prosthesis both with or without glasses. A retentive backside of the prosthesis was developed to engage the facial defect undercuts, which enhanced retention when the patient used the skin glue without glasses. A unique foam silicone was utilized to reduce the weight of the prosthesis and to permit its retention only by skin adhesive. [Abstract/Link to Full Text]

Varghese BT, Paul S, Elizabeth MI, Somanathan T, Elizabeth KA
Late post radiation laryngeal chondronecrosis with pharyngooesophageal fibrosis.
Indian J Cancer. 2004 Apr-Jun;41(2):81-4.
Chondroradionecrosis of larynx is a well recognized complication of radiation therapy, which usually occur with in the 1st year. Review of literature shows very few accounts of late radiation induced clinical chondroradionecrosis of the larynx. This condition can mimic a local recurrence and severe and life threatening involvement will require aggressive surgical management as reported in the present case. [Abstract/Link to Full Text]

Surjyo B, Anisur KB
Protective action of an anti-oxidant (L-Ascorbic acid) against genotoxicity and cytotoxicity in mice during p-DAB-induced hepatocarcinogenesis.
Indian J Cancer. 2004 Apr-Jun;41(2):72-80.
BACKGROUND: DNA damage from micronutrient deficiencies has been suggested as one major cause of cancer. Therefore studies involving vitamin supplementation, particularly with those with anti-oxidant activity, in combating cancer have routinely been carried out in both in vivo and in vitro systems, but relatively much less in mice. AIMS: The present study examines if L-Ascorbic acid (AA; vitamin C) administration has any protective abilities in combating p-DAB induced hepatocarcinogenesis in mice at cytogenetical, biochemical, histological and ultra-structural levels. SETTINGS AND DESIGN: To test if AA had a protective action against genotoxicity, cytotoxicity and tissue damage in liver during p-dimethylaminoazobenezene (p-DAB) induced hepatocarcinogenesis in mice, a group of mice were chronically fed 0.06% p-DAB and 0.05% phenobarbital (PB) for a varying period of time (7, 15, 30, 60, 90 and 120 days). A sub-group of the p-DAB plus PB fed mice were also fed 1% L-ascorbic acid. Several assays were periodically conducted (at the six intervals of fixation) for determination of genotoxic (based on chromosomal, nuclear and sperm head anomalies), cytotoxic (based on the marker enzymes aspartate transaminase; AST, alanine aminotransferase; ALT; acid phosphatase; ACP; alkaline phosphatase; ALKP; lipid peroxidation; LPO); and tissue damaging (based on optical and electron microscopic studies of liver at day 60 only) effects in these different groups of mice as compared to normal healthy control. METHODS AND MATERIAL: Adult healthy mice of Swiss Albino strain, reared and maintained in the animal house of the Department of Zoology, Kalyani University, under supervision of Animal Welfare Committee (which oversees ethical issues), served as materials for the present study. Widely practiced standard technique has been followed for each protocol. STATISTICAL ANALYSIS USED: The significance test between different series of data was conducted by student's t-test. RESULTS AND CONCLUSIONS: The results of all these studies indicated that AA had protective action against p-DAB induced hepatocarcinogenesis in mice. [Abstract/Link to Full Text]

Suri VS, Tatke M, Singh D, Sharma A
Histological spectrum of ependymomas and correlation of p53 and Ki-67 expression with ependymoma grade and subtype.
Indian J Cancer. 2004 Apr-Jun;41(2):66-71.
BACKGROUND: Clinical and histological criteria for ependymoma prognosis are well recognized. Recently few studies have been done based on Immunohistochemistry for prognostication of these tumours. In this study we have correlated the histological spectrum with immmunoexpression of p53 and Ki67 in these tumors. AIMS: To know the incidence of ependymomas; study their morphological spectrum and to evaluate expression of P53 and Ki 67 in different morphological subtypes. MATERIAL AND METHOD: A retrospective study was preformed on 70 ependymomas received in a period between 1994 and 2001. Entire tissue received was processed for routine paraffin embedded H&E stained sections. Immunocytochemistry was performed using antibodies to GFAP, EMA, Pancytokeratin and synaptophysin, to differentiate papillary ependymoma from choroid plexus papilloma; clear cell ependymoma from oligodendroglioma and central neurocytoma; ependymoblastoma from other embryonal tumours. p53 and Ki-67 immunohistochemistry was performed to correlate their expression with various tumour grades and subtypes. RESULTS: There were 3 cases (4.2%) of Grade I ependymoma (2 cases of myxopapillary ependymoma and 1 case of subependymoma); 57 cases (81.5%) of ependymoma grade II (43 of these were of classical variety, 11 of clear cell ependymoma, 2 of papillary and 1 case of cellular ependymoma). There were 9 cases (12.8%) of anaplastic ependymoma (one of these was a clear cell ependymoma and 1 case (1.5%) of ependymoblastoma CONCLUSION: p53 and Ki67 indices can be used in routine diagnostic laboratories to supplement the tumor grade on histology and more studies with follow up should be performed to analyse the prognosis of different subtypes. The expression of Ki 67 and p53 was significantly higher in anaplastic ependymomas. 4 out of 11 cases of clear cell ependymomas showed higher Ki 67 indices as compared to classical grade II ependymomas, thus further highlighting the importance of differentiating the various subtypes. [Abstract/Link to Full Text]

Rekhi B, Jaswal TS, Arora B
Premalignant lesions of prostate and their association with nodular hyperplasia and carcinoma prostate.
Indian J Cancer. 2004 Apr-Jun;41(2):60-5.
BACKGROUND: A relatively new development in the arena of prostatic histopathological study is the premalignant proliferative changes in the glandular epithelium, possibly relating to carcinoma. Two major categories have come up, namely prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH). AIMS: The aims of present study were to identify foci of the two putative premalignant conditions viz. PIN and AAH in ducto-acinar lining epithelia of 200 prostatectomy specimens and their association with nodular hyperplasia and adenocarcinoma prostate. MATERIAL AND METHODS: Micro sections from 200 prostatectomy specimens, received in the Department of Pathology, PGIMS, Rohtak, were extensively studied for the presence and association of premalignant conditions. Significant values were obtained by employing Chi-square (chi2) test, with P value < 0.05 as significant. RESULTS: Out of 177 cases of nodular hyperplasia, 53 (29.9%) showed PIN and 38 (20.3%) showed presence of AAH. All 6 cases (100%) of pure carcinoma revealed foci of PIN. Out of the remaining 23 cases of carcinoma with nodular hyperplasia, foci of PIN were observed in 16 cases (94.1%) and AAH in 2 cases (11.7%). High-grade PIN was observed in 20 cases (86.9%) of the total 23 cases of carcinoma, with/without nodular hyperplasia and 20 cases (11.2%) of nodular hyperplasia. Low-grade PIN was observed in 33 cases (18.6%) of nodular hyperplasia and in only 1 case (5.8%) of carcinoma prostate with nodular hyperplasia. CONCLUSION: PIN, especially high-grade type was the most commonly observed premalignant lesion, in cases of adenocarcinoma, thereby suggesting it to be the likely precursor of carcinoma prostate. AAH showed a weaker association with carcinoma. [Abstract/Link to Full Text]

Kulkarni PS, Parikh PM
The carcinoma of parathyroid gland.
Indian J Cancer. 2004 Apr-Jun;41(2):51-9.
Parathyroid carcinoma constitutes less than 1% of primary hyperparathyroidism. The exact etiology is not known. Prior radiation to neck, chronic renal failure and genetic factors are thought to play a role. The male to female ratio is one. Parathyroid carcinomas are slow growing, have a tendency to recur locally and metastasize late. 95% of parathyroid carcinomas are functioning. The major distinguishing features of malignant hyperparathyroidism are presence of a palpable mass in the neck and features of severe hypercalcemia. By far the most important test to diagnose primary hyperparathyroidism is serum level of Immunoreactive PTH. The diagnosis of primary hyperparathyroidism is essentially clinical and biochemical. Biopsy is not necessary before definitive surgery. CT scan appears to be the best investigation for detecting the primary tumor, its local extent and metastases. Most of the symptoms are attributable to hypercalcemia, which needs to be treated aggressively. Early surgery with 'en bloc' resection of the tumor is the only potentially curative treatment. Parathyroid carcinoma is traditionally said to be resistant to radiotherapy. Various chemotherapeutic agents have been used with partial anecdotal responses. The 5-year survival is about 50% and 10-year survival varies from 13-49%. [Abstract/Link to Full Text]

Girish V, Vijayalakshmi A
Affordable image analysis using NIH Image/ImageJ.
Indian J Cancer. 2004 Jan-Mar;41(1):47. [Abstract/Link to Full Text]

Nair V, Suri VS, Tatke M, Saran RK, Malhotra V, Singh D
Gangliogliomas: A report of five cases.
Indian J Cancer. 2004 Jan-Mar;41(1):41-6.
Gangliogliomas are rare tumors of the Central Nervous System. Five gangliogliomas were diagnosed out of 1560 brain tumours surgically resected out in a period of 5 years accounting for 0. 32%. We have tried to discuss in detail the pathological features of these tumours and have mentioned the clinical and radiological features associated with them. All the slides, tissue blocks and pathology reports of the surgical specimens of gangliglioma were reviewed and the clinical and radiological data reviewed. The ages of the patients ranged from 7-65 years with 4 males and 1 female. The tumors were located in the lateral ventricle (a rare site), temporal, parietal and the frontal lobes with duration of seizures varying from 1-9 years. The tumors were diagnosed by the presence of a dual population of neoplastic ganglionic and glial components. The glial components consisted of pilocytic astrocytes (l case), fibrillary astrocytes (2 cases), oligodendrocytes (1 case) and anaplastic astrocytes and oligodendrocytes (1 case). There was one-grade I GG, three-Grade II GGs and one-grade III GG. Astrocytes were the commonest glial component of GGs, either pilocytic or fibrillary. Oligodendrocytes as the glial component of GGs was seen in 2 cases one of which was anaplastic and this is a rare finding. [Abstract/Link to Full Text]

Chaudhary H, Raghvendran M, Dubey D, Srivastava A, Mandhani A, Kapoor R, Kumar A
Correlation of radiological and clinical features of metanephric neoplasms in adults.
Indian J Cancer. 2004 Jan-Mar;41(1):37-40.
The main objective was to determine the clinical and radiological features of metanephric neoplasms. The tumors were diagnosed on histopathological examination. The clinical data and imaging features were retrospectively analyzed. Between 1998 and 2003, 3 patients underwent radical nephrectomy for renal masses turning out as metanephric neoplasms on histopathology. Two of these tumors were metanephric adenoma (MA) and one was metanephric adenofibroma (MAF). Clinical and radiological features were reviewed. All patients were adult females who presented with flank pain. Tumor was detected on screening ultrasound as a hyperechoic lesion. In all cases CT showed a hyper-attenuating exophytic lesion with cystic areas that enhanced with IV contrast. Based on combination of clinical and imaging features it may be possible to prospectively identify metanephric neoplasms and thus avoid unnecessary radical nephrectomy in favor of conservative surgery. [Abstract/Link to Full Text]

Bhatla N, Mukhopadhyay A, Joshi S, Kumar A, Kriplani A, Pandey RM, Verma K
Visual inspection for cervical cancer screening: evaluation by doctor versus paramedical worker.
Indian J Cancer. 2004 Jan-Mar;41(1):32-6.
BACKGROUND: In the absence of an effective cervical cancer screening programme, efforts are being made to explore the feasibility of using the existing infrastructure to develop effective low-cost screening methods. AIMS: To evaluate and compare test performance of visual inspection of the cervix by a doctor and a paramedical worker. SETTING AND DESIGN: Gynaecology outpatient department (OPD), All India Institute of Medical Sciences, New Delhi; cross-sectional study. MATERIAL AND METHODS: One hundred women with complaints of vaginal discharge, irregular bleeding, post coital bleeding or unhealthy cervix underwent visual inspection with acetic acid (VIA) and Lugol's iodine (VILI) by a doctor and nurse, followed by colposcopy and biopsy. STATISTICAL ANALYSIS USED: Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each test and compared. Concordance was determined by kappa statistics. RESULTS: VIA by nurse had a higher sensitivity (100% versus 87.5%), but lower specificity (53% versus 63%) when compared with the doctor, but it was not statistically significant. There was moderate agreement between their VIA findings (kappa=0.56). VILI findings were comparable to that of the VIA, both by the doctor and nurse. There was almost perfect agreement (kappa=0.89) between VILI by the doctor and nurse. CONCLUSION: Visual inspection can be performed reliably by trained paramedical workers and doctors and is an effective screening option in low resource settings. [Abstract/Link to Full Text]

Patel PS, Shah MH, Jha FP, Raval GN, Rawal RM, Patel MM, Patel JB, Patel DD
Alterations in plasma lipid profile patterns in head and neck cancer and oral precancerous conditions.
Indian J Cancer. 2004 Jan-Mar;41(1):25-31.
BACKGROUND: The changes in lipid profile have long been associated with cancer because lipids play a key role in maintenance of cell integrity. AIMS: The present study evaluated alterations in plasma lipid profile in untreated head and neck cancer patients as well as patients with oral precancerous conditions (OPC) and its association with habit of tobacco consumption. MATERIAL AND METHODS: This hospital-based case control study included 184 head and neck cancer patients, 153 patients with OPC and 52 controls. Plasma lipids including: (i) Total cholesterol, (ii) LDL cholesterol (LDLC), (iii) HDL cholesterol (HDLC) (iv) VLDL cholesterol (VLDLC) and (v) triglycerides were analysed by spectrophotometric kits. STATISTICAL ANALYSIS USED: Student's t-test was performed to compare mean values of the parameters. RESULTS: A significant decrease in plasma total cholesterol and HDLC was observed in cancer patients (P=0.008 and P=0.000 respectively) as well as in patients with OPC (P=0.014 and P=0.000, respectively) as compared to the controls. The plasma VLDL and triglycerides levels were significantly lower in cancer patients as compared to the patients with OPC (P=0.04) and controls (P=0.059). The tobacco habituates showed lower plasma lipid levels than the non-habituates. Our data strengthen the evidence of an inverse relationship between plasma lipid levels and head and neck malignancies as well as OPC. CONCLUSION: The lower levels of plasma cholesterol and other lipid constituents in patients might be due to their increased utilization by neoplastic cells for new membrane biogenesis. The findings strongly warrant an in-depth study of alterations in plasma lipid profile in head neck cancer patients. [Abstract/Link to Full Text]

Datta NR, Rajkumar A, Basu R
Tumor regression dynamics with external radiotherapy in cancer cervix and its implications.
Indian J Cancer. 2004 Jan-Mar;41(1):18-24.
BACKGROUND: To study the external radiotherapy (EXTRT) regression patterns in cancer of the cervix. AIMS: Evaluate EXTRT tumor regression doses (TRD) for 50% (TRD50), 80% response (TRD80), normalized dose response gradient (g50) and slope (slope50) with clinical outcome. SETTINGS AND DESIGN: Patients, treated solely with radiotherapy and enrolled for other prospective studies having weekly tumor regressions recorded were considered. MATERIAL AND METHODS: Seventy-seven patients received 50Gy of EXTRT at 2 Gy/fraction followed by 18Gy of high-dose rate intracavitary brachytherapy at 6 Gy/fraction. Loco-regional regressions were assessed clinically at weekly intervals during EXTRT to generate EXTRT dose-response curves. STATISTICAL ANALYSIS USED: Student's t test, logistic regression, Kaplan Meier and Cox's proportional hazard model. Scatter plots were fitted using cubic fit. RESULTS: Age (P=0.052) and absence or presence of gross residual tumor (AGRT and PGRT respectively) following EXTRT (P<0.001) were the only determinants for complete response (CR) at 1 month following completion of radiotherapy. EXTRT tumor regression sigmoid curves obtained for various patient characteristics differed only for those with AGRT and PGRT with differences in TRD50, (P<0.001); TRD80 (P<0.001) and slope50 (P=0.001). Response status to EXTRT was a prognosticator for loco-regional disease free survival (LDFS) (AGRT vs. PGRT; P=0.046). On multivariate analysis, both TRD50 and TRD80 emerged as significant predictors for tumor status at end of EXTRT while TRD80 was the sole determinant of LDFS. CONCLUSION: Extent of tumor regression to EXTRT is an important predictor for treatment outcome in cancer cervix as evident from TRD50 and TRD80 values of EXTRT tumor regression curves. [Abstract/Link to Full Text]

Arimappamagan A, Kadambari D, Srinivasan K, Krishnan R, Elangovan S, Reddy KS
Complete axillary conversion after neoadjuvant chemotherapy in locally advanced breast cancer: a step towards conserving axilla?
Indian J Cancer. 2004 Jan-Mar;41(1):13-7.
OBJECTIVES: This study was designed to assess the clinical, sonographic and histopathological response of axillary lymph node metastasis to neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIAL AND METHODS: Forty patients with locally advanced breast cancer (LABC) with clinically palpable or sonographically detectable axillary nodes were studied. FNAC of the primary tumor and axillary nodes was done and patients were started on neoadjuvant chemotherapy. Axillary nodes were assessed clinically and sonographically for response after 3 cycles of chemotherapy. All patients underwent total mastectomy with axillary clearance and the lymph nodes in the specimen were examined for metastasis. RESULTS: 47% patients had complete clinical nodal response, while 19% showed complete sonographic response. Complete pathological nodal response was documented in 22% of patients. Ultrasonography was found to be more sensitive than clinical examination in assessing complete nodal response. 10% of the patients had complete pathological response of both primary tumor and axillary nodes. There was significant correlation between pathological response of primary tumor and lymph nodes (P=0.004). Patients with complete sonographic or clinical response were found to have no or minimal residual disease in axilla and hence axillary dissection may be avoided in them. [Abstract/Link to Full Text]

Deo SV, Ray S, Rath GK, Shukla NK, Kar M, Asthana S, Raina V
Prevalence and risk factors for development of lymphedema following breast cancer treatment.
Indian J Cancer. 2004 Jan-Mar;41(1):8-12.
BACKGROUND: Early detection and multimodality therapy has resulted in an overall improvement of survival among breast cancer patients. Despite a significant shift in the treatment approach from radical mastectomy to breast conservation a significant number of patients develop lymphedema. This study was conducted to evaluate the prevalence and risk factors for development of lymphedema. SETTINGS AND DESIGN: Retrospective analysis for prevalence of lymphedema in a tertiary care regional cancer centre. MATERIAL AND METHODS: Three hundred treated breast cancer patients with a minimum follow up of one year were evaluated for the prevalence and risk factors for lymphedema. Lymphedema was assessed using a serial circumferential measurement method. More than 3 cm difference in circumference is considered as clinical significant lymphedema. Univariate and multivariate analysis were performed for evaluating the risk factors by using the Chi square test and Cox logistic regression analysis. RESULTS: The prevalence of clinically significant lymphedema was 33.5 % and 17.2 % had severe lymphedema. The prevalence of lymphedema was 13.4 % in patients treated with surgery only where as the prevalence was 42.4% in patients treated with surgery and radiotherapy. Stage of the disease, body surface area > 1. 5 m2, presence of co-morbid conditions, post operative radiotherapy and anthracycline based chemotherapy were significant risk factors in univariate analysis where as axillary irradiation and presence of co-morbid conditions have emerged as independent risk factors in multivariate analysis (P < 0.001). CONCLUSION: Post treatment lymphedema continues to be a significant problem following breast cancer therapy. Presence of co-morbid conditions and axillary radiation significantly increases the risk of lymphedema. A combination of axillary dissection and axillary radiation should be avoided whenever feasible to avoid lymphedema. [Abstract/Link to Full Text]

Aroori S, Parshad R, Kapoor A, Gupta SD, Kumar A, Chattophadyay TK
Neoadjuvant chemotherapy in squamous cell carcinoma of the esophagus using low dose continuous infusion 5-fluorouracil and cisplatin: results of a prospective study.
Indian J Cancer. 2004 Jan-Mar;41(1):3-7.
BACKGROUND: Surgery is the treatment of choice for localized esophageal squamous cell carcinoma (ESCC). Despite curative surgical resection, the majority of patients develop local and systemic recurrence with poor 5-year survival. AIMS: To study the role of low dose continuous infusion (CI) 5-fluorouracil (5-FU) and cisplatin as neoadjuvant chemotherapy in ESCC. SETTINGS AND DESIGN: A non-randomized prospective study conducted over a period of two years (1996-1998) in the Department of Surgery, All India Institute of Medical Sciences, India. MATERIAL AND METHODS: Twenty-two patients with ESCC were included in the study. Chemotherapy consisted of a continuous 30-day infusion of 5-FU (350 mg/m2/day) and cisplatin (7.5 mg/m2/day), 5 days/week for 4 weeks. All patients had surgery following chemotherapy. RESULTS: A full course of chemotherapy was completed in 18 patients (82%). Chemotherapy was not completed due to non-compliance (n=2), thrombophlebitis (n=1), and vomiting (n=1). Grade-1 haematological and hepato-toxicity was observed in four patients. Thirteen patients developed thrombophlebitis. After chemotherapy, improvement in dysphagia was observed in 13 of 22 (59%) patients. Radiological partial response was observed in 8 patients (36.4%). 19 patients underwent surgical resection (86.4%) with zero mortality. Post-operative morbidity was observed in six patients (27%). Complete and partial pathological response was observed in two (11%) and one patient (5.5%) respectively. The overall median survival was 18 months and 4-year survival was 42%. CONCLUSIONS: Low dose CI 5-FU and cisplatin is well tolerated with minimal toxicity. Histopathological response rates and survival figures are comparable with the more toxic neoadjuvant chemotherapeutic regimens. [Abstract/Link to Full Text]

Nair A, Pai DR, Jagdish S, Krishnan R
Alveolar soft part sarcoma: a unique tumor with disputed histogenesis.
Indian J Cancer. 2003 Apr-Jun;40(2):82-3. [Abstract/Link to Full Text]

Bhansali A, Kataria RN, Subrahmanyam KA, Radotra BD, Mathur SK
Maxillary mass as the presenting manifestation of papillary thyroid carcinoma.
Indian J Cancer. 2003 Apr-Jun;40(2):80-1.
A case of follicular variant of papillary thyroid carcinoma presenting with a right maxillary mass is described. This is perhaps the first instance of maxillary metastasis from papillary thyroid carcinoma. [Abstract/Link to Full Text]

Gupta S, Gupta V, Aggarwal PN, Kant R, Khurana N, Mandal AK
Primary chondrosarcoma of the breast: a case report.
Indian J Cancer. 2003 Apr-Jun;40(2):77-9.
Mammary sarcomas are uncommon tumors. Of these pure chondrosarcoma without any other area of epithelial or mesenchymal differentiation feature as even rarer. This excludes tumors like malignant cystosarcoma phyllodes and metaplastic carcinoma where malignant cartilaginous areas may be present. Further primary chondrosarcoma arises from breast stroma and not from underlying bone or cartilage. Only five cases of pure and primary chondrosarcoma have been reported so far. The sixth case is reported here. [Abstract/Link to Full Text]