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Recent Articles in Molecular Cancer

Vollmers HP, Braendlein S
Tumors: Too sweet to remember?
Mol Cancer. 2007 Dec 4;6(1):78.
ABSTRACT: Immunity, based on a natural and an educated system, is responsible for recognition and elimination of infectious particles, cellular waste, modified self and transformed cells. This dual system guarantees that dangerous particles are removed immediately after appearance and that a memory with maturated weapons exists, if the organism is re-infected by the same particle. For malignant cells, however, the immune response seems to be restricted to innate immunity, because at least for the humoral response, all so far detected tumor-specific antibodies belong to the natural immunity. In this review we try to explain why malignant cells might be "too sweet" to induce a memory. [Abstract/Link to Full Text]

Telang S, Lane AN, Nelson KK, Arumugam S, Chesney J
The oncoprotein H-RasV12 increases mitochondrial metabolism.
Mol Cancer. 2007 Dec 1;6(1):77.
ABSTRACT: BACKGROUND: Neoplastic cells increase glycolysis in order to produce anabolic precursors and energy within the hypoxic environment of a tumor. Ras signaling is activated in several cancers and has been found to regulate metabolism by enhancing glycolytic flux to lactate. We examined the effects of sequential immortalization and H-RasV12-transformation of human bronchial epithelial cells on the anabolic fate of fully-labeled 13C-glucose-derived carbons using two-dimensional total correlated spectroscopic analysis-nuclear magnetic resonance spectroscopy (2D TOCSY-NMR). RESULTS: We found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells unexpectedly increased tricarboxylic acid cycle activity as measured by the direct conversion of 13C-glucose carbons into the anabolic substrates glutamate/ glutamine, aspartate and uridine. We then observed that immortalization and H-RasV12-transformation of bronchial epithelial cells caused a stepwise increase in oxygen consumption, a global measure of electron transport chain activity. Importantly, ectopic expression of H-RasV12 sensitized immortalized cells to the ATP-depleting and cytotoxic effects of electron transport perturbation using the complex I inhibitor rotenone. CONCLUSION: Taken together, these data indicate that the oncoprotein H-RasV12 increases mitochondrial metabolism and provide new rationale for the targeting of the tricarboxylic acid cycle and electron transport chain as anti-neoplastic strategies. [Abstract/Link to Full Text]

Uysal Onganer P, Djamgoz MB
Epidermal growth factor potentiates in vitro metastatic behaviour of human prostate cancer PC-3M cells: Involvement of voltage-gated sodium channel.
Mol Cancer. 2007 Nov 24;6(1):76.
ABSTRACT: BACKGROUND: Although a high level of functional voltage-gated sodium channel (VGSC) expression has been found in strongly metastatic human and rat prostate cancer (PCa) cells, the mechanism(s) responsible for the upregulation is unknown. The concentration of epidermal growth factor (EGF), a modulator of ion channels, in the body is highest in prostatic fluid. Thus, EGF could be involved in the VGSC upregulation in PCa. The effects of EGF on VGSC expression in the highly metastatic human PCa PC-3M cell line, which was shown previously to express both functional VGSCs and EGF receptors, were investigated. A quantitative approach, from gene level to cell behaviour, was used. mRNA levels were determined by real-time PCR. Protein expression was studied by Western blots and immunocytochemistry and digital image analysis. Functional assays involved measurements of transverse migration, endocytic membrane activity and Matrigel invasion. RESULTS: Exogenous EGF enhanced the cells' in vitro metastatic behaviours (migration, endocytosis and invasion). Endogenous EGF had a similar involvement. EGF increased VGSC Nav1.7 (predominant isoform in PCa) mRNA and protein expressions. Co-application of the highly specific VGSC blocker tetrodotoxin (TTX) suppressed the effect of EGF on all three metastatic cell behaviours studied. CONCLUSIONS: 1) EGF has a major involvement in the upregulation of functional VGSC expression in human PCa PC-3M cells. (2) VGSC activity has a significant intermediary role in potentiating effect of EGF in human PCa. [Abstract/Link to Full Text]

Seo DC, Sung JM, Cho HJ, Yi H, Seo KH, Choi IS, Kim DK, Kim JS, Abd El-Aty AM, Shin HC
Gene expression profiling of cancer stem cell in human lung adenocarcinoma A549 cells.
Mol Cancer. 2007 Nov 22;6(1):75.
ABSTRACT: BACKGROUND: The studies on cancer-stem-cells (CSCs) have attracted so much attention in recent years as possible therapeutic implications. This study was carried out to investigate the gene expression profile of CSCs in human lung adenocarcinoma A549 cells. RESULTS: We isolated CSCs from A549 cell line of which side population (SP) phenotype revealed several stem cell properties. After staining the cell line with Hoechst 33342 dye, the SP and non-side population (non-SP) cells were sorted using flow cytometric analysis. The mRNA expression profiles were measured using an Affymetrix GeneChip(R) oligonucleotide array. Among the sixty one differentially expressed genes, the twelve genes inclusive three poor prognostic genes; Aldo-keto reductase family 1, member C1/C2 (AKR1C1/C2), Transmembrane 4 L six family member 1 nuclear receptor (TM4SF1), and Nuclear receptor subfamily 0, group B, member 1 (NR0B1) were significantly up-regulated in SP compared to non-SP cells. CONCLUSIONS: This is the first report indicating the differences of gene expression pattern between SP and non-SP cells in A549 cells. We suggest that the up-regulations of the genes AKR1C1/C2, TM4SF1 and NR0B1 in SP of human adenocarcinoma A549 cells could be a target of poor prognosis in anti-cancer therapy. [Abstract/Link to Full Text]

Jiang WW, Zahurak M, Zhou ZT, Park HL, Guo ZM, Wu GJ, Sidransky D, Trink B, Califano JA
Alterations of GPI transamidase subunits in head and neck squamous carcinoma.
Mol Cancer. 2007 Nov 21;6(1):74.
ABSTRACT: BACKGROUND: GPI anchor attachment is catalyzed by the GPI transamidase (GPIT) complex. GAA1, PIG-T and PIG-U are the three of five GPIT subunits. Previous studies demonstrated amplification and overexpression of GPIT subunits in bladder and breast cancer with oncogenic function. We performed an analysis of these subunits in head and neck squamous cell carcinoma (HNSCC). RESULTS: To evaluate GAA1, PIG-T and PIG-U in HNSCC, we used quantitative PCR (QPCR) and quantitative RT-PCR (QRT-PCR) to determine the copy number of those genes in primary tumors and the matching lymphocytes in 28 patients with HNSCC and quantified RNA expression of those genes in 16 primary HNSCC patients and 4 normal control tissue samples. GAA1 showed a significant increase in normalized mRNA expression, 2.11 (95% CI: 1.43, 2.79), in comparison to that of normal controls, 0.43 (95% CI: -0.76, 1.61), p=0.014 (Mann-Whitney test). The mean genomic copy number of GAA1 was significantly increased in HNSCC, 0.59 (95% CI: 0.50, 0.79), in comparison to lymphocyte DNA, 0.35 (95% CI: 0.30, 0.50), p=0.001 (paired t-test). CONCLUSIONS: An increased expression level and elevated copy number for GAA1 suggest a role for this GPI anchor subunit in HNSCC. [Abstract/Link to Full Text]

Voortman J, Checinska A, Giaccone G
The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells.
Mol Cancer. 2007 Nov 17;6(1):73.
ABSTRACT: Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms. [Abstract/Link to Full Text]

Fujita KI, Janz S
Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF.
Mol Cancer. 2007 Oct 30;6(1):71.
ABSTRACT: BACKGROUND: Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/beta-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood. METHODS: We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation. RESULTS: We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective. CONCLUSION: Our results suggest that inhibited Wnt/beta-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss. [Abstract/Link to Full Text]

Tsou JA, Galler JS, Siegmund KD, Laird PW, Turla S, Cozen W, Hagen JA, Koss MN, Laird-Offringa IA
Identification of a panel of sensitive and specific DNA methylation markers for lung adenocarcinoma.
Mol Cancer. 2007 Oct 29;6(1):70.
ABSTRACT: BACKGROUND: Lung cancer is the number one cancer killer of both men and women in the United States. Three quarters of lung cancer patients are diagnosed with regionally or distantly disseminated disease; their 5-year survival is only 15%. DNA hypermethylation at promoter CpG islands shows great promise as a cancer-specific marker that would complement visual lung cancer screening tools such as spiral CT, improving early detection. In lung cancer patients, such hypermethylation is detectable in a variety of samples ranging from tumor material to blood and sputum. To date the penetrance of DNA methylation at any single locus has been too low to provide great clinical sensitivity. We used the real-time PCR-based method MethyLight to examine DNA methylation quantitatively at twenty-eight loci in 51 primary human lung adenocarcinomas, 38 adjacent non-tumor lung samples, and 11 lung samples from non-lung cancer patients. RESULTS: We identified thirteen loci showing significant differential DNA methylation levels between tumor and non-tumor lung; eight of these show highly significant hypermethylation in adenocarcinoma: CDH13, CDKN2A EX2, CDX2, HOXA1, OPCML, RASSF1, SFPR1, and TWIST1 (p-value <0.0001). Using the current tissue collection and 5-fold cross validation, the four most significant loci (CDKN2A EX2, CDX2, HOXA1 and OPCML) individually distinguish lung adenocarcinoma from non-cancer lung with a sensitivity of 67-86% and specificity of 74-82%. DNA methylation of these loci did not differ significantly based on gender, race, age or tumor stage, indicating their wide applicability as potential lung adenocarcinoma markers. We applied random forests to determine a good classifier based on a subset of our loci and determined that combined use of the same four top markers allows identification of lung cancer tissue from non-lung cancer tissue with 94% sensitivity and 90% specificity. CONCLUSIONS: The identification of eight CpG island loci showing highly significant hypermethylation in lung adenocarcinoma provides strong candidates for evaluation in patient remote media such as plasma and sputum. The four most highly ranked loci, CDKN2A EX2, CDX2, HOXA1 and OPCML, which show significant DNA methylation even in stage IA tumor samples, merit further investigation as some of the most promising lung adenocarcinoma markers identified to date. [Abstract/Link to Full Text]

Sam MR, Elliott BE, Mueller CR
A novel activating role of SRC and STAT3 on HGF transcription in human breast cancer cells.
Mol Cancer. 2007 Oct 29;6(1):69.
ABSTRACT: We have previously determined that the HGF promoter can be transactivated by a combination of activated Src and wild-type Stat3 in the mouse breast cell lines HC11 and SP1. To determine if this pathway is of relevance for the human disease, a series of human breast and other human cells lines were examined, and the status of key proteins in these cells determined. All of the human breast cell lines exhibited strong transactivation by a combination of activated Src and Stat3. This activation was dependent on a Stat3 recognition element present at nt-95. The exception was the ErbB2 over-expressing cell line SK-BR-3 where Stat3 alone could transactivate HGF though Src augmented this effect. Increased phosphorylation of Stat3 tyrosine 705 was also observed in this line. Analysis of three ovarian cell lines revealed that Src/Stat3 expression was not able to activate the HGF promoter in two of these lines (SKOV3 and IOSE-80PC). Src/Stat3 expression did activate HGF transcription in OVCAR3 cells, but this effect was not mediated by the Stat3 site at nt-95. Stat3 phosphorylation at tyrosine 705 was observed in IOSE-80PC cells, but was insufficient to allow for activation of the HGF promoter. Human kidney (HEK293) and cervical carcinoma (HeLa) cells were also not Src/Stat3 permissive, despite high levels of Stat3 phospho-Y705. These results suggest that human breast cells are a uniquely permissive environment for HGF transactivation by Src/Stat3 which may allow for the inappropriate activation of HGF transcription during the early stages of breast transformation. This could lead to paracrine or autocrine activation of the Met receptor in breast carcinoma cells. [Abstract/Link to Full Text]

Kuljaca S, Liu T, Tee AE, Haber M, Norris MD, Dwarte T, Marshall GM
Enhancing the anti-angiogenic action of histone deacetylase inhibitors.
Mol Cancer. 2007 Oct 25;6(1):68.
ABSTRACT: BACKGROUND: Histone deacetylase inhibitors (HDACIs) have many effects on cancer cells, such as growth inhibition, induction of cell death, differentiation, and anti-angiogenesis, all with a wide therapeutic index. However, clinical trials demonstrate that HDACIs are more likely to be effective when used in combination with other anticancer agents. Moreover, the molecular basis for the anti-cancer action of HDACIs is still unknown. In this study, we compared different combinations of HDACIs and anti-cancer agents with anti-angiogenic effects, and analysed their mechanism of action. RESULTS: Trichostatin A (TSA) and alpha-interferon (IFN alpha) were the most effective combination across a range of different cancer cell lines, while normal non-malignant cells did not respond in the same manner to the combination therapy. There was a close correlation between absence of basal p21WAF1 expression and response to TSA and IFN alpha treatment. Moreover, inhibition of p21WAF1 expression in a p21WAF1-expressing breast cancer cell line by a specific siRNA increased the cytotoxic effects of TSA and IFN alpha. In vitro assays of endothelial cell function showed that TSA and IFN alpha decreased endothelial cell migration, invasion, and capillary tubule formation, without affecting endothelial cell viability. TSA and IFN alpha co-operatively inhibited gene expression of some pro-angiogenic factors: vascular endothelial growth factor, hypoxia-inducible factor 1 alpha and matrix metalloproteinase 9, in neuroblastoma cells under hypoxic conditions. Combination TSA and IFN alpha therapy markedly reduced tumour angiogenesis in neuroblastoma-bearing transgenic mice. CONCLUSIONS: Our results indicate that combination TSA and IFN alpha therapy has potent co-operative cytotoxic and anti-angiogenic activity. High basal p21WAF1 expression appears to be acting as a resistance factor to the combination therapy. [Abstract/Link to Full Text]

Kaur P, Feldhahn N, Zhang B, Trageser D, Muschen M, Pertz V, Groffen J, Heisterkamp N
Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia.
Mol Cancer. 2007 Oct 25;6(1):67.
ABSTRACT: BACKGROUND: Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl. RESULTS: After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days. CONCLUSIONS: These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent. [Abstract/Link to Full Text]

Belyanskaya LL, Marti TM, Hopkins-Donaldson S, Kurtz S, Felley-Bosco E, Stahel RA
Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin.
Mol Cancer. 2007 Oct 22;6(1):66.
ABSTRACT: BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy. RESULTS: We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine. CONCLUSIONS: Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM. [Abstract/Link to Full Text]

Lammers T, Peschke P, Ehemann V, Debus J, Slobodin B, Lavi S, Huber P
Role of PP2Calpha in cell growth, in radio- and chemosensitivity, and in tumorigenicity.
Mol Cancer. 2007;665.
BACKGROUND: PP2Calpha is the representative member of the type 2C family of protein phosphatases, and it has recently been implicated in the regulation of p53-, TGFbeta-, cyclin-dependent kinase- and apoptosis-signaling. To investigate the role of PP2Calpha in cell growth and in radio- and chemosensitivity, wild type and PP2Calpha siRNA-expressing MCF7 cells were subjected to several different viability and cell cycle analyses, both under basal conditions and upon treatment with radio- and chemotherapy. By comparing the growth of tumors established from both types of cells, we also evaluated the involvement of PP2Calpha in tumorigenesis. RESULTS: It was found that knockdown of PP2Calpha did not affect the proliferation, the clonogenic survival and the membrane integrity of MCF7 cells. In addition, it did not alter their radio- and chemosensitivity. For PP2Calpha siRNA-expressing MCF7 cells, the number of cells in the G0/G1 phase of the cell cycle was reduced, the induction of the G1 block was attenuated, the number of cells in G2/M was increased, and the induction of the G2 block was enhanced. The tumorigenic potential of PP2Calpha siRNA-expressing MCF7 cells was found to be higher than that of wild type MCF7 cells, and the in vivo proliferation of these cells was found to be increased. CONCLUSION: Based on these findings, we conclude that PP2Calpha is not involved in controlling cell growth and radio- and chemosensitivity in vitro. It does, however, play a role in the regulation of the cell cycle, in the induction of cell cycle checkpoints and in tumorigenesis. The latter notion implies that PP2Calpha may possess tumor-suppressing properties, and it thereby sets the stage for more elaborate analyses on its involvement in the development and progression of cancer. [Abstract/Link to Full Text]

Carvalho LH, Smirnov I, Baia GS, Modrusan Z, Smith JS, Jun P, Costello JF, McDermott MW, Vandenberg SR, Lal A
Molecular signatures define two main classes of meningiomas.
Mol Cancer. 2007 Oct 15;6(1):64.
ABSTRACT: BACKGROUND: Meningiomas are common brain tumors that are classified into three World Health Organization grades (benign, atypical and malignant) and are molecularly ill-defined tumors. The purpose of this study was identify molecular signatures unique to the different grades of meningiomas and to unravel underlying molecular mechanisms driving meningioma tumorigenesis. RESULTS: We have used a combination of gene expression microarrays and array comparative genomic hybridization (aCGH) to show that meningiomas of all three grades fall into two main molecular groups designated 'low-proliferative' and 'high-proliferative' meningiomas. While all benign meningiomas fall into the low-proliferative group and all malignant meningiomas fall into the high-proliferative group, atypical meningiomas distribute into either one of these groups. High-proliferative atypical meningiomas had an elevated median MIB-1 labeling index and a greater frequency of copy number aberrations (CNAs) compared to low-proliferative atypical meningiomas. Additionally, losses on chromosome 6q, 9p, 13 and 14 were found exclusively in the high-proliferative meningiomas. We have identified genes that distinguish benign low-proliferative meningiomas from malignant high-proliferative meningiomas and have found that gain of cell-proliferation markers and loss of components of the transforming growth factor-beta signaling pathway were the major molecular mechanisms that distinguish these two groups. CONCLUSIONS: Collectively, our data suggests that atypical meningiomas are not a molecularly distinct group but are similar to either benign or malignant meningiomas. It is anticipated that identified molecular and CNA markers will potentially be more accurate prognostic markers of meningiomas. [Abstract/Link to Full Text]

Lu Y, Liang K, Li X, Fan Z
Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha.
Mol Cancer. 2007;663.
BACKGROUND: Searching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted. The purpose of the current study was to evaluate hypoxia-inducible factor-1alpha (HIF-1alpha) as a novel response marker compared with previously explored markers following treatment with an EGFR-blocking monoclonal antibody (cetuximab) and a small-molecule EGFR tyrosine kinase inhibitor (gefitinib) in a group of cancer cell lines containing wild-type or tyrosine kinase domain-mutated EGFR. RESULTS: We found that, compared with previously studied response markers, including EGFR per se and three EGFR downstream signal molecules (ERK, Akt, and STAT3), which showed variable post-treatment changes in levels of phosphorylation and no consistent link of the changes to therapeutic responses, HIF-1alpha showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1alpha downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1alpha mutant (HIF-1alpha/DeltaODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1alpha/DeltaODD-transfected cells remained sensitive to cetuximab-induced inhibition of Akt and ERK phosphorylation but were remarkably less responsive to cetuximab-induced growth inhibition compared with corresponding control cells. CONCLUSION: Our data indicates that downregulation of HIF-1alpha is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1alpha as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting. [Abstract/Link to Full Text]

Ishida K, Ito S, Wada N, Deguchi H, Hata T, Hosoda M, Nohno T
Nuclear localization of beta-catenin involved in precancerous change in oral leukoplakia.
Mol Cancer. 2007 Oct 9;6(1):62.
ABSTRACT: BACKGROUND: Oral leukoplakia is a precancerous change developed in the oral mucosa, and the mechanism that oral leukoplakia becomes malignant through atypical epithelium is not known. Here we compared the beta-catenin expression detected by immunohistochemical staining in the normal oral epithelium and in the oral leukoplakia with or without dysplasia. RESULTS: The normal oral epithelium showed beta-catenin expression only in the cell membrane, but not in the nuclei. In the oral leukoplakia without dysplasia, 7 out of 17 samples (41%) showed beta-catenin expression in the cell membrane, and 5 samples (29%) showed expression in the nuclei. In the oral leukoplakia with dysplasia, nuclear expression of beta-catenin was shown in 11 out of 12 samples (92%). Incidence of nuclear beta-catenin expression was significantly different between dysplasia and normal oral epithelium (P<0.01), and also between oral leukoplakia with dysplasia and those without dysplasia (P<0.01). Wnt3 expression was detected in the epithelial cell membrane or cytoplasm in oral leukoplakia where nuclear expression of beta-catenin was evident, but not in epithelial cells without nuclear expression of beta-catenin. CONCLUSIONS: The components of canonical Wnt pathway, such as Wnt3, beta-catenin, and cyclin D1, were detected, implying that this pathway is potentially involved in the progression of dysplasia in oral leukoplakia. [Abstract/Link to Full Text]

Cosse JP, Sermeus A, Vannuvel K, Ninane N, Raes M, Michiels C
Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines.
Mol Cancer. 2007;661.
BACKGROUND: It is more and more recognized that hypoxia plays a role in the resistance of cancer cells to chemotherapy. However, the mechanisms underlying this resistance still need deeper understanding. The aim of this study was to investigate the effect of hypoxia on this process since hypoxia is one of the hallmarks of tumor environment. RESULTS: The effect of hypoxia on the apoptosis induced by etoposide, one drug commonly used in chemotherapy, was investigated using three different cancer cell lines. Gene expression changes were also studied in order to delineate the mechanisms responsible for the hypoxia-induced chemoresistance. We observed that hypoxia differentially influenced etoposide-induced cell death according to the cancer cell type. While hypoxia inhibited apoptosis in hepatoma HepG2 cells, it had no influence in lung carcinoma A549 cells and further enhanced it in breast cancer MCF-7 cells. Etoposide increased p53 activity in all cell lines while hypoxia alone decreased it only in HepG2 cells. Hypoxia had no influence on the etoposide-induced p53 activity in A549, increased p53 abundance in MCF-7 cells but markedly decreased p53 activity in HepG2 cells. Using low density DNA arrays to detect the expression of genes involved in the regulation of apoptosis, etoposide and hypoxia were shown to each influence the expression of numerous genes, many of the ones influenced by etoposide being p53 target genes. Again, the influence of hypoxia on the etoposide-induced changes was different according to the cell type. CONCLUSION: These results evidenced that there was a striking parallelism between the effect of hypoxia on the etoposide-induced p53 stabilization as well as p53 target gene expression and its effect on the etoposide-induced apoptosis according to the cell type. They are very interesting not only because they provide one possible mechanism for the induction of chemoresistance under hypoxic conditions in cells like HepG2 but also because they indicate that not all cell types respond the same way. This knowledge is of importance in designing adequate treatment according to the type of tumors. [Abstract/Link to Full Text]

Cho WC
OncomiRs: the discovery and progress of microRNAs in cancers.
Mol Cancer. 2007;660.
microRNAs (miRNAs) are evolutionarily conserved, endogenous, small, noncoding RNA molecules of about 22 nucleotides in length that function as posttranscriptional gene regulators. They are deemed to play a crucial role in the initiation and progression of human cancer, and those with a role in cancer are designated as oncogenic miRNAs (oncomiRs). For example, miR-15 and miR-16 induce apoptosis by targeting Bcl2. miRNAs from the miR-17-92 cluster modulate tumor formation and function as oncogenes by influencing the translation of E2F1 mRNA. miR-21 modulates gemcitabine-induced apoptosis by phosphatase and tensin homolog deleted on chromosome 10-dependent activation of PI 3-kinase signaling. miR-34a acts as a suppressor of neuroblastoma tumorigenesis by targeting the mRNA encoding E2F3 and reducing E2F3 protein levels. The chromosomal translocations associating with human tumors disrupt the repression of High mobility group A2 by let-7 miRNA. In addition, the oncomiRs expression profiling of human malignancies has also identified a number of diagnostic and prognostic cancer signatures. This article introduces the roles of oncomiRs in neoplasm development, progression, diagnosis, prognostication, as well as their mechanism of actions on target mRNAs and the functional outcomes of their actions on mRNAs. The paper ends with a brief perspective to the future of oncomiRs. [Abstract/Link to Full Text]

Sola B, Renoir JM
Estrogenic or antiestrogenic therapies for multiple myeloma?
Mol Cancer. 2007;659.
Multiple myeloma (MM) is a common hematological malignancy which remains incurable due to both intrinsic and acquired resistance to conventional or more novel drugs. Estrogenic and antiestrogenic compounds are very promising drugs for the treatment of MM. Indeed, they inhibit cell proliferation in vitro. They block cell cycle and/or induce apoptosis even in drug-resistant MM cells but not normal B cells. They interfere with survival pathways often deregulated in myelomas. They co-operate with conventional drugs to enhance apoptosis or to overcome resistance. In vivo, they act also on tumoral angiogenesis in xenograft models. As a whole, they possess all the criteria which render them attractive for a new therapeutic strategy. Importantly, they are well-tolerated at the doses tested in vitro or in vivo, encouraging the rapid onset of critical trials. [Abstract/Link to Full Text]

Hamaguchi J, Nakagawa H, Takahashi M, Kudo T, Kamiyama N, Sun B, Oshima T, Sato Y, Deguchi K, Todo S, Nishimura S
Swainsonine reduces 5-fluorouracil tolerance in the multistage resistance of colorectal cancer cell lines.
Mol Cancer. 2007;658.
BACKGROUND: Drug resistance is a major problem in cancer chemotherapy. Acquisition of chemo-resistance not only reduces the effectiveness of drugs, but also promotes side effects and markedly reduces the patient's quality of life. However, a number of resistance mechanisms have been reported and are thought to be the reason for the difficulties in solving drug-resistance problems. RESULT: To investigate the mechanisms of drug resistance, a set of cell lines with different levels of sensitivity and possessing different mechanisms of resistance to 5-fluorouracil (5-FU) was established from a colorectal cancer cell line. The expression of thymidylate synthase, orotic acid phosphoribosyltransferase and dihydropyrimidine dehydrogenase, which are well known to be related to drug resistance, differed among these cell lines, indicating that these cell lines acquired different resistance mechanisms. However, swainsonine, an inhibitor of N-glycan biosynthesis, reduced 5-FU-tolerance in all resistant cells, whereas the sensitivity of the parental cells was unchanged. Further analysis of the N-glycan profiles of all cell lines showed partial inhibition of biosynthesis and no cytotoxicity at the swainsonine dosage tested. CONCLUSION: These observations suggest that N-linked oligosaccharides affect 5-FU resistance more widely than do drug-resistance related enzymes in colorectal cancer cells, and that the N-glycan could be a universal target for chemotherapy. Further, swainsonine may enhance the performance of chemotherapy by reducing tolerance. [Abstract/Link to Full Text]

Heim KC, White KA, Deng D, Tomlinson CR, Moore JH, Freemantle SJ, Spinella MJ
Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells.
Mol Cancer. 2007;657.
BACKGROUND: The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification of these genes would be of considerable interest. RESULTS: To begin to address this issue, microarray technology was employed to elucidate in a de novo fashion the global role of RIP140 in RA target gene regulation of embryonal carcinoma. Subclasses of genes were affected by RIP140 in distinct manners.Interestingly, approximately half of the RA-dependent genes were unaffected by RIP140. Hence, RIP140 appears to discriminate between different classes of RA target genes. In general, RIP140-dependent gene expression was consistent with RIP140 functioning to limit RA signaling and tumor cell differentiation. Few if any genes were regulated in a manner to support a role for RIP140 in "active repression". We also demonstrated that RIP140 silencing sensitizes embryonal carcinoma cells to low doses of RA. CONCLUSION: Together the data demonstrates that RIP140 has profound effects on RA-mediated gene expression in this cancer stem cell model. The RIP140-dependent RA target genes identified here may be particularly important in mediating RA-induced tumor cell differentiation and the findings suggest that RIP140 may be an attractive target to sensitize tumor cells to retinoid-based differentiation therapy. We discuss these data in the context of proposed models of RIP140-mediated repression. [Abstract/Link to Full Text]

de Gunst MM, Gallegos-Ruiz MI, Giaccone G, Rodriguez JA
Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain.
Mol Cancer. 2007;656.
BACKGROUND: The presence of EGFR kinase domain mutations in a subset of NSCLC patients correlates with the response to treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Although most EGFR mutations detected are short deletions in exon 19 or the L858R point mutation in exon 21, more than 75 different EGFR kinase domain residues have been reported to be altered in NSCLC patients. The phenotypical consequences of different EGFR mutations may vary dramatically, but the majority of uncommon EGFR mutations have never been functionally evaluated. RESULTS: We demonstrate that the relative kinase activity and erlotinib sensitivity of different EGFR mutants can be readily evaluated using transfection of an YFP-tagged fragment of the EGFR intracellular domain (YFP-EGFR-ICD), followed by immunofluorescence microscopy analysis. Using this assay, we show that the exon 20 insertions Ins770SVD and Ins774HV confer increased kinase activity, but no erlotinib sensitivity. We also show that, in contrast to the common L858R mutation, the uncommon exon 21 point mutations P848L and A859T appear to behave like functionally silent polymorphisms. CONCLUSION: The ability to rapidly obtain functional information on EGFR variants of unknown relevance using the YFP-EGFR-ICD assay might prove important in the future for the management of NSCLC patients bearing uncommon EGFR mutations. In addition, our assay may be used to determine the response of resistant EGFR mutants to novel second-generation TKIs. [Abstract/Link to Full Text]

Carosio R, Zuccari G, Orienti I, Mangraviti S, Montaldo PG
Sodium ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake.
Mol Cancer. 2007;655.
BACKGROUND: Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred. RESULTS: We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells. CONCLUSION: Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation. [Abstract/Link to Full Text]

Lanza G, Ferracin M, Gaf� R, Veronese A, Spizzo R, Pichiorri F, Liu CG, Calin GA, Croce CM, Negrini M
mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer.
Mol Cancer. 2007;654.
BACKGROUND: Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. RESULTS: We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. CONCLUSION: This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer. [Abstract/Link to Full Text]

Duale N, Lindeman B, Komada M, Olsen AK, Andreassen A, Soderlund EJ, Brunborg G
Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles.
Mol Cancer. 2007;653.
BACKGROUND: Testicular germ cell tumors (TGCTs) respond well to cisplatin-based chemotherapy and show a low incidence of acquired resistance compared to most somatic tumors. The reasons for these specific characteristics are not known in detail but seem to be multifactorial. We have studied gene expression profiles of testicular and colon cancer derived cell lines treated with cisplatin. The main goal of this study was to identify novel gene expression profiles with their functional categories and the biochemical pathways that are associated with TGCT cells' response to cisplatin. RESULTS: Genes that were differentially expressed between the TGCT cell lines vs the (somatic) HCT116 cell line, after cisplatin treatment, were identified using the significance analysis of microarrays (SAM) method. The response of TGCT cells was strikingly different from that of HCT116, and we identified 1794 genes that were differentially expressed. Functional classification of these genes showed that they participate in a variety of different and widely distributed functional categories and biochemical pathways. Database mining showed significant association of genes (n = 41) induced by cisplatin in our study, and genes previously reported to by expressed in differentiated TGCT cells. We identified 37 p53-responsive genes that were altered after cisplatin exposure. We also identified 40 target genes for two microRNAs, hsa-mir-372 and 373 that may interfere with p53 signaling in TGCTs. The tumor suppressor genes NEO1 and LATS2, and the estrogen receptor gene ESR1, all have binding sites for p53 and hsa-mir-372/373. NEO1 and LATS2 were down-regulated in TGCT cells following cisplatin exposure, while ESR1 was up-regulated in TGCT cells. Cisplatin-induced genes associated with terminal growth arrest through senescence were identified, indicating associations which were not previously described for TGCT cells. CONCLUSION: By linking our gene expression data to publicly available databases and literature, we provide a global pattern of cisplatin induced cellular response that is specific for testicular cancer cell lines. We have identified cisplatin-responsive functional classes and pathways, such as the angiogenesis, Wnt, integrin, and cadherin signaling pathways. The identification of differentially expressed genes in this study may contribute to a better understanding of the unusual sensitivity of TGCT to some DNA-damaging agents. [Abstract/Link to Full Text]

Zhang D, Wong LL, Koay ES
Phosphorylation of Ser78 of Hsp27 correlated with HER-2/neu status and lymph node positivity in breast cancer.
Mol Cancer. 2007;652.
BACKGROUND: Abnormal amplification/expression of HER-2/neu oncogene has been causally linked with tumorigenesis and metastasis in breast cancer and associated with shortened overall survival of patients. Recently, heat shock protein 27 (Hsp27) was reported to be highly expressed in HER-2/neu positive tumors and cell lines. However, putative functional links between phosphorylation of Hsp27 with HER-2/neu status and other clinicopathological features remain to be elucidated. RESULTS: Comparative phosphoproteomic studies of HER-2/neu positive and -negative breast tumors revealed that Hsp27, one of the identified phosphoproteins, was highly phosphorylated in HER-2/neu positive tumors. The extent of Hsp27 phosphorylation at its Ser15, Ser78 and Ser82 residues were further evaluated with site-specific antibodies in tumor samples by tissue lysate array- and tissue microarray-based analyses, and in the BT474 breast cancer cell line treated with heregulin alpha1 (HRG alpha1) or the p38 MAPK inhibitor, SB203580. The tissue lysate array study indicated that only the level of pSer78 in HER-2/neu positive tumors was more than 2-fold that in HER-2/neu negative tumors. Treatment of BT474 cells with HRG alpha1 and SB203580 indicated that Ser78 phosphorylation was mainly regulated by the HER-2/neu-p38 MAPK pathway. Immunohistochemical staining of sections from a tissue microarray with 97 breast tumors showed that positive staining of pSer78 significantly correlated with HER-2/neu (p = 0.004) and lymph node positivity (p = 0.026). CONCLUSION: This investigation demonstrated the significant correlation of enhanced phosphorylation of the Ser78 residue of Hsp27 with HER-2/neu and lymph node positivity in breast cancer. [Abstract/Link to Full Text]

Yin H, Glass J, Blanchard KL
MOZ-TIF2 repression of nuclear receptor-mediated transcription requires multiple domains in MOZ and in the CID domain of TIF2.
Mol Cancer. 2007;651.
BACKGROUND: Fusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia. Characterization of the molecular structure of the MOZ-TIF2 fusion protein suggested that the fusion protein would effect on nuclear receptor signaling. RESULTS: A series of deletions from the N-terminus of the MOZ-TIF2 fusion protein demonstrated that the MOZ portion is essential for nuclear localization of the fusion protein. Transient expression of MOZ-TIF2 dramatically decreased both basal and estradiol inducible reporter gene activity in an estrogen receptor element (ERE) driven luciferase reporter system and decreased androgen-inducible reporter gene activity in an androgen receptor element (ARE) luciferase reporter system. Deletions in the MOZ portion of the MOZ-TIF2 fusion protein reduced the suppression in the ER reporter system. Stable expression of MOZ-TIF2 inhibited retinoic acid (RA) inducible endogenous CD11b and C/EBPbeta gene response. The suppression of the reporter systems was released with either a CID domain deletion or with mutations of leucine-rich repeats in the TIF2 portion of MOZ-TIF2. The co-expression of TIF2, but not CBP, with MOZ-TIF2 partially restored the inhibition of the reporter systems. In addition, analysis of protein interactions demonstrated MOZ-TIF2 interaction with the C-terminus of CBP through both the MOZ and TIF2 portions of the fusion protein. CONCLUSION: MOZ-TIF2 inhibited nuclear receptor-mediated gene response by aberrant recruitment of CBP and both the MOZ and TIF2 portions are required for this inhibition. [Abstract/Link to Full Text]

Murray D, Doran P, MacMathuna P, Moss AC
In silico gene expression analysis--an overview.
Mol Cancer. 2007;650.
Efforts aimed at deciphering the molecular basis of complex disease are underpinned by the availability of high throughput strategies for the identification of biomolecules that drive the disease process. The completion of the human genome-sequencing project, coupled to major technological developments, has afforded investigators myriad opportunities for multidimensional analysis of biological systems. Nowhere has this research explosion been more evident than in the field of transcriptomics. Affordable access and availability to the technology that supports such investigations has led to a significant increase in the amount of data generated. As most biological distinctions are now observed at a genomic level, a large amount of expression information is now openly available via public databases. Furthermore, numerous computational based methods have been developed to harness the power of these data. In this review we provide a brief overview of in silico methodologies for the analysis of differential gene expression such as Serial Analysis of Gene Expression and Digital Differential Display. The performance of these strategies, at both an operational and result/output level is assessed and compared. The key considerations that must be made when completing an in silico expression analysis are also presented as a roadmap to facilitate biologists. Furthermore, to highlight the importance of these in silico methodologies in contemporary biomedical research, examples of current studies using these approaches are discussed. The overriding goal of this review is to present the scientific community with a critical overview of these strategies, so that they can be effectively added to the tool box of biomedical researchers focused on identifying the molecular mechanisms of disease. [Abstract/Link to Full Text]

Peters I, Rehmet K, Wilke N, Kuczyk MA, Hennenlotter J, Eilers T, Machtens S, Jonas U, Serth J
RASSF1A promoter methylation and expression analysis in normal and neoplastic kidney indicates a role in early tumorigenesis.
Mol Cancer. 2007;649.
BACKGROUND: Epigenetic silencing of the RAS association domain family 1A (RASSF1A) tumor suppressor gene promoter has been demonstrated in renal cell carcinoma (RCC) as a result of promoter hypermethylation. Contradictory results have been reported for RASSF1A methylation in normal kidney, thus it is not clear whether a significant difference between RASSF1A methylation in normal and tumor cells of the kidney exists. Moreover, RASSF1A expression has not been characterized in tumors or normal tissue as yet. RESULTS: Using combined bisulfite restriction analysis (COBRA) we compared RASSF1A methylation in 90 paired tissue samples obtained from primary kidney tumors and corresponding normal tissue. Bisulfite sequence analysis was carried out using both pooled amplicons from the tumor and normal tissue groups and subclones obtained from a single tissue pair. Expression of RASSF1A was analyzed by the use of tissue arrays and immunohistochemistry. We found significantly increased methylation in tumor samples (mean methylation, 20%) compared to corresponding normal tissues (mean methylation, 11%; P < 0.001). Densely methylated sequences were found both in pooled and individual sequences of normal tissue. Immunohistochemical analysis revealed a significant reduced expression of RASSF1A in most of the tumor samples. Heterogeneous expression patterns of RASSF1A were detected in a subgroup of histologically normal tubular epithelia. CONCLUSION: Our methylation and expression data support the hypothesis that RASSF1A is involved in early tumorigenesis of renal cell carcinoma. [Abstract/Link to Full Text]

Kashiwagi H, McDunn JE, Simon PO, Goedegebuure PS, Xu J, Jones L, Chang K, Johnston F, Trinkaus K, Hotchkiss RS, Mach RH, Hawkins WG
Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy.
Mol Cancer. 2007;648.
BACKGROUND: Resistance to modern adjuvant treatment is in part due to the failure of programmed cell death. Therefore the molecules that execute the apoptotic program are potential targets for the development of anti-cancer therapeutics. The sigma-2 receptor has been found to be over-expressed in some types of malignant tumors, and, recently, small molecule ligands to the sigma-2 receptor were found to induce cancer cell apoptosis. RESULTS: The sigma-2 receptor was expressed at high levels in both human and murine pancreas cancer cell lines, with minimal or limited expression in normal tissues, including: brain, kidney, liver, lung, pancreas and spleen. Micro-PET imaging was used to demonstrate that the sigma-2 receptor was preferentially expressed in tumor as opposed to normal tissues in pancreas tumor allograft-bearing mice. Two structurally distinct sigma-2 receptor ligands, SV119 and WC26, were found to induce apoptosis to mice and human pancreatic cancer cells in vitro and in vivo. Sigma-2 receptor ligands induced apoptosis in a dose dependent fashion in all pancreatic cell lines tested. At the highest dose tested (10 muM), all sigma-2 receptor ligands induced 10-20% apoptosis in all pancreatic cancer cell lines tested (p < 0.05). In pancreas tumor allograft-bearing mice, a single bolus dose of WC26 caused approximately 50% apoptosis in the tumor compared to no appreciable apoptosis in tumor-bearing, vehicle-injected control animals (p < 0.0001). WC26 significantly slowed tumor growth after a 5 day treatment compared to vehicle-injected control animals (p < 0.0001) and blood chemistry panels suggested that there is minimal peripheral toxicity. CONCLUSION: We demonstrate a novel therapeutic strategy that induces a significant increase in pancreas cancer cell death. This strategy highlights a new potential target for the treatment of pancreas cancer, which has little in the way of effective treatments. [Abstract/Link to Full Text]

Recent Articles in Cancer Cell International

Miller AL, Komak S, Webb MS, Leiter EH, Thompson EB
Gene expression profiling of leukemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to glucocorticoids.
Cancer Cell Int. 2007 Nov 28;7(1):18.
ABSTRACT: BACKGROUND: Glucocorticoids (GC's) play an integral role in treatment strategies designed to combat various forms of hematological malignancies. GCs also are powerful inhibitors of the immune system, through regulation of appropriate cytokines and by causing apoptosis of immature thymocytes. By activating the glucocorticoid receptor (GR), GCs evoke apoptosis through transcriptional regulation of a complex, interactive gene network over a period of time preceding activation of the apoptotic enzymes. In this study we used microarray technology to determine whether several disparate types of hematologic cells, all sensitive to GC-evoked apoptosis, would identify a common set of regulated genes. We compared gene expression signatures after treatment with two potent synthetic GCs, dexamethasone (Dex) and cortivazol (CVZ) using a panel of hematologic cells. Pediatric CD4+/CD8+ T-cell leukemia was represented by 3 CEM clones: two sensitive, CEM-C7-14 and CEM-C1-6, and one resistant, CEM-C1-15, to Dex. CEM-C1-15 was also tested when rendered GC-sensitive by several treatments. GC-sensitive pediatric B-cell leukemia was represented by the SUP-B15 line and adult B-cell leukemia by RS4;11 cells. Kasumi-1 cells gave an example of the rare Dex-sensitive acute myeloblastic leukemia (AML). To test the generality of the correlations in malignant cell gene sets, we compared with GC effects on mouse non-transformed thymocytes. RESULTS: We identified a set of genes regulated by GCs in all GC-sensitive malignant cells. A portion of these were also regulated in the thymocytes. Because we knew that the highly Dex-resistant CEM-C1-15 cells could be killed by CVZ, we tested these cells with the latter steroid and again found that many of the same genes were now regulated as in the inherently GC-sensitive cells. The same result was obtained when we converted the Dex-resistant clone to Dex-sensitive by treatment with forskolin (FSK), to activate the adenyl cyclase / protein kinase A pathway (PKA). CONCLUSION: Our results have identified small sets of genes that correlate with GC-sensitivity in cells from several hematologic malignancies. Some of these are also regulated in normal mouse thymocytes. [Abstract/Link to Full Text]

Di Cesare S, Marshall JC, Fernandes BF, Logan P, Antecka E, Bravo Filho V, Burnier MN
In vitro characterization and inhibition of the CXCR4/CXCL12 chemokine axis in human uveal melanoma cell lines.
Cancer Cell Int. 2007 Nov 14;7(1):17.
ABSTRACT: The CXCR4/CXCL12 chemokine axis may play a critical role in guiding CXCR4+ circulating malignant cells to organ specific locations that actively secrete its ligand CXCL12 (SDF-1) such as bone, brain, liver, and lungs. We sought to characterize the presence of the CXCR4/CXCL12 axis in 5 uveal melanoma (UM) cell lines in vitro. The ability of TN14003, a synthetic peptide inhibitor that targets the CXCR4 receptor complex, to inhibit this axis was also assessed. METHODS: Immunocytochemistry was performed against CXCR4 to confirm expression of this chemokine receptor in all five UM cell lines. Flow cytometry was preformed to evaluate CXCR4 cell surface expression on all human UM cell lines. A proliferation assay was also used to test effects TN14003 would have on cellular proliferation. Inhibition of cellular migration by specifically inhibiting the CXCR4/CXCL12 axis with TN14003 was also investigated. The binding efficacy of TN14003 to the CXCR4 receptor was assessed through flow cytometric methods. RESULTS: The CXCR4 receptor was present on all five UM cell lines. All five cell lines expressed different relative levels of surface CXCR4. TN14003 did not affect the proliferation of the five cell lines (p>0.05). All cell lines migrated towards the chemokine CXCL12 at a level greater than the negative control (p<0.05). All 5 cell lines pre-incubated with TN14003 prevented cellular migration towards chemokine CXCL12 (p<0.01). TN14003 preferentially binds CXCR4 to native ligand CXCL12. CONCLUSION: Interfering with the CXCR4/CXCL12 axis, using TN14003 was shown to effectively down regulate UM cell migration in vitro. Knowing that UM expresses the CXCR4 receptor, these CXCR4+ cells may be less likely to colonize distant organs that secrete the CXCL12 ligand, if treated with an inhibitor that binds CXCR4. Further studies should be pursued in order to test TN14003 efficacy in vivo. [Abstract/Link to Full Text]

Havaki S, Kouloukoussa M, Amawi K, Drosos Y, Arvanitis LD, Goutas N, Vlachodimitropoulos D, Vassilaros SD, Katsantoni EZ, Voloudakis-Baltatzis I, Aleporou-Marinou V, Kittas C, Marinos E
Altered expression pattern of integrin alphavbeta3 correlates with actin cytoskeleton in primary cultures of human breast cancer.
Cancer Cell Int. 2007;716.
ABSTRACT: BACKGROUND: Integrins are transmembrane adhesion receptors that provide the physical link between the actin cytoskeleton and the extracellular matrix. It has been well established that integrins play a major role in various cancer stages, such as tumor growth, progression, invasion and metastasis. In breast cancer, integrin alphavbeta3 has been associated with high malignant potential in cancer cells, signaling the onset of widespread metastasis. Many preclinical breast cancer studies are based on established cell lines, which may not represent the cell behavior and phenotype of the primary tumor of origin, due to undergone genotypic and phenotypic changes. In the present study, short-term primary breast cancer cell cultures were developed. Integrin alphavbeta3 localization was studied in correlation with F-actin cytoskeleton by means of immunofluorescence and immunogold ultrastructural localization. Integrin fluorescence intensities were semi-quantitatively assessed by means of computerized image analysis, while integrin and actin expression was evaluated by Western immunoblotting. RESULTS: In the primary breast cancer epithelial cells integrin alphavbeta3 immunofluorescence was observed in the marginal cytoplasmic area, whereas in the primary normal breast epithelial cells it was observed in the main cell body, i.e. in the ventrally located perinuclear area. In the former, F-actin cytoskeleton appeared well-formed, consisting of numerous and thicker stress fibers, compared to normal epithelial cells. Furthermore, electron microscopy showed increased integrin alphavbeta3 immunogold localization in epithelial breast cancer cells over the area of stress fibers at the basal cell surface. These findings were verified with Western immunoblotting by the higher expression of integrin beta3 subunit and actin in primary breast cancer cells, revealing their reciprocal relation, in response to the higher motility requirements, determined by the malignant potential of the breast cancer cells. CONCLUSION: A model system of primary breast cancer cell cultures was developed, in an effort to maintain the closest resembling environment to the tumor of origin. Using the above system model as an experimental tool the study of breast tumor cell behavior is possible concerning the adhesion capacity and the migrating potential of these cells, as defined by the integrin alphavbeta3 distribution in correlation with F-actin cytoskeleton. [Abstract/Link to Full Text]

Chaudhry MA
Base excision repair of ionizing radiation-induced DNA damage in G1 and G2 cell cycle phases.
Cancer Cell Int. 2007;715.
ABSTRACT: BACKGROUND: Major genomic surveillance mechanisms regulated in response to DNA damage exist at the G1/S and G2/M checkpoints. It is presumed that these delays provide time for the repair of damaged DNA. Cells have developed multiple DNA repair pathways to protect themselves from different types of DNA damage. Oxidative DNA damage is processed by the base excision repair (BER) pathway. Little is known about the BER of ionizing radiation-induced DNA damage and putative heterogeneity of BER in the cell cycle context. We measured the activities of three BER enzymes throughout the cell cycle to investigate the cell cycle-specific repair of ionizing radiation-induced DNA damage. We further examined BER activities in G2 arrested human cells after exposure to ionizing radiation. RESULTS: Using an in vitro incision assay involving radiolabeled oligonucleotides with specific DNA lesions, we examined the activities of several BER enzymes in the whole cell extracts prepared from synchronized human HeLa cells irradiated in G1 and G2 phase of the cell cycle. The activities of human endonuclease III (hNTH1), a glycosylase/lyase that removes several damaged bases from DNA including dihydrouracil (DHU), 8-oxoguanine-DNA glycosylase (hOGG1) that recognizes 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG) lesion and apurinic/apyrimidinic endonuclease (hAPE1) that acts on abasic sites including synthetic analog furan were examined. CONCLUSION: Overall the repair activities of hNTH1 and hAPE1 were higher in the G1 compared to G2 phase of the cell cycle. The percent cleavages of oligonucleotide substrate with furan were greater than substrate with DHU in both G1 and G2 phases. The irradiation of cells enhanced the cleavage of substrates with furan and DHU only in G1 phase. The activity of hOGG1 was much lower and did not vary within the cell cycle. These results demonstrate the cell cycle phase dependence on the BER of ionizing radiation-induced DNA damage. Interestingly no evidence of enhanced BER activities was found in irradiated cells arrested in G2 phase. [Abstract/Link to Full Text]

Al-Romaih K, Somers GR, Bayani J, Hughes S, Prasad M, Cutz JC, Xue H, Zielenska M, Wang Y, Squire JA
Modulation by decitabine of gene expression and growth of osteosarcoma U2OS cells in vitro and in xenografts: Identification of apoptotic genes as targets for demethylation.
Cancer Cell Int. 2007;714.
ABSTRACT: BACKGROUND: Methylation-mediated silencing of genes is one epigenetic mechanism implicated in cancer. Studies regarding the role of modulation of gene expression utilizing inhibitors of DNA methylation, such as decitabine, in osteosarcoma (OS) have been limited. A biological understanding of the overall effects of decitabine in OS is important because this particular agent is currently undergoing clinical trials. The objective of this study was to measure the response of the OS cell line, U2OS, to decitabine treatment both in vitro and in vivo. RESULTS: Microarray expression profiling was used to distinguish decitabine-dependent changes in gene expression in U2OS cells, and to identify responsive loci with demethylated CpG promoter regions. U2OS xenografts were established under the sub-renal capsule of immune-deficient mice to study the effect of decitabine in vivo on tumor growth and differentiation. Reduced nuclear methylation levels could be detected in xenografts derived from treated mice by immunohistochemistry utilizing a 5-methylcytidine antibody. Decitabine treatment reduced tumor xenograft size significantly (p < 0.05). Histological analysis of treated U2OS xenograft sections revealed a lower mitotic activity (p < 0.0001), increased bone matrix production (p < 0.0001), and a higher number of apoptotic cells (p = 0.0329). Microarray expression profiling of U2OS cultured cells showed that decitabine treatment caused a significant induction (p < 0.0025) in the expression of 88 genes. Thirteen had a >/=2-fold change, 11 of which had CpG-island-associated promoters. Interestingly, 6 of these 11 were pro-apoptotic genes and decitabine resulted in a significant induction of cell death in U2OS cells in vitro (p < 0.05). The 6 pro-apoptotic genes (GADD45A, HSPA9B, PAWR, PDCD5, NFKBIA, and TNFAIP3) were also induced to >/=2-fold in vivo. Quantitative methylation pyrosequencing confirmed that the tested pro-apoptotic genes had CpG-island DNA demethylationas a result of U2OS decitabine treatment both in vitro and in xenografts CONCLUSION: These data provide new insights regarding the use of epigenetic modifiers in OS, and have important implications for therapeutic trials involving demethylation drugs. Collectively, these data have provided biological evidence that one mode of action of decitabine may be the induction of apoptosis utilizing promoter-CpG demethylation of specific effectors in cell death pathways in OS. [Abstract/Link to Full Text]

Hughes MD, Kapllani E, Alexander AE, Burk RD, Schoenfeld AR
HIF-2alpha downregulation in the absence of functional VHL is not sufficient for renal cell differentiation.
Cancer Cell Int. 2007;713.
BACKGROUND: Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary as well as sporadic clear cell renal carcinomas. The product of the VHL gene, pVHL, acts to target hypoxia-inducible factor alpha (HIF-alpha) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2alpha in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2alpha toward cellular pVHL activities. RESULTS: Knockdown of HIF-2alpha resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2alpha regulation. However, cellular morphological changes and downregulation of integrins alpha5 and beta1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2alpha reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2alpha knockdown cells, indicating that these pVHL functions may occur independently of HIF-2alpha downregulation. CONCLUSION: These results indicate that HIF-2alpha regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2alpha dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis. [Abstract/Link to Full Text]

Honma K, Miyata T, Ochiya T
Type I collagen gene suppresses tumor growth and invasion of malignant human glioma cells.
Cancer Cell Int. 2007;712.
BACKGROUND: Invasion is a hallmark of a malignant tumor, such as a glioma, and the progression is followed by the interaction of tumor cells with an extracellular matrix (ECM). This study examined the role of type I collagen in the invasion of the malignant human glioma cell line T98G by the introduction of the human collagen type I alpha1 (HCOL1A1) gene. RESULTS: The cells overexpressing HCOL1A1 were in a cluster, whereas the control cells were scattered. Overexpression of HCOL1A1 significantly suppressed the motility and invasion of the tumor cells. The glioma cell growth was markedly inhibited in vitro and in vivo by the overexpression of HCOL1A1; in particular, tumorigenicity completely regressed in nude mice. Furthermore, the HCOL1A1 gene induced apoptosis in glioma cells. CONCLUSION: These results indicate that HCOL1A1 have a suppressive biological function in glioma progression and that the introduction of HCOL1A1 provides the basis of a novel therapeutic approach for the treatment of malignant human glioma. [Abstract/Link to Full Text]

Okamoto OK, Carvalho AC, Marti LC, V�ncio RZ, Moreira-Filho CA
Common molecular pathways involved in human CD133+/CD34+ progenitor cell expansion and cancer.
Cancer Cell Int. 2007;711.
BACKGROUND: Uncovering the molecular mechanism underlying expansion of hematopoietic stem and progenitor cells is critical to extend current therapeutic applications and to understand how its deregulation relates to leukemia. The characterization of genes commonly relevant to stem/progenitor cell expansion and tumor development should facilitate the identification of novel therapeutic targets in cancer. METHODS: CD34+/CD133+ progenitor cells were purified from human umbilical cord blood and expanded in vitro. Correlated molecular changes were analyzed by gene expression profiling using microarrays covering up to 55,000 transcripts. Genes regulated during progenitor cell expansion were identified and functionally classified. Aberrant expression of such genes in cancer was indicated by in silico SAGE. Differential expression of selected genes was assessed by real-time PCR in hematopoietic cells from chronic myeloid leukemia patients and healthy individuals. RESULTS: Several genes and signaling pathways not previously associated with ex vivo expansion of CD133+/CD34+ cells were identified, most of which associated with cancer. Regulation of MEK/ERK and Hedgehog signaling genes in addition to numerous proto-oncogenes was detected during conditions of enhanced progenitor cell expansion. Quantitative real-time PCR analysis confirmed down-regulation of several newly described cancer-associated genes in CD133+/CD34+ cells, including DOCK4 and SPARCL1 tumor suppressors, and parallel results were verified when comparing their expression in cells from chronic myeloid leukemia patients CONCLUSION: Our findings reveal potential molecular targets for oncogenic transformation in CD133+/CD34+ cells and strengthen the link between deregulation of stem/progenitor cell expansion and the malignant process. [Abstract/Link to Full Text]

Griffin C, Sharda N, Sood D, Nair J, McNulty J, Pandey S
Selective cytotoxicity of pancratistatin-related natural Amaryllidaceae alkaloids: evaluation of the activity of two new compounds.
Cancer Cell Int. 2007;710.
BACKGROUND: Pancratistatin (PST), a compound extracted from an Amaryllidaceae (AMD) family plant, has been shown to specifically induce apoptosis in cancer cells with no/minimal toxic effect on normal cells. A systematic synthetic approach has indicated that the minimum cytotoxic pharmacophore comprises the trans-fused b/c-ring system containing the 2, 3, 4-triol unit in the C-ring. To further explore the structure-activity relationship of this group of compounds we have investigated the anti-cancer efficacy and specificity of two PST-related natural compounds, AMD4 and AMD5. Both of these compounds lack the polyhydroxylated lycorane element of PST instead having a methoxy-substituted crinane skeleton. RESULTS: Our results indicate that AMD5 has efficacy and selectivity similar to PST, albeit at a 10-fold increased concentration. Interestingly AMD4 lacks apoptotic activity. CONCLUSION: Our results indicate that the phenanthridone skeleton in natural Amaryllidaceae alkaloids may be a significant common element for selectivity against cancer cells; furthermore, the configuration of the methoxy-side groups is responsible for higher binding affinity to the target protein/s thus making for a more efficient anti-cancer agent. [Abstract/Link to Full Text]

Sagar J, Chaib B, Sales K, Winslet M, Seifalian A
Role of stem cells in cancer therapy and cancer stem cells: a review.
Cancer Cell Int. 2007;79.
For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future. [Abstract/Link to Full Text]

Yang Z, Cox JL
Cathepsin L increases invasion and migration of B16 melanoma.
Cancer Cell Int. 2007;78.
BACKGROUND: Most cancers express elevated protease levels which contribute to certain aspects of tumor behavior such as growth, metastatic spread, and angiogenesis. Elevation of the cathepsins of the cysteine protease family correlates with increased invasion of tumor cells. Cysteine proteases such as cathepsins B, H and L type participate in tumor cell invasion as extracellular proteases, yet are enzymes whose exact roles in metastasis are still being elucidated. METHODS: We have examined the role of cathepsin L in highly metastatic B16F10 murine melanoma cells through genetic antisense constructs of cathepsin L. The effects of cathepsin L antisense were examined for melanoma cell proliferation, invasion, migration and adhesion. RESULTS: Antisense expression of cathepsin L, while decreasing enzyme activity in cell lysates, did not influence cell proliferation. Cathepsin L contributed to melanoma cell invasion and also augmented melanoma cell migration. Further, we demonstrated the adhesion of cathepsin L down-regulated clones was unaltered to fibronectin, laminin, and collagen. Finally, the inhibition of melanoma cell migration via down-regulation of cathepsin L appears to be independent of cystatin C expression. CONCLUSION: This study shows that cathepsin L facilitates high metastatic B16 melanoma cell invasion and migration. The mechanism of migration inhibition by decreased cathepsin L is independent of cystatin C levels. Since metastasis depends upon both the invasiveness and migration of tumor cells, cathepsin L may be a therapeutic target of strong clinical interest. [Abstract/Link to Full Text]

Pastila R, Leszczynski D
Ultraviolet-A radiation induces changes in cyclin G gene expression in mouse melanoma B16-F1 cells.
Cancer Cell Int. 2007;77.
BACKGROUND: We have previously shown that ultraviolet-A (UVA) radiation enhances metastatic lung colonization capacity of B16-F1 melanoma cells. The aim of this study was to examine changes in expression profile of genes in mouse melanoma B16-F1 cells exposed to UVA radiation. RESULTS: B16-F1 melanoma cells were exposed to a single UVA radiation dose of 8 J/cm2 and mRNA was isolated 4 h after the end of UVA exposure. Atlas Mouse Cancer 1.2 cDNA expression arrays were used for the large-scale screening to identify the genes involved in the regulation of carcinogenesis, tumor progression and metastasis. Physiologically relevant UVA dose induced differential expression in 9 genes in the UVA exposed melanoma cells as compared to the unexposed control cells. The expression of seven genes out of nine was upregulated (HSC70, HSP86, alpha-B-crystallin, GST mu2, Oxidative stress induced protein OSI, VEGF, cyclin G), whereas the expression of two genes was down-regulated (G-actin, non-muscle cofilin). The gene expression of cyclin G was mostly affected by UVA radiation, increasing by 4.85-folds 4 hour after exposure. The analysis of cyclin G protein expression revealed 1.36-fold increase at the 6 hour time point after UVA exposure. Cell cycle arrest in G2/M phase, which is known to be regulated by cyclin G, occurred at 4-h hour time-point, peaking 8 hours after the end of UVA irradiation, suggesting that cyclin G might play a role in the cell cycle arrest. CONCLUSION: Our results suggest that UVA radiation-induces changes in the expression of several genes. Some of these changes, e.g. in expression of cyclin G, possibly might affect cell physiology (cell cycle arrest). [Abstract/Link to Full Text]

Manna S, Chakraborty T, Damodaran S, Samanta K, Rana B, Chatterjee M
Protective role of fish oil (Maxepa) on early events of rat mammary carcinogenesis by modulation of DNA-protein crosslinks, cell proliferation and p53 expression.
Cancer Cell Int. 2007;76.
BACKGROUND: Fish oil is known to protect from many types of cancers of the colon, liver, breast, prostate and lung 123. The objective of the present study was to evaluate the role of fish oil [Maxepa, supplemented at a dose of 0.5 ml is equivalent to 90 mg eicosapentaenoic acid (EPA) and 60 mg docosahexaenoic acid (DHA)] on cell proliferation, expression of p53 tumor suppressor protein and DNA protein crosslinks (DPCs) in a defined model of chemical rat mammary carcinogenesis. Mammary carcinogenesis was initiated by a single, intravenous (i.v.) tail vein injection of 7,12 dimethylbenz(alpha)anthracene (DMBA) at a dose of 5 mg DMBA/2 ml corn oil/kg body weight in female Sprague-Dawley rats at 7 weeks of age. Fish oil supplementation was started daily, 2 weeks prior to DMBA injection and continued for 24 (31 weeks of animal age) weeks and 35 (42 weeks of animal age) weeks of post DMBA injection, for histopathological and immunohistochemical and for morphological studies, respectively. RESULTS: Our results indicate the chemopreventive effect of fish oil (Maxepa) on DMBA-induced rat mammary carcinogenesis. Administration of fish oil further showed a prominent reduction of cell proliferation (24.34%, P = 0.001); DPCs (25%, P < 0.001) and an increased expression of p53 protein (4.636 +/- 0.19, P < 0.001) in preneoplastic mammary tissue when compared to carcinogen control counterpart. Histopathological and morphological analyses were carried out as end-point biomarkers. CONCLUSION: Our study thus provides evidence for the anticarcinogenic effect of fish oil (Maxepa) in limiting mammary preneoplasia in Sprague-Dawley rats. [Abstract/Link to Full Text]

Hiss DC, Gabriels GA, Folb PI
Combination of tunicamycin with anticancer drugs synergistically enhances their toxicity in multidrug-resistant human ovarian cystadenocarcinoma cells.
Cancer Cell Int. 2007;75.
BACKGROUND: The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The UWOV2 cell line was derived from a cystadenocarcinoma in a patient refractory to combination chemotherapy with actinomycin D, vincristine (VCR), cis-diaminedichloroplatinum (II) (CDDP) and doxorubicin (DXR). In an attempt to explain drug resistance in this cell line, we examined the effects of TM on their sensitivity to various anticancer drugs, the uptake, efflux and retention of [3H]VCR, and their ability to bind [14C]DXR and [3H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp). RESULTS: TM effectively decreased the EC50 for DXR, EXR, VCR and CDDP, thus enhancing their cytotoxicity. The antibiotic also prolonged the intracellular retention time of [3H]VCR and increased the binding of both [14C]DXR and [3H]AZD to the cells. CONCLUSION: It is concluded that the pharmacomodulatory effects of TM in these cells are mediated by global inhibition of protein and glycoprotein synthesis and synergistic interaction with antineoplastic drugs. The ability of TM to enhance the sensitivity of drug resistant tumour cells may have impact on the design and optimization of novel resistance modifiers to improve the efficacy of combination treatment of intractable neoplasms. [Abstract/Link to Full Text]

Sakinah SA, Handayani ST, Hawariah LP
Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio.
Cancer Cell Int. 2007;74.
BACKGROUND: Zerumbone is a cytotoxic component isolated from Zingiber zerumbet Smith, a herbal plant which is also known as lempoyang. This new anticancer bioactive compound from Z. zerumbet was investigated for its activity and mechanism in human liver cancer cell lines. RESULTS: Zerumbone significantly showed an antiproliferative activity upon HepG2 cells with an IC50 of 3.45 +/- 0.026 microg/ml. Zerumbone was also found to inhibit the proliferation of non-malignant Chang Liver and MDBK cell lines. However the IC50 obtained was higher compared to the IC50 for HepG2 cells (> 10 microg/ml). The extent of DNA fragmentation was evaluated by the Tdt-mediated dUTP nick end labelling assay which showed that, zerumbone significantly increased apoptosis in HepG2 cells in a time-course manner. In detail, the apoptotic process triggered by zerumbone involved the up-regulation of pro-apoptotic Bax protein and the suppression of anti-apoptotic Bcl-2 protein expression. The changes that occurred in the levels of this antagonistic proteins Bax/Bcl-2, was independent of p53 since zerumbone did not affect the levels of p53 although this protein exists in a functional form. Western blotting analysis for Bax protein was further confirmed qualitatively with an immunoassay that showed the distribution of Bax protein in zerumbone-treated cells. CONCLUSION: Therefore, zerumbone was found to induce the apoptotic process in HepG2 cells through the up and down regulation of Bax/Bcl-2 protein independently of functional p53 activity. [Abstract/Link to Full Text]

Miller AL, Garza AS, Johnson BH, Thompson EB
Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells.
Cancer Cell Int. 2007;73.
BACKGROUND: Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoid-related apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone. RESULTS: The glucocorticoid-resistant clone CEM-C1-15 displays a combination of high constitutive JNK activity and dexamethasone-induced ERK activity with a weak induction of p38 upon glucocorticoid treatment. The cells become sensitive to glucocorticoid-evoked apoptosis after: (1) inhibition of JNK and ERK activity, (2) stimulation of the cAMP/PKA pathway with forskolin, or (3) inhibition of mTOR with rapamycin. Treatments 1-3 in combination with dexamethasone alter the intracellular balance of phospho-MAPKs by lowering JNK phosphorylation and increasing the level of glucocorticoid receptor phosphorylated at serine 211, a modification known to enhance receptor activity. CONCLUSION: Our data support the hypothesis that mitogen-activated protein kinases influence the ability of certain malignant lymphoid cells to undergo apoptosis when treated with glucocorticoid. Activated/phosphorylated JNK and ERK appear to counteract corticoid-dependent apoptosis. Inhibiting these MAPKs restores corticoid sensitivity to a resistant clone of CEM cells. Forskolin, which activates the cAMP pathway, and rapamycin, which inhibits mTOR, also inhibit JNK. Further, the sensitizing treatments result in a largely dexamethasone-dependent increase in the total pool of glucocorticoid receptor phosphorylated at serine 211. The phospho-serine 211 receptor is known to be more potent in activating gene transcription and apoptosis. The interactive effects demonstrated here in reverting resistant cells to corticoid sensitivity could provide therapeutic clinical potential in the treatment of lymphoid malignancies. [Abstract/Link to Full Text]

Dakubo GD, Jakupciak JP, Birch-Machin MA, Parr RL
Clinical implications and utility of field cancerization.
Cancer Cell Int. 2007;72.
Cancer begins with multiple cumulative epigenetic and genetic alterations that sequencially transform a cell, or a group of cells in a particular organ. The early genetic events might lead to clonal expansion of pre-neoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these cells drive them towards the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers owing to changes in cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remain in the organ, demonstrating the concept of field cancerization. With present technological advancement, including laser capture microdisection and high-throughput genomic technologies, carefully designed studies using appropriate control tissue will enable identification of important molecular signatures in these genetically transformed but histologically normal cells. Such tumor-specific biomarkers should have excellent clinical utility. This review examines the concept of field cancerization in several cancers and its possible utility in four areas of oncology; risk assessment, early cancer detection, monitoring of tumor progression and definition of tumor margins. [Abstract/Link to Full Text]

Jiang YN, Li YH, Ke MW, Tseng TY, Tang YB, Huang MC, Cheng WT, Ju YT
Caveolin-1 sensitizes rat pituitary adenoma GH3 cells to bromocriptine induced apoptosis.
Cancer Cell Int. 2007;71.
BACKGROUND: Prolactinoma is the most frequent pituitary tumor in humans. The dopamine D2 receptor agonist bromocriptine has been widely used clinically to treat human breast tumor and prolactinoma through inhibition of hyperprolactinemia and induction of tumor cell apoptosis, respectively, but the molecular mechanism of bromocriptine induction of pituitary tumor apoptosis remains unclear. Caveolin-1 is a membrane-anchored protein enriched on caveolae, inverted flask-shaped invaginations on plasma membranes where signal transduction molecules are concentrated. Currently, caveolin-1 is thought to be a negative regulator of cellular proliferation and an enhancer of apoptosis by blocking signal transduction between cell surface membrane receptors and intracellular signaling protein cascades. Rat pituitary adenoma GH3 cells, which express endogenous caveolin-1, exhibit increased apoptosis and shrinkage after exposure to bromocriptine. Hence, the GH3 cell line is an ideal model for studying the molecular action of bromocriptine on prolactinoma. RESULTS: The expression of endogenous caveolin-1 in GH3 cells was elevated after bromocriptine treatment. Transiently expressed mouse recombinant caveolin-1 induced apoptosis in GH3 cells by enhancing the activity of caspase 8. Significantly, caveolin-1 induction of GH3 cell apoptosis was sensitized by the administration of bromocriptine. Phosphorylation of caveolin-1 at tyrosine 14 was enhanced after bromocriptine treatment, suggesting that bromocriptine-induced phosphorylation of caveolin-1 may contribute to sensitization of apoptosis in GH3 cells exposed to bromocriptine. CONCLUSION: Our results reveal that caveolin-1 increases sensitivity for apoptosis induction in pituitary adenoma GH3 cells and may contribute to tumor shrinkage after clinical bromocriptine treatment. [Abstract/Link to Full Text]

Ch'ng S, Sullivan M, Yuan L, Davis P, Tan ST
Mast cells dysregulate apoptotic and cell cycle genes in mucosal squamous cell carcinoma.
Cancer Cell Int. 2006;628.
BACKGROUND: Mucosal squamous cell carcinoma of the head and neck is a disease of high mortality and morbidity. Interactions between the squamous cell carcinoma and the host's local immunity, and how the latter contributes to the biological behavior of the tumor are unclear. In vivo studies have demonstrated sequential mast cell infiltration and degranulation during squamous cell carcinogenesis. The degree of mast cell activation correlates closely with distinct phases of hyperkeratosis, dysplasia, carcinoma in-situ and invasive carcinoma. However, the role of mast cells in carcinogenesis is unclear. AIM: This study explores the effects of mast cells on the proliferation and gene expression profile of mucosal squamous cell carcinoma using human mast cell line (HMC-1) and human glossal squamous cell carcinoma cell line (SCC25). METHODS: HMC-1 and SCC25 were co-cultured in a two-compartment chamber, separated by a polycarbonate membrane. HMC-1 was stimulated to degranulate with calcium ionophore A23187. The experiments were done in quadruplicate. Negative controls were established where SCC25 were cultured alone without HMC-1. At 12, 24, 48 and 72 hours, proliferation and viability of SCC25 were assessed with MTT colorimetric assay. cDNA microarray was employed to study differential gene expression between co-cultured and control SCC25. RESULTS: HMC-1/SCC25 co-culture resulted in suppression of growth rate for SCC-25 (34% compared with 110% for the control by 72 hours, p < 0.001), and dysregulation of genes TRAIL, BIRC4, CDK6, Cyclin G2 and CDC6 in SCC25. CONCLUSION: We show that mast cells have a direct inhibitory effect on the proliferation of mucosal squamous cell carcinoma in vitro by dysregulating key genes in apoptosis and cell cycle control. [Abstract/Link to Full Text]

Wright B, Reimers J, Schmidt K, Burkala E, Davis N, Wei P
Mechanisms of genotoxin-induced transcription and hypermutation in p53.
Cancer Cell Int. 2006;627.
It is widely assumed that genotoxin-induced damage (e.g., G-to-T transversions) to the tumor suppressor gene, p53, is a direct cause of cancer. However, genotoxins also induce the stress response, which upregulates p53 transcription and the formation of secondary structures from ssDNA. Since unpaired bases are thermodynamically unstable and intrinsically mutable, increased transcription could be the cause of hypermutation, and thus cancer. Support for this hypothesis has been obtained by analyzing 6662 mutations in all types of cancer compared to lung and colon cancers, using the p53 mutation database. The data suggest that genotoxins have two independent effects: first, they induce p53 transcription, which increases the number of mutable bases that determine the incidence of cancer. Second, genotoxins may alter the fate, or ultimate mutation of a mutable base, for example, by causing more of the available mutable Gs to mutate to T, leaving fewer to mutate to A. Such effects on the fate of mutable bases have no impact on the incidence of cancer, as both types of mutations lead to cancer. [Abstract/Link to Full Text]

Odashiro DN, Odashiro AN, Pereira PR, Godeiro K, Antecka E, Di Cesare S, Burnier MN
Expression of EpCAM in uveal melanoma.
Cancer Cell Int. 2006;626.
BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, and nearly 40% of UM will develop metastasis that will ultimately lead to death. The Epithelial Cell Adhesion Molecule (EpCAM) is a type I transmembrane glycoprotein expressed by carcinomas of head and neck, ovary, colon, breast, kidney and lung. Recently, antibodies against EpCAM such as Edrecolomab and Catumaxomab were developed, and clinical trials with these antibodies have been used in several types of neoplasia. We studied the expression of EpCAM in UM. METHODS: 25 enucleated formalin-fixed, paraffin-embedded UM specimens were immunostained for EpCAM. Histopathological analysis of the specimens with regards to prognostic factors such as cell type, largest (linear) tumor dimension, number of mitotic figures, scleral invasion and tumor infiltrating lymphocytes were done. RESULTS: None of them was positive for this EpCAM. CONCLUSION: In our report, UM did not express EpCAM. Therefore, it is not a helpful immunohistochemical marker to predict the behavior of UM. Further studies are needed to verify if EpCAM could also be related with prognosis and treatment of UM. [Abstract/Link to Full Text]

Rajaraman R, Guernsey DL, Rajaraman MM, Rajaraman SR
Stem cells, senescence, neosis and self-renewal in cancer.
Cancer Cell Int. 2006;625.
We describe the basic tenets of the current concepts of cancer biology, and review the recent advances on the suppressor role of senescence in tumor growth and the breakdown of this barrier during the origin of tumor growth. Senescence phenotype can be induced by (1) telomere attrition-induced senescence at the end of the cellular mitotic life span (MLS*) and (2) also by replication history-independent, accelerated senescence due to inadvertent activation of oncogenes or by exposure of cells to genotoxins. Tumor suppressor genes p53/pRB/p16INK4A and related senescence checkpoints are involved in effecting the onset of senescence. However, senescence as a tumor suppressor mechanism is a leaky process and senescent cells with mutations or epimutations in these genes escape mitotic catastrophe-induced cell death by becoming polyploid cells. These polyploid giant cells, before they die, give rise to several cells with viable genomes via nuclear budding and asymmetric cytokinesis. This mode of cell division has been termed neosis and the immediate neotic offspring the Raju cells. The latter inherit genomic instability and transiently display stem cell properties in that they differentiate into tumor cells and display extended, but, limited MLS, at the end of which they enter senescent phase and can undergo secondary/tertiary neosis to produce the next generation of Raju cells. Neosis is repeated several times during tumor growth in a non-synchronized fashion, is the mode of origin of resistant tumor growth and contributes to tumor cell heterogeneity and continuity. The main event during neosis appears to be the production of mitotically viable daughter genome after epigenetic modulation from the non-viable polyploid genome of neosis mother cell (NMC). This leads to the growth of resistant tumor cells. Since during neosis, spindle checkpoint is not activated, this may give rise to aneuploidy. Thus, tumor cells also are destined to die due to senescence, but may escape senescence due to mutations or epimutations in the senescent checkpoint pathway. A historical review of neosis-like events is presented and implications of neosis in relation to the current dogmas of cancer biology are discussed. Genesis and repetitive re-genesis of Raju cells with transient "stemness" via neosis are of vital importance to the origin and continuous growth of tumors, a process that appears to be common to all types of tumors. We suggest that unlike current anti-mitotic therapy of cancers, anti-neotic therapy would not cause undesirable side effects. We propose a rational hypothesis for the origin and progression of tumors in which neosis plays a major role in the multistep carcinogenesis in different types of cancers. We define cancers as a single disease of uncontrolled neosis due to failure of senescent checkpoint controls. [Abstract/Link to Full Text]

Savas B, Kerr PE, Pross HF
Lymphokine-activated killer cell susceptibility and adhesion molecule expression of multidrug resistant breast carcinoma.
Cancer Cell Int. 2006;624.
Reports showing susceptibility of multidrug resistant (MDR) cancer cells to immune effectors, together with P-glycoprotein (P-gp) expression in immune effector subsets, including immature natural killer (NK) cells, and some activated T cells, suggest P-gp or some changes associated with it, have implications in immune-mediated mechanisms. A series of experiments were done to determine the nature of alterations associated with susceptibility to immune effector cells of MDR tumor cells. A cell line isolated from the malignant pleural effusion of a breast cancer patient was transfected with human and murine MDR1 genes, and four variants with different levels of MDR were obtained. Lymphokine-activated killer (LAK) activity was measured by a 51Chromium release, and conjugate formation assays. MDR1 transfectant P-gp+ breast carcinoma lines had increased LAK susceptibility compared to their parent line. Some part of the increased LAK susceptibility of drug-resistant cell lines was at the binding/recognition level as shown by conjugate formation assays. This suggests that differences may exist between paired cell lines with respect to the expression of cell adhesion molecules (CAMs). Monoclonal antibodies (mAbs) to CAMs and flow cytometry were used to quantitate these antigens. The CAMs studied were those previously found to be upregulated by stimulating NK cells with (interleukin-2) IL-2; ICAM-1 (CD54), LFA-3 (CD58), N-CAM (CD56), and the beta chain of LFA-1 (CD18). Although no differences in these CAMs were found between the breast carcinoma line and its MDR1-transfected variants, the target susceptibility results given above suggest that IL-2 treatment could be effective in combination with current protocols using chemotherapeutics, monoclonal antibodies (mAbs) and stem cell transplantation. [Abstract/Link to Full Text]

Rogachev VA, Likhacheva A, Vratskikh O, Mechetina LV, Sebeleva TE, Bogachev SS, Yakubov LA, Shurdov MA
Qualitative and quantitative characteristics of the extracellular DNA delivered to the nucleus of a living cell.
Cancer Cell Int. 2006;623.
BACKGROUND: The blood plasma and other intertissue fluids usually contain a certain amount of DNA, getting there due to a natural cell death in the organism. Cells of this organism can capture the extracellular DNA, whereupon it is delivered to various cell compartments. It is hypothesized that the extracellular DNA is involved in the transfer of genetic information and its fixation in the genome of recipient cell. RESULTS: The existence of an active flow of extracellular DNA into the cell is demonstrated using human breast adenocarcinoma (MCF-7) cells as a recipient culture. The qualitative state of the DNA fragments delivered to the main cell compartments (cytoplasm and interchromosomal fraction) was assessed. The extracellular DNA delivered to the cell is characterized quantitatively. CONCLUSION: It is demonstrated that the extracellular DNA fragments in several minutes reach the nuclear space, where they are processed so that their linear size increases from about 500 bp to 10,000 bp. The amount of free extracellular DNA fragments simultaneously present in the nuclear space may reach up to 2% of the haploid genome. Using individual DNA fragments with a known molecular weight and sequence as an extracellular DNA, it is found that these fragments degrade instantly in the culture liquid in the absence of a competitor DNA and are delivered into the cell as degradants. When adding a sufficient amount of competitor DNA, the initial undegraded molecules of the DNA fragments with the known molecular weight and sequence are detectable both in the cytoplasm and nuclear space only at the zero point of experiments. The labeled precursor alpha-dNTP*, added to culture medium, was undetectable inside the cell in all the experiments. [Abstract/Link to Full Text]

Taja-Chayeb L, Chavez-Blanco A, Mart�nez-Tlahuel J, Gonz�lez-Fierro A, Candelaria M, Chanona-Vilchis J, Robles E, Due�as-Gonzalez A
Expression of platelet derived growth factor family members and the potential role of imatinib mesylate for cervical cancer.
Cancer Cell Int. 2006;622.
BACKGROUND: Despite significant achievements in the treatment of cervical cancer, it is still a deadly disease; hence newer therapeutical modalities are needed. Preliminary investigations suggest that platelet-derived growth factor (PDGF) might have a role in the development of cervical cancer, therefore it is important to determine whether this growth factor pathway is functional and its targeting with imatinib mesylate leads to growth inhibition of cervical cancer cells. RESULTS: PDGF receptors (PDGFR) and their ligands are frequently expressed in cervical cancer and the majority exhibited a combination of family members co-expression. A number of intronic and exonic variations but no known mutations in the coding sequence of the PDGFRalpha gene were found in cancer cell lines and primary tumors. Growth assays demonstrated that PDGFBB induces growth stimulation that can be blocked by imatinib and that this tyrosine kinase inhibitor on its own inhibits cell growth. These effects were associated with the phosphorylation status of the receptor. CONCLUSION: The PDGFR system may have a role in the pathogenesis of cervical cancer as their members are frequently expressed in this tumor and cervical cancer lines are growth inhibited by the PDGFR antagonist imatinib. [Abstract/Link to Full Text]

Sehgal I, Foster TP, Francis J
Prostate cancer cells show elevated urokinase receptor in a mouse model of metastasis.
Cancer Cell Int. 2006;621.
BACKGROUND: The urokinase receptor (uPAR) governs several functions necessary during invasion and metastasis such as motility, degradation of the extracellular matrix and adhesion. This receptor has been recently associated with clinical prostate cancer progression. Experimentally, inhibition of uPAR reduces colonization of extra-prostatic sites in animal models. Our objective in this study was to compare uPAR expression in orthotopic vs. metastatic foci in vivo and to examine at the cellular level how uPAR might promote early stages of metastasis. RESULTS: We show that uPAR staining is significantly greater in regional lymph node metastases than in the intraprostatic tumor mass. Using transient over-expression, we found that uPAR increases in vitro motility and chemotactic invasion. Finally, we demonstrate that uPAR is up-regulated by a significant subpopulation prostate cancer cells following matrix detachment and maintenance in suspension and we provide evidence that prostate cancer cells with elevations in uPAR have an enhanced resistance to anoikis. CONCLUSION: These data provide new evidence that uPAR can be induced by cancer cells during metastasis in vivo and that this elevated uPAR enhances resistance to anoikis in vitro. [Abstract/Link to Full Text]

Eto I
"Nutritional and chemopreventive anti-cancer agents up-regulate expression of p27Kip1, a cyclin-dependent kinase inhibitor, in mouse JB6 epidermal and human MCF7, MDA-MB-321 and AU565 breast cancer cells".
Cancer Cell Int. 2006;620.
BACKGROUND: p27(Kip1) is a cyclin-dependent kinase inhibitor. When up-regulated, p27 inhibits G1-to-S phase transition of the cell cycle. This report addresses the question of whether various nutritional and chemopreventive anti-cancer agents up-regulate the expression of p27 in preneoplastic and neoplastic cells. RESULTS: Experimental evidence presented in the first half of this report shows that these agents fairly faithfully up-regulate expression of p27 in mouse epidermal (JB6) and human breast cancer (MCF7, MDA-MB-321, and AU565) cells. Up-regulation appears to be specific to p27 because expression of cyclin D1, E, and A, and p21Cip1/Waf1 was not modulated by these agents. Up-regulation of the expression of p27 is likely due to the activation of translation rather than transcription of p27 because (a) up-regulation is mediated by the 5'-untranslated region (-575) of the p27 gene and (b) the antibiotic actinomycin D, an inhibitor of transcription, did not attenuate the up-regulation of p27. This latter finding is likely to preclude the existence of cryptic transcription factor binding site(s) in the 5'-untranslated region of p27 gene. The experimental evidence, presented in the second half of this report, was obtained using the 5'-untranslated region (-575) of p27 gene. The evidence suggests that cancer preventive agents up-regulate expression of p27 by at least four different molecular signaling pathways: (a) Caloric restriction is likely to up-regulate p27 expression via 5'-AMP-activated protein kinase (AMPK; a metabolic energy sensor or cellular fuel gauge), tuberous sclerosis complex (TSC), and mammalian target of rapamycin (mTOR). Amino acid deficiencies also up-regulate the expression of p27 using some components of this pathway. (b) 4-Hydroxytamoxifen (but not tamoxifen), genistein (but not genistin), daidzein, and probably other nutritional and chemopreventive anti-cancer agents could up-regulate expression of p27 via receptor protein tyrosine kinases (RPTKs), phosphoinositide 3-kinase (PI3K), phosphoinosite-dependent kinase (PDK), Akt/PKB and mTOR. (c) Expression of p27 could also be up-regulated via RPTKs followed by MAPKs--MEK, ERK and p38MAPK--and probably MNK. Finally, (d) global hypomethylation of 5'-m7G cap of mRNAs could also up-regulate expression of p27. CONCLUSION: Based on these findings, we conclude that various nutritional and chemopreventive anti-cancer agents up-regulate expression of p27 in (pre)neoplastic cells. [Abstract/Link to Full Text]

Nath R, Mant CA, Kell B, Cason J, Bible JM
Analyses of variant human papillomavirus type-16 E5 proteins for their ability to induce mitogenesis of murine fibroblasts.
Cancer Cell Int. 2006;619.
BACKGROUND: Human papillomavirus type 16 (HPV-16) E5 protein co-operates with epidermal growth factor to stimulate mitogenesis of murine fibroblasts. Currently, little is known about which viral amino acids are involved in this process. Using sequence variants of HPV-16 E5 we have investigated their effects upon E5 transcription, cell-cycling and cell-growth of murine fibroblasts. RESULTS: We demonstrate that: (i) introduction of Thr64 into the reference E5 sequence of HPV-16 abrogates mitogenic activity: both were poorly transcribed in NIH-3T3 cells; (ii) substitution of Leu44Val65 or, Thr37Leu44Val65 into the HPV-16 E5 reference backbone resulted in high transcription in NIH-3T3 cells, enhanced cell-cycle progression and high cell-growth; and, (iii) inclusion of Tyr8 into the Leu44Val65 backbone inhibited E5 induced cell-growth and repression of p21 expression, despite high transcription levels. CONCLUSION: The effects of HPV-16 E5 variants upon mitosis help to explain why Leu44Val65 HPV-16 E5 variants are most prevalent in 'wild' pathogenic viral populations in the UK. [Abstract/Link to Full Text]

el-Awady MK, el-Din NG, el-Garf WT, Youssef SS, Omran MH, el-Abd J, Goueli SA
Antisense oligonucleotide inhibition of hepatitis C virus genotype 4 replication in HepG2 cells.
Cancer Cell Int. 2006;618.
BACKGROUND: Hepatitis C (HCV) viral infection is a serious medical problem in Egypt and it has a devastating impact on the Egyptian economy. It is estimated that over 15% of Egyptians are infected by the virus and thus finding a cure for this disease is of utmost importance. Current therapies for hepatitis C virus (HCV) genotype 4 with interferon/ribavirin have not been successful and thus the development of alternative therapy for this genotype is desperately needed. RESULTS: Although previous studies utilizing viral subgenomic or full cDNA fragments linked to reporter genes transfected into adhered cells or in a cell free system showed promise, demonstration of efficient viral replication was lacking. Thus, we utilized HepG2 cells infected with native HCV RNA genomes in a replication competent system and used antisense phosphorothioate Oligonucleotides (S-ODN) against stem loop IIId and the AUG translation start site of the viral polyprotein precursor to monitor viral replication. We were able to show complete arrest of intracellular replication of HCV-4 at 1 uM S-ODN, thus providing a proof of concept for the potential antiviral activity of S-ODN on native genomic replication of HCV genotype 4. CONCLUSION: We have successfully demonstrated that by using two S-ODNs [(S-ODN1 (nt 326-348) and S-ODN-2 (nt 264-282)], we were able to completely inhibit viral replication in culture, thus confirming earlier reports on subgenomic constructs and suggesting a potential therapeutic value in HCV type 4. [Abstract/Link to Full Text]

Dass CR, Choong PF
Targeting of small molecule anticancer drugs to the tumour and its vasculature using cationic liposomes: lessons from gene therapy.
Cancer Cell Int. 2006;617.
Cationic (positively charged) liposomes have been tested in various gene therapy clinical trials for neoplastic and other diseases. They have demonstrated selectivity for tumour vascular endothelial cells raising hopes for both antiangiogenic and antivascular therapies. They are also capable of being selectively delivered to the lungs and liver when administered intravenously. These vesicles are being targeted to the tumour in various parts of the body by using advanced liposomal systems such as ligand-receptor and antibody-antigen combinations. At present, the transferrin receptor is commonly used for cancer-targeted drug delivery systems including cationic liposomes. This review looks at the growing utility of these vesicles for delivery of small molecule anticancer drugs. [Abstract/Link to Full Text]

Recent Articles in Breast Cancer Research

Abstracts of the VII Madrid Breast Cancer Conference: Changes in the treatment of breast cancer, Madrid, Spain, 20-22 June 2007.
Breast Cancer Res. 2007;9 Suppl 1S1-24. [Abstract/Link to Full Text]

Hartman M, Lindstr�m L, Dickman PW, Adami HO, Hall P, Czene K
Is breast cancer prognosis inherited?
Breast Cancer Res. 2007;9(3):R39.
INTRODUCTION: A genetic component is well established in the etiology of breast cancer. It is not well known, however, whether genetic traits also influence prognostic features of the malignant phenotype. METHODS: We carried out a population-based cohort study in Sweden based on the nationwide Multi-Generation Register. Among all women with breast cancer diagnosed from 1961 to 2001, 2,787 mother-daughter pairs and 831 sister pairs with breast cancer were identified; we achieved complete follow-up and classified 5-year breast cancer-specific prognosis among proband (mother or oldest sister) into tertiles as poor, intermediary, or good. We used Kaplan-Meier estimates of survival proportions and Cox models to calculate relative risks of dying from breast cancer within 5 years depending on the proband's outcome. RESULTS: The 5-year survival proportion among daughters whose mothers died within 5 years was 87% compared to 91% if the mother was alive (p = 0.03). Among sisters, the corresponding proportions were 70% and 88%, respectively (p = 0.001). After adjustment for potential confounders, daughters and sisters of a proband with poor prognosis had a 60% higher 5-year breast cancer mortality compared to those of a proband with good prognosis (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.2 to 2.2; p for trend 0.002). This association was slightly stronger among sisters (HR, 1.8; 95% CI, 1.0 to 3.4) than among daughters (HR, 1.6; 95% CI, 1.1 to 2.3). CONCLUSION: Breast cancer prognosis of a woman predicts the survival in her first-degree relatives with breast cancer. Our novel findings suggest that breast cancer prognosis might be inherited. [Abstract/Link to Full Text]

Duss S, Andr� S, Nicoulaz AL, Fiche M, Bonnefoi H, Brisken C, Iggo RD
An oestrogen-dependent model of breast cancer created by transformation of normal human mammary epithelial cells.
Breast Cancer Res. 2007;9(3):R38.
INTRODUCTION: About 70% of breast cancers express oestrogen receptor alpha (ESR1/ERalpha) and are oestrogen-dependent for growth. In contrast with the highly proliferative nature of ERalpha-positive tumour cells, ERalpha-positive cells in normal breast tissue rarely proliferate. Because ERalpha expression is rapidly lost when normal human mammary epithelial cells (HMECs) are grown in vitro, breast cancer models derived from HMECs are ERalpha-negative. Currently only tumour cell lines are available to model ERalpha-positive disease. To create an ERalpha-positive breast cancer model, we have forced normal HMECs derived from reduction mammoplasty tissue to express ERalpha in combination with other relevant breast cancer genes. METHODS: Candidate genes were selected based on breast cancer microarray data and cloned into lentiviral vectors. Primary HMECs prepared from reduction mammoplasty tissue were infected with lentiviral particles. Infected HMECs were characterised by Western blotting, immunofluorescence microscopy, microarray analysis, growth curves, karyotyping and SNP chip analysis. The tumorigenicity of the modified HMECs was tested after orthotopic injection into the inguinal mammary glands of NOD/SCID mice. Cells were marked with a fluorescent protein to allow visualisation in the fat pad. The growth of the graft was analysed by fluorescence microscopy of the mammary glands and pathological analysis of stained tissue sections. Oestrogen dependence of tumour growth was assessed by treatment with the oestrogen antagonist fulvestrant. RESULTS: Microarray analysis of ERalpha-positive tumours reveals that they commonly overexpress the Polycomb-group gene BMI1. Lentiviral transduction with ERalpha, BMI1, TERT and MYC allows primary HMECs to be expanded in vitro in an oestrogen-dependent manner. Orthotopic xenografting of these cells into the mammary glands of NOD/SCID mice results in the formation of ERalpha-positive tumours that metastasise to multiple organs. The cells remain wild type for TP53, diploid and genetically stable. In vivo tumour growth and in vitro proliferation of cells explanted from tumours are dependent on oestrogen. CONCLUSION: We have created a genetically defined model of ERalpha-positive human breast cancer based on normal HMECs that has the potential to model human oestrogen-dependent breast cancer in a mouse and enables the study of mechanisms involved in tumorigenesis and metastasis. [Abstract/Link to Full Text]

Mackay A, Urruticoechea A, Dixon JM, Dexter T, Fenwick K, Ashworth A, Drury S, Larionov A, Young O, White S, Miller WR, Evans DB, Dowsett M
Molecular response to aromatase inhibitor treatment in primary breast cancer.
Breast Cancer Res. 2007;9(3):R37.
BACKGROUND: Aromatase inhibitors such as anastrozole and letrozole are highly effective suppressants of estrogen synthesis in postmenopausal women and are the most effective endocrine treatments for hormone receptor positive breast cancer in such women. Little is known of the molecular effects of these agents on human breast carcinomas in vivo. METHODS: We randomly assigned primary estrogen receptor positive breast cancer patients to treatment with anastrozole or letrozole for 2 weeks before surgery. Expression profiling using cDNA arrays was conducted on pretreatment and post-treatment biopsies. Sample pairs from 34 patients provided sufficient RNA for analysis. RESULTS: Profound changes in gene expression were seen with both aromatase inhibitors, including many classical estrogen-dependent genes such as TFF1, CCND1, PDZK1 and AGR2, but also many other genes that are likely to represent secondary responses; decrease in the expression of proliferation-related genes were particularly prominent. Many upregulated genes are involved in extracellular matrix remodelling, including collagens and members of the small leucine-rich proteoglycan family (LUM, DCN, and ASPN). No significant differences were seen between letrozole and anastrozole in terms of molecular effects. The gene changes were integrated into a Global Index of Dependence on Estrogen (GIDE), which enumerates the genes changing by at least twofold with therapy. The GIDE varied markedly between tumours and related significantly to pretreatment levels of HER2 and changes in immunohistochemically detected Ki67. CONCLUSION: Our findings identify the transcriptional signatures associated with aromatase inhibitor treatment of primary breast tumours. Larger datasets using this approach should enable identification of estrogen-dependent molecular changes, which are the determinants of benefit or resistance to endocrine therapy. [Abstract/Link to Full Text]

Conway K, Parrish E, Edmiston SN, Tolbert D, Tse CK, Moorman P, Newman B, Millikan RC
Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation.
Breast Cancer Res. 2007;9(3):R36.
INTRODUCTION: Estrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta. A point mutation in the estrogen receptor alpha gene, ESR1, referred to as A908G or K303R, was originally identified in breast hyperplasias and was reported to be hypersensitive to estrogen. We recently detected this mutation at a low frequency of 6% in invasive breast tumors of the Carolina Breast Cancer Study (CBCS). METHODS: In this report, we evaluated risk factors for invasive breast cancer classified according to the presence or absence of the ESR1 A908G mutation in the CBCS, a population-based case-control study of breast cancer among younger and older white and African-American women in North Carolina. Of the 653 breast tumors evaluated, 37 were ESR1 A908G mutation-positive and 616 were mutation-negative. RESULTS: ESR1 A908G mutation-positive breast cancer was significantly associated with a first-degree family history of breast cancer (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.15 to 6.28), whereas mutation-negative breast cancer was not. Comparison of the two case subgroups supported this finding (OR = 2.65, 95% CI = 1.15 to 6.09). There was also the suggestion that longer duration of oral contraceptive (OC) use (OR = 3.73, 95% CI = 1.16 to 12.03; Ptrend = 0.02 for use of more than 10 years) and recent use of OCs (OR = 3.63, 95% CI = 0.80 to 16.45; Ptrend = 0.10 for use within 10 years) were associated with ESR1 A908G mutation-positive breast cancer; however, ORs for comparison of the two case subgroups were not statistically significant. Hormone replacement therapy use was inversely correlated with mutation-negative breast cancer, but the effect on mutation-positive cancer was unclear due to the small number of postmenopausal cases whose tumors carried the mutation. Mutation-negative breast cancer was associated with several reproductive factors, including younger age at menarche (OR = 1.46, 95% CI = 1.09 to 1.94) and greater total estimated years of ovarian function (OR = 1.82, 95% CI = 1.21 to 2.74). CONCLUSION: These preliminary results suggest that OCs may interact with the ESR1 A908G mutant receptor to drive the development of some breast tumors. [Abstract/Link to Full Text]

Khan QJ, Kimler BF, O'Dea AP, Zalles CM, Sharma P, Fabian CJ
Mammographic density does not correlate with Ki-67 expression or cytomorphology in benign breast cells obtained by random periareolar fine needle aspiration from women at high risk for breast cancer.
Breast Cancer Res. 2007;9(3):R35.
BACKGROUND: Ki-67 expression is a possible risk biomarker and is currently being used as a response biomarker in chemoprevention trials. Mammographic breast density is a risk biomarker and is also being used as a response biomarker. We previously showed that Ki-67 expression is higher in specimens of benign breast cells exhibiting cytologic atypia that are obtained by random periareolar fine needle aspiration (RPFNA). It is not known whether there is a correlation between mammographic density and Ki-67 expression in benign breast ductal cells obtained by RPFNA. METHODS: Included in the study were 344 women at high risk for developing breast cancer (based on personal or family history), seen at The University of Kansas Medical Center high-risk breast clinic, who underwent RPFNA with cytomorphology and Ki-67 assessment plus a mammogram. Mammographic breast density was assessed using the Cumulus program. Categorical variables were analyzed by chi2 test, and continuous variables were analyzed by nonparametric test and linear regression. RESULTS: Forty-seven per cent of women were premenopausal and 53% were postmenopausal. The median age was 48 years, median 5-year Gail Risk was 2.2%, and median Ki-67 was 1.9%. The median mammographic breast density was 37%. Ki-67 expression increased with cytologic abnormality (atypia versus no atypia; P <or= 0.001) and younger age (<or=50 years versus >50 years; P <or= 0.001). Mammographic density was higher in premenopausal women (P <or= 0.001), those with lower body mass index (P < 0.001), and those with lower 5-year Gail risk (P = 0.001). Mammographic density exhibited no correlation with Ki-67 expression or cytomorphology. CONCLUSION: Given the lack of correlation of mammographic breast density with either cytomorphology or Ki-67 expression in RPFNA specimens, mammographic density and Ki-67 expression should be considered as potentially complementary response biomarkers in breast cancer chemoprevention trials. [Abstract/Link to Full Text]

Toyama T, Zhang Z, Nishio M, Hamaguchi M, Kondo N, Iwase H, Iwata H, Takahashi S, Yamashita H, Fujii Y
Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients.
Breast Cancer Res. 2007;9(3):R34.
INTRODUCTION: Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 (also known as p53) gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been suggested to play roles in many cancers. We investigated whether these SNPs were associated with patient outcome and the effect of adjuvant systemic therapy. METHODS: The genotypes of TP53 codon 72 and MDM2 SNP309 were defined among 557 primary Japanese breast cancer patients (median follow-up, 61.7 months). The effects of several variables on survival were tested by Cox's proportional hazards regression analysis. RESULTS: We showed that the Pro/Pro genotype of TP53 codon 72 was associated with poorer disease-free survival (DFS) than other genotypes by Kaplan-Meier analysis (P = 0.049) and multivariate Cox's proportional hazards regression analysis (P = 0.047, risk ratio of recurrence = 1.67), whereas MDM2 SNP309 status was not associated with DFS. The association of the Pro/Pro TP53 genotype with poorer DFS was especially significant in patients who received adjuvant chemotherapy (P = 0.009). In contrast, among the patients who had received adjuvant hormonal therapy or no adjuvant systemic therapy, TP53 codon 72 genotype was not associated with DFS. CONCLUSION: The Pro/Pro genotype of TP53 codon 72 appears to be an independent prognostic marker in breast cancer patients. [Abstract/Link to Full Text]

Vuaroqueaux V, Urban P, Labuhn M, Delorenzi M, Wirapati P, Benz CC, Flury R, Dieterich H, Spyratos F, Eppenberger U, Eppenberger-Castori S
Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome.
Breast Cancer Res. 2007;9(3):R33.
INTRODUCTION: We investigated whether mRNA levels of E2F1, a key transcription factor involved in proliferation, differentiation and apoptosis, could be used as a surrogate marker for the determination of breast cancer outcome. METHODS: E2F1 and other proliferation markers were measured by quantitative RT-PCR in 317 primary breast cancer patients from the Stiftung Tumorbank Basel. Correlations to one another as well as to the estrogen receptor and ERBB2 status and clinical outcome were investigated. Results were validated and further compared with expression-based prognostic profiles using The Netherlands Cancer Institute microarray data set reported by Fan and colleagues. RESULTS: E2F1 mRNA expression levels correlated strongly with the expression of other proliferation markers, and low values were mainly found in estrogen receptor-positive and ERBB2-negative phenotypes. Patients with low E2F1-expressing tumors were associated with favorable outcome (hazard ratio = 4.3 (95% confidence interval = 1.8-9.9), P = 0.001). These results were consistent in univariate and multivariate Cox analyses, and were successfully validated in The Netherlands Cancer Institute data set. Furthermore, E2F1 expression levels correlated well with the 70-gene signature displaying the ability of selecting a common subset of patients at good prognosis. Breast cancer patients' outcome was comparably predictable by E2F1 levels, by the 70-gene signature, by the intrinsic subtype gene classification, by the wound response signature and by the recurrence score. CONCLUSION: Assessment of E2F1 at the mRNA level in primary breast cancer is a strong determinant of breast cancer patient outcome. E2F1 expression identified patients at low risk of metastasis irrespective of the estrogen receptor and ERBB2 status, and demonstrated similar prognostic performance to different gene expression-based predictors. [Abstract/Link to Full Text]

Berishaj M, Gao SP, Ahmed S, Leslie K, Al-Ahmadie H, Gerald WL, Bornmann W, Bromberg JF
Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer.
Breast Cancer Res. 2007;9(3):R32.
INTRODUCTION: Signal transducer and activator of transcription 3 (Stat3) is constitutively tyrosine-phosphorylated in approximately 50% of primary breast carcinomas. A number of different mechanisms responsible for Stat3 activation, including abnormal activation of receptor tyrosine kinases, Src, and Janus kinases (Jaks), have been implicated in breast cancer. METHODS: We examined six breast cancer-derived cell lines expressing high or low levels of tyrosine-phosphorylated Stat3 (pStat3) as well as primary breast cancer specimens. RESULTS: Inhibition of Src or EGFR (epidermal growth factor receptor) tyrosine kinases had no effect on pStat3 levels, whereas pan-Jak inhibitor P6 resulted in complete abrogation of Stat3 phosphorylation and inhibition of growth. Jaks are required for cytokine signaling, and the glycoprotein 130 (gp130) receptor-associated Jaks are known mediators of Stat3 phosphorylation. Blockade of the gp130 receptor or sequestration of the interleukin-6 (IL-6) ligand led to a decrease of pStat3 levels. Conditioned media from those cell lines expressing high levels of pStat3 contained IL-6 and were capable of stimulating Stat3 phosphorylation. We examined IL-6 levels in primary breast tumors and found a positive correlation between pStat3 and IL-6 expression. CONCLUSION: In summary, a principal mechanism of Stat3 activation in breast cancer is through the IL-6/gp130/Jak pathway. [Abstract/Link to Full Text]

Tapia C, Savic S, Wagner U, Sch�negg R, Novotny H, Grilli B, Herzog M, Barascud AD, Zlobec I, Cathomas G, Terracciano L, Feichter G, Bubendorf L
HER2 gene status in primary breast cancers and matched distant metastases.
Breast Cancer Res. 2007;9(3):R31.
INTRODUCTION: The status of the gene encoding human EGF-like receptor 2 (HER2) is an important prognostic and predictive marker in breast cancer. Only breast cancers with HER2 amplification respond to the targeted therapy with trastuzumab. It is controversial to what degree the primary tumour is representative of distant metastases in terms of HER2 status. Discrepancies in HER2 status between primary tumours and distant metastases have been described, but their reasons remain unclear. Here, we compared HER2 status on cytological specimens of distant metastases with the result from the primary carcinomas, and explored the prevalence of and the reasons for discrepant results. METHODS: HER2 status was determined by fluorescence in situ hybridisation. HER2 gene amplification was defined as a HER2/chromosome 17 signal ratio of 2 or more. HER2 results from cytological specimens of matched distant metastases were compared with the results from the corresponding primary tumours (n = 105 patients). In addition, lymph node metastases were analysed in 31 of these patients. RESULTS: HER2 amplification was found in 20% of distant metastases. HER2 status was discordant between the primary tumour and distant metastasis in 7.6% of the 105 patients. Re-evaluation revealed that in five patients (4.7%), discrepancies were due to interpretational difficulties. In two of these patients, focal amplification had initially been overlooked as a result of heterogeneity in the primary tumours or in the metastases, respectively. A further three patients had borderline amplification with a ratio close to 2. Discrepancy remained unexplained in three patients (2.9%). CONCLUSION: HER2 gene status remains highly conserved as breast cancers metastasise. However, discrepant results do occur because of interpretational difficulties and heterogeneity of HER2 amplification. Cytological specimens from distant metastases are well suited for HER2 fluorescence in situ hybridisation analysis. [Abstract/Link to Full Text]

Langer�d A, Zhao H, Borgan �, Nesland JM, Bukholm IR, Ikdahl T, K�resen R, B�rresen-Dale AL, Jeffrey SS
TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer.
Breast Cancer Res. 2007;9(3):R30.
INTRODUCTION: Gene expression profiling of breast carcinomas has increased our understanding of the heterogeneous biology of this disease and promises to impact clinical care. The aim of this study was to evaluate the prognostic value of gene expression-based classification along with established prognostic markers and mutation status of the TP53 gene (tumour protein p53) in a group of breast cancer patients with long-term (12 to 16 years) follow-up. METHODS: The clinical and histopathological parameters of 200 breast cancer patients were studied for their effects on clinical outcome using univariate/multivariate Cox regression. The prognostic impact of mutations in the TP53 gene, identified using temporal temperature gradient gel electrophoresis and sequencing, was also evaluated. Eighty of the samples were analyzed for gene expression using 42 K cDNA microarrays and the patients were assigned to five previously defined molecular expression groups. The strength of the gene expression based classification versus standard markers was evaluated by adding this variable to the Cox regression model used to analyze all samples. RESULTS: Both univariate and multivariate analysis showed that TP53 mutation status, tumor size and lymph node status were the strongest predictors of breast cancer survival for the whole group of patients. Analyses of the patients with gene expression data showed that TP53 mutation status, gene expression based classification, tumor size and lymph node status were significant predictors of survival. Breast cancer cases in the 'basal-like' and 'ERBB2+' gene expression subgroups had a very high mortality the first two years, while the 'highly proliferating luminal' cases developed the disease more slowly, showing highest mortality after 5 to 8 years. The TP53 mutation status showed strong association with the 'basal-like' and 'ERBB2+' subgroups, and tumors with mutation had a characteristic gene expression pattern. CONCLUSION: TP53 mutation status and gene-expression based groups are important survival markers of breast cancer, and these molecular markers may provide prognostic information that complements clinical variables. The study adds experience and knowledge to an ongoing characterization and classification of the disease. [Abstract/Link to Full Text]

Savarese TM, Strohsnitter WC, Low HP, Liu Q, Baik I, Okulicz W, Chelmow DP, Lagiou P, Quesenberry PJ, Noller KL, Hsieh CC
Correlation of umbilical cord blood hormones and growth factors with stem cell potential: implications for the prenatal origin of breast cancer hypothesis.
Breast Cancer Res. 2007;9(3):R29.
INTRODUCTION: Prenatal levels of mitogens may influence the lifetime breast cancer risk by driving stem cell proliferation and increasing the number of target cells, and thereby increasing the chance of mutation events that initiate oncogenesis. We examined in umbilical cord blood the correlation of potential breast epithelial mitogens, including hormones and growth factors, with hematopoietic stem cell concentrations serving as surrogates of overall stem cell potential. METHODS: We analyzed cord blood samples from 289 deliveries. Levels of hormones and growth factors were correlated with concentrations of stem cell and progenitor populations (CD34+ cells, CD34+CD38- cells, CD34+c-kit+ cells, and granulocyte-macrophage colony-forming units). Changes in stem cell concentration associated with each standard deviation change in mitogens and the associated 95% confidence intervals were calculated from multiple regression analysis. RESULTS: Cord blood plasma levels of insulin-like growth factor-1 (IGF-1) were strongly correlated with all the hematopoietic stem and progenitor concentrations examined (one standard-deviation increase in IGF-1 being associated with a 15-19% increase in stem/progenitor concentrations, all P < 0.02). Estriol and insulin-like growth factor binding protein-3 levels were positively and significantly correlated with some of these cell populations. Sex hormone-binding globulin levels were negatively correlated with these stem/progenitor pools. These relationships were stronger in Caucasians and Hispanics and were weaker or not present in Asian-Americans and African-Americans. CONCLUSION: Our data support the concept that in utero mitogens may drive the expansion of stem cell populations. The correlations with IGF-1 and estrogen are noteworthy, as both are crucial for mammary gland development. [Abstract/Link to Full Text]

Jemal A, Ward E, Thun MJ
Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women.
Breast Cancer Res. 2007;9(3):R28.
INTRODUCTION: A recent abstract presented in a breast cancer symposium attributed the sharp decrease in female breast cancer incidence rates from 2002 to 2003 in the Surveillance, Epidemiology, and End Results (SEER) cancer registries of the United States to the reduced use of hormone replacement therapy since July 2002. However, this hypothesis does not explain the decrease that began in 1999 in the age-standardized incidence rate of invasive breast cancer in the nine oldest SEER cancer registry areas, although the trend through 2003 was not statistically significant. In this paper, we examine temporal trends in invasive and in situ female breast cancer by age, stage, tumor size, and estrogen receptor/progestin receptor (ER/PR) status in the nine oldest SEER cancer registry areas and consider the implication of these trends in relation to risk factors and screening. METHODS: We performed a joinpoint regression analysis to fit a series of joined straight lines to the trends in age-adjusted rates and described the resultant trends (slope) by annual percentage change (two-sided, P < 0.05). RESULTS: A plot of the age-specific rates of invasive breast cancer shows a decrease in all 5-year age groups from 45 years and above between 1999 and 2003 and sharp decreases largely confined to ER+ tumors in age groups from 50 to 69 years between 2002 and 2003. In joinpoint analyses by tumor size and stage, incidence rates decreased for small tumors (less than or equal to 2 cm) by 4.1% (95% confidence interval [CI], 0.2% to 7.8%) per year from 2000 through 2003 and for localized disease by 3.1% (95% CI, 1.2% to 5.0%) per year from 1999 through 2003. No decrease in incidence was observed for larger tumors or advanced-stage disease during the corresponding periods. Rates for in situ disease were stable from 2000 through 2003 after increasing rapidly since 1981. CONCLUSION: Two distinct patterns are observed in breast cancer trends. The downturn in incidence rates in all age groups above 45 years suggests a period effect that is consistent with saturation in screening mammography. The sharp decrease in incidence from 2002 to 2003 that occurred in women 50 to 69 years old who predominantly, but not exclusively, had ER+ tumors may reflect the early benefit of the reduced use of hormone replacement therapy. [Abstract/Link to Full Text]

Baynes C, Healey CS, Pooley KA, Scollen S, Luben RN, Thompson DJ, Pharoah PD, Easton DF, Ponder BA, Dunning AM
Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk.
Breast Cancer Res. 2007;9(2):R27.
INTRODUCTION: Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk. METHODS: We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene. RESULTS: No significant breast cancer associations were detected with any individual or combination of tag SNPs. CONCLUSION: It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population. [Abstract/Link to Full Text]

Broeks A, Braaf LM, Huseinovic A, Nooijen A, Urbanus J, Hogervorst FB, Schmidt MK, Klijn JG, Russell NS, Van Leeuwen FE, Van 't Veer LJ
Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study.
Breast Cancer Res. 2007;9(2):R26.
INTRODUCTION: Radiation exposure at a young age is one of the strongest risk factors for breast cancer. Germline mutations in genes involved in the DNA-damage repair pathway (DDRP) may render women more susceptible to radiation-induced breast cancer. METHODS: We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour. RESULTS: We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Those patients had an odds ratio of 2.51 (95% confidence interval 1.03 to 6.10; p = 0.049) of developing radiation-induced breast cancer, in comparison with non-carriers. CONCLUSION: This study shows that carriers of germline mutations in a DDRP gene have an increased risk of developing (contralateral) breast cancer after radiotherapy; that is, over and above the risk associated with their carrier status. The increased risk indicates that knowledge of germline status of these DDRP genes at the time of breast cancer diagnosis may have important implications for the choice of treatment. [Abstract/Link to Full Text]

Cardis E, Hall J, Tavtigian SV
Identification of women with an increased risk of developing radiation-induced breast cancer.
Breast Cancer Res. 2007;9(3):106.
In the previous issue of Breast Cancer Research, Broeks and collaborators present the results of a study suggesting that germline mutations in BRCA1, BRCA2, ATM or CHEK2 may double the risk of radiation-induced contralateral breast cancer following radiotherapy for a first breast cancer. The assocation appeared to be strongest among women who were below the age of 40 at the time of their first breast cancer and among women who developed their second cancer 5 years or more after the first. While there were a number of methodological issues that might limit the conclusions drawn from this paper, this is one of several recent studies suggesting that carriers of pathogenic alleles in DNA repair and damage recognition genes may have an increased risk of breast cancer following exposure to ionising radiation, even at low doses. This finding has important implications for the protection of breast cancer patients and their close relatives. If confirmed, mutation carriers may wish to consider alternatives to X-ray for diagnostic purposes. The need for tailored cancer treatment strategies in carriers should also be evaluated carefully. [Abstract/Link to Full Text]

Lin CY, Str�m A, Li Kong S, Kietz S, Thomsen JS, Tee JB, Vega VB, Miller LD, Smeds J, Bergh J, Gustafsson JA, Liu ET
Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer.
Breast Cancer Res. 2007;9(2):R25.
INTRODUCTION: The impact of interactions between the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, on gene expression in breast cancer biology is not clear. The goal of this study was to examine transcriptomic alterations in cancer cells co-expressing both receptors and the association of gene expression signatures with disease outcome. METHODS: Transcriptional effects of ERbeta overexpression were determined in a stably transfected cell line derived from ERalpha-positive T-47D cells. Microarray analysis was carried out to identify differential gene expression in the cell line, and expression of key genes was validated by quantitative polymerase chain reaction. Microarray and clinical data from patient samples were then assessed to determine the in vivo relevance of the expression profiles observed in the cell line. RESULTS: A subset of 14 DNA replication and cell cycle-related genes was found to be specifically downregulated by ERbeta. Expression profiles of four genes, CDC2, CDC6, CKS2, and DNA2L, were significantly inversely correlated with ERbeta transcript levels in patient samples, consistent with in vitro observations. Kaplan-Meier analysis revealed better disease outcome for the patient group with an expression signature linked to higher ERbeta expression as compared to the lower ERbeta-expressing group for both disease-free survival (p = 0.00165) and disease-specific survival (p = 0.0268). These findings were further validated in an independent cohort. CONCLUSION: Our findings revealed a transcriptionally regulated mechanism for the previously described growth inhibitory effects of ERbeta in ERalpha-positive breast tumor cells and provide evidence for a functional and beneficial impact of ERbeta in primary breast tumors. [Abstract/Link to Full Text]

Shupnik MA
Estrogen receptor-beta: why may it influence clinical outcome in estrogen receptor-alpha positive breast cancer?
Breast Cancer Res. 2007;9(3):107.
In the previous issue of the journal, Lin and coworkers present data demonstrate that increased expression of estrogen receptor (ER)-beta in ER-alpha-positive breast cancer cells antagonizes a defined group of ER-alpha/estrogen stimulated genes that are involved in cell cycle regulation and DNA replication. Similar expression patterns for these genes were found human ER-alpha positive breast tumors expressing higher levels or ER-beta, and this correlated with better clinical outcome. The implications for these data, which suggest that ER-beta is a positive actor and diagnostic marker for therapeutic outcome, are discussed. [Abstract/Link to Full Text]

Vincent-Salomon A, Gruel N, Lucchesi C, MacGrogan G, Dendale R, Sigal-Zafrani B, Longy M, Raynal V, Pierron G, de Mascarel I, Taris C, Stoppa-Lyonnet D, Pierga JY, Salmon R, Sastre-Garau X, Fourquet A, Delattre O, de Cremoux P, Aurias A
Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity.
Breast Cancer Res. 2007;9(2):R24.
INTRODUCTION: Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC). METHODS: Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs. RESULTS: All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC. CONCLUSION: Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools. [Abstract/Link to Full Text]

Elbauomy Elsheikh S, Green AR, Lambros MB, Turner NC, Grainge MJ, Powe D, Ellis IO, Reis-Filho JS
FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis.
Breast Cancer Res. 2007;9(2):R23.
BACKGROUND: The amplicon on 8p11.2 is reported to be found in up to 10% of breast carcinomas. It has been demonstrated recently that this amplicon has four separate cores. The second core encompasses important oncogene candidates, including the fibroblast growth factor receptor 1 (FGFR1) gene. Recent studies have demonstrated that specific FGFR1 amplification correlates with gene expression and that FGFR1 activity is required for the survival of a FGFR1 amplified breast cancer cell line. METHODS : FGFR1 amplification was analysed in tissue microarrays comprising a cohort of 880 unselected breast tumours by means of chromogenic in situ hybridisation using inhouse-generated FGFR1-specific probes. Chromogenic in situ hybridisation signals were counted in a minimum 30 morphologically unequivocal neoplastic cells. Amplification was defined as >5 signals per nucleus in more than 50% of cancer cells or when large gene copy clusters were seen. RESULTS: FGFR1 amplification was observed in 8.7% of the tumours and was significantly more prevalent in patients >50 years of age and in tumours that lacked HER2 expression. No association was found with other histological parameters. Survival analysis revealed FGFR1 amplification as an independent prognostic factor for overall survival in the whole cohort. Subgroup analysis demonstrated that the independent prognostic impact of FGFR1 amplification was only seen in patients with oestrogen-receptor-positive tumours, where FGFR1 amplification was the strongest independent predictor of poor outcome. CONCLUSION: Given that up to 8.7% of all breast cancers harbour FGFR1 amplification and that this amplification is an independent predictor of overall survival, further studies analysing the FGFR1 as a potential therapeutic target for breast cancer patients are warranted. [Abstract/Link to Full Text]

Montero Girard G, Vanzulli SI, Cerliani JP, Bottino MC, Bolado J, Vela J, Becu-Villalobos D, Benavides F, Gutkind S, Patel V, Molinolo A, Lanari C
Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment.
Breast Cancer Res. 2007;9(2):R22.
INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. [Abstract/Link to Full Text]

Gao F, Tan SB, Machin D, Wong NS
Confirmation of double-peaked time distribution of mortality among Asian breast cancer patients in a population-based study.
Breast Cancer Res. 2007;9(2):R21.
INTRODUCTION: Double-peaked time distributions of the mortality hazard function have been reported for breast cancer patients from Western populations treated with mastectomy alone. These are thought to reflect accelerated tumour growth at micrometastatic sites mediated by angiogenesis after primary tumour removal as well as tumor dormancy. Similar data are not available for Asian populations. We sought to investigate whether differences exist in the pattern of mortality hazard function between Western breast cancer patients and their Asian counterparts in Singapore, which may suggest underlying differences in tumor biology between the two populations. METHODS: We performed a retrospective cohort study of female unilateral breast cancer patients diagnosed in Singapore between October 1994 and June 1999. Data regarding patient demographics, tumour characteristics and death were available. Overall survival curves were calculated using the Kaplan-Meier method. The hazard rate was calculated as the conditional probability of dying in a time interval, given that the patient was alive at the beginning of the interval. The life table method was used to calculate the yearly hazard rates. RESULTS: In the 2,105 women identified, 956 patients (45.4%) had mastectomy alone. Demographic characteristics were as follows: 86.5% were Chinese, 45.2% were postmenopausal, 38.9% were hormone receptor positive, 54.6% were node negative and 44.1% had high histological grade. We observed a double-peaked mortality hazard pattern, with a first peak in mortality achieving its maximum between years 2 and 4 after mastectomy, and a second large peak in mortality during year 9. Analyses by subgroups revealed a similar pattern regardless of T stage, or node or menopausal status. This pattern was also noted in high-grade tumors but not in those that were well to moderately differentiated. The double-peaked pattern observed in Singaporean women was quantitatively and qualitatively similar to those reported in Western series. CONCLUSION: Our study confirms the existence of a double-peaked process in Asian patients, and it gives further support to the tumour dormancy hypothesis after mastectomy. [Abstract/Link to Full Text]

Locke I, Kote-Jarai Z, Fackler MJ, Bancroft E, Osin P, Nerurkar A, Izatt L, Pichert G, Gui GP, Eeles RA
Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls.
Breast Cancer Res. 2007;9(1):R20.
INTRODUCTION: Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk. METHODS: The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-beta, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid. RESULTS: Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls (p = 0.13). CONCLUSION: We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers. [Abstract/Link to Full Text]

Lebret SC, Newgreen DF, Thompson EW, Ackland ML
Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors.
Breast Cancer Res. 2007;9(1):R19.
BACKGROUND: Breast carcinoma is accompanied by changes in the acellular and cellular components of the microenvironment, the latter typified by a switch from fibroblasts to myofibroblasts. METHODS: We utilised conditioned media cultures, Western blot analysis and immunocytochemistry to investigate the differential effects of normal mammary fibroblasts (NMFs) and mammary cancer-associated fibroblasts (CAFs) on the phenotype and behaviour of PMC42-LA breast cancer cells. NMFs were obtained from a mammary gland at reduction mammoplasty, and CAFs from a mammary carcinoma after resection. RESULTS: We found greater expression of myofibroblastic markers in CAFs than in NMFs. Medium from both CAFs and NMFs induced novel expression of alpha-smooth muscle actin and cytokeratin-14 in PMC42-LA organoids. However, although conditioned media from NMFs resulted in distribution of vimentin-positive cells to the periphery of PMC42-LA organoids, this was not seen with CAF-conditioned medium. Upregulation of vimentin was accompanied by a mis-localization of E-cadherin, suggesting a loss of adhesive function. This was confirmed by visualizing the change in active beta-catenin, localized to the cell junctions in control cells/cells in NMF-conditioned medium, to inactive beta-catenin, localized to nuclei and cytoplasm in cells in CAF-conditioned medium. CONCLUSION: We found no significant difference between the influences of NMFs and CAFs on PMC42-LA cell proliferation, viability, or apoptosis; significantly, we demonstrated a role for CAFs, but not for NMFs, in increasing the migratory ability of PMC42-LA cells. By concentrating NMF-conditioned media, we demonstrated the presence of factor(s) that induce epithelial-mesenchymal transition in NMF-conditioned media that are present at higher levels in CAF-conditioned media. Our in vitro results are consistent with observations in vivo showing that alterations in stroma influence the phenotype and behaviour of surrounding cells and provide evidence for a role for CAFs in stimulating cancer progression via an epithelial-mesenchymal transition. These findings have implications for our understanding of the roles of signalling between epithelial and stromal cells in the development and progression of mammary carcinoma. [Abstract/Link to Full Text]

Tamimi RM, Cox DG, Kraft P, Pollak MN, Haiman CA, Cheng I, Freedman ML, Hankinson SE, Hunter DJ, Colditz GA
Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study.
Breast Cancer Res. 2007;9(1):R18.
INTRODUCTION: Mammographic density is one of the strongest risk factors for breast cancer and is believed to represent epithelial and stromal proliferation. Because of the high heritability of breast density, and the role of the insulin-like growth factor (IGF) pathway in cellular proliferation and breast development, we examined the association between common genetic variation in this pathway and mammographic density. METHODS: We conducted a cross-sectional analysis among controls (n = 1,121) who were between the ages of 42 and 78 years at mammography, from a breast cancer case-control study nested within the Nurses' Health Study cohort. At the time of mammography, 204 women were premenopausal and 917 were postmenopausal. We genotyped 29 haplotype-tagging SNPs demonstrated to capture common genetic variation in IGF1, IGF binding protein (IGFBP)-1, and IGFBP-3. RESULTS: Common haplotype patterns in three of the four haplotype blocks spanning the gene encoding IGF1 were associated with mammographic density. Haplotype patterns in block 1 (p = 0.03), block 3 (p = 0.009), and block 4 (p = 0.007) were associated with mammographic density, whereas those in block 2 were not. None of the common haplotypes in the three haplotype blocks spanning the genes encoding IGFBP-1/IGFBP-3 were significantly associated with mammographic density. Two haplotype-tagging SNPs in IGF1, rs1520220 and rs2946834, showed a strong association with mammographic density. Those with the homozygous variant genotype for rs1520220 had a mean percentage mammographic density of 19.6% compared with those with the homozygous wild-type genotype, who had a mean percentage mammographic density of 27.9% (p for trend < 0.0001). Those that were homozygous variant for rs2946834 had a mean percentage mammographic density of 23.2% compared with those who were homozygous wild-type with a mean percentage mammographic density of 28.2% (p for trend = 0.0004). Permutation testing demonstrated that results as strong as these are unlikely to occur by chance (p = 0.0005). CONCLUSION: Common genetic variation in IGF1 is strongly associated with percentage mammographic density. [Abstract/Link to Full Text]

Lin ML, Park JH, Nishidate T, Nakamura Y, Katagiri T
Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family.
Breast Cancer Res. 2007;9(1):R17.
INTRODUCTION: Cancer therapies directed at specific molecular targets in signaling pathways of cancer cells, such as tamoxifen, aromatase inhibitors and trastuzumab, have proven useful for treatment of advanced breast cancers. However, increased risk of endometrial cancer with long-term tamoxifen administration and of bone fracture due to osteoporosis in postmenopausal women undergoing aromatase inhibitor therapy are recognized side effects. These side effects as well as drug resistance make it necessary to search for novel molecular targets for drugs on the basis of well-characterized mechanisms of action. METHODS: Using accurate genome-wide expression profiles of breast cancers, we found maternal embryonic leucine-zipper kinase (MELK) to be significantly overexpressed in the great majority of breast cancer cells. To assess whether MELK has a role in mammary carcinogenesis, we knocked down the expression of endogenous MELK in breast cancer cell lines using mammalian vector-based RNA interference. Furthermore, we identified a long isoform of Bcl-G (Bcl-GL), a pro-apoptotic member of the Bcl-2 family, as a possible substrate for MELK by pull-down assay with recombinant wild-type and kinase-dead MELK. Finally, we performed TUNEL assays and FACS analysis, measuring proportions of apoptotic cells, to investigate whether MELK is involved in the apoptosis cascade through the Bcl-GL-related pathway. RESULTS: Northern blot analyses on multiple human tissues and cancer cell lines demonstrated that MELK was overexpressed at a significantly high level in a great majority of breast cancers and cell lines, but was not expressed in normal vital organs (heart, liver, lung and kidney). Suppression of MELK expression by small interfering RNA significantly inhibited growth of human breast cancer cells. We also found that MELK physically interacted with Bcl-GL through its amino-terminal region. Immunocomplex kinase assay showed that Bcl-GL was specifically phosphorylated by MELK in vitro. TUNEL assays and FACS analysis revealed that overexpression of wild-type MELK suppressed Bcl-GL-induced apoptosis, while that of D150A-MELK did not. CONCLUSION: Our findings suggest that the kinase activity of MELK is likely to affect mammary carcinogenesis through inhibition of the pro-apoptotic function of Bcl-GL. The kinase activity of MELK could be a promising molecular target for development of therapy for patients with breast cancers. [Abstract/Link to Full Text]

Jumppanen M, Gruvberger-Saal S, Kauraniemi P, Tanner M, Bendahl PO, Lundin M, Krogh M, Kataja P, Borg A, Fern� M, Isola J
Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers.
Breast Cancer Res. 2007;9(1):R16.
INTRODUCTION: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup. METHODS: IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed. RESULTS: From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification. CONCLUSION: Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors. [Abstract/Link to Full Text]

Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissi�re F, Laune D, Roques S, Lazennec G
Oestrogen receptor negative breast cancers exhibit high cytokine content.
Breast Cancer Res. 2007;9(1):R15.
INTRODUCTION: An emerging hypothesis suggests that cytokines could play an important role in cancer as potential modulators of angiogenesis and leucocyte infiltration. METHODS: A novel multiplexed flow cytometry technology was used to measure the expression of 17 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, granulocyte colony-stimulating factor [CSF], granulocyte-macrophage CSF, IFN-gamma, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1beta, tumour necrosis factor [TNF]-alpha) at the protein level in 105 breast carcinoma. B lymphocyte, T lymphocyte and macrophage levels were determined by immunohistochemistry. RESULTS: Fourteen of the 17 cytokines were expressed in breast carcinoma, whereas only nine cytokines could be detected in normal breast. Most cytokines were more abundant in breast carcinoma than in normal breast, with IL-6, IL-8, granulocyte CSF, IFN-gamma, MCP-1 and MIP-1beta being very abundant. IL-2, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, MIP-1beta and TNF-alpha, and to a lesser extent IL-1beta and IL-13 exhibited levels of expression that were inversely correlated to oestrogen receptor and progesterone receptor status. Most cytokines were not correlated with age at cancer diagnosis, tumour size, histological type, or lymph node status. However, IL-1beta, IL-6, IL-8, IL-10, IL-12, MCP-1 and MIP-1beta were more abundant in high-grade tumours than in low-grade tumours. In addition, IL-8 and MIP-1beta were expressed to a greater degree in HER2-positive than in HER2-negative patients. The expression of most of the studied cytokines was correlated to levels of activator protein-1, which is known to regulate numerous cytokines. Overexpression of MCP-1 and MIP-1beta were linked to B lymphocyte, T lymphocyte and macrophage infiltration, whereas high levels of IL-8 were correlated with high macrophage content in tumour. Moreover, IL-8 positive tumours exhibited increased vascularization. CONCLUSION: We found that multiple cytokines were overexpressed in oestrogen receptor negative breast carcinoma, and that the three major cytokines--MCP-1, MIP-1beta and IL-8--were correlated with inflammatory cell component, which could account for the aggressiveness of these tumours. [Abstract/Link to Full Text]

Stillfried GE, Saunders DN, Ranson M
Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity.
Breast Cancer Res. 2007;9(1):R14.
INTRODUCTION: The regulation of extracellular proteolytic activity via the plasminogen activation system is complex, involving numerous activators, inhibitors, and receptors. Previous studies on monocytic and colon cell lines suggest that plasmin pre-treatment can increase plasminogen binding, allowing the active enzyme to generate binding sites for its precursor. Other studies have shown the importance of pre-formed receptors such as annexin II heterotetramer. However, few studies have used techniques that exclusively characterise cell-surface events and these mechanisms have not been investigated at the breast cancer cell surface. METHODS: We have studied plasminogen binding to MCF-7 in which urokinase plasminogen activator receptor (uPAR) levels were upregulated by PMA (12-O-tetradecanoylphorbol-13-acetate) stimulation, allowing flexible and transient modulation of cell-surface uPA. Similar experiments were also performed using MDA-MB-231 cells, which overexpress uPAR/uPA endogenously. Using techniques that preserve cell integrity, we characterise the role of uPA as both a plasminogen receptor and activator and quantify the relative contribution of pre-formed and cryptic plasminogen receptors to plasminogen binding. RESULTS: Cell-surface plasminogen binding was significantly enhanced in the presence of elevated levels of uPA in an activity-dependent manner and was greatly attenuated in the presence of the plasmin inhibitor aprotinin. Pre-formed receptors were also found to contribute to increased plasminogen binding after PMA stimulation and to co-localise with uPA/uPAR and plasminogen. Nevertheless, a relatively modest increase in plasminogen-binding capacity coupled with an increase in uPA led to a dramatic increase in the proteolytic capacity of these cells. CONCLUSION: We show that the majority of lysine-dependent plasminogen binding to breast cancer cells is ultimately regulated by plasmin activity and is dependent on the presence of significant levels of active uPA. The existence of a proteolytic positive feedback loop in plasminogen activation has profound implications for the ability of breast cancer cells expressing high amounts of uPA to accumulate a large proteolytic capacity at the cell surface, thereby conferring invasive potential. [Abstract/Link to Full Text]

Yaar M, Eller MS, Panova I, Kubera J, Wee LH, Cowan KH, Gilchrest BA
Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells.
Breast Cancer Res. 2007;9(1):R13.
INTRODUCTION: Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways. METHODS: The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos. RESULTS: Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells. CONCLUSION: By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies. [Abstract/Link to Full Text]

Recent Articles in International Seminars in Surgical Oncology

Singh-Ranger G, Rajarajan N, Aftab S, Stoker D
Splenic peliosis - a potentially fatal condition which can mimick malignancy.
Int Semin Surg Oncol. 2007 Dec 8;4(1):27.
ABSTRACT: Isolated splenic peliosis is an extremely rare occurrence, and this disease often manifests itself with spontaneous haemoperitoneum. We report a case where an otherwise healthy patient was found to have splenomegaly on clinical examination. On computerised tomography, a diagnosis of splenic malignancy was made, and the patient underwent a splenectomy. Histological examination gave the diagnosis of splenic peliosis, which had not been considered prior to the operation. In retrospect, splenectomy was the most prudent course of action, as the risk of spontaneous haemorrhage and fatality was eliminated. This case emphasises the need to retain an index of suspicion for this condition, even in otherwise healthy patients, and is a reminder of the usefulness of total splenectomy in the current era of minimally invasive diagnostic techniques. [Abstract/Link to Full Text]

Ristagno N, Knuth A, Pestalozzi BC
Is an aggressive surgical approach worthwhile in biliary cancer?
Int Semin Surg Oncol. 2007 Oct 23;4(1):26.
ABSTRACT: BACKGROUND: Biliary cancer includes cancer of the gallbladder as well as extrahepatic and intrahepatic cholangiocarcinoma. Surgery is the only curative treatment option available. Recently, much more aggressive surgical approaches have been employed. Therefore, we have investigated outcome of biliary cancer before and after establishment of an aggressive surgical approach. METHODS: Retrospective single-center analysis comparing two time periods of 5 years each. During the second period new surgical expertise and a much more aggressive surgical approach were used. RESULTS: In the first time period (5/1995-4/2000) only 29 patients with biliary cancer were treated at our institution, while a total of 85 patients were treated during the second time period (5/2000-4/2005). Surgical resection was attempted in 55% during the first period versus 62% in the second; resection was complete in 37.5% and 58.5%, respectively. Patients undergoing resection during the second time period were more likely to be without relapse compared with patients undergoing resection in the first time period. No patient from the first period is without evidence of disease, compared to 11 patients operated in the second period. Resected patients had better survival compared with unresected patients for all tumor locations (gallbladder, extrahepatic and intrahepatic cholangiocarcinomas). Overall survival of patients was not significantly different between patients treated during the first versus the second time period. CONCLUSIONS: In patients with biliary cancer surgical resection should be attempted whenever possible. However, long-term survival can be achieved only when a complete resection is obtained. [Abstract/Link to Full Text]

Piscioli I, Morelli L, Falzone A, Del Nonno F, Neri M, Di Rocco ZC, Catalucci A, Donato S, Licci S
Epithelial-myoepithelial carcinoma of the parotid gland, unusual malignancy radiologically simulating a benign lesion: case report.
Int Semin Surg Oncol. 2007;425.
ABSTRACT: BACKGROUND: Ultrasound (US), Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are widely used in the clinical diagnosis of parotid gland tumors and their efficacy in identifying benign lesions is well documented. However, problems arise when facing some malignant lesions. Only few cases of salivary gland low grade malignant tumors have been previously reported in the literature complete with the radiological features. CASE PRESENTATION: We here describe a case of epithelial-myoepithelial carcinoma (EMC) of the parotid gland, a low grade malignant tumor, with spread to an intraparotid lymph node and with CT and MRI findings mimicking a benign lesion. CONCLUSION: All the images revealed sharply outlined profiles and a homogeneous enhancement of the nodule, suggesting a benign tumor and demonstrating that a radiological evaluation of the lesion alone may be unsatisfactory and misleading in the diagnosis of salivary gland tumours, especially in the case of low grade malignant tumors, such as EMC. [Abstract/Link to Full Text]

Halliday BP, Skipworth RJ, Wall L, Phillips HA, Couper GW, de Beaux AC, Paterson-Brown S
Neoadjuvant chemotherapy for carcinoma of the oesophagus and oesophago-gastric junction: a six-year experience.
Int Semin Surg Oncol. 2007;424.
ABSTRACT: BACKGROUND: Oesophageal cancer is a major clinical problem with a generally poor prognosis. As a result there has been interest in combining surgery with neoadjuvant chemotherapy to try and improve outcomes, although the current evidence for benefit is inconsistent. We aimed to compare, in a non-randomised study, the post-operative complication rate and short and long-term survival of patients who underwent surgical resection for carcinoma of the oesophagus and types I and II carcinoma of the oesophago-gastric junction with or without neo-adjuvant chemotherapy. METHODS: Details of all resections for oesophageal/junctional (types I and II) adenocarcinoma or squamous cell carcinoma between April 2000 and July 2006 were collected prospectively. Data from patients with T3 and/or N1 disease who underwent either neoadjuvant chemotherapy (NAC) or not (non-NAC) were compared. Data were analysed using Kaplan-Meier plots, Mann-Whitney U-test, Cox Regression modelling, and Chi-squared test with Yates' correction where sample sizes <10. RESULTS: 167 patients were included (89 NAC and 78 non-NAC). The in-hospital post-operative mortality rate of the NAC group (n = 2 deaths; 2.2%) was significantly lower (p = 0.045) than the non-NAC group (n = 6 deaths; 7.7%). Most deaths were due to cardio-respiratory complications; however, there was no significant difference in rates of chest infections, anastomotic leaks, wound infections, re-operations, readmission to ITU or overall complications between the two groups. Although both the two-year survival rate (60.7%) and long-term survival of NAC patients (median survival = 793 days; 95% CI = 390-1196) was greater than non-NAC patients (two-year survival rate = 48.7%; median survival = 554 days; 95% CI = 246-862 respectively), these differences were not statistically significant. CONCLUSION: This non-randomised study demonstrated that NAC was associated with a significant reduction in post-operative inpatient mortality rate. Whether this can be explained by a decreased co-morbidity in NAC patients or a protective phenomenon associated with NAC remains unclear. This study also demonstrated a greater two-year survival rate and overall median survival time following NAC but this was not statistically significant. [Abstract/Link to Full Text]

Biffi R, Marsiglia H, Fossa BJ, Leonardi MC, Cante D, Lazzari R, Chiappa A, Cenciarelli S, Andreoni B, Zampino MG, Orecchia R
Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients.
Int Semin Surg Oncol. 2007;423.
ABSTRACT: BACKGROUND: although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up. METHODS: patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3-4/anyN, or anyT/N1-2; ECOG Performance Status 0-2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 +/- 2 days after RT completion, adopting the total mesorectal excision technique. RESULTS: 24 men and 23 women were enrolled; median age was 55 years (r.: 39-77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18-84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence. CONCLUSION: bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT. [Abstract/Link to Full Text]

Parentes-Vieira J, Lopes-Costa P, Pires C, Dos Santos A, Pereira-Filho J, da Silva B
Quantification of angiogenesis in estrogen receptor-positive and negative breast carcinoma.
Int Semin Surg Oncol. 2007;422.
ABSTRACT: BACKGROUND: The objective of this study was to evaluate angiogenesis according to CD34 antigen expression in estrogen receptor (ER)-positive and negative breast carcinomas. METHODS: This study comprised 64 cases of infiltrating ductal carcinoma in postmenopausal women divided into two groups: Group A: ER-positive, n = 35; and Group B: ER-negative, n = 29. The anti-CD34 monoclonal antibody was used as a marker for endothelial cells. Microvessel count was carried out in 10 fields per slide using a 40x objective lens (magnification 400x). Statistical analysis of the data was performed using Student's t-test (p < 0.05). RESULTS: The mean number of vessels stained with the anti-CD34 antibody in the estrogen receptor-positive and negative tumors was 23.51 +/- 1.15 and 40.24 +/- 0.42, respectively. The number of microvessels was significantly greater in the estrogen receptor-negative tumors (p < 0.001). CONCLUSION: ER-negative tumors have significantly greater CD34 antigen expression compared to ER-positive tumors. [Abstract/Link to Full Text]

Tuli R, O'Hara BJ, Hines J, Rosenberg AL
Idiopathic granulomatous mastitis masquerading as carcinoma of the breast: a case report and review of the literature.
Int Semin Surg Oncol. 2007;421.
BACKGROUND: Idiopathic granulomatous mastitis is an uncommon, benign entity with a diagnosis of exclusion. The typical clinical presentation of idiopathic granulomatous mastitis often mimics infection or malignancy. As a result, histopathological confirmation of idiopathic granulomatous mastitis combined with exclusion of infection, malignancy and other causes of granulomatous disease is absolutely necessary. CASE PRESENTATION: We present a case of a young woman with idiopathic granulomatous mastitis, initially mistaken for mastitis as well as breast carcinoma, and successfully treated with a course of corticosteroids. CONCLUSION: There is no clear clinical consensus regarding the ideal therapeutic management of idiopathic granulomatous mastitis. Treatment options include expectant management with spontaneous remission, corticosteroid therapy, immunosuppressive agents and extensive surgery for refractory cases. [Abstract/Link to Full Text]

Aljarabah MM, Borley NR, Wheeler JM
Appendiceal adenocarcinoma presenting as left-sided large bowel obstruction, a case report and literature review.
Int Semin Surg Oncol. 2007;420.
BACKGROUND: appendiceal tumours are rare, they may be encountered unexpectedly in any acute or elective abdominal operation, many of these tumours are not appreciated intraoperatively and are diagnosed only during formal histopathological analysis of an appendicectomy specimen. Herein we present a case of appendiceal adenocarcinoma presenting as left-sided large bowel obstruction, we also review the literature of unusual presentations of appendiceal tumours. CASE PRESENTATION: we report a case of left sided large bowel obstruction found to be secondary to an appendiceal adenocarcinoma. The patient presented with abdominal pain, distension and constipation, CT scan showed large bowel obstruction thought to be due to a sigmoid tumour, on laparotomy the appendix was also noted to be abnormal. A low Hartman's was performed with en-bloc total hysterectomy and bilateral salpigo-oophorectomy. A separate ileocaecal resection with end ileostomy was also performed, pathology specimens showed that the primary neoplasm was the appendix with metastasis to the distal sigmoid. CONCLUSION: appendiceal tumours are rare, they usually present as acute appendicitis, other presentations are far less common. [Abstract/Link to Full Text]

Safioleas M, Stamatakos M, Giaslakiotis K, Smirnis A, Safioleas P
Acute abdomen due to primary omentitis: a case report.
Int Semin Surg Oncol. 2007;419.
BACKGROUND: Idiopathic segmental infarction of the greater omentum (ISIGO) is an uncommon cause of acute abdomen in children and adults and its etiology is rather vague and speculative. The clinical presentation is usually with atypical acute or subacute abdominal pain. In a number of cases radiologic imaging allows proper preoperative diagnosis and treatment. CASE PRESENTATION: We report a case of ISIGO in a 31 year old patient, who presented with acute abdominal pain, nausea, vomiting and leukocytosis. Radiologic investigation was non-specific. The patient underwent surgical resection of the infracted omentum with compete recovery. CONCLUSION: ISIGO should be considered in the differential of acute abdomen especially when presentation is atypical and all other causes have been excluded. In cases with non-specific radiologic findings, laparotomy is necessary for proper diagnosis and treatment. Surgical resection of the infracted omentum results in uneventful recovery in the majority of cases. [Abstract/Link to Full Text]

da Silva BB, Moita DS, Pires CG, Sousa-Junior EC, dos Santos AR, Lopes-Costa PV
Evaluation of insulin-like growth factor-I in postmenopausal women with breast cancer treated with raloxifene.
Int Semin Surg Oncol. 2007;418.
BACKGROUND: The objective of this study was to evaluate serum IGF-I levels in postmenopausal women with breast cancer treated primarily with raloxifene. METHODS: Twenty-two postmenopausal patients with operable, stage I or II, estrogen receptor-positive carcinomas participated in this study. Following confirmation of diagnosis, the patients received 60 mg of raloxifene for 28 days prior to definitive surgery. Blood samples were collected for evaluation of serum IGF-I levels prior to initiating medication and following a 28-day treatment course. Student's t-test for paired samples was used in the statistical analysis. Significance was established at p < 0.05. RESULTS: Mean serum IGF-I levels pre- and post-raloxifene treatment were 143.7 +/- 9.7 ng/ml and 94.8 +/- 7.6 ng/ml, respectively. This reduction in serum IGF-I levels following treatment with raloxifene was statistically significant (p < 0.001). CONCLUSION: Raloxifene significantly reduced serum IGF-I levels in postmenopausal women with breast cancer. [Abstract/Link to Full Text]

Kuker RA, Mesoloras G, Gulec SA
Optimization of FDG-PET/CT imaging protocol for evaluation of patients with primary and metastatic liver disease.
Int Semin Surg Oncol. 2007;417.
BACKGROUND: Accurate determination of the extrahepatic extent and intrahepatic distribution of disease is very important in patients with primary and metastatic liver disease for deciding whether a patient receives potentially curable surgery or palliative treatment. Our objective was to evaluate the efficacy of delayed phase FDG-PET/CT imaging in lesion detection and to define its clinical impact compared to triple-phase contrast enhanced CT (CECT). METHODS: 30 patients underwent delayed phase FDG-PET/CT imaging (90 min whole body scan followed by a delayed abdominal scan at 120 min). Maximum standard uptake values (SUVs) and SUV ratios between tumor and normal liver parenchyma (T/N) were evaluated. In addition, comparison was made to CECT obtained within 10 days of the FDG-PET/CT to evaluate for lesion concordance within individual liver segments (Couinaud designation). RESULTS: Sites of primary malignancies included: colorectal (19), breast (3), pancreas (2), lung (2), carcinoid (2), cholangiocarcinoma (1), and hepatocellular carcinoma (1). There was a significant increase in SUV value of liver lesions between early and delayed acquisition (P < 0.001). Although there was not a significant reduction in liver background activity between the two studies, there was a strong increase in T/N ratio (P < 0.001) allowing better lesion detection by visual inspection. New lesions were identified in 5 of the 30 patients, which were not appreciated on the early scan. Delayed phase FDG-PET/CT identified one lesion which was not present on the corresponding CECT. Delayed phase FDG-PET/CT revealed extrahepatic sites of metastases not appreciated on CECT in 6 patients. CONCLUSION: Delayed phase FDG-PET/CT protocol improved lesion detectability in primary and metastatic liver disease, revealing new lesions in 17% of the patients. Moreover, FDG-PET/CT identified extrahepatic disease not seen on CECT in 20% of the patients. [Abstract/Link to Full Text]

Povoski SP
Eliminating the "Pitfalls" of chronic indwelling central venous access device placement in cancer patients by utilizing a venous cutdown approach and by selectively and appropriately utilizing intraoperative venography.
Int Semin Surg Oncol. 2007;416.
There are several very obvious and simple solutions for eliminating the "Pitfalls" and for minimizing the risk of occurrence of any perioperative complications associated with placement of chronic indwelling central venous access devices in cancer patients. The first is the utilization of a venous cutdown approach, such as the cephalic vein or the external jugular vein, which essentially eliminates potentially life-threatening perioperative complications, such as pneumothorax and injury to the great vessels (with or without associated hemothorax). The second is the selective and appropriate utilization of intraoperative venography for defining the central venous anatomy and for providing a venous roadmap in those particularly challenging cases in which difficulties are encountered during chronic indwelling central venous access device placement. [Abstract/Link to Full Text]

Sand M, Uecker S, Bechara FG, Gelos M, Sand D, Wiese TH, Mann B
Simultaneous ectopic adrenocorticotropic hormone syndrome and adrenal metastasis of a medullary thyroid carcinoma causing paraneoplastic Cushing's syndrome.
Int Semin Surg Oncol. 2007;415.
Medullary thyroid carcinomas (MTC) constitute about 5 to 7 % of thyroid neoplasms. They originate from parafollicular C-cells which can secrete adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing factor (CRF) in abnormally high concentrations, potentially causing paraneoplastic Cushing's Syndrome (CS).We report on a 42-year-old male patient with a ten year history of metastatic medullary thyroid carcinoma suffering from paraneoplastic Cushing's Syndrome caused by ectopic hypersecretion of ACTH and a simultaneous Cortisol producing adrenal metastasis. [Abstract/Link to Full Text]

Hsing JM, Thakkar SG, Borden EC, Budd GT
Intimal pulmonary artery sarcoma presenting as dyspnea: case report.
Int Semin Surg Oncol. 2007;414.
BACKGROUND: We report a case of pulmonary sarcoma which is a rare cause of the common symptom of dyspnea. CASE PRESENTATION: A fifty-one year old previously healthy male presented to the emergency room with complaints of dyspnea on exertion. A cardiac workup including an exercise stress test was negative but an echocardiography showed pulmonary stenosis. Cardiac MRI showed a large mass extending from the pulmonic valve to both the right and left pulmonary arteries suggestive of sarcoma. A complete resection and repair of the pulmonary artery was done and adjuvant chemotherapy with doxorubicin and ifosfamide was recommended. The patient is currently disease free after eighteen months. CONCLUSION: Pulmonary artery sarcomas are a difficult diagnosis. The diagnosis may remain elusive for some time until the proper imaging techniques are utilized to make a diagnosis. Earlier and accurate diagnosis may lead to earlier interventions and improve survival. [Abstract/Link to Full Text]

Wyles SM, Browne G, Gui GP
Pitfalls in Portacath location using the landmark technique: case report.
Int Semin Surg Oncol. 2007;413.
A 34 year old woman diagnosed with breast cancer and liver metastases underwent a left subclavian Portacath insertion. During the procedure, the clinical features and the findings of intra-operative investigations provided conflicting evidence of the catheter position. This report highlights the potential difficulties in establishing long-term central venous access, the limitations of common investigations and safety issues relating to the process of subclavian line insertion. [Abstract/Link to Full Text]

Subramanian A, Birch H, McAvinchey R, Stacey-Clear A
Pagets disease of uncertain origin: case report.
Int Semin Surg Oncol. 2007;412.
BACKGROUND: Pagets disease of the nipple presents as an eczematous lesion, occurs in 1 - 4% of all female breast carcinoma cases and is invariably associated with underlying malignancy either overt or occult. The majority of these cases are invasive disease although 40-45% are associated with DCIS. CASE PRESENTATION: A 39 year old lady presented to our unit with a palpable lump in the right breast. Radiological and histological investigation proved this to be an extensive area of Ductal Carcinoma in Situ (DCIS) for which she underwent a simple mastectomy and immediate latissimus dorsi flap reconstruction. Histology revealed high grade DCIS with 2 small foci of invasive carcinoma. At 1 year the patient represented with a nodule adjacent to the reconstruction scar which was proved on biopsy to be consistent with Paget's disease. This was proved on formal excision. CONCLUSION: In the absence of underlying breast or apocrine tissue this case details a case of Paget's disease of uncertain origin. [Abstract/Link to Full Text]

Subramanian A, Birch H, Stacey-Clear A
An unusual cause of chest pain:case report.
Int Semin Surg Oncol. 2007;411.
BACKGROUND: Sarcomas form a heterogenous group of relatively uncommon malignant tumours which are derived from connective tissue components. In total they comprise approximately 1% of all new cancers diagnosed per year in the United Kingdom (UK). As subset of this, the 'Unclassified' Sarcoma forms approximately 4% of the total 1. They often present with as relatively slow growing, asymptomatic masses and as such may often be misdiagnosed as in this case. CASE PRESENTATION: A 52 year old man presented to his general practitioner (GP) with left sided chest pain. A strong family history of ischaemic heart disease prompted hospital referral and further investigations which all proved negative for coronary artery disease. Following weight loss and ongoing chest pain, he represented to his GP with a hard mass arising from the left pectoralis major muscle at the site of the previous pain. Surgical excision followed by later compartectomy revealed an unclassified low grade Sarcoma with lymphoma like features. CONCLUSION: In this case, chest pain masquerading as ischaemia, may have been caused by peri-neural infiltration or compression of adjacent muscle bulk by tumour, with eventual surgical resection providing a good long term prognosis. [Abstract/Link to Full Text]

Adams M, Jewell AP
The use of Complementary and Alternative Medicine by cancer patients.
Int Semin Surg Oncol. 2007;410.
The use of Complementary and Alternative Medicine (CAM) among cancer patients is widespread and appears to be increasing. However, it is not clear whether patients use CAM as an 'alternative' to standard oncology care or as an adjunct to the conventional treatment they receive. This study reviews the role of CAM therapies in the management of cancer, from the view of both patients and health professionals and it highlights issues relating to the efficacy of CAM used by cancer patients. Most patients use CAM to 'complement' the conventional therapies of radiotherapy, chemotherapy, hormone therapy and surgery. Health professionals in general have expressed positive views when CAM is used 'complementarily' and not as an 'Alternative'. Results so far published have shown that CAM can contribute to improving the quality of life of cancer patients and their general well-being. [Abstract/Link to Full Text]

Chintamani P, Singh J, Sugandhi N, Bansal A, Bhatnagar D, Saxena S
Is an aggressive approach justified in the management of an aggressive cancer--the squamous cell carcinoma of thyroid?
Int Semin Surg Oncol. 2007;48.
BACKGROUND: Primary squamous cell carcinoma of the thyroid is an extremely rare neoplasm, with less than 50 cases reported in the world literature. The prognosis is poor with a median survival of less than six months. The death is usually secondary to progression of local disease as distant metastases are rare. CASE REPORTS: Three cases, two males and one female presenting with sudden increase in the size of long standing thyroid swellings and associated pressure effects on the aero-digestive tract are reported. Exhaustive clinical, endoscopic, and radiological examinations did not reveal any primary site of squamous-cell carcinoma as the likely source of the metastases, or of any contiguous spread from neighboring structures. Two cases were managed by combined modality therapy including curative surgery with radiotherapy and one by radiotherapy alone. CONCLUSION: Primary squamous cell carcinoma is a rare malignancy with a poor outcome inspite of combined modality therapy. Out of three reported cases, two succumbed to their disease within less than one year. Aggressive surgery in the form of curative resection along with adjuvant radiotherapy is recommended, the tumor being chemo resistant. [Abstract/Link to Full Text]

Chintamani BP, Bhandari V, Bansal A, Saxena S, Bhatnagar D
The expression of mismatched repair genes and their correlation with clinicopathological parameters and response to neo-adjuvant chemotherapy in breast cancer.
Int Semin Surg Oncol. 2007;45.
BACKGROUND: The DNA mismatch repair (MMR) pathway is an important post-replicative repair process. It is involved in the maintenance of genomic stability and MMR genes have therefore been named the proofreaders of replicating DNA. These genes repair the replicative errors of DNA and are thus imperative for genomic stability. The MMR genes have been found to be involved in promoting cytotoxicity, apoptosis, p53 phosphorylation and cell cycle arrest following exposure to exogenous DNA damaging agents. Loss of MMR function prevents the correction of replicative errors leading to instability of the genome, and can be detected by polymorphisms in micro satellites (1-6 nucleotide repeat sequences scattered in whole of the genome). This phenomenon, known as micro satellite instability (MSI), is a hallmark of MMR dysfunction and can be used as a marker of MMR dysfunction in colorectal and other malignancies. An alternative method for detection of MMR dysfunction is to test the expression of protein products of the MMR genes by immunohistochemistry (IHC), as mutations in these genes lead to reduced or absent expression of their gene products. Correlation between loss of MMR function and clinical, histopathological, behavioral parameters of the tumor and its response to chemotherapy in breast cancers may be of value in predicting tumor behavior and response to neoadjuvant chemotherapy (NACT). Neoadjuvant chemotherapy is an integral part of multimodal therapy for locally advanced breast cancer and predicting response may help in tailoring regimens in patients for optimum response. MATERIALS: After approval by the IRB (Institutional Review Board) and ethical committee of the hospital, 31 cases of locally advanced breast carcinoma (LABC) were studied to assess the correlation between MMR dysfunction, clinicopathological parameters and objective clinical response to neoadjuvant chemotherapy using immunohistochemistry. The immunohistochemical analysis for four MMR protein products--MLH1, MSH2, MSH6 and PMS2 was done in the pre NACT trucut biopsy specimen and after three cycles of NACT with C AF (cyclophosphamide, adriamycin, 5-fluorouracil) regimen, in the modified radical mastectomy specimen. RESULTS AND CONCLUSION: There was no significant correlation observed between expression of MMR proteins and age, family history, tumor size or histological type. However there was a statistically significant negative correlation between MLH1, MSH2 expression and histological grade. There was also a negative correlation observed between PMS2 expression after neo-adjuvant chemotherapy and clinical response. Cases with high post NACT expression of PMS2 were poor responders to chemotherapy. MSH6 was the most frequently altered MMR gene, with a negativity rate of 48% and the patients with high expression responded poorly to NACT. The study highlights the possible role of MMR expression in predicting aggressive tumor behavior (histological grade) and response to neoadjuvant chemotherapy in patients with LABC. [Abstract/Link to Full Text]

Mohiuddin K, Nizami S, Munir A, Memon B, Memon MA
Metastatic duodenal GIST: role of surgery combined with imatinib mesylate.
Int Semin Surg Oncol. 2007;49.
BACKGROUND: The best possible treatment of metastatic high grade large duodenal GIST is controversial. Surgery (with or without segmental organ resection) remains the principal treatment for primary and recurrent GIST. However, patients with advanced duodenal GIST have a high risk of early tumour recurrence and short life expectancy. METHOD: We present a case of a young man treated with a combined modality of surgery and imatinib for an advanced duodenal GIST. RESULTS: He remains asymptomatic and disease free 42 months following this combined approach. CONCLUSION: Treatment with imatinib has dramatically improved the outlook for patients with advanced, unresectable and/or metastatic disease. [Abstract/Link to Full Text]

Osman KA, Ahmed MH, Abdulla SA, Bucknall TE, Rogers CA
Venous gangrene and cancer: a cool look at a burning issue.
Int Semin Surg Oncol. 2007;47.
Venous gangrene (VG) is defined as a clinical triad of skin necrosis and discolouration, documented evidence of venous thromboembolism (VTE) and presence of palpable or doppler-identifiable arterial pulsation. Venous gangrene is rare condition which is associated with poor prognosis in cancer patients. The pathogenesis of VG is multifactorial and could paradoxically be due to warfarin treatment. Heparin Induced Thrombocytopenia (HIT) associated venous gangrene develops when heparin therapy is discontinued and warfarin therapy initiated or continued. It has been reported that the presence of anticardiolipin antibodies appears to double the risk of thrombo-embolic events in cancer patients in comparison with those who are anticardiolipin antibody negative. The presence of anticardiolipin antibodies is therefore a warning sign for venous gangrene in cancer patients. Hypercoagulable state associated with malignancy, cancer treatment, prolonged immobilisation, surgical operations and metabolic syndrome are all associated with increased risk of VTE and VG. The current evidence suggests that cancer patients are at increased risk from recurrent venous thrombosis and venous gangrene, and LMWH provides potential promise as a safe and effective measure in the management of such patients. [Abstract/Link to Full Text]

Rmali KA, Watkins G, Douglas-Jones A, Mansel RE, Jiang WG
Angiopoietins lack of prognostic significance in ductal mammary carcinoma.
Int Semin Surg Oncol. 2007;46.
Angiopoietins (Ang) have been shown to regulate the process of vasculature and angiogenesis in tumour. Different angiopoietins have different roles during the angiogenic process. The current study sought to examine the levels of the expression of Ang-1, Ang-2, Ang-3 and their receptor Tie-2 in mammary ductal carcinoma and to assess their relevance to prognosis. Fresh frozen ductal carcinoma tissues (n = 90) and adjacent non-cancerous breast tissues (n = 32) were used. The expression of Ang-1, Ang-2 and Ang-3 transcripts in cancer and normal breast tissues were examined quantitatively using quantitative RT-PCR. The protein expression of Ang-1, Ang-2 and Tie-2 was assessed by immunohistochemistry on frozen sectioned tissues. Ang-1, Ang-2 and Ang-3 were detected in mammary tissues. Ang-1 was seen in both normal epithelial cells, breast cancer cells as well as in endothelial cells. Ang-2 was seen at a higher level than Ang-1 and it is expressed in epithelial, endothelial as well as stromal cells to certain degree. Ang-1 and Ang-2 transcripts were detected almost equally in cancer and normal breast tissue, and Ang-3 was high in cancer tissue compared to normal breast but not significant (155 +/- 123 & 24.1 +/- 22.6, P > 0.05). No significant differences were seen between patients with different predicted prognosis (using the Nottingham Prognostic Index as a guide) (Ang-1 p = 0.34, Ang-2 p = 0.26 and Ang-3 p = 0.32, respectively). No significant correlation was seen between Ang-1, Ang-2 and Ang-3 with tumour grade. When the levels of the transcripts were compared against clinical outcome (disease free, developed recurrence and patients who died of breast cancer), levels of Ang-3 transcript was found to be high in breast cancer patient who had bone metastasis 33.8 +/- 28.3, although the difference was not significant (p = 0.08). No significant difference was seen with levels of Ang-1 and Ang-2 transcripts and clinical outcomes. Furthermore, no significant trend was observed between Tie-2 receptor and clinical/pathological parameters in the cohort. These data suggest that angiopoietins (Ang-1, Ang-2 and Ang-3) are expressed in mammary tissues, both in normal and tumour. These molecules have limited value in predicting the prognosis and clinical outcome in patients with mammary ductal carcinoma. [Abstract/Link to Full Text]

Mansfield L, Sosa I, Dionello R, Subramanian A, Devalia H, Mokbel K
Current management of the axilla in patients with clinically node-negative breast cancer: a nationwide survey of United Kingdom breast surgeons.
Int Semin Surg Oncol. 2007;44.
BACKGROUND: Precise knowledge of axillary lymph node status is essential in the treatment of operable carcinoma of the breast. For many years, axillary nodal clearance (ANC) has been an integral part of the conventional management of early-stage breast cancer. During the last few decades the trend of these surgical procedures has been one of decreasing invasiveness in order to try and achieve a much lower level of morbidity. To help reach this improved level of treatment the concept of the sentinel lymph node (SLN) was utilized. Recent studies have shown that SNB can provide an accurate assessment of the axillary nodal status in clinically node negative patients, negating the need to remove the majority of the axillary contents and thus reducing morbidity. A recent meta-analysis of all the literature to date appears to reveal that the dual technique (blue dye and technetium-labelled sulfur) is the gold-standard for successful identification of the SLN in the context of early-stage breast cancer. We aim to highlight the on-going wide range of differing methods employed, and compare this to the gold-standard recommended guidelines. METHODS: A questionnaire was devised to provide a snapshot overview of the current management of the axilla in patients with clinically node-negative T1 invasive breast cancer amongst UK beast surgeons in August 2006. RESULTS: Of the 271 UK surgeons, 74 (27.3%) performed ANC as the initial management of the axilla in patients with clinically node negative T1 invasive breast cancer, 56 (20.7%) used axillary node sampling (not directed by sentinel node mapping) and a total of 141 (52.0%) used the technique of SNB, of which 50 (18.5%) used blue dye alone and 91 (33.6%) used a combination of blue dye and radioisotope. CONCLUSION: Despite the obvious advantages, our survey has revealed that the procedure is only used by 52% of British breast surgeons in this subgroup of patients (clinically node negative, tumour equal of smaller than 2 cm) most of whom have no disease within the axilla. The reasons for this include limited hospital resources and lack of surgeons training and accreditation and ARSAC license (nuclear medicine license). [Abstract/Link to Full Text]

Li Q, Wang J, Sun Y, Cui Y, Hao X
Hepatic angiosarcoma arising in an adult mesenchymal hamartoma.
Int Semin Surg Oncol. 2007;43.
The histogenesis of the hepatic sarcoma and its association with hamartoma is not well understood. We hereby present a Chinese patient with hepatic angiosarcoma arising from an adult mesenchymal hamartoma of liver. A 33-yr-old woman was diagnosed hepatic hamartoma eight years ago and presented with epigastric distention recently. Now she was admitted to our hospital with some unusual features: (a) this patient was diagnosed in mid-twenties, (b) the tumor occupied the whole liver and most importantly (c) the hepatic angiosarcoma appeared 8 years after the diagnosis of hamartoma. Based on this case and some reports, hepatic hamartoma may develop to hepatic angiosarcoma. [Abstract/Link to Full Text]

Katsoulis IE, Bossi M, Richman PI, Livingstone JI
Collision of adenocarcinoma and gastrointestinal stromal tumour (GIST) in the stomach: report of a case.
Int Semin Surg Oncol. 2007;42.
A 78-year-old woman was diagnosed with a proximal gastric adenocarcinoma and underwent an elective D2 total gastrectomy with splenectomy. Subsequent histopathology revealed the presence of another tumour at the gastric antrum. This was a small benign gastrointestinal stromal tumour (GIST) mixed with gastric adenocarcinoma cells similar to those of the main gastric tumour i.e. a collision tumour. The literature has only few previous reports of this very rare association. It is not known whether this synchronicity is incidental or there is a causative factor inducing the development of tumours of different histotypes in the same organ. Pathologists, oncologists and surgeons should be aware of this interesting condition. [Abstract/Link to Full Text]

Zbar AP, Shenoy RK, Chiappa A
Extended abdominoperineal resection in women: the Barbadian experience.
Int Semin Surg Oncol. 2007;41.
BACKGROUND AND OBJECTIVES: We report our results of a selective approach to primary direct appositional vaginal repair versus transverse rectus abdominis flap repair (TRAM) in patients with extensive rectal/anal cancer or in cases with primary cancer of cervix, vagina or vulva involving the anal canal and anal sphincters. METHODS: Eighteen female patients (mean age: 62.9 years; range: 44-81 years) with a median follow-up of 14 months (range: 2-36 months) undergoing extended abdominoperineal reconstruction with total mesorectal excision between May 2002 and September 2005, were studied. RESULTS: Twelve patients underwent an extended abdominoperineal resection with hysterectomy and vaginectomy, with 6 patients undergoing primary TRAM flap reconstruction following pelvic exenteration. Exenterative procedures were performed in 2 cases of primary vaginal cancer, following Wertheim hysterectomy for carcinoma of the cervix with recurrence after radiation and in 2 further cases of anal cancer with extensive pelvic recurrence after primary chemoradiation. Fifteen cases are alive on follow-up with no evidence of disease; 2 patients who had recurrent carcinoma of the cervix and who underwent TRAM flap reconstruction, have recurrent disease after 5 and 6 months of follow-up, respectively. DISCUSSION: Our experience shows that careful primary closure of an extended abdominoperineal resection wound is effective and safe. Our one case of wound breakdown after primary repair underwent external beam and intracavitary irradiation primarily with wound breakdown of a primary repair followed by a delayed pedicled graciloplasty. TRAM flap reconstruction has been reserved in our unit for patients undergoing total pelvic extenteration. In general, we would recommend the use of TRAM flap reconstruction in younger sexually active patients where there has been external irradiation combined with brachytherapy. [Abstract/Link to Full Text]

Mansfield L, Devalia H, Rehman N, Mokbel K
The competent sentinel node: an association with an axillary presentation and an occult or a small primary invasive breast carcinoma.
Int Semin Surg Oncol. 2006;339.
The concept of the sentinel node describes a primary or sentinel lymph node (SLN), which exists and through which tumour cells from a primary tumour in a particular location must first travel to spread to a particular regional lymph node group. In this series we present three patients presenting with a pathological axillary node associated with either an occult or very small primary breast cancer. In each case the primary tumour was found to have metastasised to the palpable node, however despite the significant enlargement of this node, no other axillary nodes were found to be affected on axillary node clearance. This has led us to postulate that the SLN in some cases contains unique characteristics that enable it to prevent further spread of the tumour up the lymphatic chain. Hence the term the competent sentinel node. [Abstract/Link to Full Text]

Tan JZ, Schlicht SM, Powell GJ, Thomas D, Slavin JL, Smith PJ, Choong PF
Multidisciplinary approach to diagnosis and management of osteosarcoma - a review of the St Vincent's Hospital experience.
Int Semin Surg Oncol. 2006;338.
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour in children and young adults. Despite advances in the diagnosis and management of osteosarcoma, there have been few recent studies describing the experiences of tertiary referral centres. This paper aims to describe and discuss the clinical features, pre-operative work-up, management and outcomes of these patients at St Vincent's Hospital (Melbourne, Australia). METHODS: Retrospective study of fifty-nine consecutive patients managed for osteosarcoma at St Vincent's Hospital between 1995 and 2005. RESULTS: Median age at diagnosis was 21 (range, 11-84) years. Gender distribution was similar, with thirty-one male and twenty-eight female patients.Twenty-five patients had osteosarcoma in the femur, eleven each were located in the humerus and tibia, six were identified in the pelvis, and one each in the clavicle, maxilla, fibula, sacrum, ulna and radius.Pre-operative tissue diagnosis of osteosarcoma was obtained through computed tomography-guided percutaneous biopsy in over ninety percent of patients.Following initial therapy, over fifty percent of patients remained relapse-free during the follow-up period, with twelve percent and twenty-seven percent of patients documented as having local and distant disease recurrence, respectively. Of patients with recurrent disease, sixty-two percent remained disease-free following subsequent surgical intervention (most commonly, pulmonary metastatectomy). CONCLUSION: Patient outcomes can be optimised through a multidisciplinary approach in a tertiary referral centre. At St Vincent's Hospital, survival and relapse rates of patients managed for osteosarcoma compare favourably with the published literature. [Abstract/Link to Full Text]

Chaudhry A, Puntis ML, Gikas P, Mokbel K
Does the timing of breast cancer surgery in pre-menopausal women affect clinical outcome? An update.
Int Semin Surg Oncol. 2006;337.
There is some evidence that breast cancer surgery during the luteal phase in pre-menopausal women is associated with a better clinical outcome, however the evidence for this is still equivocal.In this paper, after summarizing the normal physiology of the menstrual cycle, we examine how such an association may occur and provide a comprehensive review of the literature in the area. [Abstract/Link to Full Text]

Recent Articles in World Journal of Surgical Oncology

Fernandez-Acenero MJ, Lopez-Criado P, Lopez-Franco M, Meizoso T, Calvo C
Multicentric myxoid liposarcoma: report of two cases.
World J Surg Oncol. 2007 Dec 10;5(1):139.
ABSTRACT: BACKGROUND: Multicentric myxoid liposarcoma is a rather infrequent tumour that tends to behave aggressively. CASE PRESENTATION: We herein report two further cases of this tumour that have been managed in our Hospital. Both were young men with multiple sites of involvement at the moment of diagnosis and both have shown a bad prognosis with frequent recurrences after treatment and rapid death in one case. CONCLUSIONS: We comment on the diagnosis of this entity and on the therapeutic options available for these patients. [Abstract/Link to Full Text]

Senchenkov A, Patty PM, Knoetgen J, Moran SL, Johnson CH, Clay RP
Outcomes of skin graft reconstructions with the use of Vacuum Assisted Closure (VAC(R)) dressing for irradiated extremity sarcoma defects.
World J Surg Oncol. 2007 Nov 29;5(1):138.
ABSTRACT: BACKGROUND: Flaps are currently the predominant method of reconstruction for irradiated wounds. The usefulness of split-thickness skin grafts (STSG) in this setting remains controversial. The purpose of this study is to examine the outcomes of STSGs in conjunction with VAC therapy used in the treatment of irradiated extremity wounds. METHODS: The records of 17 preoperatively radiated patients with extremity sarcomas reconstructed with STSGs in conjunction with VAC(R) therapy were reviewed regarding details of radiation treatment, wound closure, and outcomes. RESULTS: STSGs healed without complications (>95% of the graft take) in 12 (71%). Minor loss (6% - 20% surface) was noted in 3 patients (17.6%), and complete loss in 2 (11.7%). Two patients (11.7%) required flap reconstructions and 12 (88%) healed without further operative procedures. CONCLUSION: Although flap coverage is an established treatment for radiated wounds, STSG in conjunction with liberal utilization of VAC therapy is an alternative for selected patients where acceptable soft tissue bed is preserved. Healing of the preoperatively radiated wounds can be achieved in the vast majority of such patients with minimal need for additional reconstructive operations. [Abstract/Link to Full Text]

Gupta N, Mittal S, Lal N, Misra R, Kumar L, Bhalla S
A rare case of primary mesenteric gastrointestinal stromal tumor with metastasis to the cervix uteri.
World J Surg Oncol. 2007 Nov 29;5(1):137.
ABSTRACT: BACKGROUND: Gastrointestinal stromal tumors are CD117 (C Kit) positive mesenchymal neoplasms, that may arise anywhere in the gastrointestinal tract. Their current therapy is imatinib mesylate before or after surgery. CASE PRESENTATION: We describe a case of 17-year-old female with metastasis to the cervix uteri of a primary mesenteric gastrointestinal tumor. CONCLUSION: Surgery remains the mainstay of known curative treatment. The manifestations of GIST are not restricted to the typical locations within the bowel; may have very unusual metastatic sites or infiltrations per continuitatem. [Abstract/Link to Full Text]

Kanthan R, Mills S
Cooperative learning in the first year of undergraduate medical education.
World J Surg Oncol. 2007 Nov 28;5(1):136.
ABSTRACT: BACKGROUND: Despite extensive research data indicating that cooperative learning promotes higher achievement, the creation of positive relationships, and greater psychological health for students at all levels in their education, cooperative learning as a teaching strategy is still underutilized in undergraduate medical education. METHODS: A cooperative learning task was introduced as part of the mandatory first Year undergraduate Pathology course. The task was to create an 8.5"x11" poster summary of pre-assigned content in self-chosen groups of four or five students. On the designated "Poster Day," the posters were displayed and evaluated by the students using a group product evaluation. Students also completed an individual group process reflection survey. An objective evaluation of their understanding was gauged at the midterm examination by specific content-related questions. RESULTS: Majority (91 -96%) of students judged the group products to be relevant, effective, easy-to-understand, and clearly communicated. The majority of the students (90-100%) agreed that their group process skills of time management, task collaboration, decision-making and task execution were effective in completing this exercise. This activity created a dynamic learning environment as was reflected in the students' positive, professional discussion, and evaluation of their posters. The content-related questions on the midterm examination were answered correctly by 70-92% of the students. This was a mutually enriching experience for the instructor and students. CONCLUSIONS: These findings demonstrate that cooperative learning as a teaching strategy can be effectively incorporated to address both content and interpersonal skill development in the early years of undergraduate medical education. [Abstract/Link to Full Text]

Piovanello P, Viola V, Costa G, Carletti M, Cecera A, Turchetta F, Iudicone R, Catalano G, Santucci A, Recchia F, Fiorillo L, Menichella MA, Baiano G
Locally advanced leiomyosarcoma of the spleen. A case report and review of the literature.
World J Surg Oncol. 2007 Nov 28;5(1):135.
ABSTRACT: BACKGROUND: Leiomyosarcomas are rare tumours, predominantly localized in the stomach, small intestine and retroperitoneum. Only one case of primary leiomyosarcoma of the spleen is described in human beings in literature. CASE PRESENTATION: We report a case of locally advanced primary leiomyosarcoma of the spleen in a 54 year-old woman, diagnosed only after splenectomy, performed with the suspicion of splenic haematoma. CONCLUSIONS: Due to the lack of cases, no specific chemotherapy regimen has been tested to provide a longer survival. [Abstract/Link to Full Text]

Nagata S, Nishimura A, Iwashita Y, Kinoshita T, Fukuzawa K, Tashiro H, Wakasugi K
Primary breast lymphoma in the right breast during treatment for left breast cancer.
World J Surg Oncol. 2007 Nov 26;5(1):134.
ABSTRACT: BACKGROUND: Primary breast lymphoma is a rare condition, and distinguishing it from breast cancer is important because their treatments differ radically. Moreover, a recent report showed that mastectomy offered no benefit in the treatment of primary breast lymphoma. CASE PRESENTATION: A 59-year-old woman was treated with adjuvant chemotherapy and local radiation after surgery for left breast cancer. She presented with a rapidly growing mass in the right breast at 20 months after surgery. Mammography and computed tomography revealed a massive tumour. She was diagnosed with primary breast lymphoma by aspiration cytology, and surgery was performed. Histopathological and immunohistochemical findings confirmed a diffuse large B-cell type primary breast lymphoma. CONCLUSION: In this case, the lymphoma exhibited rapid growth despite chemotherapy for a malignancy in the contralateral breast. The patient had developed bronchiolitis obliterans organizing pneumonia due to radiation. Therefore, surgical treatment of the lymphoma was selected. [Abstract/Link to Full Text]

Wang H, Wieczorek RL, Zenilman ME, Desoto-Lapaix F, Ghosh BC, Bowne WB
Castleman's disease in the head of the pancreas: Report of a rare clinical entity and current perspective on diagnosis, treatment, and outcome.
World J Surg Oncol. 2007 Nov 20;5(1):133.
ABSTRACT: BACKGROUND: Castleman's disease of the pancreas is a very rare condition that may resemble more common disease entities as well as pancreatic cancer. CASE PRESENTATION: Here we report the case of a 58-year-old African American male with an incidentally discovered lesion in the head of the pancreas. The specimen from his pancreaticoduodectomy contained a protuberant, encapsulated mass, exhibiting microscopic features most consistent with localized/ unicentric Castleman's disease. These included florid follicular hyperplasia with mantle/marginal zone hyperplasia along with focal progressive transformation of germinal centers admixed with involuted germinal centers. CONCLUSION: To date, eight cases of Castleman's disease associated with the pancreas have been described in the world literature. We report the first case of unicentric disease situated within the head of the pancreas. In addition, we discuss the diagnostic dilemma Castleman's disease may present to the pancreatic surgeon and review current data on pathogenesis, treatment, and outcome. [Abstract/Link to Full Text]

Mathelin C, Salvador S, Croce S, Andriamisandratsoa N, Huss D, Guyonnet JL
Optimization of sentinel lymph node biopsy in breast cancer using an operative gamma camera.
World J Surg Oncol. 2007 Nov 17;5(1):132.
ABSTRACT: BACKGROUND: Sentinel lymph node (SLN) procedure is now a widely accepted method of LN staging in selected invasive breast cancers (unifocal, size [less than or equal to] 2 cm, clinically N0, without previous treatment). Complete axillary clearance is no longer needed if the SLN is negative. However, the oncological safety of this procedure remains to be addressed in randomized clinical trials. One main pitfall is the failure to visualize SLN, resulting in incorrect tumor staging, leading to suboptimal treatment or axillary recurrence. Operative gamma cameras have therefore been developed to optimize the SLN visualization and the quality control of surgery. CASE PRESENTATION: A 44-year-old female patient with a 14-mm infiltrative ductal carcinoma underwent the SLN procedure. An operative gamma camera was used during and after the surgery. The conventional lymphoscintigraphy showed only one SLN, which was also detected by the operative gamma camera, then removed and measured (9.6 kBq). It was analyzed by frozen sections, showing no cancer cells. During this analysis, the exploration of the axillary area with the operative gamma camera enabled the identification of a second SLN with low activity (0.5 kBq) that conventional lymphoscintigraphy, surgical probe and blue staining had failed to visualize. Histological examination revealed a macrometastasis. Axillary clearance was then performed, followed by a postoperative image proving that no SLN remained. Therefore, the use of the operative gamma camera prevented an under-estimation of staging which would have resulted in a suboptimal treatment for this patient. CONCLUSION: This case report illustrates that an efficient operative gamma camera may be able to decrease the risk of false negative rate of the SLN procedure, and could be an additional tool to control the quality of the surgery. ClinicalTrials.gov Identifier: NCT00357487. [Abstract/Link to Full Text]

Sakamoto A, Matono H, Yoshida T, Tanaka K, Matsuda S, Oda Y, Iwamoto Y
Dedifferentiated liposarcoma with leukocytosis. A case report of G-CSF-producing soft-tissue tumors, possible association with undifferentiated liposarcoma lineage.
World J Surg Oncol. 2007 Nov 16;5(1):131.
ABSTRACT: BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) functions as a hematopoietic growth factor and it is responsible for leukocytosis. G-CSF-producing tumors associated with leukocytosis include various types of malignancies. CASE PRESENTATION: We report the case of a 72-year-old man with dedifferentiated liposarcoma characterized by dedifferentiated components of malignant fibrous histiocytoma (MFH)-like features in addition to well-differentiated lipoma-like liposarcoma, arising from his upper arm. Preoperative laboratory data showed leukocytosis (103,700/mul). The serum level of G-CSF was also elevated (620 pg/ml [normal, <8 pg/ml]). Nine days after the surgery, the leukocytosis was relieved (WBC; 6,920/mul) and the elevated serum G-CSF level was significantly decreased (G-CSF; 12 pg/ml). One month after the surgery, leukocytosis gradually began to appear again. Three months after the surgery metastatic lung lesions were confirmed, and the patient subsequently died of respiratory problems. In the English literature regarding soft-tissue tumors with leukocytosis, including the current case, we could review a total of 6 cases of liposarcoma with leukocytosis. The subtype of these 6 liposarcoma cases was undifferentiated liposarcoma, comprising dedifferentiated liposarcoma in 4 cases and pleomorphic liposarcoma in 2 cases. CONCLUSION: Since the only other soft-tissue tumor that was associated with leukocytosis was MFH, and since MFH is characterized by the absence of any specific differentiation, we would like to propose a possible association between G-CSF-producing soft-tissue tumors and an undifferentiated liposarcoma lineage, such as dedifferentiated liposarcoma or pleomorphic liposarcoma. [Abstract/Link to Full Text]

Brinkman JM, Bron JL, Wuisman PI, Van Diest PJ, Comans EF, Molthoff CF
The correlation between clinical, nuclear and histologic findings in a patient with Von Recklinghausen's disease.
World J Surg Oncol. 2007 Nov 12;5(1):130.
ABSTRACT: BACKGROUND: Malignant peripheral nerve sheath tumours (MPNST) are known to develop in patients with Neurofibromatosis type I (NF1) resulting in a decreased overall survival. The association between NF1 and the development of such MPNST has been investigated in detail. The biological behaviour however of multiple disseminated neurofibromas in patients with NF1 and the risk factors for malignant transformation remain unknown. Clinical signs are unreliable and additional imaging techniques are therefore required. Of such, positron emission tomography using [18F]-2-fluoro-2-deoxy-D-glucose (18FDG PET) is used to detect malignant changes in neurofibromas. CASE PRESENTATION: A case is presented of a patient suffering from NF1 with clinical signs of malignant change and accumulation of 18FDG in multiple neurofibromas. Histopathological examination of 20 lesions however, did not reveal any malignant features. There was no statistically significant relation between18FDG accumulation and malignant change, but rather with pain, size and growth. CONCLUSIONS: This case adds to the knowledge of the diverse biological behaviour of neurofibromas in patients with NF1. [Abstract/Link to Full Text]

Sadat U, Theivacumar NS, Vat J, Jah A
Angioleiomyoma of the small intestine- a rare cause of gastrointestinal bleeding.
World J Surg Oncol. 2007 Nov 8;5(1):129.
ABSTRACT: BACKGROUND: Benign tumors are a rare cause of gastrointestinal hemorrhage of which angioleiomyomas constitute a very small minority. They have been reported in literature to present with volvulus, bleeding or intussusceptions. CASE PRESENTATION: An interesting case of a patient presenting with gastrointestinal bleeding from an underlying angioleiomyoma is discussed along with its management options. CONCLUSIONS: Angioleiomyoma though rare can be managed successfully by surgical and/or minimally invasive endovascular procedures. [Abstract/Link to Full Text]

Durai R, Yang SY, Seifalian AM, Goldspink G, Winslet MC
Role of insulin-like growth factor binding protein-4 in prevention of colon cancer.
World J Surg Oncol. 2007 Nov 7;5(1):128.
ABSTRACT: BACKGROUND: Insulin-like growth factors (IGFs) are important for the proliferation of cancer cells. One of their binding proteins, known as insulin-like growth factor binding protein -4 (IGFBP-4) is well known for its inhibitory action on IGFs in vitro. We assessed the effect of IGFBP-4 in prevention of development of colon cancer in vivo. METHODS: Nude mice were subcutaneously inoculated with HT-29 colon cancer cells and they were also simultaneously injected either gene construct containing mammalian expression vector pcDNA3 with or without IGFBP-4 gene or phosphate buffered saline. The effect was assessed 4 weeks later by evaluating the tumours for mitosis, necrosis, apoptosis, and expressions of IGFBP-4, Bcl-2 and Bax proteins. RESULTS: The results showed that the IGFBP-4 gene therapy did not prevent the tumour establishment but it increased the tumour apoptosis which was associated with an increase in Bcl-2 and Bax expressions. The IGFBP-4 protein was low in tumours which received IGFBP-4 gene construct which may be due to a feed back mechanism of IGFBP-4 upon its own cells. CONCLUSION: IGFBP-4 gene therapy in the form localised gene transfer did not prevent colon cancer initiation and establishment but it resulted in increased apoptosis and Bax protein expression and a decrease in tumour cellular mitosis. [Abstract/Link to Full Text]

Venkitaraman R, George MK
Primary non Hodgkin's lymphoma of the lacrimal sac.
World J Surg Oncol. 2007 Nov 6;5(1):127.
ABSTRACT: BACKGROUND: Primary Non Hodgkin's Lymphoma (NHL) of the lacrimal sac is rare. METHODS: The clinical features of a 78 year old female who presented with epiphora and swelling of the left lacrimal sac are described. RESULTS: Computerised tomography showed a mass involving the left lacrimal sac. Histopathological examination revealed a diffuse large B cell NHL. Immunohistological examination demonstrated B cell origin. Chemotherapy could not be administered due to co morbid conditions. The patient was treated with radiotherapy to a dose of 45 Gy in 25 fractions. Patient is disease free and on follow up after 36 months. CONCLUSION: Primary radiotherapy is a treatment option with curative potential for localized NHL of the lacrimal sac and may be considered in patients who cannot tolerate appropriate chemotherapy. [Abstract/Link to Full Text]

Dennis RJ, Alberts JC
The implications of an incidental chronic lymphocytic leukaemia in a resection specimen for colorectal adenocarcinoma.
World J Surg Oncol. 2007 Oct 30;5(1):126.
ABSTRACT: BACKGROUND: Colorectal cancer and B cell chronic lymphocytic leukaemia (CLL) have a significant incidence, which are increasing with the aging population. Evidence has been presented in the literature to suggest that the synchronous presentation of colorectal cancer and B cell CLL may be more than simply coincidental for these two common malignancies. We report an unusual case of a presumed B cell CLL diagnosed on the basis of histological analysis of lymph nodes recovered from a resection specimen for rectal adenocarcinoma. We considered aetiological factors which may have linked the synchronous diagnosis of the two malignancies and the potential implications for the natural history of the two malignancies on one another. CASE PRESENTATION: A 70-year-old male underwent low anterior resection with total mesorectal excision for a rectal adenocarcinoma. His co-morbid conditions were chronic obstructive airways disease and ischaemic heart disease. General examination revealed no lymphadenopathy. Full blood count, urea and electrolytes and liver function tests were all within normal limits. As well as confirming a pT3 N1 adenocarcinoma, histological analysis showed lymph nodes with an infiltrate of small lymphoid cells. Immunohistochemical studies showed these cells to be in keeping with B cell CLL. CONCLUSIONS: Whilst unable to identify any common aetiological factors in the two malignancies in our patient, immunosuppression and genetic abnormalities have been identified as possible bases for an observed epidemiological association between colorectal cancer and haematological malignancies. Examples such as our case of synchronous diagnosis of two malignancies in a patient are likely to increase with the aging population. The potential affects of one malignancy on the natural history of the other warrants further study. In our case, we considered that slow progression of the B cell CLL may increase the risk of recurrent rectal adenocarcinoma. [Abstract/Link to Full Text]

Matsuda A, Kato S, Furuya M, Shimizu Y, Okino T, Sasaki J, Tajiri T
Multiple early gastric cancer with duodenal invasion: report of a case.
World J Surg Oncol. 2007 Oct 30;5(1):125.
ABSTRACT: BACKGROUND: Early gastric cancers with duodenal invasion are rare, and no previous case of multiple early gastric cancer, one invading the duodenal bulb, has been reported. CASE PRESENTATION: A 79-year-old woman was investigated for upper abdominal discomfort. Endoscopic examination revealed an irregular nodulated lesion in the antrum area, and a reddish aggregated-type semi-circumferential nodulated lesion extending from the prepyloric area to the duodenal bulb through the normal mucosa with the antrum lesion. Biopsy revealed a tubular adenoma for the antrum lesion and a well-differentiated tubular adenocarcinoma for the prepyloric lesion. Distal gastrectomy with sufficient duodenal resection was performed. Microscopically, the antrum lesion appeared as a papillary adenocarcinoma, and the prepyloric lesion as a mainly papillary adenocarcinoma which partially invaded the submucosa without any sequential elongation for endoscopic findings. The lesion extended into the duodenal bulb, and was 12 mm in length from the oral end of Brunner's gland's area and limited within the duodenal mucosa. CONCLUSION: Here, we present an unusual case of multiple early gastric cancer, one of which invaded the duodenum with relative wide mucosal spreading. This case illustrates that even early stage cancers located in the gastric antrum, particularly in the prepyloric area can invade the duodenum directly. [Abstract/Link to Full Text]

Povoski SP
The utilization of an ultrasound-guided 8-gauge vacuum-assisted breast biopsy system as an innovative approach to accomplishing complete eradication of multiple bilateral breast fibroadenomas.
World J Surg Oncol. 2007 Oct 29;5(1):124.
ABSTRACT: BACKGROUND: Ultrasound-guided vacuum-assisted breast biopsy technology is extremely useful for diagnostic biopsy of suspicious breast lesions and for attempted complete excision of appropriately selected presumed benign breast lesions. CASE PRESENTATION: A female patient presented with 16 breast lesions (eight within each breast)that were documented on ultrasound and were all presumed to be fibroadenomas. Over a ten and one-half month period of time, 14 of these 16 breast lesions were removed under ultrasound guidance during a total of 11 separate 8-gauge Mammotome(R) excision procedures performed during seven separate sessions. Additionally, two of these 16 breast lesions were removed by open surgical excision. A histopathologic diagnosis of fibroadenoma and/or fibroadenomatous changes was confirmed at all lesion excision sites. Interval follow-up ultrasound imaging revealed no evidence of a residual lesion at the site of any of the 16 original breast lesions. CONCLUSIONS: This report describes an innovative approach of utilizing ultrasound-guided 8-gauge vacuum-assisted breast biopsy technology for assisting in achieving complete eradication of multiple bilateral fibroadenomas in a patient who presented with 16 documented breast lesions. As such, this innovative approach is highly recommended in similar appropriately selected patients. [Abstract/Link to Full Text]

Luh SP, Lai YS, Tsai CH, Tsao TC, Wong LC, Huang PC
Extramedullary Plasmacytoma (EMP): Report of a Case Manifested as a Mediastinal Mass and Multiple Pulmonary Nodules and Review of Literature.
World J Surg Oncol. 2007 Oct 27;5(1):123.
ABSTRACT: BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare plasma cell neoplasm of soft tissue without bone marrow involvement or other systemic characteristics of multiple myeloma. CASE PRESENTATION: A 42 year-old woman presented with intermittent dry cough of 10 months duration. Her breathing sound was slightly coarse without rales or rhonchi on auscultation. CT scan revealed a right anterior mediastinal shadow with multiple pulmonary nodular lesions. A video-assisted thoracoscopic surgery (VATS) was performed. Histopathology showed it to be a myeloma. CONCLUSION: This is the first presentation of EMP with a mediastinal mass with multiple pulmonary nodules. [Abstract/Link to Full Text]

Abbas SM, Merrie AE
Resection of peritoneal metastases causing malignant small bowel obstruction.
World J Surg Oncol. 2007 Oct 24;5(1):122.
ABSTRACT: BACKGROUND: Resection of peritoneal metastases has been shown to improve survival in patients with abdominal metastatic disease from abdominal or extra abdominal malignancy. This study evaluates the benefit of peritoneal metastatic resection in patients with malignant small bowel obstruction and a past history of treated cancer. Patients and methods Patients undergoing laparotomy for resection of peritoneal metastases from recurrence of previous cancer between 1992-2003 were reviewed retrospectively. Data were collected about type of primary cancer, interval to recurrence, extent of the disease and completeness of resection, morbidity and mortality and long-term survival. RESULTS: Between 1992 and 2003 there were 79 patients (median age 62, range 19-91) who had laparotomy for small bowel obstruction due to recurrent cancer. The primary cancer was colorectal (31), gynaecologic cancer (19), melanoma (16) and others (13). Overall, the rate of complications was 35% and mortality was 10%. Median survival was 5 months; patients with history of colorectal cancer had better survival than other cancer (median survival 7 months vs. 4 months; p=0.02). Multivariate analysis showed that the extent of recurrent disease was the only factor that affected overall survival. CONCLUSIONS: Laparotomy for small bowel obstruction is a worthwhile option for patients with malignant small bowel obstruction. Although it is associated with significant morbidity and mortality it offers a reasonable survival benefit in particular for patients with completely resectable disease. [Abstract/Link to Full Text]

Engin G, Asoglu O, Kapran Y, Mert G
A gastrointestinal stromal tumor with mesenteric and retroperitoneal invasion.
World J Surg Oncol. 2007 Oct 24;5(1):121.
ABSTRACT: BACKGROUND: Gastrointestinal stromal tumors are rare visceral sarcomas arising in the gastrointestinal tract wall. In this report we present a case of gastrointestinal stromal tumors with mesenteric and retroperitoneal invasion, describe and discuss its computed tomography findings. CASE PRESENTATION: A 57-years-old male patient has been complaining of abdominal distention, weight lose, and hematuria. During physical examination, significant distention and multiple palpable tumor masses were identified on the abdomen. Abdominal computed tomography showed multiple, well-defined, soft tissue masses with homogenous and heterogeneous pattern, in the mesenteric and retroperitoneal areas. Unlike specific features of gastrointestinal stromal tumor, renal obstruction and atypical central calcification without chemotherapy which have not been yet described were seen in this case. Computed tomography did not reveal liver metastases and/or the lymph nodes with pathological size. Ultrasonography-guided true-cut(R) biopsy was made, histopathologic and immunohistochemical analyses demonstrated stromal tumor which, C-KIT (+). The patient underwent left ureterectomy, left nephrectomy and total colectomy. Postoperative histopathological analyses revealed lower grade malignant GISTs. As of 17 months after the surgery, he is alive and free of recurrence. CONCLUSIONS: When intraabdominal, multiple, large (>5 cm), well-circumscribed, homogenous or heterogeneous mass lesions without ascites, omental caking and lymph nodes metasteses were seen, gastrointestinal stromal tumors should be considered in the differential diagnosis. [Abstract/Link to Full Text]

Kontogiorgi M, Exarchos D, Charitos C, Floros I, Rontogianni D, Roussos C, Routsi C
Primary right atrium angiosarcoma mimicking pericarditis.
World J Surg Oncol. 2007 Oct 22;5(1):120.
ABSTRACT: BACKGROUND: Primary cardiac neoplasms occur rarely and most of them are benign. Malignant tumors including angiosarcoma are extremely rare and have a non specific clinical presentation and a poor prognosis. CASE PRESENTATION: We present a case of a young male who was transferred to our hospital because of shock and multiple organ failure after a complicated pericardial biopsy. During the previous seven months he presented with recurrent episodes of pericardial effusions and tamponade. Chest computed tomography revealed a mass in the right atrium, infiltrating the myocardium and pericardium. During emergency surgery that followed, the patient died because of uncontrolled hemorrhage. Autopsy revealed the mass of the right atrium, which was identified on histological examination as primary cardiac angiosarcoma. CONCLUSION: This case highlights the difficulties both in early diagnosis and in the management of patients with cardiac angiosarcoma. [Abstract/Link to Full Text]

Hossain FS, Koak Y, Khan FH
Primary gastric Hodgkin's lymphoma.
World J Surg Oncol. 2007;5119.
BACKGROUND: Primary Hodgkin's disease of the stomach is an extremely rare entity. Nearly all cases of primary gastric lymphoma are of the non-Hodgkin's variety. Diagnoses in such cases are difficult due to considerable histological similarities between the 2 disease entities. CASE PRESENTATION: We report the case of a 77 year old lady with a 1 year history of weight loss and poor appetite. Physical examination was unremarkable. Subsequent multiple upper GI endoscopies revealed a large malignant looking ulcer which was deemed to be histologically benign. Following CT imaging the patient underwent a radical gastrectomy. Postoperatively histology and immunohistochemistry failed to confirm a diagnosis. As such a second opinion was sought. Employing an extended array of immunohistological staining a diagnosis of 'Classical Hodgkin's' disease of the stomach was achieved. CONCLUSION: Our case illustrates the significant difficulties in achieving a rare diagnosis of primary Hodgkin's lymphoma of the stomach. The non-specific nature of symptoms and a lack of histological features make a preoperative diagnosis extremely difficult. While immunohistochemistry is widely employed in aiding the evaluation of such cases, one should be wary of the considerable overlap in differentiating between Hodgkin's and non-Hodgkin's disease entities using this technique. [Abstract/Link to Full Text]

Brahmania M, Kanthan CS, Kanthan R
Collision tumor of the colon - colonic adenocarcinoma and ovarian granulosa cell tumor.
World J Surg Oncol. 2007 Oct 20;5(1):118.
ABSTRACT: BACKGROUND: Collision tumors of the colon are rare. We report the first case, to our knowledge in the English literature, of a collision tumor composed of a colonic adenocarcinoma arising in a sigmoid diverticulum coexisting with a recurrent ovarian granulosa cell tumor. CASE PRESENTATION: A 64-year old woman presented with small bowel obstruction and a large, heterogenous, solid/cystic serosal based pelvic mass consistent with a gastrointestinal stromal tumor on imaging. Her significant past history 16-years ago included a bilateral salpingo-oophrectomy with hysterectomy. Surgical removal of the mass and pathological examination revealed the presence of a colonic adenocarcinoma arising in a large sigmoid diverticulum coexistent with a second neoplastic tumor phenotype; confirmed to be a delayed recurrent ovarian granulosa cell tumor. Though coexistent, the two tumor phenotypes respected their boundaries with no diffuse intermingling or transition between them. She developed lung metastases from the recurrent ovarian tumor within 6 months and died within a year of follow-up. CONCLUSION: Collision tumors of the colon are rare. This is the first case reported of a collision tumor composed of adenocarcinoma colon and recurrent granulosa cell tumor representing an example of two independent tumors in a unique one-on-another collision. Clinical awareness and recognition of such tumors are important as they will dictate appropriate treatment strategies dependent on the individual biological aggressiveness of each of the tumor components. Our report highlights the need for histopathologists, surgeons, and oncologists to be aware of the rare possibility of collisions tumors. As seen in our case, the delayed recurrence of granulosa cell tumor of the ovary sixteen years after the initial presentation was the key determining factor in tumor recurrence, tumor progression, and tumor metastasis within three months, which ultimately lead to accelerated death within a year of clinical presentation. Thus accurate identification and recognition of the second neoplasm is important as prognosis and survival may be determined by this component as seen in our index case. [Abstract/Link to Full Text]

Boghossian V, Owen ID, Nuli B, Xiao PQ
Neuroendocrine (Merkel cell) carcinoma of the retroperitoneum with no identifiable primary site.
World J Surg Oncol. 2007;5117.
BACKGROUND: Neuroendocrine carcinoma is an aggressive neoplasm that mainly affects elderly Caucasians and typically arises in sun-exposed areas of the skin. The disease is rather rare and only a relatively few cases present with no apparent primary lesion. CASE PRESENTATION: We report a case of an 81-year-old Caucasian male with neuroendocrine carcinoma, which initially presented as a large retroperitoneal mass. Pathological and immunohistochemical analysis of the transabdominal CT-guided biopsy specimen revealed tissue consistent with neuroendocrine carcinoma. The patient underwent exploratory laparotomy and the mass was successfully excised along with an associated mesenteric lymph node. DISCUSSION: There are currently two possible explanations for what occurred in our patient. First, the retroperitoneal mass could be a massively enlarged lymph node where precursor cells became neoplastic. This would be consistent with a presumptive diagnosis of primary nodal disease. Alternatively, an initial skin lesion could have spontaneously regressed and the retroperitoneal mass represents a single site of metastasis. Since Merkel cell precursors have never been identified within lymph nodes, the latter theory seems more befitting. Moreover, metastasis to the retroperitoneal lymph nodes has been reported as relatively common when compared to other sites such as liver, bone, brain and skin. CONCLUSION: Wide local excision of the primary tumor is the surgical treatment of choice for localized disease. We propose that further studies are needed to elucidate the true efficacy of chemotherapy in conventional as well as unconventional patients with neuroendocrine carcinoma. [Abstract/Link to Full Text]

Bagwan IN, Cook G, Mudan S, Wotherspoon A
Unusual presentation of metastatic adenocarcinoma.
World J Surg Oncol. 2007;5116.
BACKGROUND: The most common tumours of the adrenal gland are adenoma, pheochromocytoma, adrenocortical carcinoma, and metastases. Although the imaging features of these tumours are established, the imaging characteristics of uncommon adrenal masses are less well known. In patients with extradrenal tumour, incidental discovery of an adrenal mass necessitates excluding the possibility of metastatic malignancy. CASE PRESENTATION: A 52 year-old female was diagnosed with oesophageal adenocarcinoma and treated with oesophagectomy and adjuvant chemotherapy. Sixteen months later on staging CT scan a 2 x 2 cm adrenal mass was detected, which increased in size over a period of time to 3 x 3 cm in size. Adrenalectomy was performed and histological examination revealed metastatic adenocarcinoma within an adrenal adenoma. CONCLUSION: The present case highlights the unusual behaviour of an oesophageal adenocarcinoma causing metastasis to an adrenocortical adenoma. [Abstract/Link to Full Text]

Kim T, Grobmyer SR, Liu C, Hochwald SN
Primary presacral neuroendocrine tumor associated with imperforate anus.
World J Surg Oncol. 2007;5115.
ABSTRACT: BACKGROUND: Presacral masses are unusual growths that have a limited differential diagnosis, typically not including neuroendocrine tumors (NETs). Classically, NETs are well-differentiated gastroenteropancreatic tumors of probable benign behavior. These tumors are associated with a typical morphologic pattern and involve the distal colon, rectum, and genitourinary tract; they are considered less aggressive, frequently asymptomatic, and rarely cause carcinoid syndrome, even when metastatic. Neuroendocrine tumors of the presacral region are extremely rare and few have been described in the literature. They have not been previously reported as being associated with imperforate anus. CASE PRESENTATION: We present an interesting case of a woman with a history of imperforate anus that was found to have a primary neuroendocrine tumor of the presacral region with no rectal wall involvement. CONCLUSION: We argue that this is a primary gastroenteropancreatic neuroendocrine tumor which likely originated from cells of hindgut origin that underwent an abnormal migration during embryonic development. [Abstract/Link to Full Text]

Knauer M, Haid A, Ammann K, Lang A, Offner F, Tuertscher M, Cerkl P, Wenzl E
Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome.
World J Surg Oncol. 2007 Oct 11;5(1):114.
ABSTRACT: BACKGROUND: Different molecular therapies like the EGFR-inhibiting antibody cetuximab have come into clinical practice. Cetuximab is EMEA-approved for metastatic colorectal cancer and advanced squamous-cell head and neck cancer. Administration is said to be safe and well tolerated with common, usually mild dermatologic side effects. CASE PRESENTATION: We present the case of a patient with fatal complications after oesophagectomy and neoadjuvant chemotherapy including cetuximab for squamous-cell esophageal cancer. A transthoracic en-bloc oesophagectomy was performed. Few days later the patient died due to gas exchange dysfunction and circulation instability after a previously unseen combination of drain-erosion of the stomach with subsequent pleurisy and air leak of the left main bronchus. CONCLUSIONS: So far we have never observed this fatal combination of drain erosion of the stomach with fibrinous pleurisy and unmanageable progressive tracheal defect before. The role of cetuximab in the multifactorial aetiology of damages of stomach and trachea after oesophagectomy remains unclear since we are not able to link the complication directly to cetuximab or definitely exclude it as a sole surgical complication. Clinicians should be aware of the possibility of fatal side effects and careful recording of all complications is necessary in ongoing and planned studies to obtain more evidence about safety and tolerance of targeted therapies. [Abstract/Link to Full Text]

Lordan JT, Jones RL, Karanjia ND, de Sanctis S, Woodland JG, Middleton G, Menezes N
A rare case of a retroperitoneal enterogenous cyst with in-situ adenocarcinoma.
World J Surg Oncol. 2007;5113.
ABSTRACT: BACKGROUND: Retroperitoneal enterogenous cysts are uncommon and adenocarcinoma within such cysts is a rare complication. CASE PRESENTATION: We present the third described case of a retroperitoneal enterogenous cyst with adenocarcinomatous changes and only the second reported case whereby the cyst was not arising from any anatomical structure. CONCLUSION: This case demonstrates the difficulties in making a diagnosis as well as the importance of a multi-disciplinary approach, and raises further questions regarding post-operative treatment with chemotherapy. [Abstract/Link to Full Text]

Schreinemakers JM, Zonnenberg BA, Hoppener JW, Hes FJ, Borelrinkes IH, Lips CJ
A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL) syndrome type 2C.
World J Surg Oncol. 2007 Oct 8;5(1):112.
ABSTRACT: BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership. CASE PRESENTATION: A 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser) in exon 1 of the VHL gene on chromosome 3 (p25 - p26) was shown in the patient, her father and her daughter confirming the diagnosis of VHL. CONCLUSIONS: In almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas. [Abstract/Link to Full Text]

Kanellopoulos AD, Mavrogenis AF, Papagelopoulos PJ, Soucacos PN
Elastic intramedullary nailing and DBM-bone marrow injection for the treatment of simple bone cysts.
World J Surg Oncol. 2007;5111.
BACKGROUND: Simple or unicameral bone cysts are common benign fluid-filled lesions usually located at the long bones of children before skeletal maturity. METHODS: We performed demineralized bone matrix and iliac crest bone marrow injection combined with elastic intramedullary nailing for the treatment of simple bone cysts in long bones of 9 children with a mean age of 12.6 years (range, 4 to 15 years). RESULTS: Two of the 9 patients presented with a pathological fracture. Three patients had been referred after the failure of previous treatments. Four patients had large lesions with impending pathological fractures that interfered with daily living activities. We employed a ratio to ascertain the severity of the lesion. The extent of the lesion on the longitudinal axis was divided with the normal expected diameter of the long bone at the site of the lesion. The mean follow-up was 77 months (range, 5 to 8 years). All patients were pain free and had full range of motion of the adjacent joints at 6 weeks postoperatively. Review radiographs showed that all 7 cysts had consolidated completely (Neer stage I) and 2 cysts had consolidated partially (Neer stage II). Until the latest examination there was no evidence of fracture or re-fracture. CONCLUSION: Elastic intramedullary nailing has the twofold benefits of continuous cyst decompression, and early immediate stability to the involved bone segment, which permits early mobilization and return to the normal activities of the pre-teen patients. [Abstract/Link to Full Text]

Liedtke C, Kersting C, B�rger H, Kiesel L, W�lfing P
Caveolin-1 expression in benign and malignant lesions of the breast.
World J Surg Oncol. 2007;5110.
ABSTRACT: BACKGROUND: Caveolin-1 is thought to have an important impact on both signal transduction and mediation of intracellular processes. Furthermore, it has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. We examined the potential clinical relevance of Caveolin-1 in normal, benign and malignant breast tissue specimens. METHODS: Using tissue microarray (TMA) technology cases of invasive breast cancer, DCIS, benign breast disease (i.e. fibroadenoma, sclerosing adenosis, ductal hyperplasia and radial scar) and normal breast tissue were evaluated for Caveolin-1 expression. Immunohistochemical staining with an anti-Caveolin-1-antibody was performed. Staining intensity was quantified semiquantitatively. In invasive lesions staining results were correlated with clinical and pathological data. RESULTS: No Caveolin-1 expression was observed in epithelial cells of normal breast tissue (n = 5), benign breast disease (n = 295) and DCIS (n = 108). However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%). Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers. CONCLUSION: In this study we demonstrated expression of Caveolin-1 in one third of invasive breast cancers. A significant increase in Caveolin-1 expression was observed comparing invasive breast cancer to both benign breast tissue and non-invasive breast cancer. Since inhibitors of Caveolin-1 signalling are available, targeting Caveolin-1 in breast cancer may represent a potential option for future breast cancer treatment. [Abstract/Link to Full Text]

Recent Articles in Journal of Carcinogenesis

Vidjaya Letchoumy P, Chandra Mohan KV, Prathiba D, Hara Y, Nagini S
Comparative evaluation of antiproliferative, antiangiogenic and apoptosis inducing potential of black tea polyphenols in the hamster buccal pouch carcinogenesis model.
J Carcinog. 2007 Dec 3;6(1):19.
ABSTRACT: BACKGROUND: To evaluate the relative chemopreventive efficacy of two black tea polyphenols, Polyphenon-B [P-B] and BTF-35 on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. METHODS: Hamsters were divided into 6 groups. The right buccal pouches of animals in groups 1-3 were painted with 0.5% of DMBA three times a week for 14 weeks. While hamsters in group 1 received no further treatment, animals in groups 2 and 3 received diet containing 0.05% P-B and BTF-35 respectively, four weeks before DMBA painting that was continued until the end of the experiments. Animals in groups 4 and 5 were given P-B and BTF-35 alone respectively as in groups 2 and 3. Group 6 animals served as the untreated control. All the animals were sacrificed after 18 weeks. The expression of p21, cyclin D1, glutathione S-transferase pi (GST-P), nuclear factor kappa B (NF-kB), Bcl-2, Bax, cytochrome C, caspase-3, caspase-9, poly(ADP-ribose) polymerase (PARP), cytokeratins and vascular endothelial growth factor (VEGF) was analysed by RT-PCR, immunohistochemical and Western blot analyses. RESULTS: DMBA treated animals developed buccal pouch carcinomas that displayed increased expression of p21, cyclin D1, GST-P, NF-kB, cytokeratins, VEGF and Bcl-2 with decreased expression of Bax, cytochrome C, caspase-3, caspase-9, and PARP. Dietary administration of both P-B and BTF-35 reduced the incidence of DMBA-induced HBP carcinomas by modulating markers of cell proliferation, cell survival, tumour infiltration, angiogenesis, and apoptosis. CONCLUSION: The results of the present study provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. The greater efficacy of BTF-35 in inhibiting HBP carcinogenesis and modulating multiple molecular targets may have a potential role in the prevention of oral cancer. [Abstract/Link to Full Text]

Vegh I, Enriquez-de-Salamanca R
Prolactin, TNF alpha and nitric oxide expression in nitroso-N-methylurea-induced mammary tumours.
J Carcinog. 2007 Nov 28;6(1):18.
ABSTRACT: BACKGROUND: The N-Nitrosomethylurea breast cancer model induced in rats is used for the study of carcinogenesis in mammary cancer, prostate, pancreas, etc. This model is very similar to human neoplastic disease. METHODS: The present experimental study was designed to assess whether metoclopramide administration has any effect on development of MNU-induced tumours, and evaluate the treatment of gosereline acetate on PRL, TNF alpha and NO expression. NMU was administered to female Wistar rats on 2 occasions (5mg/100g body w/rat). PRL and TNF alpha were performed by immune-assay. Nitric Oxide by semi automated-assay and ploidy analyses by flow cytometry. RESULTS: The administration of metoclopramide made the induction time shorter and increased the incidence and average of tumours per rat. Tumours development was inhibited by a gosereline chronic administration. The ploidy of adenocarcinoma was polyploid-aneuploid type (average S=60%). It was higher basal PRL plasma levels in rats with NMU induced tumours than in basal controls without tumour (p<0.001). The gosereline "in bolus" administration showed maximal inhibition of plasma PRL at 90 min. Plasmatic TNF alpha expression was inhibited at 60 min and also remained inhibited in tissue homogenate post chronic treatment (P<0.0125). Plasmatic NO expression is higher in rats with induced tumours than healthy controls (P<0.001). In tissue homogenate NO values were inhibited at 90 min (P<0.01), as well during chronically gosereline treatment (P<0.005). CONCLUSIONS: The increase of blood PRL levels in NMU-induced rats may be an indicator of a poor prognosis of mammary cancer evolution. The metoclopramide administration accelerates tumour growth. However gosereline administration achieves regression in tumour development associated to inhibition PRL, TNF alpha and NO expression. [Abstract/Link to Full Text]

Marshall JC, Caissie A, Cruess SR, Cools-Lartigue J, Burnier MN
The effects of a cyclooxygenase-2 (COX-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production.
J Carcinog. 2007 Nov 27;6(1):17.
ABSTRACT: BACKGROUND: Cyclooxygenase-2 (COX-2) expression has previously been identified in uveal melanoma although the biological role of COX-2 in this intraocular malignancy has not been elucidated. This study aimed to investigate the effect of a COX-2 inhibitor on the proliferation rate of human uveal melanoma cells, as well as its effect on the cytotoxic response of macrophages. METHODS: Human uveal melanoma cell lines were transfected to constitutively express COX-2 and the proliferative rate of these cells using two different methods, with and without the addition of Amfenac, was measured. Nitric oxide production by macrophages was measured after exposure to melanoma-conditioned medium from both groups of cells as well as with and without Amfenac, the active metabolite of Nepafenac. RESULTS: Cells transfected to express COX-2 had a higher proliferation rate than those that did not. The addition of Amfenac significantly decreased the proliferation rate of all cell lines. Nitric oxide production by macrophages was inhibited by the addition of melanoma conditioned medium, the addition of Amfenac partially overcame this inhibition. CONCLUSIONS: Amfenac affected both COX-2 transfected and non-transfected uveal melanoma cells in terms of their proliferation rates as well as their suppressive effects on macrophage cytotoxic activity. [Abstract/Link to Full Text]

Houben R, Ortmann S, Becker JC
RKIP does not contribute to MAP kinase pathway silencing in the Merkel Cell Carcinoma cell line UISO.
J Carcinog. 2007 Oct 24;6(1):16.
ABSTRACT: BACKGROUND: The Raf kinase inhibitor protein (RKIP) has been shown to block MAP kinase pathway as well as NF-kappaB signalling. By means of immunohistochemistry, we previously demonstrated that the MAP kinase pathway is virtually inactive in Merkel cell carcinoma (MCC). Similarly to MCC in situ high RKIP expression accompanies absence of ERK phosphorylation in the MCC cell line UISO suggesting that RKIP might be causative for MAP kinase pathway silencing. METHODS: Applying an siRNA approach RKIP expression was knocked down in UISO cells and a possible influence on MAP kinase pathway activity was assessed by Western blot analysis using phospho-specific antibodies. Moreover, a possible effect of RKIP knock down in UISO cells on proliferation as well as chemosensitivity to cisplatin were examined applying the MTS assay. RESULTS: Surprisingly the absence of phosphorylation of the MAP kinases ERK1 and ERK 2 even following growth factor stimulation was not affected by the RKIP knock down indicating that RKIP is not essential for blocking the MAP kinase pathway in the MCC cell line UISO. Moreover, proliferation as well as chemosensitivity towards cisplatin were not altered upon knock down of RKIP. [Abstract/Link to Full Text]

Gisselsson D, Lundberg G, Ora I, H�glund M
Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas.
J Carcinog. 2007;615.
ABSTRACT: BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process. METHODS: We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression. RESULTS: Tumours clustered in four sub-groups, dominated respectively by (1) gene amplification in double minute chromosomes and few other aberrations, (2) gene amplification and loss of 1p sequences, (3) loss of 1p and other structural aberrations including gain of 17q, and (4) whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1-3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number. CONCLUSION: The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms. [Abstract/Link to Full Text]

Meyer P, Zuern C, Hermanns N, Haak T
The association between paternal prostate cancer and type 2 diabetes.
J Carcinog. 2007;614.
ABSTRACT: OBJECTIVE: Increasing evidence indicates that type 2 diabetic patients are at elevated risk for developing different kinds of cancers. However, diabetes mellitus may be a protective factor for prostate cancer since both were found to be negatively associated. Based on the same genetic background, parents of diabetic patients might show similar risks concerning cancers. RESEARCH DESIGN AND METHODS: We conducted a case-control study, where familiy history of 794 type 2 diabetic cases and 775 non-diabetic controls was ascertained. Then, we expanded our study up to 801 type 2 diabetic cases and 1267 non-diabetic controls. RESULTS: Concerning the 794 type 2 diabetic patients and 775 controls, we observed that cancer of cervix uteri was elevated among mothers of controls (odds ratio (OR) 0.19; 95% confidence interval (CI) 0.02 to 0.88; p = 0.033). Mothers of diabetic patients showed an increased history of cancers of the liver and biliary tract (OR 5.23; 95% CI 1.87 to 19.9; p = 0.0009) and stomach (OR 3.84; 95% CI 1.47 to 12.4; p = 0.0049). Pancreatic cancers were found to be elevated in fathers of diabetic patients (OR 4.92; 95% CI 1.07 to 46.7; p = 0.039). Most notably, a lower number of prostate cancers was observed in fathers of diabetic patients (OR 0.47; 95% CI 0.22 to 0.94; p = 0.032). Since diabetic patients were 14.3 years older than the controls, higher levels of cancer history among parents of diabetic patients would have been expected. Thus, the observed lower level of history of prostate cancer can be regarded as highly reliable.The analysis of 801 type 2 diabetics and 1267 controls showed that cancer of stomach was elevated among mothers of controls (OR 2.67; p = 0.0106). In addition, stomach cancers were found to be elevated in fathers of diabetic patients (OR 2.10; p = 0.0141). In accordance with the previous investigation, we again obseved a lower number of prostate cancers in fathers of diabetic patients (OR 0.49; p = 0.0279).However, the application of the statistical method of Mantel-Haenszel showed no significant result concerning any of the cancer histories. CONCLUSION: Fathers of patients suffering from type 2 diabetes were diagnosed less frequently with prostate cancer compared to fathers of non-diabetic controls. As first-degree relatives, e.g. diabetic patients and their fathers, share 50% of their genes, it appears plausible that genetic factors may play an important role in the negative association between diabetes and prostate cancer. However, different statistic analyses showed controversial results concerning the effect of type 2 diabetes on prostate cancers. [Abstract/Link to Full Text]

Demir A, Altin S, Pehlivan D, Demir M, Yakar F, Seyhan EC, Dincer SI
The role of GSTM1 gene polymorphisms in lung cancer development in Turkish population.
J Carcinog. 2007;613.
ABSTRACT: BACKGROUND: Glutathione S-transferase (GSTs) plays an important role in the detoxification of many xenobiotics involved in the etiology of cancer. In different ethnic groups, variations in null allele frequency have been observed. We have investigated GSTM1 gene polymorphisms in healthy subjects and lung cancer patients in the Turkish population and reviewed the control subjects of the studies performed in the Turkish population. METHODS: Following blood sampling from patients and controls, DNA samples were extracted from the whole blood and were amplified by using polymerase chain reaction (PCR) method in all of the 256 cases, consisting of 102 previously diagnosed with lung cancer and 154 healthy controls. RESULTS: The prevalence of GSTM1-null genotype in the lung cancer patients was 49%, compared to 52.6% in the control group (OR = 1.39, 95% CI = 0.70-1.90, p = 0.57). There were also no significant relationships in GSTM1 genotypes among histopathologic types of lung cancers (p > 0.05). The frequency of GSTM1 was found to be 41.2% (n = 1809) when the control subjects of the studies performed in Turkish population were reviewed. CONCLUSION: We have observed that GSTM1 genotype is not an independent risk factor for lung cancer. [Abstract/Link to Full Text]

Saleh F, Abdeen S
Pathobiological features of breast tumours in the State of Kuwait: a comprehensive analysis.
J Carcinog. 2007 Sep 24;6(1):12.
ABSTRACT: BACKGROUND: Breast cancer accounts for 30.3% of all cancer types in Kuwaiti women. Death occurs in approximately 43% of these patients. Our goal was to conduct a comprehensive analysis of the pathobiological characteristics of the tumours in an attempt to determine any particular trend that could be present. METHODS: One hundred and sixty-six cases were included in this study. All the pathology reports and paraffin blocks pertaining to these cases were collected. Four micrometer sections were taken from each block, and immunostaining against Her-2, ER, and PgR was performed. Both the proportion and intensity of immunostaining were scored according to the Allred's method, and typing of the tumour was done according the WHO criteria regarding tumour classification. Grading of invasive carcinomas was done according to the modified Bloom-Richardson-Elston's method, and tumour stage was determined according to the criteria set by the American Joint Committee on Cancer. RESULTS: The mean age of the patients below 55 years was 40, as compared to 68 for those above 55 (p < 0.0001). More than half of the cases were in the right breast, and were surgically treated by total mastectomy with axillary clearance. The majority of the tumours had irregular (stellate) margins, was invasive, and had a surrounding breast tissue of adenosis or fibrocystic type. Their mitotic index was 10-20 or >20 with a marked to moderate nuclear pleomorphism. They were mostly grade II or III, sized 2-5 or > 5 cm, had absent or scanty tumour lymphocytes, and were stage II or III. The in situ tumours were mainly ductal carcinoma (DCIS) of which comedo and cribriform were the major histological subtypes. The major histological subtypes of the invasive tumours were ductal-not otherwise specified, lobular, and tubular/cribriform. In this study, we also found a significant (p < 0.05) association between overexpression of Her-2, lack of expression of ER and some of the characteristics mentioned above. CONCLUSION: Breast cancer in Kuwait seems to be more aggressive than what is currently seen in Europe, North America, Australia, and parts of Asia. Further investigations regarding the features observed in this study need to be performed. [Abstract/Link to Full Text]

Shield K, Riley C, Quinn MA, Rice GE, Ackland ML, Ahmed N
Alpha2beta1 integrin affects metastatic potential of ovarian carcinoma spheroids by supporting disaggregation and proteolysis.
J Carcinog. 2007;611.
BACKGROUND: Ovarian cancer is characterized by a wide-spread intra-abdominal metastases which represents a major clinical hurdle in the prognosis and management of the disease. A significant proportion of ovarian cancer cells in peritoneal ascites exist as multicellular aggregates or spheroids. We hypothesize that these cellular aggregates or spheroids are invasive with the capacity to survive and implant on the peritoneal surface. This study was designed to elucidate early inherent mechanism(s) of spheroid survival, growth and disaggregation required for peritoneal metastases METHODS: In this study, we determined the growth pattern and adhesive capacity of ovarian cancer cell lines (HEY and OVHS1) grown as spheroids, using the well established liquid overlay technique, and compared them to a normal ovarian cell line (IOSE29) and cancer cells grown as a monolayer. The proteolytic capacity of these spheroids was compared with cells grown as a monolayer using a gelatin zymography assay to analyze secreted MMP-2/9 in conditioned serum-free medium. The disaggregation of cancer cell line spheroids was determined on extracellular matrices (ECM) such as laminin (LM), fibronectin (FN) and collagen (CI) and the expression of alpha2, alpha3, alphav, alpha6 and beta1 interin was determined by flow cytometric analysis. Neutralizing antibodies against alpha2, beta1 subunits and alpha2beta1 integrin was used to inhibit disaggregation as well as activation of MMPs in spheroids. RESULTS: We demonstrate that ovarian cancer cell lines grown as spheroids can sustain growth for 10 days while the normal ovarian cell line failed to grow beyond 2 days. Compared to cells grown as a monolayer, cancer cells grown as spheroids demonstrated no change in adhesion for up to 4 days, while IOSE29 cells had a 2-4-fold loss of adhesion within 2 days. Cancer cell spheroids disaggregated on extracellular matrices (ECM) and demonstrated enhanced expression of secreted pro-MMP2 as well as activated MMP2/MMP9 with no such activation of MMP's observed in monolayer cells. Flow cytometric analysis demonstrated enhanced expression of alpha2 and diminution of alpha6 integrin subunits in spheroids versus monolayer cells. No change in the expression of alpha3, alphav and beta1 subunits was evident. Conversely, except for alphav integrin, a 1.5-7.5-fold decrease in alpha2, alpha3, alpha6 and beta1 integrin subunit expression was observed in IOSE29 cells within 2 days. Neutralizing antibodies against alpha2, beta1 subunits and alpha2beta1 integrin inhibited disaggregation as well as activation of MMPs in spheroids. CONCLUSION: Our results suggest that enhanced expression of alpha2beta1 integrin may influence spheroid disaggregation and proteolysis responsible for the peritoneal dissemination of ovarian carcinoma. This may indicate a new therapeutic target for the suppression of the peritoneal metastasis associated with advanced ovarian carcinomas. [Abstract/Link to Full Text]

Ganesh IM, Subramani D, Halagowder D
Mucin glycoarray in gastric and gallbladder epithelia.
J Carcinog. 2007;610.
BACKGROUND: Mucins are critical cytoprotective glycoproteins and alterations of epithelial gastric mucins have been described in different pathological conditions. The purpose of the present study was to evaluate the putative usefulness of mucins in understanding the progression of gastric cancer and gallstone formation in a better perspective. METHODS: Formalin-fixed paraffin-embedded gastric biopsy specimens and surgically resected gallbladder tissue samples were sectioned. Alcian Blue (AB) staining was performed to identify sialomucins (staining blue at pH 2.5) and sulfomucins (staining brown at pH 1.0) and then Periodic acid-Schiff's (PAS) staining to visualize the neutral mucins (staining magenta). RESULTS: In normal gastric and gallbladder mucosae, we found that neutral mucins were predominant, whereas in intestinal metaplasia, gastric carcinoma and stone-containing gallbladder, a significant increase of acidic mucins was found. CONCLUSION: We suggest that the sulfomucins have a greater role in gallstone formation than the neutral mucins and also that the sialomucins and sulfomucins play an important role in cancer progression and metastasis. Our results challenge the glycobiologists to delve deeper in elucidating the role of mucins in gastric malignancy and in gallstone formation. [Abstract/Link to Full Text]

Kuznetsova EB, Kekeeva TV, Larin SS, Zemlyakova VV, Khomyakova AV, Babenko OV, Nemtsova MV, Zaletayev DV, Strelnikov VV
Methylation of the BIN1 gene promoter CpG island associated with breast and prostate cancer.
J Carcinog. 2007;69.
BACKGROUND: Loss of BIN1 tumor suppressor expression is abundant in human cancer and its frequency exceeds that of genetic alterations, suggesting the role of epigenetic regulators (DNA methylation). BIN1 re-expression in the DU145 prostate cancer cell line after 5-aza-2'-deoxycytidine treatment was recently reported but no methylation of the BIN1 promoter CpG island was found in DU145. METHODS: Methylation-sensitive arbitrarily-primed PCR was used to detect genomic loci abnormally methylated in breast cancer. BIN1 CpG island fragment was identified among the differentially methylated loci as a result of direct sequencing of the methylation-sensitive arbitrarily-primed PCR product and subsequent BLAST alliance. BIN1 CpG island cancer related methylation in breast and prostate cancers was confirmed by bisulphite sequencing and its methylation frequency was evaluated by methylation sensitive PCR. Loss of heterozygosity analysis of the BIN1 region was performed with two introgenic and one closely adjacent extragenic microsatellite markers.BIN1 expression was evaluated by real-time RT-PCR. RESULTS: We have identified a 3'-part of BIN1 promoter CpG island among the genomic loci abnormally methylated in breast cancer. The fragment proved to be methylated in 18/99 (18%) and 4/46 (9%) breast and prostate tumors, correspondingly, as well as in MCF7 and T47D breast cancer cell lines, but was never methylated in normal tissues and lymphocytes as well as in DU145 and LNCaP prostate cancer cell lines. The 5'-part of the CpG island revealed no methylation in all samples tested. BIN1 expression losses were detected in MCF7 and T47D cells and were characteristic of primary breast tumors (10/13; 77%), while loss of heterozygosity was a rare event in tissue samples (2/22 informative cases; 9%) and was ruled out for MCF7. CONCLUSION: BIN1 promoter CpG island is composed of two parts differing drastically in the methylation patterns in cancer. This appears to be a common feature of cancer related genes and demands further functional significance exploration. Although we have found no evidence of the functional role of such a non-core methylation in BIN1 expression regulation, our data do not altogether rule this possibility out. [Abstract/Link to Full Text]

Yancy HF, Mason JA, Peters S, Thompson CE, Littleton GK, Jett M, Day AA
Metastatic progression and gene expression between breast cancer cell lines from African American and Caucasian women.
J Carcinog. 2007;68.
African American (AA) women have a lower overall incidence of breast cancer than do Caucasian (CAU) women, but a higher overall mortality. Little is known as to why the incidence of breast cancer is lower yet mortality is higher in AA women. Many studies speculate that this is only a socio-economical problem. This investigation suggests the possibility that molecular mechanisms contribute to the increased mortality of AA women with breast cancer. This study investigates the expression of 14 genes which have been shown to play a role in cancer metastasis. Cell lines derived from AA and CAU patients were analyzed to demonstrate alterations in the transcription of genes known to be involved in cancer and the metastatic process. Total RNA was isolated from cell lines and analyzed by RT-PCR analysis. Differential expression of the 14 targeted genes between a spectrum model (6 breast cancer cell lines and 2 non-cancer breast cell lines) and a metastasis model (12 metastatic breast cancer cell lines) were demonstrated. Additionally, an in vitro comparison of the expression established differences in 5 of the 14 biomarker genes between African American and Caucasian breast cell lines. Results from this study indicates that altered expression of the genes Atp1b1, CARD 10, KLF4, Spint2, and Acly may play a role in the aggressive phenotype seen in breast cancer in African American women. [Abstract/Link to Full Text]

Wada R, Sato K, Ichida T, Maekawa H, Ogawa K, Maekawa T
Where did the super-small sized large bowel advanced cancer come from?
J Carcinog. 2007;67.
Our study suggested that the super-small sized (less than 15 mm in maximum diameter) large bowel advanced cancers, which were sometimes found, were derived from the superficial depressed-type or flat elevation-type of the colorectal early cancers, not polyp-type of those. [Abstract/Link to Full Text]

Fernandes BF, Odashiro AN, Saraiva VS, Logan P, Antecka E, Burnier MN
Immunohistochemical expression of melan-A and tyrosinase in uveal melanoma.
J Carcinog. 2007;66.
BACKGROUND: Melan-A and tyrosinase are new immunohistochemical markers that can be used in the diagnosis of melanocytic lesions. The aim of this study was to investigate the correlation between radiotherapy or clinicohistopathological parameters and the expression of melan-A and tyrosinase in uveal melanoma. METHODS: Thirty-six enucleated cases of uveal melanoma were studied. The formalin-fixed, paraffin-embedded specimens were immunostained with monoclonal antibodies against melan-A and tyrosinase. The samples were classified as either positive or negative. The chi-square or the Student-t tests were used to test for the correlation of the expression rates of melan-A and tyrosinase with clinico-pathological parameters. RESULTS: Melan-A and tyrosinase were positive in 33 (91.7%) and 35 (97.2%) of the specimens, respectively. There was no significant association between the expression of melan-A or tyrosinase and radiotherapy or any clinico-pathological parameter. All specimens were positive for at least one of the immunohistochemical markers. CONCLUSION: To the best of our knowledge this is the first study concluding that the expression of melanocytic markers such as melan-A and tyrosinase is not influenced by radiotherapy or any clinico-pathological parameter. Moreover, when tyrosinase and melan-A are used together, 100% of the formalin-fixed, paraffin-embedded uveal melanoma samples tested positive for one of those markers. [Abstract/Link to Full Text]

Garc�a-Rom�n R, P�rez-Carre�n JI, M�rquez-Qui�ones A, Salcido-Neyoy ME, Villa-Trevi�o S
Persistent activation of NF-kappaB related to IkappaB's degradation profiles during early chemical hepatocarcinogenesis.
J Carcinog. 2007;65.
BACKGROUND: To define the NF-kappaB activation in early stages of hepatocarcinogenesis and its IkappaB's degradation profiles in comparison to sole liver regeneration. METHODS: Western-blot and EMSA analyses were performed for the NF-kappaB activation. The transcriptional activity of NF-kappaB was determined by RT-PCR of the IkappaB-alpha mRNA. The IkappaB's degradation proteins were determined by Western-blot assay. RESULTS: We demonstrated the persistent activation of NF-kappaB during early stages of hepatocarcinogenesis, which reached maximal level 30 min after partial hepatectomy. The DNA binding and transcriptional activity of NF-kappaB, were sustained during early steps of hepatocarcinogenesis in comparison to only partial hepatectomy, which displayed a transitory NF-kappaB activation. In early stages of hepatocarcinogenesis, the IkappaB-alpha degradation turned out to be acute and transitory, but the low levels of IkappaB-beta persisted even 15 days after partial hepatectomy. Interestingly, IkappaB-beta degradation is not induced after sole partial hepatectomy. CONCLUSION: We propose that during liver regeneration, the transitory stimulation of the transcription factor response, assures blockade of NF-kappaB until recovery of the total mass of the liver and the persistent NF-kappaB activation in early hepatocarcinogenesis may be due to IkappaB-beta and IkappaB-alpha degradation, mainly IkappaB-beta degradation, which contributes to gene transcription related to proliferation required for neoplastic progression. [Abstract/Link to Full Text]

Coates EM, Popa G, Gill CI, McCann MJ, McDougall GJ, Stewart D, Rowland I
Colon-available raspberry polyphenols exhibit anti-cancer effects on in vitro models of colon cancer.
J Carcinog. 2007;64.
BACKGROUND: There is a probable association between consumption of fruit and vegetables and reduced risk of cancer, particularly cancer of the digestive tract. This anti-cancer activity has been attributed in part to anti-oxidants present in these foods. Raspberries in particular are a rich source of the anti-oxidant compounds, such as polyphenols, anthocyanins and ellagitannins. METHODS: A "colon-available" raspberry extract (CARE) was prepared that contained phytochemicals surviving a digestion procedure that mimicked the physiochemical conditions of the upper gastrointestinal tract. The polyphenolic-rich extract was assessed for anti-cancer properties in a series of in vitro systems that model important stages of colon carcinogenesis, initiation, promotion and invasion. RESULTS: The phytochemical composition of CARE was monitored using liquid chromatography mass spectrometry. The colon-available raspberry extract was reduced in anthocyanins and ellagitannins compared to the original raspberry juice but enriched in other polyphenols and polyphenol breakdown products that were more stable to gastrointestinal digestion. Initiation--CARE caused significant protective effects against DNA damage induced by hydrogen peroxide in HT29 colon cancer cells measured using single cell microgelelectrophoresis. Promotion--CARE significantly decreased the population of HT29 cells in the G1 phase of the cell cycle, effectively reducing the number of cells entering the cell cycle. However, CARE had no effect on epithelial integrity (barrier function) assessed by recording the trans-epithelial resistance (TER) of CACO-2 cell monolayers. Invasion--CARE caused significant inhibition of HT115 colon cancer cell invasion using the matrigel invasion assay. CONCLUSION: The results indicate that raspberry phytochemicals likely to reach the colon are capable of inhibiting several important stages in colon carcinogenesis in vitro. [Abstract/Link to Full Text]

Wang J, Eltoum IE, Lamartiniere CA
Genistein chemoprevention of prostate cancer in TRAMP mice.
J Carcinog. 2007;63.
Epidemiological studies suggest an inverse association between soy intake and prostate cancer risk. Genistein, the predominant phytoestrogen in soy food, has been proposed as a potential chemopreventive agent due to its anti-estrogen and tyrosine kinase inhibitory effects. To determine the most effective period for genistein chemoprevention, the Transgenic adenocarcinoma mouse prostate (TRAMP) model was used. The treatments were 250 mg genistein/kg AIN-76A diet 1) prepubertally only, 2) in adulthood only or 3) through out life. Controls received AIN-76A diet. By 28 weeks of age, 100% TRAMP mice fed control diet developed prostatic intraepithelial neoplasia (PIN) or adenocarcinomas with 6%, 16%, 44% and 34% developing high grade PIN, well differentiated, moderately differentiated and poorly differentiated prostatic adenocarcinomas, respectively. Prepubertal only (1-35 days postpartum) and adult only genistein treatments (12-28 weeks) resulted in 6% and 29% decreases in poorly-differentiated cancerous lesions compared with controls, respectively. The most significant effect was seen in the TRAMP mice exposed to genistein throughout life (1-28 weeks) with a 50% decrease in poorly-differentiated cancerous lesions. In a separate experiment in castrated TRAMP mice, dietary genistein suppressed the development of advanced prostate cancer by 35% compared with controls. Of the tumors that developed in castrated TRAMP mice, 100% were poorly-differentiated in contrast to the 37% of noncastrated TRAMP mice that developed poorly-differentiated tumors. ICI 182,780 (ICI), genistein and estrogen down-regulated androgen receptor (AR), estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) in the prostates of C57BL/6 mice, and act independently of ER. Our data obtained in intact and castrated transgenic mice suggest that genistein may be a promising chemopreventive agent against androgen-dependent and independent prostate cancers. [Abstract/Link to Full Text]

Di Cesare S, Marshall JC, Logan P, Antecka E, Faingold D, Maloney SC, Burnier MN
Expression and migratory analysis of 5 human uveal melanoma cell lines for CXCL12, CXCL8, CXCL1, and HGF.
J Carcinog. 2007;62.
BACKGROUND: The aim of this study was to characterize the presence and roles of CXCL12, CXCL8, CXCL1, and HGF in five human uveal melanoma cell lines, using different methods, in order to ascertain their significance in this disease. METHODS: Five human uveal melanoma cell lines (92.1, SP6.5, MKT-BR, OCM-1, and UW-1) of known proliferative, invasive, and metastatic potential were used in this experiment. A migration assay was used in order to assess the responsiveness of each cell line towards the four chosen chemotactic factors. Immunohistochemistry was then performed for all five cell lines (cytospins) using antibodies directed toward CXCL1, CXCL8 and their receptors CXCR2 and CXCR1 respectively. Quantitative real-time PCR was then performed on all five cell lines in order to establish the presence of these four chemotactic factors. RESULTS: All five human uveal melanoma cell lines migrated towards the four chosen chemotactic factors at a level greater than that of the negative control. Chemokines CXCL1 and CXCL8 resulted in the greatest number of migrating cells in all five of our cell lines. Immunohistochemistry confirmed the expression of CXCL1, CXCL8, and their receptors CXCR2 and CXCR1 in all five of the cell lines. Quantitative real-time PCR results established expression of CXCL8, CXCL1, and HGF in all 5 cell lines tested. CXCL1 and CXCL8 are highly expressed in SP6.5 and UW-1. None of the five cell lines expressed any detectable levels of CXCL12. CONCLUSION: The migratory ability of the 5 human uveal melanoma cell lines was positively influenced by the four chemotactic factors tested, namely CXCL12, CXCL8, CXCL1, and HGF. Self-expression of chemotactic factors CXCL8, CXCL1, and HGF may indicate an autocrine system, which perhaps contributes to the cells' metastatic ability in vivo. [Abstract/Link to Full Text]

Aikhionbare FO, Mehrabi S, Kumaresan K, Zavareh M, Olatinwo M, Odunsi K, Partridge E
Mitochondrial DNA sequence variants in epithelial ovarian tumor subtypes and stages.
J Carcinog. 2007;61.
BACKGROUND: A majority of primary ovarian neoplasms arise from cell surface epithelium of the ovaries. Although old age and a positive family history are associated risk factors, the etiology of the epithelial ovarian tumors is not completely understood. Additionally, knowledge of factors involved in the histogenesis of the various subtypes of this tumor as well as those factors that promote progression to advanced stages of ovarian malignancy are largely unknown. Current evidence suggests that mitochondrial alterations involved in cellular signaling pathways may be associated with tumorigenesis. METHODS: In this study, we determined the presence of polymorphisms and other sequence variants of mitochondrial DNA (mtDNA) in 102 epithelial ovarian tumors including 10 matched normal tissues that paired with some of the tumors. High-resolution restriction endonucleases and PCR-based sequencing were used to assess the mtDNA variants spanning 3.3 kb fragment that comprised the D-Loop and 12S rRNA-tRNAphe, tRNAval, tRNAser, tRNAasp, tRNAlys, ATPase 6, ATPase 8, cytochrome oxidase I and II genes. RESULTS: Three hundred and fifty-two (352) mtDNA sequence variants were identified, of which 238 of 352 (68%) have not been previously reported. There were relatively high frequencies of three mutations in the 12S rRNA gene at np 772, 773, and 780 in stage IIIC endometrioid tumors, two of which are novel (773delT and 780delC), and occurred with a frequency of 100% (7/7). Furthermore, two mutations were observed in serous tumors only at np 1657 in stage IV (10/10), and at np 8221delA in benign cystadenomas (3/3) and borderline tumors (4/4). A high frequency, 81% (13/16) of TC insertion at np 310 was found only in early stages of serous subtype (benign cystadenomas, 3/3; borderline tumors, 4/4; stage I tumors, 2/5 and matched normal tissues 4/4). CONCLUSION: Our findings indicate that certain mtDNA mutations can reliably distinguish the different histologic subtypes of epithelial ovarian tumors. In addition, these data raise the possibility that certain mtDNA mutations may be useful biomarkers for predicting tumor aggressiveness and may play a potential role in tumorigenesis. [Abstract/Link to Full Text]

Sri Balasubashini M, Karthigayan S, Somasundaram ST, Balasubramanian T, Rukkumani R, Menon VP
FV peptide induces apoptosis in HEp 2 and HeLa cells: an insight into the mechanism of induction.
J Carcinog. 2006;527.
The present study is an attempt to evaluate the antiproliferative potential of peptide (7.6 kDa) from lionfish (Pterios volitans) venom on cultured HEp2 and HeLa cells. Different dose of purified peptide (1, 2 and 4 microg/ml) at different time points (12, 24 and 36 hrs) were tested for antiproliferative index of the peptide. Among them, 2 microg/ml at 24 hrs was found to effectively inhibit cancer cell growth in vitro and did not cause any adverse effect on normal human lymphocytes. Apoptosis was examined by propidium iodide staining, confirmed by the expression of caspase-8 and caspase-3, down regulation of Bcl-2 expression and DNA fragmentation in treated cells, when compared to untreated HEp2 and HeLa cells. Thus fish venom peptide was found to selectively induce apoptosis in cancer cell. [Abstract/Link to Full Text]

Alsarra IA, Brockmann WG, Cunningham ML, Badr MZ
Hepatocellular proliferation in response to agonists of peroxisome proliferator-activated receptor alpha: a role for Kupffer cells?
J Carcinog. 2006;526.
BACKGROUND: It has been proposed that PPARalpha agonists stimulate Kupffer cells in rodents which in turn, release mitogenic factors leading to hepatic hyperplasia, and eventually cancer. However, Kupffer cells do not express PPARalpha receptors, and PPARalpha agonists stimulate hepatocellular proliferation in both TNFalpha- and TNFalpha receptor-null mice, casting doubt on the involvement of Kupffer cells in the mitogenic response to PPARalpha agonists. This study was therefore designed to investigate whether the PPARalpha agonist PFOA and the Kupffer cell inhibitor methylpalmitate produce opposing effects on hepatocellular proliferation and Kupffer cell activity in vivo, in a manner that would implicate these cells in the mitogenic effects of PPARalpha agonists. METHODS: Male Sprague-Dawley rats were treated intravenously via the tail vein with methylpalmitate 24 hrs prior to perfluorooctanoic acid (PFOA), and were sacrificed 24 hrs later, one hr after an intraperitoneal injection of bromodeoxyuridine (BrdU). Sera were analyzed for TNFalpha and IL-1beta. Liver sections were stained immunohistochemically and quantified for BrdU incorporated into DNA. RESULTS: Data show that PFOA remarkably stimulated hepatocellular proliferation in the absence of significant changes in the serum levels of either TNFalpha or IL-1beta. In addition, methylpalmitate did not alter the levels of these mitogens in PFOA-treated animals, despite the fact that it significantly blocked the hepatocellular proliferative effect of PFOA. Correlation between hepatocellular proliferation and serum levels of TNFalpha or IL-1beta was extremely poor. CONCLUSION: It is unlikely that mechanisms involving Kupffer cells play an eminent role in the hepatic hyperplasia, and consequently hepatocarcinogenicity attributed to PPARalpha agonists. This conclusion is based on the above mentioned published data and the current findings showing animals treated with PFOA alone or in combination with methylpalmitate to have similar levels of serum TNFalpha and IL-1beta, which are reliable indicators of Kupffer cell activity, despite a remarkable difference in hepatocellular proliferation. [Abstract/Link to Full Text]

Schniewind B, Heintz K, Kurdow R, Ammerpohl O, Trauzold A, Emme D, Dohrmann P, Kalthoff H
Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways.
J Carcinog. 2006;525.
BACKGROUND: Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC) inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB) and the nucleoside analogue gemcitabine (GEM) was evaluated and the mechanisms underlying increased cell death were analyzed. METHODS: Dose escalation studies evaluating the cytotoxicity of PB (0.01-100 mM), GEM (0.01-100 microg/ml) and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62). Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. RESULTS: Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50-80% (p = 0.012) more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2-2.7 fold) compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093) and topoisomerase IIalpha (KNS62: p = 0.008; Ben: p = 0.064) proliferation indices were clearly reduced in tumors treated by combination therapy, whereas the apoptotic index was comparably low in all groups. CONCLUSION: Therapy combining GEM and the HDAC inhibitor PB initiates a spectrum of apoptosis-inducing mitochondrial and further JNK-dependent events, thereby overcoming the therapeutic resistance of NSCLC tumor cells. In vivo, the combination therapy substantially reduced tumor cell proliferation, suggesting that the well tolerated PB is a useful supplemental therapeutic agent in NSCLC. [Abstract/Link to Full Text]

Diehl D, Oesterle D, Elmlinger MW, Hoeflich A, Wolf E, Lahm H
IGF-II transgenic mice display increased aberrant colon crypt multiplicity and tumor volume after 1,2-dimethylhydrazine treatment.
J Carcinog. 2006;524.
In colorectal cancer insulin-like growth factor II (IGF-II) is frequently overexpressed. To evaluate, whether IGF-II affects different stages of tumorigenesis, we induced neoplastic alterations in the colon of wild-type and IGF-II transgenic mice using 1,2-dimethylhydrazine (DMH). Aberrant crypt foci (ACF) served as markers of early lesions in the colonic mucosa, whereas adenomas and carcinomas characterized the endpoints of tumor development. DMH-treatment led initially to significantly more ACF in IGF-II transgenic than in wild-type mice. This increase in ACF was especially prominent for those consisting of > or =three aberrant crypts (AC). Nevertheless, adenomas and adenocarcinomas of the colon, present after 34 weeks in both genetic groups, were not found at different frequency. Tumor volumes, however, were significantly higher in IGF-II transgenic mice and correlated with serum IGF-II levels. Immunohistochemical staining for markers of proliferation and apoptosis revealed increased cell proliferation rates in tumors of IGF-II transgenic mice without significant affection of apoptosis. Increased proliferation was accompanied by elevated localization of beta-catenin in the cytosol and cell nuclei and reduced appearance at the inner plasma membrane. In conclusion, we provide evidence that IGF-II, via activation of the beta-catenin signaling cascade, promotes growth of ACF and tumors without affecting tumor numbers. [Abstract/Link to Full Text]

Tug E, Tug T, Elyas H, Coskunsel M, Emri S
Tumor suppressor gene alterations in patients with malignant mesothelioma due to environmental asbestos exposure in Turkey.
J Carcinog. 2006;523.
BACKGROUND: Environmental asbestos exposure can cause the grave lung and pleura malignancies with a high mortality rate, and it is also associated with increased rate of other organ malignancies. Asbestos exposure can develop genotoxic effects and damage in the pleura and lungs. OBJECTIVE: In this study, we aimed to determine tumor suppressor gene (TSG) loss in genomic DNA which was isolated from pleural fluid and blood samples of patients with Malignant Pleural Mesothelioma (MPM) due to environmental asbestos exposure. DESIGN AND PATIENTS: Prospective study of period from 2001 to 2003 in 17 patients with MPM. METHODS: A total of 12 chromosomal regions were researched by comparing genomic DNA samples isolated from blood and pleural effusion (using PCR, and polyacrylamide gel electrophoresis denaturizing), on 2 different chromosomes which have 9 different polymorphic determinants at 6q and 3 different polymorphic determinants at 9p using molecular genetic methods on 13 patients clinico-pathologically diagnosed MPM. RESULTS: Loss of Heterozygosity (LOH) was determined at D6S275 in one patient, at D6S301 in another, at D6S474 in 2, at ARG1 in 2, at D6S1038 in 2 and at D6S1008 in 3 patients. In 7 (54%) of the 13 patients, we found LOH in at least one site. No LOH was determined at any informative loci in 6 patients. Of the 13 patients, no investigated markers were determined at 9p. CONCLUSION: In this study, genomic DNA samples obtained from MPM patients with asbestos exposure revealed that they contained important genotoxic damage. We found no other study on this subject at molecular level in pleural effusion either in Turkey or in the Med-line literature. We believe that this study will provide important support for other research into molecular-genetic variations, both on this subject and other malignancies, and may also constitute a base for early diagnosis and gene therapy research in the future. [Abstract/Link to Full Text]

Zhang H, Fu WL, Huang Q
Mapping of the methylation pattern of the hMSH2 promoter in colon cancer, using bisulfite genomic sequencing.
J Carcinog. 2006;522.
The detailed methylation status of CpG sites in the promoter region of hMSH2 gene has yet not to be reported. We have mapped the complete methylation status of the hMSH2 promoter, a region that contains 75 CpG sites, using bisulfite genomic sequencing in 60 primary colorectal cancers. And the expression of hMSH2 was detected by immunohistochemistry. The hypermethylation of hMSH2 was detected in 18.33% (11/60) of tumor tissues. The protein of hMSH2 was detected in 41.67% (25/60) of tumor tissues. No hypermethylation of hMSH2 was detected in normal tissues. The protein of hMSH2 was detected in all normal tissues. Our study demonstrated that hMSH2 hypermethylation and protein expression were associated with the development of colorectal cancer. [Abstract/Link to Full Text]

Godeiro KD, Frota AC, Antecka E, Odashiro AN, Maloney S, Fernandes B, Burnier MN
Prostate-specific membrane antigen is undetectable in choroidal neovascular membrane.
J Carcinog. 2006;521.
BACKGROUND: Choroidal neovascular membrane (CNVM) is one of the leading causes of severe visual loss and is often associated with age-related macular degeneration (AMD). Various modalities of treatment, including photocoagulation and surgery, are being considered as options, but with limited success. Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein expressed in benign and malignant prostatic tissues, in some non-prostatic tissues, and in the endothelium of tumor-associated neovasculature of non-prostatic neoplasm. Some studies have suggested that the expression of PSMA is restricted to endothelium from tumor-associated neovasculature and might be stimulated by some tumor-secreted angiogenic factors. However, no previous study demonstrating PSMA expression in non-related tumor neovasculature, such as CNVM, has been performed to date. Furthermore, demonstration of PSMA expression in CNVM in AMD patients could reveal a novel target for antineovascular therapy. The purpose of this study was to evaluate the immunohistochemical expression of PSMA in CNVM from AMD. METHODS: Immunohistochemical analysis, with a standard avidin-biotin complex technique, was performed using an anti-PSMA mouse monoclonal antibody in 30 specimens of surgically excised CNVM from AMD patients. Antibody to an endothelial cell specific marker, factor VIII, was used to confirm the location of the endothelial cells. RESULTS: The angiogenic microvessels of the 30 cases demonstrated negative staining to PSMA while factor VIII was expressed in all cases. Seventy-five percent of the secretory-acinar epithelium of the prostatic hyperplasia specimen stained positive, confirming that the immunohistochemical technique was correctly performed. CONCLUSION: The absence of PSMA expression in non-tumoral neovasculature supports the theory, previously suggested, that endothelial cell PSMA expression may be stimulated by one or more tumor-secreted angiogenic factors. Angiogenesis is very important in neoplasia and the endothelial expression of PSMA in tumor-associated neovasculature may represent a target for antineovasculature-based therapy. The absence of PSMA expression in CNVM suggests that PSMA may not be a potential target for antineovasculature-based therapy. [Abstract/Link to Full Text]

Figueiro MG, Rea MS, Bullough JD
Does architectural lighting contribute to breast cancer?
J Carcinog. 2006;520.
OBJECTIVES: There is a growing interest in the role that light plays on nocturnal melatonin production and, perhaps thereby, the incidence of breast cancer in modern societies. The direct causal relationships in this logical chain have not, however, been fully established and the weakest link is an inability to quantitatively specify architectural lighting as a stimulus for the circadian system. The purpose of the present paper is to draw attention to this weakness. DATA SOURCES AND EXTRACTION: We reviewed the literature on the relationship between melatonin, light at night, and cancer risk in humans and tumor growth in animals. More specifically, we focused on the impact of light on nocturnal melatonin suppression in humans and on the applicability of these data to women in real-life situations. Photometric measurement data from the lighted environment of women at work and at home is also reported. DATA SYNTHESIS: The literature review and measurement data demonstrate that more quantitative knowledge is needed about circadian light exposures actually experienced by women and girls in modern societies. CONCLUSION: Without such quantitative knowledge, limited insights can be gained about the causal relationship between melatonin and the etiology of breast cancer from epidemiological studies and from parametric studies using animal models. [Abstract/Link to Full Text]

Liao DJ, Wang Y, Wu J, Adsay NV, Grignon D, Khanani F, Sarkar FH
Characterization of pancreatic lesions from MT-tgf alpha, Ela-myc and MT-tgf alpha/Ela-myc single and double transgenic mice.
J Carcinog. 2006;519.
In order to identify good animal models for investigating therapeutic and preventive strategies for pancreatic cancer, we analyzed pancreatic lesions from several transgenic models and made a series of novel findings. Female MT-tgf alpha mice of the MT100 line developed pancreatic proliferation, acinar-ductal metaplasia, multilocular cystic neoplasms, ductal adenocarcinomas and prominent fibrosis, while the lesions in males were less severe. MT-tgf alpha-ES transgenic lines of both sexes developed slowly progressing lesions that were similar to what was seen in MT100 males. In both MT100 and MT-tgf alpha-ES lines, TGF alpha transgene was expressed mainly in proliferating ductal cells. Ela-myc transgenic mice with a mixed C57BL/6, SJL and FVB genetic background developed pancreatic tumors at 2-7 months of age, and half of the tumors were ductal adenocarcinomas, similar to what was reported originally by Sandgren et al 1. However, in 20% of the mice, the tumors metastasized to the liver. MT100/Ela-myc and MT-tgf alpha-ES/Ela-myc double transgenic mice developed not only acinar carcinomas and mixed carcinomas as previously reported but also various ductal-originated lesions, including multilocular cystic neoplasms and ductal adenocarcinomas. The double transgenic tumors were more malignant and metastasized to the liver at a higher frequency (33%) compared with the Ela-myc tumors. Sequencing of the coding region of p16ink4, k-ras and Rb cDNA in small numbers of pancreatic tumors did not identify mutations. The short latency for tumor development, the variety of tumor morphology and the liver metastases seen in Ela-myc and MT-tgf alpha/Ela-myc mice make these animals good models for investigating new therapeutic and preventive strategies for pancreatic cancer. [Abstract/Link to Full Text]

Chaudhary A, Jain V, Dwivedi RS, Misra S
Invasive aspergillosis causing small bowel infarction in a patient of carcinoma breast undergoing chemotherapy.
J Carcinog. 2006;518.
BACKGROUND: To report a 45 year old lady presenting with proximal jejunal gangrene due to invasive Aspergillosis. The patient was undergoing adjuvant chemotherapy for advance carcinoma of breast (Stage IV). METHODS: The patient was referred to our surgical emergency for acute abdominal symptoms for 6 hours. Histopathology revealed bowel wall necrosis and vascular invasion by Aspergillus Fumigatus. Postoperative recovery was uneventful and the patient received Amphotericin-B (1 mg/kg/day) for invasive aspergillosis. Invasive pulmonary aspergillosis was confirmed by isolating Aspergillus Fumigatus from bronchoalveolar lavage and by a positive circulating galactomannan test (ELISA Assay). RESULTS: Detailed history revealed dry cough and two episodes of haemoptesis for 2 weeks. Haemogram and counts revealed anemia and neutropenia. Plain X-ray of the abdomen showed multiple air fluid levels and ultrasound of the abdomen revealed distended bowel loops. On exploration small bowel was found to be gangrenous. The patient was successfully managed by supportive treatment and conventional intravenous Amphotericin-B for 2 weeks. The lady was discharged one week after completion of antifungal therapy and one month later she underwent toilet mastectomy. The lady came to follow up for 1 year and she is currently under hormone therapy. CONCLUSION: With the emergence of new and powerful immunosuppressive, anticancer drugs and potent antibiotics the survival of transplant and critically ill patients has remarkably increased but it has shown a significant rise in the incidence of invasive opportunistic fungal infections. We conclude hat the diagnosis of invasive gastrointestinal aspergillosis may be considered in a neutropenic patient with acute abdominal symptoms. [Abstract/Link to Full Text]

Hosseini-Asl S, Modarressi MH, Atri M, Salhab M, Mokbel K, Mehdipour P
The association between telomerase activity and expression of its RNA component (hTR) in breast cancer patients: the importance of DNase treatment.
J Carcinog. 2006;517.
Telomerase is a ribonucleoprotein enzyme that compensates for the telomere length shortening which occurs during the cell cycle. Telomerase activity has been detected in most tumours but not in somatic cells. However, hTR; the RNA component of telomerase; has been reported to be universally expressed in both cancerous and non-cancerous tissues. Tumour samples from 50 patients with primary invasive breast cancer were collected. The TRAP assay was used to detect telomerase activity. RT-PCR on cDNA and DNased cDNA samples and control groups was used to detect the expression of hTR, GAPDH and PGM1 genes. Seventy-two percent of samples showed telomerase activity. DNA contamination was detected in 36 (72%) of RNA samples. Without performing DNase treatment, 49 (98%) of all samples showed hTR expression, but with the application of this strategy, hTR expression decreased from 98% to 64%. A significant association (p < 0.001) between hTR expression and telomerase activity was observed. Among the 32 hTR positive samples, 30 had telomerase activity and among the 18 hTR negative samples, telomerase activity was observed in 6 cases. Thus the application of this strategy could provide an applicable tool to use instead of the TRAP assay thus facilitating telomerase research in cancer genetic investigations. [Abstract/Link to Full Text]

Recent Articles in The Oncologist

Wang WS, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Chiou TJ, Liu JH, Yen CC, Chen PM
In reply.
Oncologist. 2007 Nov;12(11):1372-3. [Abstract/Link to Full Text]

Argyriou AA, Polychronopoulos P, Chroni E
The usefulness of nerve conduction studies in objectively assessing oxaliplatin-induced peripheral neuropathy.
Oncologist. 2007 Nov;12(11):1371-2; author reply 1372-3. [Abstract/Link to Full Text]

Khorana AA
The NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease: strategies for improving VTE prophylaxis in hospitalized cancer patients.
Oncologist. 2007 Nov;12(11):1361-70.
The risk for venous thromboembolism (VTE) is high in hospitalized cancer patients, and is associated with an elevated risk for recurrent thrombosis, bleeding complications, and use of health care resources. Thromboembolism is the second leading cause of death in hospitalized cancer patients. Thromboprophylaxis with unfractionated heparin or low-molecular-weight heparins has been clinically proven to reduce the risk for VTE and improve outcomes. However, VTE prophylaxis continues to be underprescribed in cancer patients. Recognizing the clinical burden of VTE in cancer patients, the National Comprehensive Cancer Network (NCCN) recently released guidelines for VTE prevention and management. These NCCN guidelines recommend evidence-based prophylactic anticoagulant therapy for all patients admitted to hospital with a diagnosis of cancer who do not have contraindications to anticoagulant use. However, there continue to be barriers to the implementation of clinical practice guidelines and appropriate use of VTE prophylaxis. Multifaceted active educational and electronic interventions are necessary to raise awareness and reduce the burden of cancer-associated thrombosis and its attendant consequences. [Abstract/Link to Full Text]

Tascilar M, Loos WJ, Seynaeve C, Verweij J, Sleijfer S
The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas.
Oncologist. 2007 Nov;12(11):1351-60.
The treatment outcome of patients with locally advanced and metastatic soft tissue sarcomas is poor. Doxorubicin is regarded as standard treatment, but its use is featured by the occurrence of cardiotoxicity. This hinders the administration of this drug at high doses or in combination with, in theory, attractive newly developed targeted drugs, such as vascular endothelial growth factor (VEGF) pathway inhibitors. The combination of doxorubicin and VEGF pathway inhibitors has been shown to yield an unacceptable high rate of cardiomyopathy. Ifosfamide is the only drug that consistently shows response rates comparable to those of doxorubicin. The lack of cardiotoxicity renders this drug a much more attractive alternative than doxorubicin to be explored at high doses or as part of new drug combinations. This review addresses the clinical pharmacology, metabolism, and present role of ifosfamide in the treatment of locally advanced and/or metastatic soft tissue sarcomas, excluding gastrointestinal stromal tumors, the Ewing-like sarcomas, and other small blue round cell tumors. Furthermore, this review focuses on the anticipated growing role of ifosfamide in the development of new treatment strategies. [Abstract/Link to Full Text]

Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH
Chordoma: the nonsarcoma primary bone tumor.
Oncologist. 2007 Nov;12(11):1344-50.
Chordomas are rare, slowly growing, locally aggressive neoplasms of bone that arise from embryonic remnants of the notochord. These tumors typically occur in the axial skeleton and have a proclivity for the spheno-occipital region of the skull base and sacral regions. In adults, 50% of chordomas involve the sacrococcygeal region, 35% occur at the base of the skull near the spheno-occipital area, and 15% are found in the vertebral column. Craniocervical chordomas most often involve the dorsum sella, clivus, and nasopharynx. Chordomas are divided into conventional, chondroid, and dedifferentiated types. Conventional chordomas are the most common. They are characterized by the absence of cartilaginous or additional mesenchymal components. Chondroid chordomas contain both chordomatous and chondromatous features, and have a predilection for the spheno-occipital region of the skull base. This variant accounts for 5%-15% of all chordomas and up to 33% of cranial chordomas. Dedifferentiation or sarcomatous transformation occurs in 2%-8% of chordomas. This can develop at the onset of the disease or later. Aggressive initial therapy improves overall outcome. Patients who relapse locally have a poor prognosis but both radiation and surgery can be used as salvage therapy. Subtotal resection can result in a stable or improved status in as many as 50% of patients who relapse after primary therapy. Radiation therapy may also salvage some patients with local recurrence. One series reported a 2-year actuarial local control rate of 33% for patients treated with proton beam irradiation. [Abstract/Link to Full Text]

Berg SL
Ethical challenges in cancer research in children.
Oncologist. 2007 Nov;12(11):1336-43.
Clinical research has led to great advances in cancer therapy for children, and a greater proportion of children than adults with cancer participate in clinical trials. Despite this success, there remain important ethical challenges in conducting this research. There are challenges in obtaining informed consent and assent when children are research subjects; challenges arising from study design issues in phase III, II, or I clinical trials; and challenges related to the development of new classes of drugs, especially molecularly targeted therapies. It is important for researchers and clinicians to understand these challenges so that progress in cancer treatment is achieved in a sound ethical and regulatory fashion. [Abstract/Link to Full Text]

Rajasekhar A, George TJ
Gemcitabine-induced reversible posterior leukoencephalopathy syndrome: a case report and review of the literature.
Oncologist. 2007 Nov;12(11):1332-5.
Gemcitabine is a commonly used chemotherapeutic agent for a variety of tumor types. Although this nucleoside analogue antineoplastic agent is similar in structure to cytarabine, central nervous system toxicities have rarely been attributed to gemcitabine. Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare but increasingly identifiable clinicoradiologic process in cancer patients associated with cytotoxic and immunosuppressive agents. The syndrome is characterized by acute to subacute onset of headache, nausea, vomiting, altered mental status, seizures, stupor, and visual disturbances. The pathophysiology of RPLS continues to remain controversial but likely involves loss of cerebrovascular autoregulation leading to arteriole leakage. Radiologically, posterior occipital white matter edema is noted, with characteristic findings on magnetic resonance imaging. Often the syndrome is reversible with treatment of concurrent hypertension or removal of the causative agent; however, failure to quickly recognize the syndrome and discontinue the offending agent may result in profound and permanent central nervous system dysfunction or death. This article describes a case of RPLS attributed to gemcitabine use for pancreatic cancer. Such a descriptive case serves as a platform for the discussion of the syndrome, proposed mechanisms of central nervous system damage, and review of the currently available literature on the topic. With increased awareness of RPLS by oncologists and other medical providers, cancer patient care may be improved and further insight into this complication of therapy through continued research may be gained. [Abstract/Link to Full Text]

de Villa V, Lo CM
Liver transplantation for hepatocellular carcinoma in Asia.
Oncologist. 2007 Nov;12(11):1321-31.
Hepatocellular carcinoma (HCC) is a leading cause of cancer death, particularly in Asia where the major etiology, chronic hepatitis B virus infection, is endemic. The tumor frequently develops in a background of cirrhosis, and liver transplantation offers a chance to cure both the tumor and the underlying cirrhosis. The Milan criteria based on tumor size and number as an estimate of tumor burden are conventionally the gold standard in determining eligibility for transplantation, and the outcome is excellent. The shortage of organs from deceased donors has curtailed the adoption of extended criteria and led to the problems of long waiting times and dropouts. Several measures have been taken to tackle these issues, including prioritization of patients with HCC, use of pretransplant adjuvant treatment to prevent tumor progression, and living donor liver transplantation (LDLT). With a high incidence of HCC and a low organ donation rate, Asia has developed a distinctive pattern of indication and strategy in the application of liver transplantation. Over the last decade, the number of liver transplants in Asia has increased rapidly, by 10-fold, largely as a result of the development of LDLT. The proportion of patients who undergo liver transplantation for HCC is increasing and HCC comprises one third of the indication for liver transplantation in Asia. LDLT is the dominant strategy, accounting for 96% of the liver transplants for HCC. Many transplant programs accept patients beyond the Milan criteria, and the reported 3-year survival rate is about 60%. With the promotion of organ donation, better quantification of the benefit of LDLT for extended indications, and identification of predictors for survival, the practice of liver transplantation for HCC in Asia will continue to evolve. [Abstract/Link to Full Text]

Czito BG, Willett CG
Commentary: rectal cancer an evolution of treatment.
Oncologist. 2007 Nov;12(11):1319-20. [Abstract/Link to Full Text]

Glynne-Jones R, Harrison M
Locally advanced rectal cancer: what is the evidence for induction chemoradiation?
Oncologist. 2007 Nov;12(11):1309-18.
The concept of spatial cooperation in neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer is attractive. Chemotherapy may, as a component of CRT, not only act as a radiosensitizing agent but also potentially eradicate distant micrometastases. Recent trials have demonstrated that the addition of concurrent 5-fluorouracil (5-FU)-based chemotherapy to radiation increases the pathological complete response rate, and reduces local recurrence, but as yet, a survival advantage has not been observed. AIMS: This review aims to examine the evidence for induction CRT in locally advanced rectal cancer. The endpoints of pathological complete response, a negative circumferential margin, sphincter-sparing surgery, local control, disease-free survival (DFS), and overall survival (OS) are examined, as are acute and late morbidity, surgical complications, and late functional results. METHODS: The information to produce this review was compiled by searching PubMed and MEDLINE for English language articles published until April 2007. The search term included "induction, neoadjuvant, chemotherapy, radiotherapy, chemoradiation, combined modality" in association with rectal cancer. CONCLUSIONS: CRT in the European randomized trials of rectal cancer improves tumor downstaging, pathological complete response, and local control over radiotherapy alone, but does not translate into a benefit in terms of longer DFS or OS, or a higher chance of sphincter preservation. Metastatic disease remains a significant problem, which provides a strong rationale for the integration of a second cytotoxic drug, or biologically targeted agents. [Abstract/Link to Full Text]

Schwartz S, Borner K, M�ller K, Martus P, Fischer L, Korfel A, Auton T, Thiel E
Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy.
Oncologist. 2007 Nov;12(11):1299-308.
OBJECTIVE: Leucovorin and extracorporeal removal of methotrexate (MTX) have limited efficacy in delayed MTX elimination after high-dose methotrexate (HD-MTX) therapy. Glucarpidase (carboxypeptidase G2) cleaves MTX into nontoxic metabolites, but experience with this enzyme is limited in adult patients. We evaluated the effects of glucarpidase intervention in adult and elderly patients with delayed MTX elimination. PATIENTS AND METHODS: Forty-three patients (age, 18-78 years) with MTX serum concentrations (sMTX) of 1-1,187 micromol/l received glucarpidase, leucovorin rescue guided by MTX immunoassay, and standard supportive care. MTX and MTX metabolites were quantified in serum (24 patients) and urine (8 patients) by high-performance liquid chromatography. Contributory risk factors, toxicities, and survival were recorded in all patients. RESULTS: Glucarpidase was well tolerated and resulted in an immediate >97% reduction in sMTX, with a 0.2%-35% urinary recovery of the total MTX dose as inactive MTX metabolites. Forty (93%) of 43 patients had normalization (n = 25) or improvement (n = 15) of their serum creatinine. Frequent grade III-IV MTX toxicities were hematological (60%) and mucositis (35%); only eight (19%) patients developed grade III-IV nephrotoxicity. Ten (23%) of 43 patients experienced fatal complications associated with HD-MTX therapy. Patients with three or more contributory risk factors for delayed MTX elimination had a significantly poorer survival than patients with fewer than three risk factors (hazard ratio, 3.64; confidence interval, 1.14-17.54). CONCLUSIONS: Glucarpidase is well tolerated and produces a rapid inactivation of substantial amounts of MTX. However, overall results are still unsatisfactory in adult and elderly patients, suggesting that earlier recognition of delayed MTX elimination and more rapid intervention are needed. [Abstract/Link to Full Text]

Morabito A, Piccirillo MC, Monaco K, Pacilio C, Nuzzo F, Chiodini P, Gallo C, de Matteis A, Perrone F
First-line chemotherapy for HER-2 negative metastatic breast cancer patients who received anthracyclines as adjuvant treatment.
Oncologist. 2007 Nov;12(11):1288-98.
The treatment decision for patients with metastatic breast cancer who have received anthracyclines within the course of adjuvant chemotherapy is troublesome, particularly if trastuzumab and hormonal treatment are not indicated. In the first part of this review we discuss the value of retreatment with anthracyclines, a topic that has been indirectly evaluated by retrospective studies with conflicting results and within a small phase III trial with a negative outcome. Evidence on liposomal anthracyclines is also reviewed. In the second part of the review, alternative options of first-line chemotherapy are discussed. These include taxanes as single agents, taxanes in combination with other cytotoxic drugs, combinations without anthracyclines and taxanes, and innovative treatments including target-based agents. Both the amount and the quality of evidence on these treatments are poor. Few phase III studies are available and most of them have been performed with registrative aims sponsored by the companies who own the winning drug. Beyond indications derived from such studies, there is a great need for more clinical research in this setting. [Abstract/Link to Full Text]

Boughey JC, Gonzalez RJ, Bonner E, Kuerer HM
Current treatment and clinical trial developments for ductal carcinoma in situ of the breast.
Oncologist. 2007 Nov;12(11):1276-87.
Ductal carcinoma in situ (DCIS) is the fastest growing subtype of breast cancer, mainly because of the aging of our populations and improvements in diagnostic mammography and core biopsy. DCIS represents a proliferation of malignant-appearing cells that have not invaded beyond the ductal basement membrane and is a precursor for the development of invasive breast cancer (IBC). Approximately 40% of patients with DCIS treated with biopsy alone, without complete excision or further therapy, develop IBC. Most DCIS itself is harmless if it is detected and excised before it can progress to IBC, and the current approach to DCIS treatment is aimed at just that goal. Typically, it consists of multimodal treatment including segmental mastectomy followed by radiation therapy to the whole breast and then hormonal therapy or total mastectomy followed by hormonal therapy. This review discusses the state-of-the-art in DCIS detection and treatment and highlights promising new strategies in the care of DCIS patients. The data regarding the effectiveness of breast-conserving surgery versus total mastectomy, the possible avoidance of radiation therapy in some subgroups of patients, and the role of hormonal agents are reviewed. Neoadjuvant therapy and the use of trastuzumab for DCIS are currently under investigation and may be future treatment options for DCIS. [Abstract/Link to Full Text]

Leffall LD
C-change: our credo.
Oncologist. 2007 Nov;12(11):1274-5. [Abstract/Link to Full Text]

Ross SD, Allen IE, Probst CA, Sercus B, Crean SM, Ranganathan G
Efficacy and safety of erythropoiesis-stimulating proteins in myelodysplastic syndrome: a systematic review and meta-analysis.
Oncologist. 2007 Oct;12(10):1264-73.
OBJECTIVE: The objective was to assess the efficacy and safety of erythropoiesis-stimulating proteins (ESPs) in anemia of myelodysplastic syndrome (MDS). METHOD: A systematic review and meta-analysis was conducted covering English-language studies published from 1980 to December 2005. RESULTS: Fifty-nine studies qualified: five controlled trials (n = 354), all epoetin versus control (EvC); 51 epoetin single-arm studies (n = 1,650); and three darbepoetin single-arm studies (n = 102). In the EvC studies, epoetin patients demonstrated a significant advantage over controls in terms of hemoglobin (Hb) response (odds ratio, 5.2; 95% confidence interval, 2.5-10.8). Hb response was 48.1% in single-arm darbepoetin studies, 32.1% in epoetin single-arm studies, and 27.3% in EvC studies. Major Hb response averaged 38.8% in darbepoetin studies, 24.5% in epoetin single-arm studies, and 11.4% in EvC studies. Stratified analyses suggest that lower baseline erythropoietin levels, longer treatment durations, and concurrent iron may be associated with greater Hb response to ESPs. None of the analyzable predictors of Hb response (gender, baseline Hb, ESP type, and ESP duration) were significant in meta-regression analyses. In the few studies with quality-of-life measures, ESP groups attained a pre-post change (Functional Assessment of Cancer Therapy - Fatigue) that exceeded minimum clinically important differences. Selected adverse event rates did not differ between the epoetin and darbepoetin groups. CONCLUSION: Published studies suggest that ESPs are efficacious in anemia of MDS. Hb response appears higher in darbepoetin patients than in epoetin patients, and safety appears comparable, but darbepoetin data are sparse, and there are as yet no direct comparison studies. [Abstract/Link to Full Text]

Charu V, Saidman B, Ben-Jacob A, Justice GR, Maniam AS, Tomita D, Rossi G, Rearden T, Glaspy J
A randomized, open-label, multicenter trial of immediate versus delayed intervention with darbepoetin alfa for chemotherapy-induced anemia.
Oncologist. 2007 Oct;12(10):1253-63.
The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 microg every 3 weeks) to maintain hemoglobin levels > or =10 g/dl in patients with CIA (hemoglobin > or =10.5 g/dl and < or =12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to <10 g/dl). In 201 evaluable patients, there was a significant difference between the two groups in the Kaplan-Meier proportion of patients with a hemoglobin decrease to <10 g/dl during weeks 1-13 (test period) (primary endpoint): 29% for immediate-intervention patients versus 65% for observation patients. Sixty-four patients in the observation group received darbepoetin alfa (delayed-intervention subgroup). The Kaplan-Meier proportion of patients who received transfusions was lower in the immediate-intervention group than in the delayed-intervention subgroup (14% versus 31% for the test period; 17% versus 36% over the whole study). The target hemoglobin level (> or =11 g/dl) was achieved by a higher percentage of patients (crude percentage) in less time in the immediate-intervention group (94% in 2 weeks) than in the delayed-intervention subgroup (73% in 6 weeks); hemoglobin endpoints for the delayed-intervention subgroup were calculated from recalibrated study week 1 (the date patients first received darbepoetin alfa). For both groups, a higher mean change in hemoglobin from baseline led to a greater improvement in Functional Assessment of Cancer Therapy-Fatigue scores. In conclusion, immediate intervention resulted in a significantly lower proportion of patients who experienced a decline in hemoglobin, lower requirement for transfusions, and greater proportion of patients achieving and maintaining the target hemoglobin level. [Abstract/Link to Full Text]

Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R
FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.
Oncologist. 2007 Oct;12(10):1247-52.
On October 6, 2006, the U.S. Food and Drug Administration granted regular approval to vorinostat (Zolinza(R); Merck & Co., Inc., Whitehouse Station, NJ), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The pivotal study supporting approval was a single-arm open-label phase II trial that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). Patients received vorinostat at a dose of 400 mg orally once daily, which could be reduced for toxicity to 300 mg daily or 300 mg 5 days a week. The median age of patients was 61 years. Sixty-one patients (82%) had stage IIB or higher CTCL and 30 patients (41%) had S�zary syndrome. The median duration of protocol treatment was 118 days. The primary efficacy endpoint was objective response assessed by the Severity-Weighted Assessment Tool. The objective response rate was 30% (95% confidence interval [CI], 19.7%-41.5%), the estimated median response duration was 168 days, and the median time to tumor progression was 202 days. An additional single-center study enrolled 33 patients with similar baseline and demographic features as the pivotal trial. Thirteen of the 33 received vorinostat (400 mg/day). The response rate in these 13 patients was 31% (95% CI, 9.1%-61.4%). The most common clinical adverse events (AEs) of any grade were diarrhea (52%), fatigue (52%), nausea (41%), and anorexia (24%). Grade 3 or 4 clinical AEs included fatigue (4%) and pulmonary embolism (5%). Hematologic laboratory abnormalities included thrombocytopenia (26%) and anemia (14%). Chemistry laboratory abnormalities included increased creatinine (16%), increased serum glucose (69%), and proteinuria (51%). Most abnormalities were National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2. Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine. [Abstract/Link to Full Text]

Chintagumpala M, Chevez-Barrios P, Paysse EA, Plon SE, Hurwitz R
Retinoblastoma: review of current management.
Oncologist. 2007 Oct;12(10):1237-46.
The most common ocular cancer in children is retinoblastoma. It affects approximately 300 children in the U.S. every year. It can affect one or both eyes and the disease can be inherited. Altered discoloration of the pupil and strabismus are the usual symptoms that lead to medical attention. Subsequent appropriate diagnostic studies and care provided by a multidisciplinary team, including an ophthalmologist, a pediatric oncologist, a radiation oncologist, and a geneticist, among others, often result in optimal short-term and long-term care. The best initial and subsequent treatments are based on whether the child has unilateral or bilateral disease, the stage of the disease, and the age of the child. Enucleation, chemotherapy, and various forms of radiation therapy along with local ophthalmic therapies can be used in the treatment of retinoblastoma. Cure rates are high in children when the tumor is confined to the eye and has not spread systemically or into the orbit or brain. Children with the heritable form of retinoblastoma are at high risk for developing subsequent malignancies, most commonly sarcomas. This risk is greater for those children with the heritable form of the disease who were exposed to ionizing radiation at age <1 year. Exciting discoveries using animal models are providing new insights into the development of this disease and opening new avenues for targeted therapies that may lead to high cure rates with minimal toxicities. [Abstract/Link to Full Text]

Tabernero MD, Espinosa AB, Maillo A, Rebelo O, Vera JF, Sayagues JM, Merino M, Diaz P, Sousa P, Orfao A
Patient gender is associated with distinct patterns of chromosomal abnormalities and sex chromosome linked gene-expression profiles in meningiomas.
Oncologist. 2007 Oct;12(10):1225-36.
The female predominance of meningiomas has been established, but how this is affected by hormones is still under discussion. We analyzed the characteristics of meningiomas from male (n = 53) and female (n = 111) patients by interphase fluorescence in situ hybridization (iFISH). In addition, in a subgroup of 45 (12 male and 33 female) patients, tumors were hybridized with the Affymetrix U133A chip. We show a higher frequency of larger tumors (p = .01) and intracranial meningiomas (p = .04) together with a higher relapse rate (p = .03) in male than in female patients. Male patients had a higher percentage of del(1p36) (p < .001), while loss of an X chromosome was restricted to tumors from female patients (p = .008). In turn, iFISH studies showed a higher frequency of chromosome losses, other than monosomy 22 alone, in meningiomas from male patients (p = .002), while female patients displayed a higher frequency of chromosome gains (p = .04) or monosomy 22 alone (p = .03) in the ancestral tumor clone. Interestingly, individual chromosomal abnormalities had a distinct impact on the recurrence-free survival rate of male versus female patients. In turn, gene expression showed that eight genes (RPS4Y1, DDX3Y, JARID1D, DDX3X, EIF1AY, XIST, USP9Y, and CYorf15B) had significantly different expression patterns (R(2) > 0.80; p < .05) in tumors from male and female patients. In summary, we show the existence of different patterns of chromosome abnormalities and gene-expression profiles associated with patient gender, which could help to explain the slightly different clinical behavior of these two patient groups. [Abstract/Link to Full Text]

Fasola G, Belvedere O, Aita M, Zanin T, Follador A, Cassetti P, Meduri S, De Pangher V, Pignata G, Rosolen V, Barbone F, Grossi F
Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial--an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002).
Oncologist. 2007 Oct;12(10):1215-24.
OBJECTIVE: To evaluate the feasibility of using low-dose computed tomography (LDCT) for the early diagnosis of lung cancer and malignant pleural mesothelioma in an asbestos-exposed population. METHODS: Between February 2002 and October 2003, 1,045 volunteers already enrolled in a surveillance program for asbestos-exposed workers and former workers were recruited. The main eligibility criteria were: written informed consent, definite exposure to asbestos, age 40-75, no prior cancer or severe concomitant conditions, no chest CT scan in the past 2 years. A smoking history was not required. After a structured interview, chest X-ray (CXR) and LDCT were performed. Participants with negative examinations were assigned to annual LDCT. Participants with positive findings received high-resolution CT and additional diagnostic workup as appropriate. RESULTS: Baseline characteristics of the screened population were: median asbestos exposure time, 30 years; median age, 58; median pack-years in smokers/former smokers, 18.5. Thirty-four percent had never smoked. On LDCT, 834 noncalcified nodules were identified in 44% of participants, versus 43 nodules in 4% on CXR. Pleural abnormalities were observed in 44% and 70% of participants by CXR and LDCT, respectively. Overall, LDCT identified nine cases of non-small cell lung cancer-eight stage I, one stage IIA-and one thymic carcinoid, corresponding to 1% of the enrolled population. All cases were radically treated. None had been detected by CXR. No pleural mesothelioma was diagnosed. There were 11 false-positive results. CONCLUSIONS: Our findings first suggest that LDCT may be at least as useful in asbestos workers as in heavy smokers for the early diagnosis of lung cancer; this benefit is evident even in a poor-risk population, with low rates of smoking prevalence and a previous history of radiological surveillance. The role of spiral tomography in screening for pleural mesothelioma remains uncertain. [Abstract/Link to Full Text]

Solli P, Spaggiari L
Indications and developments of video-assisted thoracic surgery in the treatment of lung cancer.
Oncologist. 2007 Oct;12(10):1205-14.
The term video-assisted thoracic surgery (VATS) is used to describe a modern minimally invasive surgical technique that nowadays represents a valid alternative to open procedures (i.e., thoracotomy) for many chest diseases. The VATS approach is presently used in many intrathoracic disorders, but while well established in benign chest disease, its role continues to evolve regarding the management of lung cancer. It is currently considered for the evaluation and treatment of suspected (or known) pleural effusion and in the diagnosis of indeterminate pulmonary nodules, and it has a complementary role to standard cervical mediastinoscopy in the invasive staging of mediastinal lymph nodes. It has also become an accepted approach for resection of peripheral early-stage lung cancer (stage I) in many centers worldwide and considerable experience has been accumulated in respect to this field, but absolute indications have yet to be firmly defined. This paper reviews indications and current data regarding minimally invasive approaches for the staging and treatment of lung cancer. [Abstract/Link to Full Text]

O'Brien M, Eckardt J, Ramlau R
Recent advances with topotecan in the treatment of lung cancer.
Oncologist. 2007 Oct;12(10):1194-204.
Topotecan is a semisynthetic derivative of camptothecin that specifically targets topoisomerase I. It has well-established antineoplastic properties and has been successfully combined with other antineoplastic agents with activity dependent on DNA disruption, such as cisplatin and etoposide. Topotecan is indicated for the treatment of small cell lung cancer (SCLC) sensitive disease after failure of first-line chemotherapy and metastatic ovarian carcinoma after failure of initial or subsequent chemotherapy. Since the approval of topotecan for the second-line treatment of SCLC, studies have been conducted in the first-line setting. Recent studies demonstrate the utility of i.v. topotecan in combination with cisplatin for untreated SCLC. Further, an oral formulation of topotecan is currently under investigation and may provide added convenience for patients. Oral topotecan has been studied in the first- and second-line settings for both SCLC and non-small cell lung cancer (NSCLC). Three recent phase III trials have demonstrated the activity of oral topotecan. In the first study of chemotherapy-na�ve patients with extensive-disease SCLC, oral topotecan plus cisplatin provided efficacy and safety similar to those of etoposide plus cisplatin. In a second study of patients with relapsed SCLC, treatment with oral topotecan showed a statistically significant and clinically meaningful longer overall survival time and improvement in dyspnea and quality of life compared with best supportive care alone in all prognostic groups. Finally, in previously treated patients with NSCLC, single-agent oral topotecan was shown to be noninferior in 1-year survival rate relative to the current standard of i.v. docetaxel. In future studies, oral topotecan will represent a good candidate for combination therapy with other i.v. or oral chemotherapy agents, monoclonal antibodies, and small molecule tyrosine kinase inhibitors. [Abstract/Link to Full Text]

Gridelli C, Maione P, Rossi A, De Marinis F
The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments.
Oncologist. 2007 Oct;12(10):1183-93.
The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease, and despite the improvement in efficacy and safety outcomes with platinum-based chemotherapy, this standard cytotoxic approach has reached a therapeutic plateau, with the prognosis for this clinical condition remaining poor. Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. Bevacizumab, an anti-growth factor vascular endothelial growth factor (VEGF) monoclonal antibody, is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment. Bevacizumab, combined with platinum-based chemotherapy, has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials. These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease (especially with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor) and the integration of this agent into combined modality approaches for the treatment of early-stage and locally advanced disease. [Abstract/Link to Full Text]

Beldner M, Jacobson M, Burges GE, Dewaay D, Maize JC, Chaudhary UB
Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib.
Oncologist. 2007 Oct;12(10):1178-82.
The development of multitargeted tyrosine kinase inhibitors has provided significant advances in the treatment of renal cell carcinoma. This case describes initial therapy for managing renal cell cancer with the administration of sorafenib, a multitargeted tyrosine kinase inhibitor. We report the development of localized palmar-plantar epidermal hyperplasia, a rare but significant cutaneous adverse event from sorafenib therapy. Mild-to-moderate dermatologic toxicity from sorafenib has been well described in the literature. We also review the current knowledge and the proposed hypothesis for the development of cutaneous events related to tyrosine kinase inhibitors. This particular case represents a unique form of dermatologic toxicity to sorafenib that has not previously been described in the literature. [Abstract/Link to Full Text]

Ekman S, Bergqvist M, Heldin CH, Lennartsson J
Activation of growth factor receptors in esophageal cancer--implications for therapy.
Oncologist. 2007 Oct;12(10):1165-77.
Esophageal cancer is a highly aggressive disease and is the seventh most common cause of cancer-related death in the western world. Worldwide, it ranks as the sixth most frequent cause of cancer death. Despite advances in surgical techniques and treatment, the prognosis of esophageal cancer remains poor, with very few long-term survivors. The need for novel strategies to detect esophageal cancer earlier and to improve current therapy is urgent. It is well established that growth factors and growth factor receptor-mediated signaling pathways are important components of the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are emerging possibilities to use growth factor signal transduction pathways in targeted therapy. This review provides a summary of the role of growth factors and their receptors in esophageal cancer and discusses their potential roles as biomarkers and as targets in therapy. [Abstract/Link to Full Text]

Jones LW, Haykowsky M, Pituskin EN, Jendzjowsky NG, Tomczak CR, Haennel RG, Mackey JR
Cardiovascular reserve and risk profile of postmenopausal women after chemoendocrine therapy for hormone receptor--positive operable breast cancer.
Oncologist. 2007 Oct;12(10):1156-64.
Purpose. To examine cardiovascular function and risk profile of postmenopausal women treated with chemoendocrine therapy (CET) for hormone receptor-positive operable breast cancer. Methods. Forty-seven breast cancer patients and 11 age-matched healthy controls were studied. Participants performed a cardiopulmonary exercise test with expired gas analysis and impedance cardiography to assess peak aerobic power (VO(2peak)) and cardiovascular function (stroke volume, cardiac output, cardiac power output, and cardiac reserve). Traditional (i.e., body mass index, lipid profile, and fasting insulin and glucose) and novel (i.e., C-reactive protein, brain natriuretic peptide) cardiovascular risk biochemical factors were also assessed. Results. Breast cancer patients had significantly lower peak exercise stroke volume (68 +/- 9 versus 76 +/- 11 ml/beat), cardiac output (10.4 +/- 1.5 versus 11.7 +/- 2.4 l/minute), cardiac power output (3.0 +/- 0.5 versus 3.5 +/- 0.9 Watts), cardiac power output reserve (1.7 +/- 0.6 versus 2.4 +/- 0.8 Watts), and VO(2peak) (1.3 +/- 0.3 versus 1.6 +/- 0.2 l x min(-1)) than control subjects (p-values < .05). Patients with the greatest impairment in VO(2peak) had the worse cardiovascular risk profile. Exploratory analyses revealed several differences in study outcomes between the 26 patients receiving hormonal therapy with tamoxifen (TAM) and the 21 patients receiving aromatase inhibitor (AI) therapy. Conclusion. Breast cancer patients treated with adjuvant CET have a significantly and markedly lower cardiorespiratory fitness and cardiac functional reserve compared with age- and sex-matched controls. AI therapy may be associated with a more unfavorable cardiovascular risk profile than TAM. Prospective studies are required to further investigate the clinical value of these findings. [Abstract/Link to Full Text]

Gurpide A, Sadaba B, Martin-Algarra S, Azanza JR, Lopez-Picazo JM, Campanero MA, Cabello JP, Gil-Aldea I, de la Cruz S, Fernandez Gallego V, Reyna C, Olier Garate C, Blanco-Prieto MJ, Ceballos J, Garcia-Foncillas J, Perez-Gracia JL
Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy.
Oncologist. 2007 Sep;12(9):1151-5.
BACKGROUND: 5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron. PATIENTS AND METHODS: Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance. RESULTS: From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration-time curve for 0-12 hours (AUC(0-12h)) and higher levels at 12 hours, with similar values for AUC(0-24h). The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration. CONCLUSION: Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients. [Abstract/Link to Full Text]

Jordan K, Sippel C, Schmoll HJ
Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations.
Oncologist. 2007 Sep;12(9):1143-50.
Clinicians should be aware that chemotherapy-induced nausea and vomiting (CINV) is still one of the most feared side effects of chemotherapy. With the correct use of antiemetics, CINV can be prevented in almost 70% to up to 80% of patients. Treatment guidelines are useful tools that enable physicians to integrate the latest clinical research into their practices. The large volume of rapidly evolving clinical data has been summarized and incorporated into treatment recommendations by well-known and reliable institutions, including the Multinational Association of Supportive Care in Cancer, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network. Despite the availability of such guidelines, however, there is evidence that adherence to and implementation of treatment recommendations are less than optimal. This review focuses, in particular, on the conformity and differences of these three guidelines. Furthermore, open questions and trends in the field of antiemesis are discussed as well. [Abstract/Link to Full Text]

Mayer F, Aebert H, Rudert M, K�nigsrainer A, Horger M, Kanz L, Bamberg M, Ziemer G, Hartmann JT
Primary malignant sarcomas of the heart and great vessels in adult patients--a single-center experience.
Oncologist. 2007 Sep;12(9):1134-42.
BACKGROUND: Sarcomas arising in the heart or the great vessels are rare entities. The prognosis of the patients is dismal. METHODS: Between January 1993 and September 2006, of 1,429 patients registered to the Sarcoma Center, 14 had a primary sarcoma of the heart or large vessels. RESULTS: Tumors were located in the left ventricle (n = 3), left/right atrium (n = 2/3), pulmonary artery (n = 2), and ventricular septum, aorta, pericardium, and inferior vena cava (n = 1 each). The most frequently encountered histologic subtypes were leiomyosarcoma and angiosarcoma. Six patients presented with distant metastases to the lungs (n = 5), lymph nodes (n = 2), and liver (n = 1). Eight patients had localized disease. Six of them underwent resection with curative intent. Of those, two developed local recurrence within 2 and 10 months from surgery. Eleven patients received palliative chemotherapy, seven of those as initial treatment. Eight patients attained a response to treatment, two had disease stabilization for 6 and 12 months. After a median follow-up of 14.5 months (range, 2-156), three patients were alive with no evidence of disease 11, 52, and 156 months after diagnosis. Two patients were alive with disease and nine patients had died. CONCLUSIONS: Patients with primary sarcomas of the heart and the large vessels were of a young age, and more than half of them presented with advanced disease. Given the promising response to chemotherapy, an optimized treatment approach including neoadjuvant chemo-/radiotherapy in patients with locally advanced disease should be pursued. [Abstract/Link to Full Text]

Mercuro G, Cadeddu C, Piras A, Dess� M, Madeddu C, Deidda M, Serpe R, Massa E, Mantovani G
Early epirubicin-induced myocardial dysfunction revealed by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers.
Oncologist. 2007 Sep;12(9):1124-33.
A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated patients with cancer at different sites with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. All patients underwent conventional echocardiography, as well as tissue Doppler imaging (TDI) with strain (sigma) and strain rate (SR), a very accurate technique for detecting minimal changes in cardiac left ventricular (LV) function. Moreover, echocardiographic changes identified during epirubicin treatment were compared with those of a series of biochemical markers of both myocardial damage and inflammation/oxidative stress. Sixteen patients (male-to-female ratio, 3:13; mean age +/- standard deviation, 56 +/-3 years; range, 27-75 years) with histologically confirmed tumors at different sites, scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled in the study. A significant impairment in systolic LV function was observed after 200 mg/m2 of epirubicin; this was shown by a lower SR peak compared with baseline (1.82 +/- 0.57/second versus 1.45 +/- 0.44/second), whereas sigma remained unchanged. The following significant changes in LV diastolic function occurred only after 300 mg/m2 of epirubicin: a decrease in conventional early/late diastolic (E/A) velocities (1.16 +/- 0.31 versus 0.93 +/- 0.24) and a reduction in both the E(m) wave in the basal portion of the interventricular septum (8.86 +/- 1.73 cm/second versus 7.51 +/- 2.30 cm/second) and in the E(m)/A(m) ratio (1.09 +/- 0.51 versus 0.83 +/- 0.51), as measured using the TDI technique. No significant changes in LV ejection fraction were observed. Baseline values of brain natriuretic peptide, troponin I, myoglobin, and creatine kinase-myocardial subfraction were within the normal range and no significant changes were observed throughout the study. Levels of interleukin (IL)-6 and its soluble receptor (sIL-6R) and reactive oxygen species increased significantly, whereas glutathione peroxidase (GPx) levels decreased significantly, after 200 mg/m2 of epirubicin. Significant correlations between the reduction in the SR peak (deltaSR) after 200 mg/m2 of epirubicin and the increase in IL-6 and ROS and decrease in GPx were observed. The multiple regression analysis showed that the only independent predictive variable for deltaSR was ROS level. Our data show that: (a) subtle cardiac abnormalities may occur at epirubicin doses significantly below those known to be potentially clinically harmful and (b) the earliest myocardial impairment affects LV systolic rather than diastolic function. Early contractility impairment during epirubicin treatment was associated with high levels of ROS and markers of inflammation. The clinical meaningfulness of our findings warrants further investigations in a larger number of patients for a longer period of follow-up. [Abstract/Link to Full Text]

Recent Articles in CA: A Cancer Journal for Clinicians

Eyre HJ, Gansler T
Reviewer acknowledgment 2007.
CA Cancer J Clin. 2007 Nov-Dec;57(6):379. [Abstract/Link to Full Text]

Eriksen M, Chaloupka F
The economic impact of clean indoor air laws.
CA Cancer J Clin. 2007 Nov-Dec;57(6):367-78.
Clean indoor air laws are easily implemented, are well accepted by the public, reduce nonsmoker exposure to secondhand smoke, and contribute to a reduction in overall cigarette consumption. There are currently thousands of clean indoor air laws throughout the Unites States, and the majority of Americans live in areas where smoking is completely prohibited in workplaces, restaurants, or bars. The vast majority of scientific evidence indicates that there is no negative economic impact of clean indoor air policies, with many studies finding that there may be some positive effects on local businesses. This is despite the fact that tobacco industry-sponsored research has attempted to create fears to the contrary. Further progress in the diffusion of clean indoor air laws will depend on the continued documentation of the economic impact of clean indoor air laws, particularly within the hospitality industry. This article reviews the spread of clean indoor air laws, the effect on public health, and the scientific evidence of the economic impact of implementation of clean indoor air laws. [Abstract/Link to Full Text]

Sarfaty M, Wender R
How to increase colorectal cancer screening rates in practice.
CA Cancer J Clin. 2007 Nov-Dec;57(6):354-66.
A recommendation from a physician is the most influential factor in determining whether a patient is screened for colorectal cancer. While the vast majority of primary care physicians report that they screen for colorectal cancer, many patients do not receive the recommendation they need. Evidence-based strategies can help the physician ensure that every appropriate patient leaves the office with the needed recommendation. Choosing an office system that can be implemented by the physician or office staff can fuel efforts to achieve higher screening rates. Reminder systems, tracking systems, communication strategies, and policies that reinforce use of evidence-based guidelines may contribute. [Abstract/Link to Full Text]

Gilson AM, Joranson DE, Maurer MA
Improving state pain policies: recent progress and continuing opportunities.
CA Cancer J Clin. 2007 Nov-Dec;57(6):341-53.
The National Institutes of Health reports that 100 million Americans suffer from chronic pain, including pain associated with the disease of cancer. Painful conditions can strike anyone, including cancer patients and cancer survivors. Unrelieved severe pain can limit a person's functioning and sometimes even destroy the will to live. When the quality of pain relief provided is inadequate, it is usually the result of failures to apply existing knowledge about pain and its treatment, including the appropriate use of opioids. But pain relief also can be affected by the regulatory environment and fear of being investigated for excessive prescribing. The importance of evaluating and improving policies governing pain management has been recognized by national and international authorities, including the Institute of Medicine and the World Health Organization. A pilot examination of state laws and regulatory policies demonstrated that they contained a number of outdated medical concepts and prescribing restrictions and did not contain key elements of law that can make pain management a priority for licensed medical practitioners. The Pain & Policy Studies Group developed a research program to evaluate US federal and state policy governing the medical use of pain medication. This article describes 3 national policy evaluations and how the results are being used to document improvements in state pain policies. An emerging role for clinicians and their professional organizations to improve their state's pain policies is discussed. [Abstract/Link to Full Text]

Sedjo RL, Byers T, Barrera E, Cohen C, Fontham ET, Newman LA, Runowicz CD, Thorson AG, Thun MJ, Ward E, Wender RC, Eyre HJ
A midpoint assessment of the American Cancer Society challenge goal to decrease cancer incidence by 25% between 1992 and 2015.
CA Cancer J Clin. 2007 Nov-Dec;57(6):326-40.
In 1998, the American Cancer Society (ACS) set a challenge goal for the nation to reduce cancer incidence by 25% over the period between 1992 and 2015. This report examines the trends in cancer incidence between 1992 and 2004. Trends were calculated using data on incident malignant cancer cases from the Surveillance, Epidemiology, and End Results (SEER) Registry. Delay-adjusted incidence trends for all cancer sites; all cancer sites without prostate cancer included; all cancer sites stratified by gender, age, and race; and for 20 selected cancer sites are presented. Over the first half of the ACS challenge period, overall cancer incidence rates have declined by about 0.6% per year. The greatest overall declines were observed among men and among those aged 65 years and older. The pace of incidence reduction over the first half of the ACS challenge period was only half that necessary to put us on target to achieve the 25% cancer incidence reduction goal in 2015. New understandings of preventable factors are needed, and new efforts are also needed to better act on our current knowledge about how we can prevent cancer, especially by continuing to reduce tobacco use and beginning to reverse the epidemic of obesity. [Abstract/Link to Full Text]

Cancer patients at risk of drug interactions.
CA Cancer J Clin. 2007 Sep-Oct;57(5):258-9. [Abstract/Link to Full Text]

Uninsured present with more advanced cancer.
CA Cancer J Clin. 2007 Sep-Oct;57(5):257-8. [Abstract/Link to Full Text]

Katzel JA, Hari P, Vesole DH
Multiple myeloma: charging toward a bright future.
CA Cancer J Clin. 2007 Sep-Oct;57(5):301-18.
Multiple myeloma (MM) is an incurable clonal B-cell malignancy with terminally differentiated plasma cells. It afflicts approximately 55,000 people in the United States. Over the past 5 years, significant progress has been made in the diagnosis and assessment of patients with MM. Significant advances include a simplified staging system, which has replaced the more cumbersome Durie-Salmon staging system; an updated uniform international response criteria; the development of a sensitive new serum test to detect free light chain production (free light chain assay); the recognition of specific adverse cytogenetic abnormalities; and the evolution of genomics, which will identify specific and targeted therapies for individual MM patients. For the first time in decades, major therapeutic advances have been implemented in the treatment of MM patients. These include 2 new classes of agent: immunomodulatory drugs and proteosome inhibitors. In addition, clinical trials have solidified the role of hematopoietic stem cell transplant and established the benefits of post-transplant maintenance therapy. Finally, a number of new agents are in development that specifically target the myeloma cells and/or the bone marrow microenvironment. These advances have resulted in expanded treatment options, prolonged disease control and survival, and improved quality of life for patients with MM. [Abstract/Link to Full Text]

Lipscomb J, Gotay CC, Snyder CF
Patient-reported outcomes in cancer: a review of recent research and policy initiatives.
CA Cancer J Clin. 2007 Sep-Oct;57(5):278-300.
There is growing recognition that patient-reported outcome (PRO) measures--encompassing, for example, health-related quality of life--can complement traditional biomedical outcome measures (eg, survival, disease-free survival) in conveying important information for cancer care decision making. This paper provides an integrated review and interpretation of how PROs have been defined, measured, and used in a range of recent cancer research and policy initiatives. We focus, in turn, on the role of PRO measurement in the evaluation and approval of cancer therapies, the assessment of cancer care in the community, patient-provider decision making in clinical oncology practice, and population surveillance of cancer patients and survivors. The paper concludes with a discussion of future challenges and opportunities in PRO measure development and application, given the advancing state of the science in cancer outcomes measurement and the evolving needs of cancer decision makers at all levels. [Abstract/Link to Full Text]

Duffy C, Perez K, Partridge A
Implications of phytoestrogen intake for breast cancer.
CA Cancer J Clin. 2007 Sep-Oct;57(5):260-77.
Phytoestrogens are a group of plant-derived substances that are structurally or functionally similar to estradiol. Interest in phytoestrogens has been fueled by epidemiologic data that suggest a decreased risk of breast cancer in women from countries with high phytoestrogen consumption. Women with a history of breast cancer may seek out these "natural" hormones in the belief that they are safe or perhaps even protective against recurrence. Interpretation of research studies regarding phytoestrogen intake and breast cancer risk is hampered by differences in dietary measurement, lack of standardization of supplemental sources, differences in metabolism amongst individuals, and the retrospective nature of much of the research in this area. Data regarding the role of phytoestrogens in breast cancer prevention is conflicting, but suggest early exposure in childhood or early adolescence may be protective. In several placebo-controlled randomized trials among breast cancer survivors, soy has not been found to decrease menopausal symptoms. There is very little human data on the role of phytoestrogens in preventing breast cancer recurrence, but the few studies conducted do not support a protective role. There is in vivo animal data suggesting the phytoestrogen genistein may interfere with the inhibitive effects of tamoxifen on breast cancer cell growth. [Abstract/Link to Full Text]

Bleyer A
Young adult oncology: the patients and their survival challenges.
CA Cancer J Clin. 2007 Jul-Aug;57(4):242-55.
One in every 168 Americans develops invasive cancer between age 15 to 30 years. During this age interval, cancer is unique in the distribution of types that occur and rarely related to either environmental carcinogens, a recognizable inherited predisposition, or a family cancer syndrome. Patients in this age group have the lowest rate of health insurance coverage, frequent delays in diagnosis, and the lowest accrual to clinical trials. Their psychosocial needs are unique and generally less well attended to than in any other age group. Despite an intrinsically equal ability to tolerate chemotherapy, older adolescents and young adults frequently receive lower dose intensities than do younger patients, and at times less than in older patients. Whereas the 15- to 29-year age group once had a better overall survival rate than either younger or older patients, a relative lack of progress has resulted in the majority of cancers in the age group having a worse overall survival rate than in younger patients, and several of these having a worse prognosis than in older patients. Against this background, young adults with cancer have unique survival challenges--medically, psychosocially, and economically--that are now beginning to be appreciated and addressed with a national initiative. [Abstract/Link to Full Text]

Loberg RD, Bradley DA, Tomlins SA, Chinnaiyan AM, Pienta KJ
The lethal phenotype of cancer: the molecular basis of death due to malignancy.
CA Cancer J Clin. 2007 Jul-Aug;57(4):225-41.
The last decade has seen an explosion in knowledge of the molecular basis and treatment of cancer. The molecular events that define the lethal phenotype of various cancers--the genetic and cellular alterations that lead to a cancer with a poor or incurable prognosis--are being defined. While these studies describe the cellular events of the lethal phenotype of cancer in detail, how these events result in the common clinical syndromes that kill the majority of cancer patients is not well understood. It is clear that the central step that makes most cancers incurable is metastasis. Understanding the traits that a cancer acquires to successfully grow and metastasize to distant sites gives insight into how tumors produce multiple factors that result in multiple different clinical syndromes that are lethal for the patient. [Abstract/Link to Full Text]

Torigian DA, Huang SS, Houseni M, Alavi A
Functional imaging of cancer with emphasis on molecular techniques.
CA Cancer J Clin. 2007 Jul-Aug;57(4):206-24.
A multitude of noninvasive, quantitative, functional imaging techniques are currently in use to study tumor physiology, to probe tumor molecular processes, and to study tumor molecules and metabolites in vitro and in vivo using computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (US), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and optical imaging (OI). Such techniques can be used in conjunction with structural imaging techniques to detect, diagnose, characterize, or monitor tumors before and after therapeutic intervention. These can also be used to study tumor gene expression, to track cells and therapeutic drugs, to optimize individualized treatment planning for patients with tumors, and to foster new oncologic drug development. In this article, we review the rich variety of functional imaging techniques that are available for these purposes, which are becoming increasingly important for optimal individualized patient treatment in this day and age of "personalized medicine." [Abstract/Link to Full Text]

McCracken M, Olsen M, Chen MS, Jemal A, Thun M, Cokkinides V, Deapen D, Ward E
Cancer incidence, mortality, and associated risk factors among Asian Americans of Chinese, Filipino, Vietnamese, Korean, and Japanese ethnicities.
CA Cancer J Clin. 2007 Jul-Aug;57(4):190-205.
Many studies demonstrate that cancer incidence and mortality patterns among Asian Americans are heterogeneous, but national statistics on cancer for Asian ethnic groups are not routinely available. This article summarizes data on cancer incidence, mortality, risk factors, and screening for 5 of the largest Asian American ethnic groups in California. California has the largest Asian American population of any state and makes special efforts to collect health information for ethnic minority populations. We restricted our analysis to the 4 most common cancers (prostate, breast, lung, colon/rectum) and for the 3 sites known to be more common in Asian Americans (stomach, liver, cervix). Cancer incidence and mortality were summarized for 5 Asian American ethnic groups in California in order of population size (Chinese, Filipino, Vietnamese, Korean, and Japanese). Chinese Americans had among the lowest incidence and death rate from all cancer combined; however, Chinese women had the highest lung cancer death rate. Filipinos had the highest incidence and death rate from prostate cancer and the highest death rate from female breast cancer. Vietnamese had among the highest incidence and death rates from liver, lung, and cervical cancer. Korean men and women had by far the highest incidence and mortality rates from stomach cancer. Japanese experienced the highest incidence and death rates from colorectal cancer and among the highest death rates from breast and prostate cancer. Variations in cancer risk factors were also observed and were for the most part consistent with variations in cancer incidence and mortality. Differences in cancer burden among Asian American ethnic groups should be considered in the clinical setting and in cancer control planning. [Abstract/Link to Full Text]

Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ
Adjuvant treatment of colorectal cancer.
CA Cancer J Clin. 2007 May-Jun;57(3):168-85.
Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Approximately three quarters of patients are diagnosed with disease limited to the bowel wall or surrounding lymph nodes. Over the past decade, significant progress has been made in the treatment of localized colorectal cancer due to advances in surgery, radiotherapy, and chemotherapy. For patients with Stage III colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy through the inclusion of oxaliplatin into adjuvant treatment programs. For patients with Stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at high risk for disease recurrence. In the treatment of patients with rectal cancer, improved outcomes have been noted with the use of total mesorectal excision and preoperative concurrent chemoradiotherapy. Current randomized clinical trials in the adjuvant therapy of colorectal cancer are examining the value of adding agents known to be active in metastatic disease, including those that modify specific molecular targets. [Abstract/Link to Full Text]

Klein WM, Stefanek ME
Cancer risk elicitation and communication: lessons from the psychology of risk perception.
CA Cancer J Clin. 2007 May-Jun;57(3):147-67.
Cancer risk perceptions are a key predictor of risk-reduction practices, health behaviors, and processing of cancer information. Nevertheless, patients and the general public (as well as health care providers) exhibit a number of errors and biases in the way they think about risk, such that their risk perceptions and decisions deviate greatly from those prescribed by normative decision models and by experts in risk assessment. For example, people are more likely to engage in screening behaviors such as mammography when faced with loss-based messages than gain-framed messages, and they often ignore the base rate of a given disease when assessing their own risk of obtaining this disease. In this article, we review many of the psychological processes that underlie risk perception and discuss how these processes lead to such deviations. Among these processes are difficulties with use of numerical information (innumeracy), cognitive processes (eg, use of time-saving heuristics), motivational factors (eg, loss and regret aversion), and emotion. We conclude with suggestions for future research in the area, as well as implications for improving the elicitation and communication of personal cancer risk. [Abstract/Link to Full Text]

Greene FL, Kercher KW, Nelson H, Teigland CM, Boller AM
Minimal access cancer management.
CA Cancer J Clin. 2007 May-Jun;57(3):130-46.
Minimal access approaches in the treatment of a variety of solid tumors of the stomach, large bowel, and genitourinary system are now being advocated in several surgical specialty areas. The laparoscope has evolved from a diagnostic tool to a modality that allows for removal of tumors using small incisions and the application of pneumoperitoneum with carbon dioxide. Through studies using animal models and patient investigation, the immunologic benefits of laparoscopic cancer procedures appear to be beneficial when compared with conventional laparotomy. Overall benefits of analgesic reduction, more rapid postoperative recovery, and patient satisfaction are the byproducts of minimal access approaches. Patients with cancers of the stomach, colon, and kidney show similar long-term outcomes when compared with conventional open techniques. Caution, however, should be exercised in recommending laparoscopic approaches for routine management of primary tumors of the rectum and adrenal gland. [Abstract/Link to Full Text]

Garcia JA, Rini BI
Recent progress in the management of advanced renal cell carcinoma.
CA Cancer J Clin. 2007 Mar-Apr;57(2):112-25.
A better understanding of the molecular biology of renal cell carcinoma (RCC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease. Historically, a nonspecific immune approach using cytokines was employed, but recently this has transitioned to a molecularly-targeted approach against vascular endothelial growth factor (VEGF) and related pathways. Several anti-VEGF agents, including ligand-binding agents such as bevacizumab and the small molecule inhibitors of VEGF and related receptors such as sunitinib and sorafenib, have demonstrated clinical activity in patients with metastatic RCC. Other agents that inhibit alternative targets such as the mammalian target of rapamycin (mTOR) have also demonstrated activity. This generation of novel molecular targeted therapies continues to show great promise. The purpose of this review is to summarize the current management and to discuss potential future directions in the management of metastatic RCC. [Abstract/Link to Full Text]

Solomon D, Breen N, McNeel T
Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines.
CA Cancer J Clin. 2007 Mar-Apr;57(2):105-11.
The remarkable success achieved in cervical cancer prevention is largely attributable to cervical cytology screening, also known as the Papanicolaou (Pap) test. The American Cancer Society (ACS) revised screening guidelines for Pap testing in 2002. The impact of these changes on future numbers of Pap tests has not been assessed. Using National Health Interview Survey (NHIS) data to determine historical screening patterns, we extrapolate the numbers of Pap tests that would be performed through 2010, under 5 different scenarios of implementation of screening guidelines. From 1993 to 2003, there was a steady increase in the number of Pap tests, with an estimated 65.6 million Pap tests performed in 2003. Approximately two thirds of women born after 1930 reported having been screened within the previous year, and 85% within the previous 3 years. Fifteen percent of Pap tests were performed in hysterectomized women, most of whom, according to current guidelines, should not be screened. Based on population projections, if screening behavior remains unchanged, 75 million Pap tests will be performed in 2010. Full compliance with ACS guidelines would approximately halve the total number of tests to 34 million. Potentially, with more appropriate allocation of resources according to guidelines, all women could be screened and the total number of Pap tests reduced, despite projected increases in the population. [Abstract/Link to Full Text]

Smith RA, Cokkinides V, Eyre HJ
Cancer screening in the United States, 2007: a review of current guidelines, practices, and prospects.
CA Cancer J Clin. 2007 Mar-Apr;57(2):90-104.
Each year, the American Cancer Society (ACS) publishes a summary of its recommendations for early cancer detection, including guideline updates, emerging issues that are relevant to screening for cancer, and a summary of the most current data on cancer screening rates for US adults. In 2006, there were no updates to ACS guidelines for early cancer detection. In this issue of the journal, we describe criteria for successful screening, discuss recent evidence and policy changes that have implications for cancer screening, summarize the ACS guidelines and describe guidelines reviews that are underway, and provide an update of the most recent data pertaining to participation rates in cancer screening from the Centers for Disease Control and Prevention's (CDC's) Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS). [Abstract/Link to Full Text]

Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, Morris E, Pisano E, Schnall M, Sener S, Smith RA, Warner E, Yaffe M, Andrews KS, Russell CA
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CA Cancer J Clin. 2007 Mar-Apr;57(2):75-89.
New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20-25% or greater lifetime risk of breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin disease. There are several risk subgroups for which the available data are insufficient to recommend for or against screening, including women with a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts on mammography. Diagnostic uses of MRI were not considered to be within the scope of this review. [Abstract/Link to Full Text]

Huerta E, Grey N
Cancer control opportunities in low- and middle-income countries.
CA Cancer J Clin. 2007 Mar-Apr;57(2):72-4. [Abstract/Link to Full Text]

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ
Cancer statistics, 2007.
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66.
Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. This report considers incidence data through 2003 and mortality data through 2004. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007. Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 0.3% per year in women; and a 13.6% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population. [Abstract/Link to Full Text]

Pickle LW, Hao Y, Jemal A, Zou Z, Tiwari RC, Ward E, Hachey M, Howe HL, Feuer EJ
A new method of estimating United States and state-level cancer incidence counts for the current calendar year.
CA Cancer J Clin. 2007 Jan-Feb;57(1):30-42.
The American Cancer Society (ACS) has published the estimated number of new cancer cases and deaths in the current year for the United States that are commonly used by cancer control planners and the media. The methods used to produce these estimates have changed over the years as data (incidence) and statistical models improved. In this paper we present a new method that uses statistical models of cancer incidence that incorporate potential predictors of spatial and temporal variation of cancer occurrence and that account for delay in case reporting and then projects these estimated numbers of cases ahead 4 years using a piecewise linear (joinpoint) regression method. Based on evidence presented here that the new method produces more accurate estimates of the number of new cancer cases for years and areas for which data are available for comparison, the ACS has elected to use it to estimate the number of new cancer cases in Cancer Facts & Figures 2007 and in Cancer Statistics, 2007. [Abstract/Link to Full Text]

From the American Cancer Society: vaccines to prevent cervical cancer.
CA Cancer J Clin. 2007 Jan-Feb;57(1):29. [Abstract/Link to Full Text]

Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, Goldie SJ, Harper DM, Kinney W, Moscicki AB, Noller KL, Wheeler CM, Ades T, Andrews KS, Doroshenk MK, Kahn KG, Schmidt C, Shafey O, Smith RA, Partridge EE, Garcia F
American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors.
CA Cancer J Clin. 2007 Jan-Feb;57(1):7-28.
The American Cancer Society (ACS) has developed guidelines for the use of the prophylactic human papillomavirus (HPV) vaccine for the prevention of cervical intraepithelial neoplasia and cervical cancer. These recommendations are based on a formal review of the available evidence. They address the use of prophylactic HPV vaccines, including who should be vaccinated and at what age, as well as a summary of policy and implementation issues. Implications for screening are also discussed. [Abstract/Link to Full Text]

Wender RC
Preserving primary care: the front line in the war against cancer.
CA Cancer J Clin. 2007 Jan-Feb;57(1):4-5. [Abstract/Link to Full Text]

Heck RK, Peabody TD, Simon MA
Staging of primary malignancies of bone.
CA Cancer J Clin. 2006 Nov-Dec;56(6):366-75.
Staging of bone sarcomas is the process whereby patients are evaluated with regard to histology, as well as the local and distant extent, of disease. Bone sarcomas are staged based on grade, size, and the presence and location of metastases. The system is designed to help stratify patients according to known risk factors. Proper staging helps define the prognosis for patients and helps guide their treatment. Furthermore, staging allows meaningful comparisons to be done among groups of patients. [Abstract/Link to Full Text]

Connor TH, McDiarmid MA
Preventing occupational exposures to antineoplastic drugs in health care settings.
CA Cancer J Clin. 2006 Nov-Dec;56(6):354-65.
The toxicity of antineoplastic drugs has been well known since they were introduced in the 1940s. Because most antineoplastic drugs are nonselective in their mechanism of action, they affect noncancerous as well as cancerous cells, resulting in well-documented side effects. During the 1970s, evidence came to light indicating health care workers may be at risk of harmful effects from antineoplastic drugs as a result of occupational exposure. Since that time, reports from several countries have documented drug contamination of the workplace, identified drugs in the urine of health care workers, and measured genotoxic responses in workers. Evidence also exists of teratogenic and adverse reproductive outcomes and increased cancers in health care workers. During the past 30 years, professional organizations and government agencies have developed guidelines to protect health care workers from adverse effects from occupational exposure to antineoplastic drugs. Although many safety provisions were advanced to reduce worker exposure in the 1980s, recent studies have shown that workers continue to be exposed to these drugs despite safety policy improvements. In 2004, the National Institute for Occupational Safety and Health (NIOSH) published an alert reviewing the most recent information available and promoting a program of safe handling during their use. [Abstract/Link to Full Text]

Doyle C, Kushi LH, Byers T, Courneya KS, Demark-Wahnefried W, Grant B, McTiernan A, Rock CL, Thompson C, Gansler T, Andrews KS
Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices.
CA Cancer J Clin. 2006 Nov-Dec;56(6):323-53.
Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplement use 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 from 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; select nutrition and physical activity issues such as body weight, food choices, and food safety; issues related to select cancer sites; and common questions about diet, physical activity, and cancer survivorship. [Abstract/Link to Full Text]

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

Finn MA, Vrionis FD, Schmidt MH
Spinal radiosurgery for metastatic disease of the spine.
Cancer Control. 2007 Oct;14(4):405-11.
BACKGROUND: Metastatic tumor in the spinal column is common, causing symptomatic spinal cord compression in approximately 25,000 patients annually. Although surgical treatment of spinal metastases has become safer, less invasive, and more efficacious in recent years, there remains a subset of patients for whom other treatment modalities are needed. Stereotactic radiosurgery, which has long been used in the treatment of intracranial lesions, has recently been applied to the spine and enables the effective treatment of metastatic lesions. METHODS: We review the evolution of stereotactic radiosurgery and its applications in the spine, including a description of two commercially available systems. RESULTS: Although a relatively new technique, the use of stereotactic radiosurgery in the spine has advanced rapidly in the past decade. Spinal stereotactic radiosurgery is an effective and safe modality for the treatment of spinal metastatic disease. CONCLUSIONS: Future challenges involve the refinement of noninvasive fiducial tracking systems and the discernment of optimal doses needed to treat various lesions. Additionally, dose-tolerance limits of normal structures need to be further developed. Increased experience will likely make stereotactic radiosurgery of the spine an important treatment modality for a variety of metastatic lesions. [Abstract/Link to Full Text]

Bessler P, Aung M, Jolly P
Factors affecting uptake of cervical cancer screening among clinic attendees in trelawny, Jamaica.
Cancer Control. 2007 Oct;14(4):396-404.
BACKGROUND: Use of the Pap test has resulted in a decline in cervical cancer mortality in developed countries. Yet, despite established cervical cancer screening programs, a significant portion of Jamaican women are not undergoing screening for cervical cancer. This study was carried out to identify factors that affect Jamaican women's decisions to screen for cervical cancer. METHODS: A population survey was administered to 367 clinic-attending women 25 to 54 years of age in the Parish of Trelawny from May to July of 2005. An interviewer-administered questionnaire assessed the women's knowledge, attitudes, and practices regarding cervical cancer and cervical cancer screening. RESULTS: Overall, 11% of the women had never had a Pap smear and only 38% had a Pap test within the last year. Annual visits to a health provider have a strong influence on women's decisions to regularly screen for cervical cancer. Provider recommendation also positively affected initial receipt of a Pap smear as well as continued regular screening. CONCLUSIONS: Programs that promote annual health checkups, encourage consistent provider recommendations, and emphasize screening as a preventive measure might positively influence women's decisions to screen for cervical cancer. [Abstract/Link to Full Text]

Reyes-Ortiz CA, Camacho ME, Amador LF, Velez LF, Ottenbacher KJ, Markides KS
The impact of education and literacy levels on cancer screening among older latin american and Caribbean adults.
Cancer Control. 2007 Oct;14(4):388-95.
BACKGROUND: There is limited information related to the effects of education and literacy on cancer screening practices among older adults in Latin American and Caribbean countries. METHODS: To determine the association between education and cancer screening use, we developed a cross-sectional study using data from the Health, Well-Being and Aging in Latin America and the Caribbean Study. The sample included 4,183 men and 6,708 women aged 60 years and older from seven cities. The outcomes are mammogram and Pap smear use in women and prostate examination use in men within the last 2 years. RESULTS: In general, illiterate or lower-educated older men and women have the lowest rates of cancer screening use compared with higher-educated counterparts. Multivariate logistic models, by city and in a combined sample of six cities showed that high education is associated with higher odds of having a mammogram or a Pap smear in women and a prostate examination in men. CONCLUSIONS: Older adults with low educational or literacy levels should be targeted for screening programs in these populations. [Abstract/Link to Full Text]

Walker MS, Farria D, Schmidt M, Monsees B, Wiele K, Bokern J, Swatske ME
Educational intervention for women undergoing image-guided breast biopsy: results of a randomized clinical trial.
Cancer Control. 2007 Oct;14(4):380-7.
BACKGROUND: The process of informed consent has been examined for patients undergoing various procedures but not breast biopsy. Our study was a randomized trial that examined the effect of an educational flip chart as part of the informed consent. METHODS: A total of 122 patients referred for stereotactic or ultrasound-guided core breast biopsy were randomly assigned to receive an informed consent discussion with or without an illustrated flip chart. The chart included information about breast anatomy, pathology, and diagnostic procedures. Outcome measures included objective knowledge, subjective knowledge, anxiety, and satisfaction. RESULTS: Analysis showed few significant main effects of the intervention. However, results showed interactions between experimental condition and race/ethnicity, indicating that the intervention was effective in enhancing objective and subjective knowledge for African American but not Caucasian patients. Anxiety after consultation was higher among patients assigned to the flip chart condition, possibly because they were better informed about the risks of the procedure. Patients who underwent biopsy sooner after learning they needed one were more satisfied with their care. CONCLUSIONS: The usual care consent process is effective for many but not all patients. Informed consent that employs visual aids may help overcome characteristics of the consent process that are ineffective for some patients. [Abstract/Link to Full Text]

Wells KJ, Roetzheim RG
Health disparities in receipt of screening mammography in latinas: a critical review of recent literature.
Cancer Control. 2007 Oct;14(4):369-79.
BACKGROUND: Increased use of screening mammography is associated with lower death rates from breast cancer in the United States. Despite recommendations that women over 40 years of age should obtain regular screening mammography at least every 2 years, many women do not adhere to these guidelines. Historically, women from underserved and minority populations have been less likely to receive screening mammography. METHODS: A critical review of recent research literature was conducted to evaluate whether Latinas are less likely to receive screening mammography, determine whether disparities in screening mammography persist when controlling for other variables, and examine what other variables are associated with screening mammography. The articles were obtained from a search of the PubMed database. RESULTS: Fifteen published articles met the inclusion criteria and were critically reviewed. The unadjusted odds ratios (ORs) of the association between Hispanic ethnicity and screening mammography ranged from 0.40 to 0.93. For the most part, the ORs adjusted for other variables in multiple logistic regression analyses increased (range: 0.3 to 1.67). Age, education, income, health insurance, having a usual source of care, and having a recent visit to a physician were consistently related to screening mammography in multiple logistic regression analysis. CONCLUSIONS: Hispanic ethnicity is a risk factor for lack of adherence to screening mammography. However, other demographic, socioeconomic, and health system variables account for some of the disparity related to Hispanic ethnicity. [Abstract/Link to Full Text]

Laronga C, Drake RR
Proteomic approach to breast cancer.
Cancer Control. 2007 Oct;14(4):360-8.
BACKGROUND: Breast cancer is the most common cancer affecting women worldwide. Despite tremendous advances in screening, diagnosis, and treatment, the causes of this disease remain elusive and complex. Proteomics is a rapidly developing field that can explore the heterogeneity of breast cancer and supplement the wealth of information gained from genomics. METHODS: This article serves as an overview of the application of matrix-assisted laser desorption/ionization source with a time-of-flight (MALDI-TOF) proteomic techniques as applied to breast cancer. Examples of the clinical applicability of MALDI-TOF mass spectrometry are provided but represent only a fraction of the potential uses yet to be discovered. In addition, a brief summary of the bioinformatics issues that surround proteomics is included. RESULTS: Mass spectrometry has provided new proteomic approaches to unravel the complexities of clinical specimens relevant to breast cancer diagnostics. In particular, MALDI-TOF mass spectrometry analysis has been used to differentiate cancer profiles from benign profiles in samples from sera, plasma, tissue, nipple fluid, and ductal lavage. Some discriminating proteins have subsequently been identified. CONCLUSIONS: Mass spectrometry applications to breast cancer diagnostics continue to be developed but are evolving faster than bioinformatics/statistical analysis can adapt. The future of these techniques in terms of clinical investigation is limitless, but in terms of general applicability, these applications are currently cost-prohibitive. [Abstract/Link to Full Text]

Lang JE, Kuerer HM
Breast ductal secretions: clinical features, potential uses, and possible applications.
Cancer Control. 2007 Oct;14(4):350-9.
BACKGROUND: Nipple discharge accounts for approximately 5% of visits to a breast specialist surgical practice and may be encountered as the chief complaint by many other types of physicians. The vast majority of breast cancers originate in the ductal system, which prompted interest in the evaluation of the intraductal approach to breast cancer. Ductoscopy, nipple aspiration, and ductal lavage have emerged as innovative fields of study that may have clinical applications. METHODS: We performed a literature search of published manuscripts using the keywords nipple discharge, breast ductal secretions, and intraductal approach. We also report our single-institution experience in managing nipple discharge. RESULTS: We present our institutional algorithm for the management of nipple discharge. The possible etiologies of nipple discharge and the appropriate workup are reviewed. Three evolving minimally invasive techniques for the evaluation of high-risk patients include ductoscopy, nipple aspiration, and ductal lavage. Nipple aspiration and ductal lavage fluid may be assayed for cytology, genomic, gene expression, and proteomic studies. Several different translational approaches are being undertaken to investigate the local microenvironment associated with the development and progression of breast carcinoma. CONCLUSIONS: Nipple aspiration fluid and ductal lavage offer the opportunity to study the local microenvironment of the ductal system, which is where most breast cancers originate. These powerful approaches to biomarker analysis could be applied to the prevention and treatment of breast cancer. [Abstract/Link to Full Text]

Berman CG
Recent advances in breast-specific imaging.
Cancer Control. 2007 Oct;14(4):338-49.
BACKGROUND: Imaging the breast is a vital component not only for breast cancer screening, but also for diagnosis, evaluation, treatment, and follow-up of patients with breast cancer. METHODS: The author reviews recent advances and also provides her personal experience in describing the status of digital mammography, computer-aided detection, dedicated magnetic resonance imaging (MRI), and positron-emission mammography for evaluating the breast. RESULTS: Full-field digital mammography is superior to standard mammography in women under 50 years of age and in those with dense breasts. Computer-aided detection assists inexperienced mammographers and enhances detection of microcalcifications in dense breasts. Breast MRI is useful in preoperative evaluation, clarification of indeterminate mammograms, and follow-up of BRCA mutation carriers. The specificity of MRI remains problematic, however. Positron-emission mammography promises enhanced detection of ductal carcinoma in situ (DCIS), even when not associated with microcalcifications, and should aid surgical planning. CONCLUSIONS: These four significant advances in breast imaging have all improved the sensitivity of detecting breast abnormalities. Cost issues, however, may limit the widespread application of these advances. [Abstract/Link to Full Text]

Allain DC, Sweet K, Agnese DM
Management Options After Prophylactic Surgeries in Women With BRCA Mutations: A Review.
Cancer Control. 2007 Oct;14(4):330-7.
BACKGROUND: Although breast cancer is relatively common, only about 5% of cases are due to inheritance of highly penetrant cancer susceptibility genes. The majority of these are caused by mutations in the BRCA1 and BRCA2 genes, which are also associated with an increased risk of ovarian cancer. Increased surveillance, chemoprevention, and prophylactic surgeries are standard options for the effective medical management of mutation carriers. However, optimal management of female carriers who choose to undergo prophylactic surgeries is still poorly understood. METHODS: The authors provide an overview of the current literature regarding medical management options for women carriers of BRCA1 and BRCA2 gene mutations and the implications for those individuals who have chosen to undergo prophylactic surgeries. RESULTS: BRCA mutation carriers who opt for prophylactic surgeries are still at risk for development of malignancy, and appropriate monitoring is warranted. CONCLUSIONS: There are limited data on the appropriate medical management for BRCA mutation carriers after prophylactic surgeries. However, a management plan can be extrapolated from the general management recommendations for surveillance and other risk-reducing strategies in BRCA-positive individuals. [Abstract/Link to Full Text]

Kiluk JV, Acs G, Hoover SJ
High-risk benign breast lesions: current strategies in management.
Cancer Control. 2007 Oct;14(4):321-9.
BACKGROUND: High-risk benign breast lesions can create confusion for both the patient and the clinician. This paper reviews the characteristics of these lesions to help direct appropriate management. METHODS: The authors reviewed the literature regarding high-risk breast lesions and include management guidelines that we employ at our institute. RESULTS: High-risk breast lesions offer varying degrees of increased risk for the future development of breast cancer. Chemoprevention may be used to help decrease the risks from some lesions. CONCLUSIONS: The management of high-risk benign breast lesions can be confusing. Clinicians should assess the risk of future breast cancer and develop a proper screening and prevention strategy for each individual patient. [Abstract/Link to Full Text]

Rocha-Lima CM, Soares HP, Raez LE, Singal R
EGFR targeting of solid tumors.
Cancer Control. 2007 Jul;14(3):295-304.
BACKGROUND: Recent clinical trials suggest that epidermal growth factor receptor (EGFR)-targeted agents could benefit many patients with cancer. METHODS: We review the current status of several EGFR-targeted therapies in cancer patients and address the efficacy of theses drugs as monotherapy or in combination with other drugs and/or treatments. RESULTS: Cetuximab is the most widely studied anti-EGFR monoclonal antibody. Other monoclonal antibody agents under investigation are panitumumab, matuzumab, MDX-447, nimutozumab, and mAb806. Extensive research has also evaluated the efficacy of EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib, EKB-569, lapatinib (GW572016), PKI-166, and canertinib (CI-1033). All of these agents have been studied for the treatment of colorectal, lung, breast, pancreatic, renal, head and neck, gynecologic, and prostate cancer. Currently, cetuximab and panitumumab are FDA approved for the treatment of metastatic colorectal cancer. Additionally, cetuximab is approved for head and neck cancer. Erlotinib is FDA approved for advanced/metastatic lung cancer. Erlotinib in combination with gemcitabine is approved for advanced/metastatic pancreatic cancer treatment. CONCLUSIONS: EGFR-targeted agents have already shown utility in different scenarios. Researchers are continuously investigating additional cancer types and combined treatment modalities that could also benefit from the use of EGFR-targeted agents. Careful patient selection through the identification of specific biologic markers, such as gene expression, genomic polymorphism, and posttranslational modifications of EGFR downstream effectors, most likely will contribute to the successful use of these agents. [Abstract/Link to Full Text]

Homsi J, Daud AI
Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors.
Cancer Control. 2007 Jul;14(3):285-94.
BACKGROUND: Angiogenesis plays an important role in tumor growth and metastasis. METHODS: We review the function of the vascular endothelial growth factor (VEGF) in vessel formation that is complemented by platelet-derived growth factor (PDGF). We also review the agents designed to target VEGF, PDGF, and/or their receptors. RESULTS: VEGF plays a central role in tumor angiogenesis. It is expressed at increased levels in colorectal, liver, lung, thyroid, breast, as well as in bladder, ovary, uterine cancers, and in angiosarcomas, germ cell tumors, intracranial tumors, and others. VEGF blockade has been shown to have a direct and rapid antivascular effect in both animal and human tumors, through deprivation of tumor vascular supply and inhibition of endothelial proliferation. Overexpression of PDGFs and their receptors has also been reported in many types of cancers such as prostate, ovarian, and non-small-cell lung cancer. Many VEGF and PDGF inhibitors are available. The use of some of these inhibitors has significantly improved the survival of cancer patients. Several agents are in development and currently are being tested in clinical trials. CONCLUSIONS: Angiogenic agents inhibiting VEGF and PDGF have shown promising clinical results. Targeting more than one pathway by combining different agents may increase the antitumor activity of these drugs. The implementation of reliable radiologic and pathologic angiogenesis monitoring techniques is necessary to implement antiangiogenic therapies in cancer. [Abstract/Link to Full Text]

Hughes Halbert C, Barg FK, Weathers B, Delmoor E, Coyne J, Wileyto EP, Arocho J, Mahler B, Malkowicz SB
Differences in cultural beliefs and values among African American and European American men with prostate cancer.
Cancer Control. 2007 Jul;14(3):277-84.
BACKGROUND: Although cultural values are increasingly being recognized as important determinants of psychological and behavioral outcomes following cancer diagnosis and treatment, empirical data are not available on cultural values among men. This study evaluated differences in cultural values related to religiosity, temporal orientation, and collectivism among African American and European American men. METHODS: Participants were 119 African American and European American men who were newly diagnosed with early-stage and locally advanced prostate cancer. Cultural values were evaluated by self-report using standardized instruments during a structured telephone interview. RESULTS: After controlling for sociodemographic characteristics, African American men reported significantly greater levels of religiosity (Beta = 24.44, P < .001) compared with European American men. African American men (Beta = 6.30, P < .01) also reported significantly greater levels of future temporal orientation. In addition, men with more aggressive disease (eg, higher Gleason scores) (Beta = 5.11, P < .01) and those who were pending treatment (Beta = -6.42, P < .01) reported significantly greater levels of future temporal orientation. CONCLUSIONS: These findings demonstrate that while ethnicity is associated with some cultural values, clinical experiences with prostate cancer may also be important. This underscores the importance of evaluating the effects of both ethnicity and clinical factors in research on the influence of cultural values on cancer prevention and control. [Abstract/Link to Full Text]

McMillan SJ, Haley E, Zollman-Huggler P, Johnson Avery E, Winchenbach MG, Bell JL
Breast health education for working women in Appalachia: insights from focus group research.
Cancer Control. 2007 Jul;14(3):265-76.
BACKGROUND: This study seeks to understand rural working women, their knowledge of health systems, and how breast health issues fit into their lives. A key aim of this study was to identify regionally and culturally specific factors that influence how these women approach breast health and to identify ways that more positive breast health behaviors can be achieved. METHODS: Five focus groups (N = 42) were conducted among women at sites where the Breast Health Outreach Program (BHOP) had been conducted. Focus groups were composed of 7 to 10 women who were in about the same age cohort. RESULTS: Women provided multiple insights about their attitudes and behaviors related to breast heath concerns. Analysis of the data revealed that many of the comments clustered around two types of "systems" in these women's lives: the professional health care system and personal community systems. The BHOP provides a bridge between these two systems and seems to facilitate positive actions. Workplace health professionals also provide a bridge between professional and personal systems. CONCLUSIONS: Women exhibited the general distrust of the medical system that the literature indicates is often associated with Appalachian culture. However, this study found that distrust can be overcome with education programs that meet women where they live and work. Such programs are most likely to be successful when the materials and methods are sensitive to Appalachian culture and when medical services are brought into the community. [Abstract/Link to Full Text]

Correa JJ, Politis C, Rodriguez AR, Pow-Sang JM
Laparoscopic retroperitoneal lymph node dissection in the management of testis cancer.
Cancer Control. 2007 Jul;14(3):258-64.
BACKGROUND: The surgical approach to management of testis cancer has been traditionally through an open incision, but in the last decade, several centers have reported their experience with laparoscopic retroperitoneal lymph node dissection (LRPLND). METHODS: We reviewed the English literature, summarized the outcomes, and included our initial experience with the LRPLND procedure. RESULTS: Improvements in operative time, complications, and morbidity have occurred as surgical experience has increased. The procedure is more challenging in postchemotherapy patients. Outcomes at our institute are comparable to reported series from other institutions, and LRPLND is our current procedure of choice for RPLND. CONCLUSIONS: LRPLND has been shown to be a safe, effective, minimally invasive procedure in the management of testicular cancer patients who require surgery to address the retroperitoneal lymph nodes. [Abstract/Link to Full Text]

Pow-Sang JM, Velasquez J, Myers MD, Rodriguez AR, Kang LC
Pure laparoscopic and robotic-assisted laparoscopic radical prostatectomy in the management of prostate cancer.
Cancer Control. 2007 Jul;14(3):250-7.
BACKGROUND: Until recently, open radical prostatectomy was the only approach for the surgical management of prostate cancer. Laparoscopy is now increasingly used as an alternative approach. The procedure can be performed directly or with robot assistance. METHODS: We review the relevant literature regarding oncologic and functional outcomes with laparoscopic surgery in the management of localized prostate cancer. RESULTS: Oncologic and functional outcomes are similar between open and laparoscopic radical prostatectomy. Pure laparoscopic prostatectomy and robotic assisted laparoscopic prostatectomy result in less blood loss and shorter convalescence. Costs associated with the initial investment, disposables, and maintenance of the robot system are higher than for pure laparoscopic prostatectomy. CONCLUSIONS: Laparoscopic radical prostatectomy, either pure or robotic, is becoming the preferred approach for the surgical management of localized prostate cancer. Oncologic and functional outcomes are similar to the open approach. [Abstract/Link to Full Text]

Murat FJ, Poissonnier L, Pasticier G, Gelet A
High-intensity focused ultrasound (HIFU) for prostate cancer.
Cancer Control. 2007 Jul;14(3):244-9.
BACKGROUND: The growing interest in high-intensity focused ultrasound (HIFU) is mainly due to its potential applications as a minimally invasive therapy. HIFU has been assessed for its role in the treatment of localized prostate cancer in patients who otherwise would not have benefited from surgery and in local recurrences after radiation failure. METHODS: Relevant information on HIFU treatment was identified through a MEDLINE search using specified terms. Papers that presented original outcomes were included in the present review. RESULTS: High biochemical efficacy, excellent tumor local control and favorable mid-term oncological data with a low morbidity rate have been proven in many series of patients. CONCLUSIONS: Although HIFU is a recent and emerging technology, it has been well studied and developed to a point that HIFU will undoubtedly be an effective alternative to radiation therapy. [Abstract/Link to Full Text]

Heysek RV
Modern brachytherapy for treatment of prostate cancer.
Cancer Control. 2007 Jul;14(3):238-43.
BACKGROUND: Prostate cancer is the most common cancer diagnosed in men. An increasing number of these patients are seeking minimally invasive procedures such as transperineal interstitial permanent radioactive seed prostate brachytherapy. METHODS: This paper reviews the historical perspective and the current advances in transperineal interstitial permanent radioactive seed prostate brachytherapy. The 10- to 15-year results data now published for brachytherapy alone or in combination with external-beam irradiation are also reviewed. RESULTS: Modern brachytherapy using transperineal interstitial permanent radioactive seed prostate brachytherapy offers patients an excellent quality of life with convenient outpatient treatment with long-term (10- to 15-year) biochemical relapse-free survival rates ranging from 67% to 87%, depending on risk stratification. CONCLUSIONS: Modern-day brachytherapy utilizing either radioactive iodine-125 or palladium-103 alone or in combination with supplemental external-beam treatment offers patients a successful treatment outcome with acceptable toxicity. [Abstract/Link to Full Text]

Chin JL, Lim D, Abdelhady M
Review of primary and salvage cryoablation for prostate cancer.
Cancer Control. 2007 Jul;14(3):231-7.
BACKGROUND: Cryosurgery has gained popularity as a minimally invasive treatment option for primary and recurrent prostate cancer. Herein we present a review and summary reports on primary cryoablation for prostate cancer and salvage cryoablation following radiation failure. METHODS: We reviewed the current published literature in the English language on these topics, along with some historic articles dating back to the 1960s for background and development of the procedure. The material is supplemented by some commentary based on our own 13-year experience with cryoablation for prostate cancer. The review is divided into two sections: primary and salvage cryoablation. RESULTS: For primary cryoablation, success rates are proportional to the risk categories of the primary cancers. A pretreatment prostate-specific antigen (PSA) <or= 10 ng/mL and an undetectable PSA nadir following cryoablation are associated with a more favorable long-term outcome. Safety profile and quality of life are acceptable in carefully selected patients. Similarly, for salvage cryoablation following radiation failure, patient selection is of paramount importance. The most consistently identified predictive factors for poor cryoablation outcomes were pre-cryoablation PSA > 10 ng/mL and post-cryoablation nadir PSA > 1 ng/mL for salvage procedures. Side effects are more prevalent and serious than with primary cryoablation but for carefully selected patients, the long-term results are favorable. CONCLUSIONS: Patient selection is the key to success with cryoablation, in both the primary and salvage setting. The modality can offer long-term cancer control in carefully selected patient with properly executed techniques. [Abstract/Link to Full Text]

Al-Qudah HS, Rodriguez AR, Sexton WJ
Laparoscopic management of kidney cancer: updated review.
Cancer Control. 2007 Jul;14(3):218-30.
BACKGROUND: Laparoscopy has emerged as the preferred option for the surgical management of kidney cancer. Although many reports have been published regarding the operative outcome of renal cell carcinoma (RCC) and upper-tract transitional cell carcinoma (TCCA) treated laparoscopically, few review the oncologic outcome of these pathologies treated with laparoscopic techniques. METHODS: We review the literature regarding the laparoscopic approaches, the complications related to laparoscopic surgery, and the long-term oncologic results of laparoscopic radical nephrectomy, partial nephrectomy, and nephroureterectomy. RESULTS: Laparoscopic radical nephrectomy has become the new standard of care for most patients with suspected RCCs that are not amenable to nephron-sparing procedures. Laparoscopic techniques for managing RCC and TCCA are safe, follow well-established guidelines for surgical dissection, and meet or exceed perioperative convalescence and oncologic outcomes compared to traditional open procedures. The surgical techniques and the long-term outcome data for laparoscopic partial nephrectomy continue to mature. CONCLUSIONS: Laparoscopy is a minimally invasive option available to most patients with kidney cancer. The immediate benefits of laparoscopy are well established and include less estimated blood loss, decreased pain, shorter perioperative convalescence, and improved cosmesis. Long-term oncologic outcomes of patients treated laparoscopically for kidney tumors resemble those of the open surgical approach. [Abstract/Link to Full Text]

Hafron J, Kaouk JH
Cryosurgical ablation of renal cell carcinoma.
Cancer Control. 2007 Jul;14(3):211-7.
BACKGROUND: Small renal masses are being commonly diagnosed incidentally in older patients. A partial nephrectomy is the first-line nephron sparing treatment option for these lesions. However, probe ablative therapy such as cryoablation is emerging as an alternative option for select patients requiring nephron sparing surgery. METHODS: The current literature regarding the management of small renal lesions with cryoablation was retrospectively reviewed. We selected six of the largest published series of renal cryoablation with a total of 320 patients. The diagnosis, staging, treatment options, mechanism, efficacy and morbidity associated with renal cryoablation were evaluated. RESULTS: Renal cryoablation for localized small renal masses is well tolerated and associated with a low complication rate. The range of mean tumor size in our literature review series (320 patients) was 2.3 to 2.6 cm. After a range of mean follow-up of 5.9 to 72 months, including a series with a minimum of 5 years of follow-up, the cancer specific survival was 97% to 100% and overall patient survival was 82% to 90.2%. CONCLUSIONS: Renal cryoablation, based on available clinical reports, appears to be a curative option for patients with small localized renal cell carcinomas (RCCs) who are unwilling or unable to undergo a partial nephrectomy. With encouraging intermediate oncological follow-up available, longer-term follow-up is needed to validate the use of cryoablation as a primary treatment option. [Abstract/Link to Full Text]

Park S, Cadeddu JA
Outcomes of radiofrequency ablation for kidney cancer.
Cancer Control. 2007 Jul;14(3):205-10.
BACKGROUND: The incidence of small (< 4 cm) solid enhancing renal masses has been rising, and the majority (60% to 80%) of these tumors are renal cell carcinomas (RCCs) when pathologic analysis is performed. Needle ablation for small incidental renal masses is an attractive therapeutic option. Reasons include its decreased morbidity, shorter convalescence, and the ability to avert the higher risk of extirpative surgery in an aging patient population. Radiofrequency ablation (RFA) is a thoroughly studied needle ablative method used for RCC. METHODS: The current published literature on renal tumor RFA was reviewed. The in vitro experiments, animal studies and clinical experience with RFA for treatment of small RCCs were analyzed and various controversies in renal RFA are presented for discussion. RESULTS: Percutaneous and laparoscopic renal RFA can be safely performed and can eradicate small RCCs with cancer specific survival rates over 90% to 95% in many series. While long-term (5 years or greater) cancer control data are not yet available, these intermediate-term results are similar to those achieved with traditional nephron-sparing surgical options. However, the optimal method to perform RFA for renal masses is still evolving. CONCLUSIONS: While long-term cancer control data are not yet available, the current literature suggests that RFA can effectively eradicate small RCCs. Further research is needed to elucidate the influence of various treatment variables, including impedance vs temperature-controlled RFA, sonographic vs computed tomographic guidance, general anesthetic vs conscious sedation, and radiologist vs urologist delivery of renal RFA. [Abstract/Link to Full Text]

Teschendorf B, Schwartz C, Ferrans CE, O'Mara A, Novotny P, Sloan J
Caregiver role stress: when families become providers.
Cancer Control. 2007 Apr;14(2):183-9.
BACKGROUND: In view of the large number of families engaged in caregiving, this study was initiated to describe informal cancer care provision from the perspective of the caregiver. METHODS: A professional data collection site was used to convene focus groups in four cities. Participants included 63 caregivers, 87% of whom were female, mean age of 56 years. Caregivers responded to an open-ended question regarding the challenges of providing care. The study utilized qualitative analysis of verbatim transcripts. Transcript coding with four independent raters, using an iterative process, achieved a high inter-rater reliability. RESULTS: The project elucidates self-reported concerns confronted in cancer caregiving. Five primary themes emerged: supportive care demands, emotional toll, impact on health status, coping strategies, and rewards and affirmation. Providing supportive care introduced a balancing act in caregivers' lives as they attempted to address complex and overlapping roles. They felt alone in their decisions, were under-prepared for tasks they assumed, and tried to shield the care recipient. CONCLUSIONS: This qualitative approach confirmed past research while identifying novel concepts related to maintaining well-being and a sense of purpose despite caregiving hardships. Some aspects of caregiver suffering were identified. Caregiver self-regulation strategies revealed by this work suggest ideas for psychosocial interventions caregivers could use to protect themselves and the care recipient from impending distress. [Abstract/Link to Full Text]

Mojica CM, Bastani R, Boscardin WJ, Ponce NA
Low-income women with breast abnormalities: system predictors of timely diagnostic resolution.
Cancer Control. 2007 Apr;14(2):176-82.
BACKGROUND: Incomplete or delayed diagnostic resolution of breast abnormalities suspicious for cancer may contribute to poor breast cancer outcomes. We examine system predictors of timely diagnostic resolution in low-income, mostly Latina women with breast abnormalities at two Los Angeles County public hospitals. METHODS: We collected medical record data on 1,671 women. The outcome--timely diagnostic resolution--was defined as receipt of definitive diagnosis (malignant or benign) within six months of the index referral. Predictors of the outcome were examined with bivariate and multivariate logistic regression models. RESULTS: Only 56% of women received timely diagnostic resolution; however, the proportion was higher at Hospital B (67%) compared to Hospital A (51%). The effect of predictors differed by hospital. At Hospital B, the odds of timely diagnostic resolution were lower for women with self-identified abnormalities (P <.033) and higher for women referred to Radiology rather than Surgery for their first appointment (P <.005). At Hospital A, the odds of timely diagnostic resolution were higher for women with self-identified abnormalities (P <.043) and lower for women referred to Radiology rather than Surgery for their first appointment (P <.001). CONCLUSIONS: Rates and predictors of timely diagnostic resolution differed by hospital. System barriers may be a function of referral processes and patient tracking. Interventions may need to be tailored to a hospital's unique culture. [Abstract/Link to Full Text]

Kelly KM, Phillips CM, Jenkins C, Norling G, White C, Jenkins T, Armstrong D, Petrik J, Steinkuhl A, Washington R, Dignan M
Physician and staff perceptions of barriers to colorectal cancer screening in Appalachian Kentucky.
Cancer Control. 2007 Apr;14(2):167-75.
BACKGROUND: Data indicate that in 1997 to 1999, only 44% of Appalachian Kentuckians underwent colorectal cancer screening consistent with guidelines. We investigated the reasons for, barriers to, and follow-up of colorectal cancer (CRC) screening recommendations in primary care practices seeing patients from Appalachian Kentucky. METHODS: A mixed-methods [qualitative (focus group) and quantitative (survey)] approach was used to gather and analyze data in five primary care practices. A total of 34 participated in the focus groups. RESULTS: In focus groups, physicians and office staff reported a number of indicators for CRC screening; physician, patient, and procedural barriers to CRC screening; and strategies to overcome these barriers to screening. Most physicians used personal experience to guide screening, but it was unclear what was meant by personal experience. Commonly cited patient barriers to screening were fear and embarrassment. Physicians reported several approaches to overcome these barriers, including establishing trust and educating patients. Survey data identified a number of resources to assist practices in promoting screening, most commonly, patient educational materials. Finally, fecal occult blood test was most commonly recommended because it is inexpensive and easy to administer. CONCLUSIONS: Our mixed methods approach not only helped to understand the physicians' perceptions of the problems and barriers to CRC screening in Appalachian Kentucky, but also elucidated how practices endeavor to overcome these barriers and identified the additional resources practices would like in order to promote CRC screening. [Abstract/Link to Full Text]

Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B
Evidence-based medicine for rare diseases: implications for data interpretation and clinical trial design.
Cancer Control. 2007 Apr;14(2):160-6.
BACKGROUND: The randomized, controlled trial (RCT) is the "gold standard" for establishing the effect of any intervention. This approach, however, is often not feasible with rare diseases such as cutaneous T-cell lymphoma. METHODS: We review the principles of evidence-based medicine to see which are particularly pertinent to the study of rare diseases. RESULTS: When an RCT is not feasible, attention is given to determining all the available prior data. Evaluation of the new data and the historic base requires attention to biases, but can allow estimation of a "true" study result. CONCLUSIONS: Even when an RCT cannot be performed because of insufficient cases, utilization of evidence-based methodology can help minimize bias and maximize the truth of observed new data. [Abstract/Link to Full Text]

Rezania D, Cualing HD, Ayala E
The diagnosis, management, and role of hematopoietic stem cell transplantation in aggressive peripheral T-cell neoplasms.
Cancer Control. 2007 Apr;14(2):151-9.
BACKGROUND: Peripheral T-cell neoplasms (PTCNs) comprise a group of uncommon and heterogeneous lymphoid malignancies. They are more difficult to diagnose and treat and have a worse prognosis than B-cell lymphomas. Although PTCNs initially show a significant degree of chemosensitivity, the outcome of treatment with conventional dose chemotherapy remains poor. METHODS: We reviewed the literature on the diagnosis, treatment, and collective transplant reports regarding PTCNs. RESULTS: The correct diagnosis of peripheral T-cell lymphoma requires a combination of clinical presentation, morphology, immunophenotype, and molecular study. While no specific treatment other than conventional dose chemotherapy is currently available for aggressive PTCN, histone acetylase inhibitors and monoclonal antibodies such as anti-CD7 and anti-CD52 are being studied in T-cell malignancies. The role of autologous and allogeneic transplantation is being investigated for high-risk, relapsed, and refractory PTCNs with some promising results. CONCLUSIONS: Access to hematopathology expertise in a tertiary care setting may lead to earlier and more accurate diagnoses of these diseases. PTCNs comprise a heterogeneous group of diseases with no widely accepted standard of care, and accurate determination of their histologic subtypes correlates with prognosis. Patients in first complete remission with poor risk features and patients with relapsed and refractory disease should be considered for bone marrow transplant due to the poor outcomes obtained with conventional chemotherapy. [Abstract/Link to Full Text]

Alekshun TJ, Sokol L
Diseases of large granular lymphocytes.
Cancer Control. 2007 Apr;14(2):141-50.
BACKGROUND: Clonal diseases of large granular lymphocytes (LGLs) are rare lymphoproliferative malignancies that arise from either mature T-cell (CD3+) or natural killer (NK)-cell (CD3-) lineages. They manifest a distinct biologic behavior that ranges from indolent to very aggressive. METHODS: We discuss four distinct diseases involving LGLs: indolent T-cell LGL leukemia, aggressive T-cell LGL leukemia, chronic NK-cell leukemia, and aggressive NK-cell leukemia. Furthermore, we present an up-to-date systematic review of therapies for each entity. RESULTS: Sustained LGLs, characteristic immunophenotype, clonal origin of leukemic cells, and clinical presentation are the most important features that distinguish indolent from aggressive subtypes of LGL leukemia and guide the selection of therapy. Patients with symptomatic indolent T-cell or NK-cell LGL leukemia are usually treated with immunosuppressive therapies in contrast to aggressive T-cell and NK-cell LGL leukemia, which require intensive chemotherapy induction regimens. Novel targeted therapies using monoclonal antibodies against receptors, including CD2, CD52, the beta subunit of the interleukin-2 receptor, and small molecules such as tipifarnib, are undergoing evaluation in clinical trials. CONCLUSIONS: Future scientific advances focusing on the delineation of molecular pathogenic mechanisms and the development of new targeted therapies for each distinct LGL leukemia entity should lead to improved outcomes of patients with these disorders. [Abstract/Link to Full Text]

Yasunaga J, Matsuoka M
Human T-cell leukemia virus type I induces adult T-cell leukemia: from clinical aspects to molecular mechanisms.
Cancer Control. 2007 Apr;14(2):133-40.
BACKGROUND: Human T-cell leukemia virus type I (HTLV-I) is a causative virus of adult T-cell leukemia (ATL), HTLV-I-associated myelopathy/tropical spastic paraparesis, and HTLV-I-associated uveitis. ATL is a neoplastic disease of CD4-positive T lymphocytes that is characterized by pleomorphic tumor cells with hypersegmented nuclei, termed "flower cells." The mechanisms of leukemogenesis have not been fully clarified. METHODS: The authors reviewed the virological, clinical, and immunological features of HTLV-I and ATL and summarized recent findings on the oncogenic mechanisms of ATL and therapeutic advances. RESULTS: Multiple factors, such as viral genes, genetic and epigenetic alterations, and the host immune system, may be implicated in the leukemogenesis of ATL. Among them, viral genes, tax, and HBZ have been thought to play important roles. The prognosis of aggressive-type ATL remains poor, regardless of intensive chemotherapy. Effectiveness of allogeneic stem cell transplantation for ATL has been recently reported. CONCLUSIONS: Although the precise mechanism of leukemogenesis of ATL remains unclear, recent progress provides important clues in oncogenesis by HTLV-I. Future research should focus on the composition of novel therapeutic strategies, including prevention, based on the evidence in the leukemogenic mechanisms. [Abstract/Link to Full Text]

Droc C, Cualing HD, Kadin ME
Need for an improved molecular/genetic classification for CD30+ lymphomas involving the skin.
Cancer Control. 2007 Apr;14(2):124-32.
BACKGROUND: The spectrum of diseases that constitute the CD30+ lymphomas, with lymphomatoid papulosis (LyP) at one end, and anaplastic large-cell lymphoma (ALCL) at the other end, shows variable morphology, immunophenotype, and clinical behavior. The border between these diseases is sometimes difficult to establish and there are many grey zones in their classification. METHODS: We reviewed the clinical and research literature and guided by our experiences attempted to discern molecular and phenotypic criteria to improve the classification and identify molecular targets for therapy of CD30-positive cutaneous lymphomas. RESULTS: Functional studies of ALCL cell lines clonally derived from LyP have revealed loss of growth inhibition by transforming growth factor beta (TGF-beta), due to TGF-beta receptor mutations. Studies of genetic variants of the CD30 promoter showed distinct microsatellite alleles associated with development of LyP and lymphoma progression. Studies of LyP and cutaneous ALCL tissues and cell lines suggest a dual role for CD30/CD30 ligand interactions in regression of LyP and progression to lymphoma. CD30 signaling activates NF-kappaB in cell lines derived from cutaneous ALCL but not anaplastic lymphoma kinase (ALK)-positive systemic ALCL in which growth arrest occurs through cell cycle inhibitor p21WAF1/Cip1. Other likely biomarkers of disease progression include differential expression of Bcl-2, fascin, cutaneous lymphocyte antigen, and T-cell receptor clonality. These may lead to improved classification, diagnoses, and therapeutic targets. CONCLUSIONS: The current clinicopathologic classification of CD30+ cutaneous lymphoproliferative disorders is insufficient. Incorporating genetic and molecular criteria would better define the borders between benign/ malignant and aggressive/nonaggressive disorders. [Abstract/Link to Full Text]

Recent Articles in Pathology Oncology Research

Szomor A, Al Saati T, Delsol G, Kereskai L, Szij�rt� Z, Losonczy H
Primary bone marrow T-cell anaplastic large cell lymphoma with triple m gradient.
Pathol Oncol Res. 2007;13(3):260-2.
We present a case of a 60-year-old male patient with primary bone marrow anaplastic large cell lymphoma. He was admitted to the hospital with the symptoms of anemia and fever. There was no evidence of lymphadenopathy or splenomegaly. Immunoelectrophoresis showed the presence of a triple M gradient (double IgM and an IgG), with the IgG and one of the IgM paraproteins functioning as a cryoglobulin. The patient had no hepatitis C virus infection. Bone marrow biopsy showed massive CD30-positive, ALK-negative large lymphoid cell infiltration of T-cell origin with anaplastic morphology. PCR analysis of lymphoid cells separated from the bone marrow demonstrated the presence of a B/T hybrid genotype disorder with no evidence of the t(2;5), nor t(1;2) translocations. The patient entered a period of remission following CHOP chemotherapy. The patient subsequently died of sepsis as a consequence of serious humoral immunodeficiency. [Abstract/Link to Full Text]

Schiffer C, Schiesser M, Lehr J, Tariverdian G, Glaeser D, Gabriel H, Mikuz G, Sergi C
Unique Occurrence of Brachmann-de Lange Syndrome in a Fetus whose Mother Presented with a Diffuse Large B-Cell Lymphoma.
Pathol Oncol Res. 2007;13(3):255-9.
Brachmann-De Lange Syndrome (BDLS, MIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by a variable phenotype including intrauterine fetal growth retardation, limb reduction and distinctive facial and skull features (low frontal hairline, synophrys, anteverted nostrils, long philtrum, downturned corners of the mouth, micro- and retrognathia, low-set ears and micro-/brachycephaly), as well as a significant psychological developmental delay. A proposed classification system for BDLS include a classic type with characteristic facial and skull changes, a mild type where similar changes may develop with time or may be partially expressed, and a third type including phenocopies, where phenotypic changes are casually related to chromosomal aneuploidies or teratogenic exposures. We report on a 22-week gestation fetus with BDLS, showing intrauterine fetal growth retardation, brachycephaly, micro-/retrognathia and monolateral single bone of the forearm, in a woman harboring diffuse large B-cell lymphoma. Meticulous family history was negative for malformations, syndromes, congenital anomalies or psychiatric disorders. There are very few reports of BDLS at early gestation, but to the best of our knowledge, this is the first case occurring simultaneously with a hematological neoplastic disease of the mother. [Abstract/Link to Full Text]

B�rdi E, Bobok I, V Ol�h A, Kappelmayer J, Kiss C
Anthracycline antibiotics induce acute renal tubular toxicity in children with cancer.
Pathol Oncol Res. 2007;13(3):249-53.
Experimental evidence suggests that anthracyclines, widely used in cancer chemotherapy, may impair kidney function. We assessed kidney function by serum creatinine, urinary N-acetyl-beta-D-glucosaminidase activity indices (NAGi) and microalbuminuria (MA) in 160 serum and urine samples obtained from 66 children with cancer. The effect of dexrazoxane was analyzed in 6 children on dexrazoxane supportive therapy in conjunction with daunorubicin (DNR) treatment, as compared with 6 children not receiving this agent. NAGi was significantly (p<0.05) elevated after treatment by DNR, doxorubicin, epirubicin (EPI) and idarubicin (IDA). MA proved to be a less sensitive indicator of kidney damage than NAGi. DNR resulted in a progressive deterioration of proximal tubular function as determined by linear regression analysis. The mean NAGi in the dexrazoxanetreated group was significantly (p<0.005) lower than in children not receiving dexrazoxane prior to DNR treatment. In conclusion, our study demonstrated that DNR, EPI and IDA induced an acute renal tubular damage similar to known tubulotoxic agents as cisplatin, carboplatin, cyclophosphamide and ifosfamide. The damage was clinically mild and only a minor proportion of patients can be expected to develop long-lasting tubulopathy with negative impact on the quality of life. [Abstract/Link to Full Text]

Ma�sz A, Kisfali P, Horvatovich K, Moh�s M, Mark� L, Cs�ngei V, Farag� B, J�romi L, Magyari L, S�fr�ny E, Sipeky C, Wittmann I, Melegh B
Apolipoprotein A5 T-1131C Variant Confers Risk for Metabolic Syndrome.
Pathol Oncol Res. 2007;13(3):243-7.
The -1131C is a naturally occurring variant of the apolipoprotein A5 (ApoA5) gene, which has been shown to associate with increased triglyceride levels. This variant has also been shown to confer risk for development of ischemic heart disease and stroke. The gene is in linkage disequilibrium with factors known to correlate with impaired glucose homeostasis. These observations prompted us to study the prevalence of the ApoA5 -1131C allele in patients with metabolic syndrome. A total of 201 metabolic syndrome patients and 210 controls were studied. In both groups the triglyceride levels of patients with -1131C allele were significantly increased compared to the subjects with -1131T allele (3.22+/-0.43 mmol/l vs. 2.24+/-0.12 mmol/l, p<0.01 in the metabolic syndrome patients; 2.10+/-0.19 mmol/l vs. 1.22+/-0.05 mmol/l, p<0.01 in the controls). In metabolic syndrome patients the prevalence of the ApoA5 -1131C variant was increased compared to the healthy controls (11% vs. 6.20%). Multiplex regression analysis model adjusted for age, gender, serum total cholesterol levels, acute myocardial infarction and stroke events revealed that the examined ApoA5 variant confers risk for the development of metabolic syndrome: the odds ratio at 95% confidence interval was 3.622 (1.200-10.936), p=0.02. Our findings strongly suggest that this variant is a risk factor for the development of hypertriglyceridemia and metabolic syndrome. [Abstract/Link to Full Text]

Keresztes K, Szollosi Z, Simon Z, Tarkanyi I, Nemes Z, Illes A
Retrospective Analysis of the Prognostic Role of Tissue Eosinophil and Mast Cells in Hodgkin's Lymphoma.
Pathol Oncol Res. 2007;13(3):237-42.
The composition of reactive cell populations, which constitute the majority of tumor load in Hodgkin's lymphoma (HL), can influence the prognosis of the disease. Besides widely accepted and applied prognostic scores, the authors evaluate biological factors that may have a prognostic impact. Previous data indicate that the rate of eosinophils and mast cells in the reactive cell population, determined already at diagnosis, can be used for this purpose. Histological samples from 104 patients with HL with an average follow-up period of 110 (24-214) months were retrospectively analyzed. Mast cell positivity was associated with better overall survival, although this difference was only of borderline statistical significance (p=0.092). No significant difference was found in parameters like overall survival (OS, p=0.906) or event-free survival (EFS, p=0.307) of eosinophil-positive vs. -negative cases or in EFS (p=0.742) of mast cell-positive vs. -negative individuals (criterion for a positive specimen was more than 5% of appropriate cells in the reactive cell population). Looking at the effect of eosinophilia and mastocytosis together, there was no significant difference between the subgroups categorized according to the combined presence of the two cell types. It seems that tissue eosinophil and mast cell predominance have no prognostic value that could be used in clinical practice, although a tendency for correlation of mast cell positivity with overall survival could be seen. For a definitive statement, multicenter studies should be performed involving a higher number of patients suffering from HL. [Abstract/Link to Full Text]

Bov�ri J, Cz�mp�ly T, Olasz K, Arnold HH, Balogh P
Complex organizational defects of fibroblast architecture in the mouse spleen with nkx2.3 homeodomain deficiency.
Pathol Oncol Res. 2007;13(3):227-35.
The capacity of secondary lymphoid organs to provide suitable tissue environment for mounting immune responses is dependent on their compartmentalized stromal constituents, including distinct fibroblasts. In addition to various members of the tumor necrosis factor/lymphotoxin beta family as important morphogenic regulators of peripheral lymphoid tissue development, the formation of stromal elements of spleen is also influenced by the Nkx2.3 homeodomain transcription factor in a tissue-specific fashion. Here we extend our previous work on the role of Nkx2.3-mediated regulation in the development of spleen architecture by analyzing the structure of reticular fibroblastic meshwork of spleen in inbred Nkx2.3-deficient mice. Using immunohistochemistry and dual-label immunofluorescence we found both distributional abnormalities, manifested as poor reticular compartmentalization of T-zone and circumferential reticulum, and developmental blockade, resulting in the absence of a complementary fibroblast subpopulation of white pulp. The disregulated distribution of fibroblasts was accompanied with an increased binding of immunohistochemically detectable complement factor C4 by T-cell zone-associated reticular fibroblasts, distinct from follicular dendritic cells with inherently high-level expression of bound C4. These data indicate that the impact of Nkx2.3 gene deficiency on fibroblast ontogeny within the spleen extends beyond its distributional effects, and that the formation of various white pulp fibroblast subsets is differentially affected by the presence of Nkx2.3 activity, possibly also influencing their role in various immune functions linked with complement activation and deposition. [Abstract/Link to Full Text]

Celikel C, Eren F, Gulluoglu B, Bekiroglu N, Turhal S
Relation of neuroendocrine cells to transforming growth factor-alpha and epidermal growth factor receptor expression in gastric adenocarcinomas: prognostic implications.
Pathol Oncol Res. 2007;13(3):215-26.
The presence of neuroendocrine (NE) cells in gastric adenocarcinoma (GCa) is well documented, however, their significance is controversial. There is no evidence in the literature concerning the possible effect of these cells on the expression of TGF-alpha and EGFR, which are believed to confer growth advantage to tumor cells. 101 partial or total gastrectomy specimens from patients operated for conventional gastric adenocarcinoma were included in the study. In each case immunohistochemistry was performed on sequential tissue sections for chromogranin A (ChrA), TGF-alpha and EGFR. Samples were graded based on the number of ChrA-positive cells (0-3). TGF-alpha and EGFR expressions were evaluated according to both the intensity (0-2) and quantification of the positively stained areas (0-3). Follow-up data was available in 54 patients. Twenty-seven patients died of disease, while 27 patients were alive with a follow-up of at least 15 months. ChrA expression was detected in 54.4% of the tumor specimens. TGF-alpha was stained positively in 42.6% and EGFR in 49.5% of the cases. NE cells in GCa was related to TGF-alpha (p<0.0001) and EGFR expression (p<0.05), and TGF-alpha/EGFR coexpression (p<0.001). Among histopathologic variables, the presence of NE cells was significantly related to grade, stage and lymph node status. Although the presence of NE cells had no effect on survival, the expression of EGFR (p<0.0001) and TGF-alpha (p=0.002) were related to survival. The results of our study suggest that the presence of NE cells may have an effect on the expression of TGF-alpha and EGFR in GCa, and the autocrine mechanism between TGF-alpha and EGFR plays an important role in the prognosis of gastric carcinoma. [Abstract/Link to Full Text]

Bereczki L, Kis G, Bagdi E, Krenacs L
Optimization of PCR Amplification for B- and T-cell Clonality Analysis on Formalin-fixed and Paraffin-embedded Samples.
Pathol Oncol Res. 2007;13(3):209-14.
In many cases, particularly in retrospective studies, only formalin-fixed and paraffin-embedded (FFPE) tissue samples are available for molecular studies. DNA recovered from FFPE tissues generally consists of fragmented small target sequences with chemical alterations. Clonality analysis is not easy on FFPE samples, in fact, it requires even more experience than that of performed on fresh samples or is more complicated than most genomic PCR amplifications for somatic genes. In our study, we have performed a multi-parameter PCR evaluation investigating immunoglobulin heavy chain gene (IgH) and T-cell receptor gamma gene (TCRgamma) rearrangements on non-purified crude lysates of FFPE samples, in order to establish the significance of different variables on performance of PCR amplification. The results showed that a slight decrease in the concentration of primers in combination with a slight increase in MgCl2 and Taq polymerase concentrations, as well as the use diluted crude template and a standard amount of dNTPs can be the modifications of choice while adjusting IgH and TCRgamma clonality tests on poor quality DNA FFPE samples. Using our improved protocol, 74% (17/23) of the tested B-cell lymphomas and 68% (31/46) of the tested T-cell lymphomas demonstrated monoclonal PCR product, proving the applicability of our optimized method. Our experience may be of help during the optimization process in technically difficult cases as well as to determine which parameters and how should be changed to minimize false-negative and false-positive results. [Abstract/Link to Full Text]

P�rez-Guti�rrez S, Gonz�lez-C�mpora R, Am�rigo-Navarro J, Beato-Moreno A, S�nchez-Le�n M, Pareja Meg�a JM, Virizuela-Echaburu JA, L�pez-Beltr�n A
Expression of P-glycoprotein and Metallothionein in Gastrointestinal Stromal Tumor and Leiomyosarcomas. Clinical Implications.
Pathol Oncol Res. 2007;13(3):203-8.
We investigated the expression of P-glycoprotein (P-GP) and metallothionein (MT) in a series of 92 GIST and 14 gastrointestinal leiomyosarcomas (GILMS) with the purpose to expand our knowledge on the biological bases of GIST chemo-resistance and to ascertain their significance in patients' prognosis. P-GP expression was more frequent in GIST than in GI-LMS (83.7% vs. 21.4%, p<0.001), with no difference between low- and high-risk GIST (p=1.000) or low- and high-grade GI-LMS (p=0.538). P-GP expression was unrelated to anatomic location (gastric vs. intestinal) in GIST (39/45 vs. 35/43, p=0.770) and in GI-LMS (0/2 vs. 2/6, p=1.000). MT expression was non-significantly higher in GI-LMS than in GIST (35.7% vs. 14.1%, p=0.060), with no difference between low- and high-risk GIST (p=1.000) or low- and high-grade GI-LMS (p=1.000). MT expression was unrelated to the anatomic location (gastric vs. intestinal) in GIST (7/45 vs. 6/43) and GI-LMS (0/2 vs. 1/6) (p=1.000 and p=0.1000, respectively). Overall tumor-specific survival (p< 0.001) and disease-free survival (p<0.001) were different in GIST as compared with GI-LMS, and the number of events was higher in GI-LMS. When the survival analysis took into consideration P-GP or MT expression, the overall survival in GIST was influenced by the expression of MT (p=0.021) but not by that of P-GP (p=0.638). However, in GI-LMS, P-GP expression influenced disease-free survival (p=0.050); in addition, it is important to recognize the limited value of these results because of the low number of cases involved in the study. Differential expression of P-GP and MT might explain the known variability in response to systemic chemotherapy in these tumors. Detection of P-GP and MT seems to add certain prognostic value in GIST (MT) or GI-LMS (P-GP). [Abstract/Link to Full Text]

Suba Z
Gender-related hormonal risk factors for oral cancer.
Pathol Oncol Res. 2007;13(3):195-202.
Oral cancer (OC) is a neoplasm with fairly high male to female ratio in most populations. The conspicuously lower incidence of this tumor among women than man is suggestive of certain endocrine involvement in its development. The aim of the present case-control study was to clarify the origin of this gender-specific risk of OC incidence. 2660 inpatients (530 females and 2130 males) with squamous cell OC at the Department of Oral and Maxillofacial Surgery were included in a case-control study. Smoking, alcohol consumption, elevated fasting serum glucose level and menopausal histories of female cases were registered. Smoking and excessive alcohol intake proved to be strong risk factors for OC both in the male and female group. However, moderate alcohol consumption was a weaker risk factor for male patients, and it presented no risk for female cases. Elevated fasting glucose level was not a demonstrable OC risk factor among males, however, it proved to be strong risk factor for OC among female patients, especially in gingival cancer cases. The almost exclusively postmenopausal state of female OC patients and the long mean interval (17 years) between their menopause and OC diagnosis suggested an important role of estrogen deficiency in OC epidemiology. The significantly younger mean age at menopause and the significantly higher rate of hysterectomy among female OC cases in comparison with their controls also support the estrogen deficiency hypothesis. This novel hypothesis of estrogen deficiency and elevated fasting glucose as risk factors for OC in postmenopausal women may provide new insights into the etiology of oral malignancies. [Abstract/Link to Full Text]

Riesz P, Lotz G, P�ska C, Szendr�i A, Majoros A, N�meth Z, T�rzs�k P, Szarvas T, Kovalszky I, Schaff Z, Romics I, Kiss A
Detection of Bladder Cancer from the Urine using Fluorescence in situ Hybridization Technique.
Pathol Oncol Res. 2007;13(3):187-94.
The authors report on their first experiences with the UroVysion fluorescence in situ hybridization (FISH) kit developed for the detection of bladder cancer. This new non-invasive diagnostic application of the FISH technique in the field of urology was elaborated to replace cystoscopy. The special urine examination method detects genetic alterations of the urothelial cells found in the urine, using fluorescent directlabeled DNA probes binding to the peri-centromeric regions of chromosomes 3, 7 and 17 as well as on the 9p21 locus. We aimed to evaluate the utility of UroVysion test in the light of the histological diagnosis. Urine samples from 43 bladder cancer patients and 12 patients with no or benign alterations were studied using a new application of FISH technique: the UroVysion reagent kit. The obtained FISH results were compared with the histological findings of the transurethral surgical resection specimens. The study rated the specificity and sensitivity of the technique 100% and 87%, respectively. Therefore, the technique could well fit into the diagnostic process of bladder carcinomas. Statistical analyses showed significant correlation between tumor progression and the severity of the genetic alterations detected by this FISH technique. Furthermore, positive correlation was found between tumor grade and the proportion of tumor cells showing genetic abnormality. The noninvasiveness, the robustness of evaluation and the high specificity/sensitivity are all in favor of this technique. The disadvantages are the higher costs of the technical background and the required future clinical studies to determine whether this technique can replace cystoscopy. [Abstract/Link to Full Text]

Beser AR, Tuzlali S, Guzey D, Dolek Guler S, Hacihanefioglu S, Dalay N
HER-2, TOP2A and Chromosome 17 Alterations in Breast Cancer.
Pathol Oncol Res. 2007;13(3):180-5.
HER-2 amplification is a biomarker for identifying patients who respond to trastuzumab and has been evaluated as a factor predicting the response to anthracyclines. The relationship between HER-2 and response to anthracycline therapy may also be the result of the close localization of TOP2A on 17q. It has been a matter of debate whether these two genes, HER-2 and TOP2A, behave separately on different amplicons or act together thus making it possible to predict the TOP2A status from the HER-2 status. In this study TOP2A, HER-2 and chromosome 17 aneusomy were investigated by fluorescent in situ hybridization (FISH) in 50 consecutive breast cancer patients. HER-2 amplification was detected in 11 patients (22%) and TOP2A changes were seen in 6 patients (12%); two amplifications and two deletions were observed in HER-2-amplified cases and two deletions in HER-2-nonamplified cases. Three of the TOP2A-deleted cases had polysomy 17. HER-2 copy number was higher than the TOP2A copy number in one patient with co-amplification. Polysomy was observed in 9 cases (18%) and monosomy in 6 cases (12%). Aneusomy was the sole anomaly in 11 patients (22%). We conclude that the TOP2A status cannot be predicted from the HER-2 status and evaluation of the TOP2A status only in patients with HER-2 overexpression may lead to missing cases with TOP2A deletion with possible resistance to therapy. Other factors modulating topo II activity may also affect the response to therapy. Studies evaluating different parameters that can modulate topo II activity and the response to the drugs targeting the enzyme are necessary. [Abstract/Link to Full Text]

Sari A, Uyaroglu MA, Ermete M, Oder M, Girgin C, Dincer C
Microcystic urothelial carcinoma of the urinary bladder metastatic to the penis.
Pathol Oncol Res. 2007;13(2):170-3.
Metastatic spread of primary bladder cancer to the penis is an extremely rare event. Microcystic urothelial carcinoma is a very rare variant of urothelial carcinoma. Due to its rareness and insufficient clinical follow-up data, the prognosis of microcystic urothelial carcinoma is still not clear. Here in we report a case of a penile metastasis from microcystic urothelial carcinoma of urinary bladder, in a 56-year-old man who died 6 months after radical cystoprostatectomy and total penectomy. To the best of our knowledge this is the first case report of microcystic variant of urothelial carcinoma which has metastasized to the penis. [Abstract/Link to Full Text]

Perez DE, Magrin J, de Almeida OP, Kowalski LP
Multiple cutaneous metastases from a parotid adenoid cystic carcinoma.
Pathol Oncol Res. 2007;13(2):167-9.
Cutaneous metastasis from salivary gland adenoid cystic carcinoma is extremely rare. We report a case of a 39-year-old man that presented multiple cutaneous metastases from a parotid salivary gland adenoid cystic carcinoma. The clinical, histopathological and immunohistochemical features are described and discussed. This case shows the importance of a detailed and periodical skin examination in patients treated for salivary gland adenoid cystic carcinoma. [Abstract/Link to Full Text]

Andreadis D, Nomikos A, Barbatis C
Metastatic renal clear cell carcinoma in the parotid gland: a study of immunohistochemical profile and cell adhesion molecules (CAMs) expression in two cases.
Pathol Oncol Res. 2007;13(2):161-5.
Metastasis of renal cell carcinoma (RCC) may involve any organ, including the parotid salivary gland. While the definition of salivary gland neoplasms with clear cell transformation can be concluded by the synchronous presence of areas showing typical morphology, sometimes the definition of a metastatic RCC in the parotid is difficult and the application of immunohistochemistry may support the clinical and radiographic observations in the final diagnosis. The aim of this paper was to describe the heterogeneous immunohistochemical features and, furthermore, to characterize the pattern of expression of cell adhesion molecules (CAMs) E-cadherin, beta4-integrin, desmoglein-2, ICAM-1 and CD44s (HCAM) in two cases of metastatic parotid RCC. [Abstract/Link to Full Text]

Csire M, Mikala G, J�k� J, Masszi T, J�nosi J, Dolgos J, F�le T, Tordai A, Berencsi G, V�lyi-Nagy I
Persistent long-term human herpesvirus 6 (HHV-6) infection in a patient with langerhans cell histiocytosis.
Pathol Oncol Res. 2007;13(2):157-60.
Langerhans cell histiocytosis (eosinophilic granuloma) was first diagnosed in the adolescence of a male patient presented. Several years later persisting human herpesvirus 6 (HHV-6) infection was recognized. The HHV-6 infection could be verified retrospectively in his historical histological samples; the continuous presence of HHV-6 could be established through 17 years of disease course. The patient was operated several times during this period for painful relapses, and developed diabetes insipidus. At variable time points during the clinical course, Varicella zoster (VZV), Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) infections were temporarily detected from blood samples and biopsy specimens. HHV-6 was the only virus continuously identified throughout the entire follow-up period. Antiviral therapy effectively cleared EBV and HHV-8, but HHV-6 remained detectable throughout the disease course. Since DNA sequences of HHV-6 could be detected in the pathologic histiocytes of eosinophilic granuloma, and from other samples taken later on, it is suggested that long-term HHV-6 infection may be associated with development or progression of Langerhans cell histiocytosis. [Abstract/Link to Full Text]

Sitic S, Korac P, Peharec P, Zovko G, Perisa MM, Gasparov S
Bcl-2 and MALT1 Genes are not involved in the oncogenesis of uterine tumors resembling ovarian sex cord tumors.
Pathol Oncol Res. 2007;13(2):153-6.
Uterine tumors resembling ovarian sex cord tumors (UTROSCT) are rare entities. They were described by Clement and Scully in 1976 who classified them into groups I and II. Group I comprises typical endometrial stromal neoplasms with focal areas resembling ovarian sex cord elements and group II are predominantly or completely composed of ovarian sex cord-like elements. We report a case of UTROSCT type II with cytogenetic analysis. The tumor occurred in a 76-year-old woman who presented with vaginal bleeding. The tumor was lobulated, firm, yellow and histologically composed of sex cord-like elements. Tumor cells expressed vimentin, CD10, CD99 and alpha-actin. Cytogenetic analysis in a previously reported case detected translocation t(4;18)(q21.1;q21.3) in the majority of cells. Bcl-2 and MALT1 genes are located at or near the translocation breakpoints, and the aim of this study was to determine whether these genes were involved in chromosomal translocation or tumorigenesis. We did not find IgH translocation or the most common MALT translocations. Bcl-2 was also not involved in this oncogenesis. [Abstract/Link to Full Text]

B�d�r C, Schmidt O, Csernus B, Rajnai H, Szende B
DNA and RNA isolated from tissues processed by microwave-accelerated apparatus MFX-800-3 are suitable for subsequent PCR and Q-RT-PCR amplification.
Pathol Oncol Res. 2007;13(2):149-52.
Over the past decade, methods of molecular biology have appeared in diagnostic pathology and are routinely applied on formalin-fixed, paraffin-embedded histological samples, processed via conventional embedding methods. Due to its reagent- and cost-effectiveness, embedding techniques that utilize microwave acceleration in one or more steps of histoprocessing are increasingly used by numerous laboratories. The demand arises that tissues processed this way should also be suitable for the requirements of molecular pathology. In this study, both conventionally embedded and MFX-800-3 machine-processed tissue samples from the same source were used for isolation of DNA and RNA and for performing PCR and real-time PCR. PCR amplification of the beta-globin gene, as well as the real-time PCR amplification of the ABL mRNA was successful in all cases. Our conclusion is that samples processed by the vacuum assisted automatic microwave histoprocessor MFX-800-3 are perfectly applicable for DNA and RNA isolation and provide appropriate templates for further PCR and realtime PCR studies. [Abstract/Link to Full Text]

Kavantzas N, Paraskevakou H, Tseleni-Balafouta S, Aroni K, Athanassiades P, Agrogiannis G, Patsouris E
Association between microvessel density and histologic grade in renal cell carcinomas.
Pathol Oncol Res. 2007;13(2):145-8.
Angiogenesis seems to contribute to tumor growth and the development of metastases. There may be an association between the vascular density of individual tumors and their prognosis. In the present survey we studied 53 cases of renal cell carcinoma investigating possible relationship between histologic grade and microvessel density (MVD) measured by an image analysis system. According to our results MVD was significantly associated with the histologic grade, higher grades being accompanied with a higher MVD. Further studies are needed to investigate a possible connection of MVD with the prognostic role of grade in RCCs. [Abstract/Link to Full Text]

Baintner K, Bodn�r Z, Kiss P, Kiss AL, Luk�ts A
Effect of intraperitoneally administered plant lectins on leukocyte diapedesis and visceral organ weight in rats and mice.
Pathol Oncol Res. 2007;13(2):139-43.
The effects of intraperitoneally administered plant lectins were examined in rats and mice. Intraperitoneally injected ConA transiently decreased the leukocyte count in the peritoneal cavity, due to the agglutination and attachment of cells to the peritoneal lining. Subsequently the total cell count was increased for hours, exceeding initial values. Peritoneal fluid aspartate transaminase (AST) concentration showed little change during the accumulation of ascitic fluid. The most marked histological alterations were found when wheat germ lectin was injected ip. (WGA, 10 mg/kg, 6 h). Neutrophil granulocytes migrated across the wall of both arterioles and venules, but the response was highly variable among adjacent vessels. The wall of the arterioles may have impeded the migration of neutrophil granulocytes, resulting in their accumulation in the muscular layer. Granulocyte accumulation was also observed in patches under the mesothelium and in other sites of the interstitium. Marked dilatation and thrombosis of a few venules were also observed. Kidney bean lectin (PHA) induced similar but less pronounced changes. The neutrophil diapedesis suggests the release of mediator(s) from mesothelial cells and/or peritoneal white cells. The cytokine-induced neutrophil chemoattractant CINC-1, injected as control, resulted in the diapedesis of predominantly mononuclear cells in the omentum within 40 minutes. In rats ip. injected ConA increased the wet weight of spleen and liver within 6 and 10 h, respectively, but kidney weight did not change. Intravascular clumping of red blood cells, thrombosis and organ weight changes also suggest the absorption of ConA into the circulation. The experiments show that plant lectins, used as models of bacterial lectins, can reproduce some aspects of peritonitis. [Abstract/Link to Full Text]

Croce MV, Isla-Larrain M, Rabassa ME, Demichelis S, Colussi AG, Crespo M, Lacunza E, Segal-Eiras A
Lewis x is highly expressed in normal tissues: a comparative immunohistochemical study and literature revision.
Pathol Oncol Res. 2007;13(2):130-8.
An immunohistochemical analysis was employed to determine the expression of carbohydrate antigens associated to mucins in normal epithelia. Tissue samples were obtained as biopsies from normal breast (18), colon (35) and oral cavity mucosa (8). The following carbohydrate epitopes were studied: sialyl-Lewis x, Lewis x, Lewis y, Tn hapten, sialyl-Tn and Thomsen-Friedenreich antigen. Mucins were also studied employing antibodies against MUC1, MUC2, MUC4, MUC5AC, MUC6 and also normal colonic glycolipid. Statistical analysis was performed and Kendall correlations were obtained. Lewis x showed an apical pattern mainly at plasma membrane, although cytoplasmic staining was also found in most samples. TF, Tn and sTn haptens were detected in few specimens, while sLewis x was found in oral mucosa and breast tissue. Also, normal breast expressed MUC1 at a high percentage, whereas MUC4 was observed in a small number of samples. Colon specimens mainly expressed MUC2 and MUC1, while most oral mucosa samples expressed MUC4 and MUC1. A positive correlation between MUC1VNTR and TF epitope (r=0.396) was found in breast samples, while in colon specimens MUC2 and colonic glycolipid versus Lewis x were statistically significantly correlated (r=0.28 and r=0.29, respectively). As a conclusion, a defined carbohydrate epitope expression is not exclusive of normal tissue or a determined localization, and it is possible to assume that different glycoproteins and glycolipids may be carriers of carbohydrate antigens depending on the tissue localization considered. [Abstract/Link to Full Text]

Sharma S, Sharma MC, Johnson MH, Lou M, Thakar A, Sarkar C
Esthesioneuroblastoma - a clinicopathologic study and role of DNA topoisomerase alpha.
Pathol Oncol Res. 2007;13(2):123-9.
Esthesioneuroblastoma (ENB) differs from adrenal neuroblastomas in its histopathologic and biologic characteristics. Hyams grading and Kadish staging have shown correlation with survival. Scant data are available on proliferation indices and prognosis. We retrospectively reviewed the clinicopathologic characteristics of ENB. Both Kadish and UCLA staging systems were used. Hyams grading was simplified into low and high grade. DNA topoisomerase II alpha labeling index (T2alpha LI) was obtained in 8 cases using immunohistochemistry. Of the 19 cases studied, 14 were males and 5 females. Age range was 2 to 62 years (average 27 years). The mass primarily involved the nose in 12 (63%) and paranasal sinuses in 7 cases (37%). Patients presented with nose block in 19 (100%), epistaxis in 10 (53%), proptosis in 9 (47%) and loss of vision in 6 cases (32%). Bony involvement was seen in 7 cases (37%), and intracranial spread in one case (5%). Thirteen (68%) were low-grade tumors and 6 were (32%) high-grade. There was no statistically significant difference between the low- and high-grade ENB in age (years) (p=0.2882), duration of symptoms (months) (p=0.5636), and either in the Kadish (p=0.5456) or the UCLA staging system (p=0.7771). The difference in DNA topoisomerase alpha labeling index between the low- and highgrade ENB (medians: 10.4 and 22.3, respectively) was not statistically significant (p=0.0714), but it was suggestive of a positive association. The results of this study should be interpreted with caution, because of the limited sample size. Three cases recurred locally, one each stage A, B and C, but all low-grade. This preliminary study suggests the need to combine a simplified histologic grading with accurate staging in a reasonable attempt to assess local progression in esthesioneuroblastoma. Larger studies may clarify the role of T2alpha LI in improving histologic grading. [Abstract/Link to Full Text]

J�ks� P, Kereskai L, Moln�r L, Pajor L
Lineage-specific clonality analysis of chronic myeloproliferative disorders and myelodysplastic syndrome by human androgen receptor assay.
Pathol Oncol Res. 2007;13(2):114-22.
In myelodysplastic syndrome (MDS) as well as chronic myeloproliferative disorders (CMPD) others than chronic myeloid leukemia the frequency of pathognomonic genetic aberrations is very low and, therefore, X chromosome inactivation (XI) assays may help in assessing the clonality. To establish specific clonality criteria on XI, human androgen receptor assay (HUMARA) was performed on sorted myeloid and lymphoid peripheral blood cells of 21 healthy females. Clonality criteria 1 and 2 conferring at least 90% specificity were set based on the ranges and differences of XI number (XIN) describing the ratio of representation of the two alleles in as well as in between reactive myeloid and lymphoid compartments. Spiking experiments indicated that the test identifies clonality reliably when no more than 40-50% reactive cells are admixed. In the CMPD and MDS cases peripheral myeloid cells were monoclonal by one of the two criteria in 71-100%, whereas lymphoid cells in 28-75%. The results of HUMARA, available in 73% of the female patients, supported the clinicopathological data in 84% as well as proved pluripotent stem cell origin in 31-75% and 21% of CMPDs and MDS, respectively. [Abstract/Link to Full Text]

Sanada Y, Yoshida K, Ohara M, Tsutani Y
Expression of orotate phosphoribosyltransferase (OPRT) in hepatobiliary and pancreatic carcinoma.
Pathol Oncol Res. 2007;13(2):105-13.
The purpose of this study was to clarify the role of orotate phosphoribosyltransferase (OPRT) in the progression of hepatobiliary and pancreatic carcinomas. Representative sections from 8 surgically resected pancreatic carcinomas, 5 gallbladder carcinomas and 19 hepatocellular carcinomas (HCCs) were examined microscopically. Sites of pancreatic intraepithelial neoplasia (PanIN) were counted, and histologic subtypes of invasive ductal carcinoma of the pancreas (IDC) were determined. Gallbladder carcinomas and HCCs were examined histologically, and the subtypes and spread patterns were assessed. Expression of OPRT was examined immunohistochemically. A total of 75 PanINs were identified. Expression of OPRT increased as lesions progressed from early to high-grade PanINs (PanIN-1A and -1B versus PanIN-2 and -3, p=0.0004). Three (37.5%) of the 8 pancreatic IDCs were positive for OPRT. In the remaining 5 cases, OPRT was expressed only in the neoplastic ducts adjacent to PanIN-3s. In gallbladder carcinomas, mucosal neoplastic epithelium showed dense cytoplasmic expression in 4 of the 5 cases, but expression was absent in the deeply invasive lesions. Among HCCs, 15 of the 19 cases were negative for OPRT in the central area of the tumor, but 8 of the 19 cases expressed OPRT in vascularly invasive lesions. Our data suggest that OPRT is involved in early events of pancreatic and gallbladder carcinogenesis and invasion of HCC. [Abstract/Link to Full Text]

Badalian G, Barbai T, R�s� E, Derecskei K, Szendr�i M, T�m�r J
Phenotype of bone metastases of non-small cell lung cancer: epidermal growth factor receptor expression and K-RAS mutational status.
Pathol Oncol Res. 2007;13(2):99-104.
Bone metastasis is a frequent complication of lung cancer progression, however, studies on bone metastatic tissues are scanty. Here we have collected a small cohort of 11 non-small cell lung cancer cases where primary tumors and corresponding bone metastases were available for pathological analysis. We have tested two molecular markers: EGFR protein expression and K-RAS mutation at codon 12 using immunohistochemistry and RFLPPCR, respectively. We have shown that using improved protocols, EGFR protein (both the extracellular as well as the cytoplasmic domain) is readily detectable in decalcified bone tissue. We found that the EGFR expression status is highly similar in bone metastases compared to the primary tumors, although the expression levels may change. Individual comparison of corresponding primary and metastatic NSCLC tissues indicated that downregulation of EGFR was a rare event (2/11) compared to upregulation (4/11) in bone metastases. On the other hand, our data indicate that the K-RAS mutational status of the primary tumor does not predict the status of the bone metastatic tissue of NSCLC, since we have observed both emergence of mutant clones in metastases from wild-type (wt) primary tumors and loss of mutant clones in metastases from mutant primaries in addition to the maintained mutant status. Our data support that at least two progression models occur in NSCLC, the samegene as well as the clonal selection one. It is noteworthy that in NSCLC cases with wt- or mutant KRAS, downregulation of EGFR expression was a rare event although upregulation in bone metastases was observed more frequently in wt K-RAS cases. [Abstract/Link to Full Text]

Kr�ger S, Ola V, Feller AC, Fischer D, Friedrich M
Expression of cancer-testis antigen CT7 (MAGE-C1) in breast cancer: an immunohistochemical study with emphasis on prognostic utility.
Pathol Oncol Res. 2007;13(2):91-6.
High expression of the cancer-testis antigen CT7, also referred to as MAGE-C1, has been recently described in a variety of malignant tumors, including breast carcinoma. To our knowledge, no data concerning the prognostic utility of CT7 expression in breast cancer are available. In this retrospective study, we evaluated the relationship between CT7 immunoreactivity and clinicopathological parameters as well as relapse-free survival (RFS) and metastasis-free survival (MFS) of 124 women with invasive breast cancer. A positive CT7 status, defined as immunoreactivity in more than 50% of tumor cells, was found in 18% of cases and correlated significantly with high tumor grade (p=0.004), but with no other clinicopathological parameter. In a univariate analysis, CT7 status showed an association with RFS by trend (p=0.107; relative risk [RR]: 1.85) and a significant association with MFS (p=0.043; RR: 2.02). In a multivariate analysis, tumor grade, stage, nodal status, angioinvasion, HER2 expression as well as estrogen and progesterone receptor expression were identified as significant independent prognostic factors of RFS and/or MFS. In this respect, CT7 expression showed a weak, statistically not significant trend towards an independent prognostic relevance concerning prediction of MFS (p=0.147; RR: 1.95). Our data suggest that estimation of CT7 immunoreactivity is of limited prognostic usefulness in breast cancer. It may provide additional information concerning assessment of MFS in selected cases. [Abstract/Link to Full Text]

Tschaharganeh D, Ehemann V, Nussbaum T, Schirmacher P, Breuhahn K
Non-specific effects of siRNAs on tumor cells with implications on therapeutic applicability using RNA interference.
Pathol Oncol Res. 2007;13(2):84-90.
Elimination of protein expression using RNA interference (RNAi) significantly improves the understanding of gene function and represents a promising technique for the treatment of diseases such as cancer and neurological disorders. Accumulating evidence suggests the so-called interferon-independent non-specific gene silencing of short interfering RNA (siRNA); however, its biological and functional cellular consequences are largely unidentified. We therefore analyzed the effects of different nonsense siRNAs on characteristic bio-parameters such as cell viability, proliferation, cell cycle distribution, apoptosis, and migration of tumor cells. All analyzed cellular aspects have been observed to be significantly affected by the presence of siRNA in an interferon-independent manner: viability, mitosis, and motility were significantly diminished and programmed cell death was significantly elevated. Moreover, all cell cycle stages (G0/G1-, G2/M-, and S-phase) were moderately shifted. Together, these results support the hypothesis that siRNA, due to sequence-specific cellular consequences, modulate bio-functionality independent of the target sequence. This phenomenon affects the design of siRNA experiments for future in vitro but also for in vivo tests as well as for potential therapeutic and preventive strategies. Moreover, monitoring interferon response after transfection of siRNAs is necessary but not sufficient to exclude potential off-target effects in non-diseased cells. [Abstract/Link to Full Text]

Kojima M, Matsumoto M, Miyazawa Y, Shimizu K, Itoh H, Masawa N
Follicular lymphoma with prominent sclerosis ("sclerosing variant of follicular lymphoma") exhibiting a mesenteric bulky mass resembling inflammatory pseudotumor. Report of three cases.
Pathol Oncol Res. 2007;13(1):74-7.
We present three cases of follicular lymphoma (FL) exhibiting prominent sclerosis (sclerosing variant of follicular lymphoma), resembling inflammatory pseudotumor (IPT) of the lymph node, arising from mesenteric lymph node. Clinically all three cases represented bulky masses of the mesenteric lymph node. Histologically, the lesions were characterized by neoplastic lymphoid follicles separated by stromal collagenization and sclerotic process, with cellular infiltrate extending into the adjacent adipose tissue. The lesions contained variable cellular spindle cell proliferation and inflammatory infiltrate including numerous reactive T cells and histiocytes. Small capillary proliferation with vascular change was also noted. Immunohistochemical study demonstrated the myofibroblastic nature of the spindle cells. Moreover, neoplastic follicles were composed of intermediate to medium-sized lymphocytes, somewhat resembling reactive lymphoid aggregates. The overall histomorphological findings of the three lesions were similar to those of IPT of the lymph node. However, CD10, Bcl-2 and Bcl-6 immunostaining demonstrated the neoplastic nature of the lymphoid follicles and the lesions were diagnosed as FL grade 1. The present three cases indicate that the sclerosing variant of grade 1 FL should be added to the differential diagnosis from IPT of the lymph node. [Abstract/Link to Full Text]

Atmaca AF, Akbulut Z, Demirci A, Belenli O, Alici S, Balbay DM
Multiple subcutaneous nodular metastases from transitional cell carcinoma of the bladder.
Pathol Oncol Res. 2007;13(1):70-2.
Skin metastasis from transitional cell carcinoma (TCC) of the bladder is rare. In this report an uncommon metastasis of TCC of the bladder is presented. [Abstract/Link to Full Text]

V�gso G, T�th M, H�dv�gi M, Toronyi E, Langer RM, Dinya E, T�th A, Perner F, J�ray J
Malignancies after renal transplantation during 33 years at a single center.
Pathol Oncol Res. 2007;13(1):63-9.
This study provides an analysis of incidence and characteristics of malignant tumors of 2535 patients who underwent renal transplantation between 1973 and 2007 at the Transplantation Center in Budapest. One hundred ninety-three malignant diseases were found in 188 patients (7.6%). The incidence of thyroid-, renal- hepatic-, skin- and gastric cancers as well as of Kaposi sarcoma and lymphomas increased in our transplant patient cohort compared to the figures of the general population based on the data of our Cancer Registry. On the other hand, colorectal-, oralprostate and lung cancers were underrepresented in our patient cohort. The mean time of diagnosis of malignancies following kidney transplantation was 58.5+/-44.8 months. One fifth of the tumors were detected within the first year. Patients with malignancies were distributed into four groups based on the immunosuppressive regimen: group I (8.5%), azathioprine + prednisone; group II (59.0%), cyclosporine + prednisone; group III (26.6%), cyclosporine + mycophenolate mofetil + prednisone; group IV (5.9%), tacrolimus + mycophenolate mofetil + prednisone. The mean age of patients was 47.3, 53.5, 55.5 and 58.1 years in group I, II, III and IV, respectively. Oncologic and immunosuppressive therapy was decided individually. Immunosuppression was switched to rapamycin-containing regimens in 63 cases. We lost 92 patients (48.9%) with a mean survival time of 25.8+/-39.4 months. Cumulative 1- and 5-year survivals were 69.5% and 52%, respectively. The increasing number of cancers seen early after transplantation and the increased risk of developing a cancer due to the older age of recipients draw attention to the importance of regular oncologic screening in patients on the waiting list and after transplantation. [Abstract/Link to Full Text]