Erratum: Willenbacher, E., et al. Curcumin: New Insights into an Ancient Ingredient against Cancer. Int. J. Mol. Sci. 2019, 20, 1808.

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Cost-comparison analysis of a multiplatform tumour profiling service to guide advanced cancer treatment.

BACKGROUND: Tumor profiling is increasingly used in advanced cancer patients to define treatment options, especially in refractory cases where no standard treatment is available. Caris Molecular Intelligence (CMI) is a multiplatform tumor profiling service that is comprehensive of next-generation sequencing (NGS) of DNA and RNA, immunohistochemistry (IHC) and in situ hybridisation (FISH). The aim of this study is to compare costs of CMI-guided treatment with prior or planned treatment options in correlation with outcome results. METHODS: Retrospective data from five clinical trials were collected to define the treatment decision prior to the receipt of the CMI report (n = 137 patients). A systematic review of treatment data from 11 clinical studies of CMI (n = 385 patients) allowed a comparison of planned vs actual (n = 137) and prior vs actual (n = 229) treatment costs. RESULTS: Treatment plan was changed in 88% of CMI-profiled cases. The actual CMI guided treatment cost per cycle was £995 in 385 treated patients. Planned treatment costs were comparable to actual treatment costs (£979 vs £945; p = 0.7123) and prior treatment costs were not significantly different to profiling-guided treatments (£892 vs £850; p = 0.631). CONCLUSIONS: Caris Molecular Intelligence guided treatment cost per cycle was in the range of prior or planned treatment cost/cycle. Due to beneficial overall survival the additional cost of performing CMI's multiplatform testing to the treatment costs seems to be cost-effective.

Curcumin: New Insights into an Ancient Ingredient against Cancer.

Cancer patients frequently use complementary medicine. Curcumin (CUR) and its derivates (from the extract of Curcuma longa L.) represent some of the most frequently used ones, having a long history in traditional Asian medicine. CUR was demonstrated, both in vitro and in vivo, to have significant anti-inflammatory effects, thus potentially counteracting cancer-promoting inflammation, which is a hallmark of cancer. CUR modulate a plethora of signaling pathways in cancer cells, comprising the NF-κB (nuclear factor k-light-chain-enhancer of activated B cells), the JAK/STAT (Janus-Kinase/Signal Transducers and Activators of Transcription), and the TGF-ß (transforming growth factor-ß) pathways. Furthermore, CUR confers properties of electron receptors, which destabilize radical oxygen species (ROS), explaining its antioxidant and anti-apopototic effects. Although CUR has a low bioavailability, its role in advanced cancer treatment and supportive care was addressed in numerous clinical trials. After promising results in phase I⁻II trials, multiple phase III trials in different indications are currently under way to test for direct anti-cancer effects. In addition, CUR exerts beneficial effects on cancer treatment-related neurotoxcity, cardiotoxicity, nephrotoxicity, hemato-toxicity, and others. More efficient galenic formulations are tested to optimze CUR's usability in cancer treatment. This review should provide a comprehensive overview of basic science, and pre-clinical and clinical data on CUR in the field of oncology.

What's new in small cell lung cancer - extensive disease? An overview on advances of systemic treatment in 2016.

Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials. Furthermore, a potential benefit of new agents targeting DLL3, Aurora A kinase and PARP-inhibitor was reported. In this review we summarize new developments and critically highlight the most important and promising data in the relapsed small cell lung cancer disease.

Predominant expression of truncated EpCAM is associated with a more aggressive phenotype and predicts poor overall survival in colorectal cancer.

Regulated intramembrane proteolysis (RIP) has been shown to be an important mechanism for oncogenic activation of EpCAM through nuclear translocation of the intracellular domain EpICD. Recently, we identified two different membranous EpCAM variants namely EpCAM(MF) (full-length) and EpCAM(MT) (truncated) to be expressed in the majority of human epithelial tumors. The aim of our study was to evaluate the potential role of these two protein variants as additional prognostic biomarkers in colorectal cancer. In most studies only one antibody targeting the extracellular domain of EpCAM (EpEX) has been used, whereas in the present study additionally an antibody which detects the intracellular domain (EpICD) was applied to discriminate between different EpCAM variants. Using immunohistochemistry, we analyzed the expression of EpCAM(MF) and EpCAM(MT) variants in 640 patients with colorectal cancer and determined their correlations with other prognostic factors and clinical outcome. A statistically significant association was observed for EpCAM(MT) with advanced tumor stage (p < 0.001), histological grade (p = 0.01), vascular (p < 0.001) and marginal (p = 0.002) invasion. Survival analysis demonstrated reduced overall survival (p < 0.004) in patients with tumors expressing the EpCAM(MT) phenotype when compared to patients with tumors expressing the EpCAM(MF) variant. In conclusion, this study for the first time indicates that expression of EpCAM(MT) is associated with a more aggressive phenotype and predicts poor survival in patients with colorectal cancer.

Reviewing the Osteotropism in Neuroendocrine Tumors: The Role of Epithelial-Mesenchymal Transition.

BACKGROUND: Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated. METHODS: We reviewed all published reports of histologically confirmed bone metastatic NETs and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 152 patients. We then evaluated immunohistochemical expression of a panel of eight epithelial-mesenchymal transition (EMT)-related factors including SNAIL, TGF-ß1, CTGF, IL-11, PTHrP, EpCAM, CXCR4 and RANK in an independent cohort of 44 archival primary NETs. Biomarker expression was correlated with clinicopathological variables, including skeletal involvement, and tested for survival prediction. RESULTS: We found that 55% of NET patients with bone metastases were male, with a median age of 55 years at diagnosis. Metastases were restricted to the skeleton in 34% of the NET population, and axial and osteoblastic lesions were prevalent. NETs differently expressed proteins involved in EMT activation. High CXCR4 (p < 0.0001) and low TGF-ß1 levels (p = 0.0015) were significantly associated with increased risk of skeletal metastases, suggesting that EMT is implicated in NET osteotropism. By applying an algorithm measuring distinct immunohistochemical predictors of osteotropism on primary tumors, we were able to identify NET patients with bone metastases with a sensitivity and specificity of 91 and 100%, respectively (p < 0.0001). Patients whose primary tumors expressed CTGF (p = 0.0007) as well as the truncated form of EpCAM (p = 0.06) showed shorter survival. CONCLUSION: Although underestimated, bone metastases are a prominent feature of NETs, and the tumor expression of EMT markers at diagnosis may predict concurrent or subsequent skeleton colonization.

Clinical outcomes in octogenarians treated with docetaxel as first-line chemotherapy for castration-resistant prostate cancer.

AIM: To assess clinical outcomes in octogenarians treated with docetaxel (DOC) for metastatic castration-resistant prostate cancer. PATIENTS & METHODS: The multicenter retrospective study was based on a review of the pre- and post-DOC clinical history, DOC treatment and outcomes. RESULTS: We reviewed the records of 123 patients (median age: 82 years) who received DOC every 3 weeks or weekly, without significant grade 3-4 toxicities. Median progression-free survival was 7 months; median overall survival from the start of DOC was 20 months, but post-progression treatments significantly prolonged overall survival. CONCLUSION: The findings of this study suggest that toxicity is acceptable, survival is independent of patient's age and survival can be significantly prolonged by the use of new agents.

Epigenetic stem cell signature in cancer.

Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.

Effectiveness of an additional individualized multi-component complementary medicine treatment on health-related quality of life in breast cancer patients: a pragmatic randomized trial.

The aim of this study was to evaluate the effectiveness of an additional, individualized, multi-component complementary medicine treatment offered to breast cancer patients at the Merano Hospital (South Tyrol) on health-related quality of life compared to patients receiving usual care only. A randomized pragmatic trial with two parallel arms was performed. Women with confirmed diagnoses of breast cancer were randomized (stratified by usual care treatment) to receive individualized complementary medicine (CM group) or usual care alone (usual care group). Both groups were allowed to use conventional treatment for breast cancer. Primary endpoint was the breast cancer-related quality of life FACT-B score at 6 months. For statistical analysis, we used analysis of covariance (with factors treatment, stratum, and baseline FACT-B score) and imputed missing FACT-B scores at 6 months with regression-based multiple imputation. A total of 275 patients were randomized between April 2011 and March 2012 to the CM group (n = 136, 56.3 ± 10.9 years of age) or the usual care group (n = 139, 56.0 ± 11.0). After 6 months from randomization, adjusted means for health-related quality of life were higher in the CM group (FACT-B score 107.9; 95 % CI 104.1-111.7) compared to the usual care group (102.2; 98.5-105.9) with an adjusted FACT-B score difference between groups of 5.7 (2.6-8.7, p < 0.001). Thus, an additional individualized and complex complementary medicine intervention improved quality of life of breast cancer patients compared to usual care alone. Further studies evaluating specific effects of treatment components should follow to optimize the treatment of breast cancer patients.

Soluble EpCAM levels in ascites correlate with positive cytology and neutralize catumaxomab activity in vitro.

BACKGROUND: EpCAM is highly expressed on membrane of epithelial tumor cells and has been detected as soluble/secreted (sEpCAM) in serum of cancer patients. In this study we established an ELISA for in vitro diagnostics to measure sEpCAM concentrations in ascites. Moreover, we evaluated the influence of sEpCAM levels on catumaxomab (antibody)--dependent cellular cytotoxicity (ADCC). METHODS: Ascites specimens from cancer patients with positive (C+, n = 49) and negative (C-, n = 22) cytology and ascites of patients with liver cirrhosis (LC, n = 31) were collected. All cell-free plasma samples were analyzed for sEpCAM levels with a sandwich ELISA system established and validated by a human recombinant EpCAM standard for measurements in ascites as biological matrix. In addition, we evaluated effects of different sEpCAM concentrations on catumaxomab-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood mononuclear cells (PBMNCs) and human tumor cells. RESULTS: Our ELISA showed a high specificity for secreted EpCAM as determined by control HEK293FT cell lines stably expressing intracellular (EpICD), extracellular (EpEX) and the full-length protein (EpCAM) as fusion proteins. The lower limit of quantification was 200 pg/mL and the linear quantification range up to 5,000 pg/mL in ascites as biological matrix. Significant levels of sEpCAM were found in 39% of C+, 14% of C- and 13% of LC ascites samples. Higher concentrations of sEpCAM were detectable in C+ (mean: 1,015 pg/mL) than in C- (mean: 449 pg/mL; p = 0.04) or LC (mean: 326 pg/mL; p = 0.01). Soluble EpCAM concentration of 1 ng/mL significantly inhibited ADCC of PBMNCs on EpCAM overexpressing target cells. CONCLUSION: Elevated concentrations of sEpCAM can be found in a subgroup of C+ and also in a small group of C- patients. We consider that sEpCAM levels in different tumor entities and individual patients should be evaluated prior to applying anti-EpCAM antibody-based cancer therapies, since sEpCAM neutralizes catumaxomab activity, making therapy less efficient.

Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer.

AIMS: Epithelial cell adhesion molecule (EpCAM) is a widely used immunohistochemical marker for epithelial human malignancies. Antibodies to target EpCAM are usually directed against its ectodomain (EpEX), but do not detect the intracellular domain (EpICD). The aim of this study was to compare membranous EpEX versus EpICD expression by immunohistochemistry. METHODS AND RESULTS: Concurrent EpEX and EpICD expression was investigated retrospectively in cancerous and matched non-neoplastic tissue samples from patients with pancreatic adenocarcinoma. In total, 317 paired samples of pancreatic tissue from 88 patients were analysed and correlated with clinicopathological parameters. In non-cancerous tissue, a high concordance of membranous EpEX and EpICD expression was observed and defined as the expression of the full-length EpCAM (EpEX(+)/EpICD(+) phenotype, EpCAM(MF)), which was highly predominant. In contrast, while most tumour samples were EpEX positive, loss of membranous EpICD expression (EpEX(+)/EpICD(-) phenotype, EpCAM(MT)) was observed in one-third of cases, and these patients had a significantly shortened disease-free and overall survival. CONCLUSIONS: This study demonstrates for the first time that loss of membranous EpICD expression is a frequent event and predicts poor prognosis in patients with pancreatic cancer. Additional studies evaluating the predictive and prognostic value of the expression of different membranous EpCAM variants are warranted in epithelial cancers.

Potential value of rapid prostate-specific antigen decline in identifying primary resistance to abiraterone acetate and enzalutamide.

AIM: To identify factors predicting primary resistance to new-generation hormonal agents (NHAs), abiraterone acetate and enzalutamide in patients with castration-resistant prostate cancer (CRPC). PATIENTS & METHODS: Our hospital has conducted two successive named patient NHA programs. A total of 57 patients with progressive CRPC previously treated with first-line docetaxel-based chemotherapy received standard NHA doses: abiraterone acetate 1000 mg once-daily combined with prednisone (5 mg twice daily) or enzalutamide 160 mg once-daily. Patients, who were assessed monthly to check their hematological parameters and prostate-specific antigen (PSA) levels, also underwent imaging investigations every 3-4 months. In total, 24 variables were assessed as potential predictors of primary NHA resistance. RESULTS: Univariate analysis indicated that baseline pain and lactate dehydrogenase levels, and PSA levels after 1 month's treatment were predictive of primary NHA resistance. Only the predictive value of PSA levels after 1 month of treatment was confirmed at multivariate analysis. This factor strongly predicted progression-free and overall survival. CONCLUSION: RESULTS suggest the use of a simple and rapid method of identifying patients with primary resistance to NHAs: patients not achieving a ≥ 50% reduction in PSA levels within the first treatment month should undergo intensive investigations to verify whether they have primary resistance to NHAs.

EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth.

INTRODUCTION: The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. However, effects of EpCAM overexpression on normal breast epithelial cells have never been studied before. Therefore, we analyzed effects of transient adenoviral overexpression of EpCAM on proliferation, migration and differentiation of primary human mammary epithelial cells (HMECs). METHODS: HMECs were transfected by an adenoviral system for transient overexpression of EpCAM. Thereafter, changes in cell proliferation and migration were studied using a real time measurement system. Target gene expression was evaluated by transcriptome analysis in proliferating and polarized HMEC cultures. A Chicken Chorioallantoic Membrane (CAM) xenograft model was used to study effects on in vivo growth of HMECs. RESULTS: EpCAM overexpression in HMECs did not significantly alter gene expression profile of proliferating or growth arrested cells. Proliferating HMECs displayed predominantly glycosylated EpCAM isoforms and were inhibited in cell proliferation and migration by upregulation of p27(KIP1) and p53. HMECs with overexpression of EpCAM showed a down regulation of E-cadherin. Moreover, cells were more resistant to TGF-ß1 induced growth arrest and maintained longer capacities to proliferate in vitro. EpCAM overexpressing HMECs xenografts in chicken embryos showed hyperplastic growth, lack of lumen formation and increased infiltrates of the chicken leukocytes. CONCLUSIONS: EpCAM revealed oncogenic features in normal human breast cells by inducing resistance to TGF-ß1-mediated growth arrest and supporting a cell phenotype with longer proliferative capacities in vitro. EpCAM overexpression resulted in hyperplastic growth in vivo. Thus, we suggest that EpCAM acts as a prosurvival factor counteracting terminal differentiation processes in normal mammary glands.

Low expression of junctional adhesion molecule A is associated with metastasis and poor survival in pancreatic cancer.

BACKGROUND: Characterized by its highly aggressive tumor biology, pancreatic cancer still remains a fatal diagnosis. The junctional adhesion molecule A (JAM-A) is a type I transmembrane glycoprotein, which recently has been shown to affect the prognosis of several human malignancies. METHODS: JAM-A antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumor tissue samples from a series (n = 186) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated by Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. RESULTS: Low expression of JAM-A was observed in 79 (42 %) of 186 pancreatic cancer specimens and was significantly associated with poor overall survival (P < 0.01). By univariate analysis, low expression of JAM-A was found to correlate with positive lymph node status (P = 0.02), the presence of distant metastasis (P = 0.05), and tumor grade (P = 0.04), suggesting it may be an important event involved in cancer progression. Furthermore, in the subgroup of patients with surgically resected pancreatic cancer, low expression of JAM-A significantly correlated with decreased progression-free survival (P < 0.01). Multivariate analysis revealed JAM-A to be an independent predictor of poor outcome. DISCUSSION: These findings suggest for the first time that low levels of JAM-A expression in pancreatic cancer are associated with poor clinical outcome. JAM-A may represents a target molecule for functional inactivation and serve as a novel biomarker of adverse prognosis in pancreatic cancer.

Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines.

BACKGROUND: The epithelial cell adhesion molecule (EpCAM) has been shown to be overexpressed in breast cancer and stem cells and has emerged as an attractive target for immunotherapy of breast cancer patients. This study analyzes the effects of EpCAM on breast cancer cell lines with epithelial or mesenchymal phenotype. METHODS: For this purpose, shRNA-mediated knockdown of EpCAM gene expression was performed in EpCAMhigh breast cancer cell lines with epithelial phenotype (MCF-7, T47D and SkBR3). Moreover, EpCAMlow breast carcinoma cell lines with mesenchymal phenotype (MDA-MB-231, Hs578t) and inducible overexpression of EpCAM were used to study effects on proliferation, migration and in vivo growth. RESULTS: In comparison to non-specific silencing controls (n/s-crtl) knockdown of EpCAM (E#2) in EpCAMhigh cell lines resulted in reduced cell proliferation under serum-reduced culture conditions. Moreover, DNA synthesis under 3D culture conditions in collagen was significantly reduced. Xenografts of MCF-7 and T47D cells with knockdown of EpCAM formed smaller tumors that were less invasive. EpCAMlow cell lines with tetracycline-inducible overexpression of EpCAM showed no increased cell proliferation or migration under serum-reduced growth conditions. MDA-MB-231 xenografts with EpCAM overexpression showed reduced invasion into host tissue and more infiltrates of chicken granulocytes. CONCLUSIONS: The role of EpCAM in breast cancer strongly depends on the epithelial or mesenchymal phenotype of tumor cells. Cancer cells with epithelial phenotype need EpCAM as a growth- and invasion-promoting factor, whereas tumor cells with a mesenchymal phenotype are independent of EpCAM in invasion processes and tumor progression. These findings might have clinical implications for EpCAM-based targeting strategies in patients with invasive breast cancer.

Impact and Novel Perspective of Immune Checkpoint Inhibitors in Patients with Early and Intermediate Stage HCC.

Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages.

Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer.

PURPOSE: Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer. Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared with wild-type (WT) colorectal cancers to gain insights into potential rationales for therapeutic strategies. EXPERIMENTAL DESIGN: A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and IHC. An independent cohort was used to validate our findings. RESULTS: The discovery cohort consisted of 7,245 colorectal cancer samples. RSPOfp and RNF43 mutations were detected in 1.3% (n = 94) and 6.1% (n = 443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g., IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison with WT colorectal cancers, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A, and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared with WT cases (4.4% vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared with WT samples. Although RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a tumor mutation burden ≥10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings. CONCLUSIONS: This is the largest series of RSPOfp/RNF43-mut colorectal cancers reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy.

Effects of EpCAM overexpression on human breast cancer cell lines.

BACKGROUND: Recently, EpCAM has attracted major interest as a target for antibody- and vaccine-based cancer immunotherapies. In breast cancer, the EpCAM antigen is overexpressed in 30-40% of all cases and this increased expression correlates with poor prognosis. The use of EpCAM-specific monoclonal antibodies is a promising treatment approach in these patients. METHODS: In order to explore molecular changes following EpCAM overexpression, we investigated changes of the transcriptome upon EpCAM gene expression in commercially available human breast cancer cells lines Hs578T and MDA-MB-231. To assess cell proliferation, a tetrazolium salt based assay was performed. A TCF/LEF Reporter Kit was used to measure the transcriptional activity of the Wnt/ß-catenin pathway. To evaluate the accumulation of ß-catenin in the nucleus, a subcellular fractionation assay was performed. RESULTS: For the first time we could show that expression profiling data of EpCAM transfected cell lines Hs578TEpCAM and MDA-MB-231EpCAM indicate an association of EpCAM overexpression with the downregulation of the Wnt signaling inhibitors SFRP1 and TCF7L2. Confirmation of increased Wnt signaling was provided by a TCF/LEF reporter kit and by the finding of the nuclear accumulation of ß-catenin for MDA-MB-231 EpCAM but not Hs578T EpCAM cells. In Hs578T cells, an increase of proliferation and chemosensitivity to Docetaxel was associated with EpCAM overexpression. CONCLUSIONS: These data show a cell type dependent modification of Wnt signaling components after EpCAM overexpression in breast cancer cell lines, which results in marginal functional changes. Further investigations on the interaction of EpCAM with SFRP1 and TCF7L2 and on additional factors, which may be causal for changes upon EpCAM overexpression, will help to characterize unique molecular properties of EpCAM-positive breast cancer cells.

Clinical aspects, diagnostic challenges and management of patients with neuroendocrine tumors (NETs).

Neuroendocrine tumor (NET) entities are rare malignancies. Higher awareness and improved diagnostic methods have led to an increasing incidence of these diseases, and most oncologists deal with such patients in their daily practice. The symposium on NETs that was held in Merano (Italy) in October 2009 was organized by the German-speaking European School of Oncology (dESO) and gathered specialists from different disciplines of transalpine countries to bring together experiences and observations regarding these tumors. The goal of the meeting and of this review was to illustrate both well- and poorly differentiated NETs and to encourage interdisciplinary approaches.

Transfusion-associated circulatory overload in gastroenterology.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a rare life-threatening event associated with transfusion. This study aimed to identify any case of TACO in a large cohort of highly transfused patients with gastrointestinal tract (GI) bleeding. MATERIALS AND METHODS: Data from patients who underwent an oesophago-gastro-duodenoscopy (OGD) were collected over one year from the gastroenterology service of a regional hospital. RESULTS: A total of 278 patients were identified, of which 81 required transfusion. In total, 811 blood components were transfused (red cell concentrate, platelets, plasma), leading to a cumulative TACO incidence of 12.3%. The probability of developing TACO was greater for patients aged ≥80 years (OR=3.9%; p=0.0058), with renal disease (OR=1.9%, p=not significant) and with cardiac disease (OR 11.1%; p=0.003). Patients with TACO had a lower overall survival (52 vs 20% at 3 years, p=0.034, HR=2.19, 95% CI: 1.04-4.63) compared to patients with cirrhosis without TACO (57 vs 28% at 3 years, p=0.003, HR=2.20, 95% CI: 1.30-3.72). Patients with an advanced stage of liver cirrhosis (Child Pugh c10 or more) were most likely to develop TACO. DISCUSSION: This study shows that within the GI setting TACO may be markedly under-reported. Clinical awareness for potential TACO development in GI patients with cardiac or renal disease or age >80 years is now required.