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Background: A significant number of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) present with metastatic disease and with unknown primary in about 15% of cases., Materials and Methods: We analyzed 163 primaries of GEP NET and 115 metastases for expression of caudal type homebox 2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), somatostatin receptor 2a (SSTR2a) and Ki67., Results: PR was most often positive in pancreatic NET and only rarely in non-pancreatic NET (p<0.001). ER was more frequently expressed in non-pancreatic NET (p<0.001) and was more often positive in females than males (p=0.019). CDX2 was positive in all primaries of the duodenum, ileum and appendix, but was also detected in 24% of metastases with pancreatic primary. SSTR2a and Ki67 did not differ significantly between primaries and metastases., Conclusion: Our data substantiate the value of PR, ER and CDX2 in GEP NET, and steroid hormone receptors, being differentially expressed in male and female patients. Differences between primaries and metastases were small but potentially relevant., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Angioimmunoblastic T-cell lymphomas (AITLs) are the second most frequent peripheral T-cell lymphomas in humans worldwide and histomorphologically well characterized. MicroRNAs are a group of small non-coding RNAs that can negatively regulate gene expression on a posttranscriptional level. Their dysregulation has been shown to be of importance in numerous tumour entities., Materials and Methods: As a first step towards understanding the possible influence of microRNA-dysregulation in AITL, we analyzed the expression signatures of 760 microRNAs in 30 nodal AITLs in comparison to reactive lymphadenitis with T-zone hyperplasia., Results: We found miR-34a, miR-146a and miR-193b to be up-regulated, as well as miR-140-3p, let-7g, miR-30b and miR-664 to be down-regulated in AITL to a significant level., Conclusion: The microRNA-signatures of AITL reveal some overlap to autoimmune diseases, virus-triggered lymphomas and angiogenic factors that, coupled with future studies, will potentially provide better understanding of this disease., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) frequently observed in young patients. High-dose immunochemotherapy constitutes the current therapeutic gold-standard, despite significant toxicity and serious late effects. Several hotspots harboring oncogenic gain-of-function mutations were recently shown to pose vital hallmarks in activated B-cell like (ABC-) (CD79B, CARD11 and MYD88) and germinal center like (GCB-) DLBCL (EZH2), respectively. Several promising targeted-therapy approaches, derived from these findings, are currently under development., Materials and Methods: We thoroughly characterized a cohort of 25 untreated patients with de novo PMBL by immunohistochemical and cytogenetic means and assessed the prevalence of activating mutations affecting EZH2, CD79B and CARD11 utilizing a polymerase chain reaction (PCR)-based capillary sequencing approach. Moreover, the MYD88 p. L265P status was assessed by employing a pyrosequencing approach., Results: PMBLs included in this study did not harbor any of the reported hotspot mutations activating the nuclear factor (NF)-kappa B signaling cascade or the EZH2-mediated epigenetic deregulation of gene expression. Immunohistochemical characterization revealed an ABC phenotype in 44% (n=11) of cases., Conclusion: We report that genetic alterations of these genes are rare events in PMBL unlike other subtypes of DLBCL. Our findings suggest that a substantial subset of PMBL patients may benefit from treatment approaches targeting BCR-mediated activation of NF-kappa B., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: To present long-term results regarding the role of vascular endothelial growth factor (VEGF) and its receptor-1 (VEGFR-1) for esophageal cancer., Patients and Methods: In 68 esophageal cancer patients, VEGF, VEGFR-1 plus ten other factors were analyzed for locoregional control (LRC), metastases-free survival (MFS) and survival up to 10 years., Results: On multivariate analysis, improved LRC was associated with hemoglobin during radiotherapy ≥12 g/dl (p=0.001). VEGF-negativity showed a trend for better LRC on univariate analysis. On multivariate analysis, better MFS was associated with hemoglobin ≥12 g/dl (p=0.012), better performance status (p=0.009) and lower tumor stage (p=0.032). On multivariate analysis, improved survival was associated with hemoglobin ≥12 g/dl (p<0.001) and better performance status (p=0.005). Trends for improved survival were observed for VEGF-negativity and VEGFR-1-negativity on univariate analysis., Conclusion: VEGF showed a trend towards worse LRC and survival, VEGFR-1 towards worse survival. Outcomes were associated with hemoglobin, performance status and tumor stage., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Long-term results of a study investigating potential prognostic factors for treatment outcomes in patients with stage III esophageal cancer are presented., Patients and Methods: In 64 patients, the impact of tumor cell expression of erythropoietin (EPO) and erythropoietin-receptor (EPO-R) and ten additional factors (age, gender, performance status, tumor length, tumor stage (T-stage), nodes (N-stage), histology/grading, hemoglobin levels during radiotherapy, surgery) on survival and loco-regional control was evaluated up to 10 years following radio-chemotherapy., Results: On multivariate analysis, improved survival was associated with low EPO-R expression (p=0.034) and hemoglobin levels during radiotherapy ≥ 12 g/dl (p=0.026). Low EPO expression was associated with survival on univariate (p=0.010) but not on multivariate analysis (p=0.42). On multivariate analysis, improved loco-regional control was significantly associated with hemoglobin levels during radiotherapy ≥ 12 g/dl (p<0.001)., Conclusion: The long-term results confirm that hemoglobin levels during radiotherapy and tumor cell expression of EPO-R are significant prognostic factors in patients with locally advanced esophageal cancer., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: MicroRNAs are regulators of gene expression implicated in vital cellular processes including differentiation, cell growth and apoptosis. Distinct microRNA signatures have been identified for many malignancies including follicular lymphoma (FL). However, no microRNA expression profile characteristic of FL subtypes, e.g. FL with B-cell lymphoma-6 (BCL6) locus rearrangement (FL(BCL2+/BCL6+), FL(BCL2-/BCL6+)) or FL with diffuse growth pattern have been reported., Materials and Methods: MicroRNA signatures from 44 cases of FL were generated employing a quantitative real-time polymerase chain reaction approach. 15 cases of diffuse FL and 15 cases of FL(BCL2+/BCL6+)/FL(BCL2-/BCL6+) were compared against 14 cases of typical FL(BCL2+/BCL6-)., Results: Numerous microRNAs were found to be differentially expressed between FL(BCL2+/BCL6+) and FL(BCL2-/BCL6+), as well as diffuse FL, when compared to typical cases of FL. Up-regulation of several oncogenic microRNAs as well as down-regulation of tumor-suppressor microRNAs was identified. Cluster analysis, however, revealed no microRNA signatures distinct from the reference group for either subtype., Conclusion: These results indicate an involvement of microRNAs in the pathogenesis of FL and its subtypes. Marked de-regulation of oncogenic RNAs and tumor suppressors appears to correspond with a more aggressive phenotype frequently observed in FL(BCL2+/BCL6+), FL(BCL2-/BCL6+) and diffuse FL.

Background: The translocation t(14;18)IgH/BCL2 is the molecular hallmark of follicular lymphomas (FL). A subset of cases harbours translocations involving the BCL6-gene locus. This study aimed to determine the frequency of BCL2- and BCL6-translocations in FL and to identify morphological and immuno-histochemical features with respect to the presence of BCL2- and BCL6-translocations., Materials and Methods: Fluorescence-in-situ-hybridisation (FISH) was used to determine the BCL2- and BCL6-translocation status of 102 FL and these were compared to morphological and immunohistochemical parameters., Results: Lymphomas with BCL6- and BCL2-translocations were very similar to t(14;18)-positive lymphomas without BCL6-translocations. In contrast, t(14;18)-negative lymphomas with BCL6-translocations were amongst others of higher grade, less often CD10-positive, involved the bone marrow less frequently and did not infiltrate the lymph node capsule., Conclusion: BCL2- and BCL6-translocations correlate with particular phenotypes of follicular lymphomas. BCL6-translocations seem to affect the phenotype only when they are not accompanied by BCL2-translocations.

Background: MicroRNAs (miRNAs) are approximately 22 nucleotide long, non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region of target mRNAs and also a variety of cellular processes. It has recently been established that dysregulation of miRNA expression can be detected in the majority of human cancers. A variety of high-throughput screening methods has been developed to identify dysregulated miRNA species in tumours. For retrospective clinical studies formalin-fixed, paraffin-embedded (FFPE) tissue is the most widely used material., Materials and Methods: The miRNA expression profiles of freshly frozen (CRYO) and FFPE tissues of seven tonsil and four liver samples were compared, using a qPCR-based assay, profiling 157 miRNA species., Results: The significance of miRNA-profiles was barely influenced by FFPE treatment in both tissues and the variance induced by FFPE treatment was much smaller than the variance caused by biologically based differential expression., Conclusion: FFPE material is well suited for miRNA profiling.

Background: Matrix metalloproteinases are involved in tumor invasion and metastatic spread. Expression of metalloproteinases is induced by the extracellular matrix metalloproteinase inducer (EMMPRIN). Their activity can be inhibited by several tissue inhibitors of metalloproteinases (TIMP1-to-4). Whereas TIMP-1 expression is described for high-grade malignant lymphomas and seems to be correlated with unfavourable prognosis, there are no data on the expression of EMMPRIN in malignant lymphoma., Materials and Methods: We investigated 60 cases of Hodgkin's lymphoma and anaplastic large cell lymphoma for TIMP-1 and EMMPRIN expression using immunohistochemistry., Results: EMMPRIN was expressed in all but four cases. EMMPRIN and TIMP-1 were co-expressed in two-thirds of the Hodgkin's lymphomas and anaplastic large cell lymphomas., Conclusion: This is the first report on the expression of EMMPRIN in malignant lymphoma. We speculate that EMMPRIN and TIMP-1 may be important in the pathogenesis of anaplastic large cell lymphoma and Hodgkin's disease.