Chymase-positive Mast cells correlate with tumor angiogenesis: first report in pancreatic cancer patients.

OBJECTIVE: Mast cells (MCs) are known to be involved in several physiological and pathological processes in humans and animals. Recently, their potential role in tumor development and angiogenesis has been investigated, arising interesting results to be potentially applied in clinics. Mast cells' granules contain a huge quantity of protease enzymes that, through different mechanisms, induce the formation of new microvessels, feeding tumor burden. Among them, tryptase and chymase are the most abundant enzymes: tryptase is well known for its multiple activities, on the contrary, the role of chymase in pancreatic cancer angiogenesis has not been investigated yet. PATIENTS AND METHODS: Our research aims to correlate to each other and to angiogenesis four different tissue parameters (MCs density positive to chymase, MCs area positive to chymase, microvascular density and endothelial area) together with the main clinical-pathological characteristics in 52 patients surgically resected for pancreatic ductal adenocarcinoma, employing immunohistochemistry and image analysis system. RESULTS: All reported tissue parameters match to confirm the correlation between chymase enzyme and angiogenesis in pancreatic cancer. CONCLUSIONS: This evidence could become a starting point for a new potential therapeutic route exploiting chymase inhibitors as a novel anti-angiogenetic strategy in pancreatic cancer patients.

Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue.

Background: Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.

Expression of metalloproteinases MMP-2 and MMP-9 in sentinel lymph node and serum of patients with metastatic and non-metastatic breast cancer.

The objective of this study was to evaluate the expression of MMP-2 and MMP-9 in sentinel lymph node and serum of breast cancer patients in order to evaluate their clinical significance and usefulness as diagnostic tumour markers. Expression of MMP-2 and MMP-9 was performed on sentinel lymph node by immunohistochemistry while gelatine zymography was used to determinate the serum expression. The association of gelatinases with clinicopathological features, were analysed. Metastatic and non-metastatic breast cancer patients and 34 healthy women were involved. Gelatinases expression were significantly higher in metastatic breast cancer in comparison to non-metastatic cancer and the control group both in the sentinel lymph node and serum. Results showed a statistically significant correlation between MMP-2 or MMP-9 and cancer familiality, MMP-9 and CA 15.3 levels, and MMP-9 and grading. This study suggests a clinical utility of these proteolytic markers in malignant tumour, growth, invasion and metastasis in breast cancer.

A possible role of thymidine phosphorylase expression and 5-fluorouracil increased sensitivity in oropharyngeal cancer patients.

Thymidine Pi deoxyribosyltransferase (TP) is an enzyme involved in DNA synthesis up-regulated in tumours and it is also a pro-angiogenic factor. TP cannot activate capecitabine, because capecitabine first needs conversion by carboxylesterase and cytidine deaminase into 5-deoxy-fluorouridine. This compound can be activated by TP to 5-fluorouracil (5-FU). Although TP is not necessary for 5-FU toxicity, experimental data suggest that high levels of TP correlate with an enhanced response to 5-FU therapy. In this study, we have analysed by immunohistochemistry CD34, CD68 and TP positive cells in bioptic samples from 53 patients with T(1-3) N(0-1) M(0) oropharyngeal squamous cell carcinoma (OSC) and from 24 patients with non-dysplastic oropharyngeal leukoplakia (NDOLP). Results showed that the mean of TP-positive cells, CD68 positive macrophages and CD34 positive endothelial cells eval-uated as microvessel density (MVD) was significantly higher in OSC than in NDOLP. Moreover, at a median follow-up of 19 months, patients with TP expression and higher MVD showed a better survival rate as compared to those with low MVD, probably as a consequence of 5-FU-based therapy.We hypothesized a role for TP in oropharyngeal tumourigenesis and 5-FU activation in the adjuvant setting of OSC patients.

A rare case of extra-adrenal pheochromocytoma masquerading as an ovarian mass treated by laparoscopic surgery.

BACKGROUND: Extra-adrenal pheochromocytoma, or paraganglioma, is a rare tumour arising from paraganglion chromaffin cells of the sympathetic nervous system. In adults, pheochromocytomas are often called the "10% tumor" because approximately 10% occur above the diaphragm, 10% of intraabdominal pheochromocytomas are extra-adrenal, 10% are bilateral, 10% are multiple, 10% are familial, 10% are malignant, and 10% recur postoperatively. In children, instead, this tumor occurs in ectopic sites in 30-40% of the cases. This paper reports the successful laparoscopic resection of an extra-adrenal pheochromocytoma, simulating an ovarian tumor, combined with a laparoscopic cholecystectomy for gallstones. CASE REPORT: The case of a 48-year-old woman affected by an extra-adrenal pheochromocytoma that had been unsuspected for a long time is presented. The patient had some clinical symptoms that had been taken for a climacteric syndrome given her premenopausal age. The atypical and rare location of the pheochromocytoma (parauterine) had contributed to misdiagnosing it as an ovarian tumor. Laparoscopic surgery was chosen for the removal of the tumor because it is a safe technique requiring a shorter hospital stay; a concomitant cholecystectomy was performed due to the presence of gallstones. CONCLUSION: Surgical resection is the only treatment option for extra-adrenal pheochromocytomas. With adequate preoperative adrenergic receptor blockers and vascular filling, the laparoscopic approach appears to be a valid alternative to open surgery for paragangliomas. Gynecologists should consider the possibility, although rare, of an extra-adrenal pheocromocytoma when preparing to surgically remove a pelvic mass.

Thymidine phosphorylase profiles in nonmalignant and malignant pancreatic tissue. Potential therapeutic role of capecitabine on tumoral and endothelial cells and tumor-infiltrating macrophages.

The drug capecitabine (CAP) is a thymidine Pi-deoxyribosyltransferase (TP) activated oral fluorpyrimidine that generates 5-fluorouracil (5-FU), preferentially, within tumors. Here, in 38 patients with pancreatic cancer we analyzed immunohistochemical TP expression in pancreatic cancer tissue (PCT) and adjacent nonmalignant pancreatic tissue (ANMPT). In addition, a correlation with the main clinical pathological features was made. Furthermore, TP-positive macrophages (MO) isolated from neoplastic tissue were determined. The mean of TP-positive epithelial cells and endothelial cells in terms of microvessel density was significantly higher in PCT than in ANMPT. Because pancreatic cancer is sensitive to 5-FU, TP-activated oral CAP in tumoral and endothelial cells and tumor infiltrating MO could increase the concentration of 5-FU at tumor site, thus resulting in an enhanced antitumor activity.