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Mace T.A.,Divisions of Medical Oncology | Ameen Z.,Divisions of Medical Oncology | Mair M.,Divisions of Medical Oncology | Young G.S.,Arthur G James Cancer Hospital And Richard J Solove Research Institute | And 4 more authors.
Cancer Research | Year: 2013

Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n 1/4 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, a-smooth muscle actin (a-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n 1/4 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target. Cancer Res; 73(10); 3007-18. © 2013 AACR.

Volante M.,University of Turin | Monica V.,University of Turin | Birocco N.,Divisions of Medical Oncology | Brizzi M.P.,University of Turin | And 10 more authors.
Neuroendocrinology | Year: 2015

Background: Mixed neuroendocrine/nonneuroendocrine carcinomas are heterogeneous tumors with poorly defined diagnostic and clinical features and without pathological or molecular markers of prognosis or markers predicting their response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of patients with mixed carcinomas from different sites as compared to the patients' outcome. Methods: Relative cDNA quantification of ribonucleotide reductase, large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR on microdissected neuroendocrine and nonneuroendocrine tumor components of 42 mixed cases (from the lung as well as the gastrointestinal and genitourinary tracts) and on 45 control cases of pure neuroendocrine and nonneuroendocrine carcinomas. Results: The expression levels of all genes were stable comparing nonneuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples) but significantly different as compared to control nonneuroendocrine and neuroendocrine tumors. In the multivariate analysis including all clinical and pathological parameters and gene expression levels available, a predominant nonneuroendocrine component, the administration of additional therapy other than surgery and a high thymidylate synthase expression in nonneuroendocrine tumor tissue were significantly associated with a lower risk of a patient's death. Conclusions: Our data show that mixed neuroendocrine/nonneuroendocrine carcinomas are different at the molecular level from their pure neuroendocrine and nonneuroendocrine counterparts, and detailed analyses of their clinical, pathological and molecular features may improve the clinical strategies for the treatment of these rare and underestimated tumors. © 2015 S. Karger AG, Basel.

Lock M.,90 Commissioners Rd E | Sinclair K.,90 Commissioners Rd E | Welch S.,Divisions of Medical Oncology | Younus J.,Divisions of Medical Oncology | Salim M.,90 Commissioners Rd E
Oncology Letters | Year: 2011

Radiation recall is common following treatment with certain chemotherapy drugs and presents frequently as a skin reaction. With gemcitabine, such a recall phenomenon may affect internal tissues and presents itself as myositis. Although such reactions have previously been reported in the literature, whether or not to continue chemotherapy during such reactions remains controversial. We reported a case of radiation recall in a patient treated with gemcitabine and radiation therapy that presented as myositis. We were able to continue palliative chemotherapy and manage the side effects with supportive care treatment. This case report provides partial support for the continuation of chemotherapy when required even when a recall reaction is encountered.

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