PD-0498: Use of STAT in prostate cancer: correlation with risk factors and identification of residual cohort

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EP-1349: Long term results of a phase I-II study of moderate hypofractionated IGRT in prostate cancer

Pregnant women diagnosed with gestational diabetes mellitus subjected to diet (GDMd) that do not reach normal glycaemia are passed to insulin therapy (GDMi). GDMd associates with increased human cationic amino acid transporter 1 (hCAT-1)-mediated transport of L-arginine and nitric oxide synthase (NOS) activity in foetoplacental vasculature, a phenomenon reversed by exogenous insulin. Whether insulin therapy results in reversal of the GDMd effect on the foetoplacental vasculature is unknown. We assayed whether insulin therapy normalizes GDMd-associated foetoplacental endothelial dysfunction. Primary cultures of human umbilical vein endothelial cells (HUVECs) from GDMi pregnancies were used to assay L-arginine transport kinetics, NOS activity, p44/42mapk and protein kinase B/Akt activation, and umbilical vein rings reactivity. HUVECs from GDMi or GDMd show increased hCAT-1 expression and maximal transport capacity, NOS activity, and eNOS, and p44/42mapk, but not Akt activator phosphorylation. Dilation in response to insulin or calcitonin-gene related peptide was impaired in umbilical vein rings from GDMi and GDMd pregnancies. Incubation of HUVECs in vitro with insulin (1 nmol/L) restored hCAT-1 and eNOS expression and activity, and eNOS and p44/42mapk activator phosphorylation. Thus, maternal insulin therapy does not seem to reverse GDMd-associated alterations in human foetoplacental vasculature.Fondo Nacional de Desarrollo Científico y Tecnológico Chileno 1150377 , 1150344 , 11150083Servicio de Salud de Medicina Oriente de Chile 1938–2016Marie Curie International Research 295185 - EULAMDIM

822 Local radiotherapy synergizes with tumor-specific TCR redirected T cells in the rejection of prostate cancer

Background Adoptive T cell therapy (ACT) has become a promising option for cancer patients. While tumor-infiltrating lymphocytes were initially exploited as a source of tumor reactive lymphocytes, T cells genetically redirected to the tumor by TCR/CAR gene transfer are now in clinical validation. In the case of solid tumors, unfavorable immunosuppressive microenvironments remain recognized barriers to therapeutic efficacy. We have recently reported that the therapeutic activity of ACT against poorly immunogenic and indolent prostate cancer is improved by the concurrent targeting of the tumor stroma by mean of T cells redirected to an ubiquitously expressed minor histocompatibility antigen or a tumor vessel targeted TNF derivative. We have now taken the concept further and hypothesized that local radiotherapy (RT), might also synergize with ACT by promoting lymphocyte endothelial transmigration and tumor recognition, and ultimately favor abscopal effects. Methods We investigated the combination of local RT and ACT in TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice and in mice bearing subcutaneous B16/B16-OVA (MO4) or TRAMP-C2/TRAMP-C2-OVA tumors. Local RT was delivered by X-RAD SmART (the Small Animal Radiation Therapy) microirradiator in single dose or hypo-fractioned regimens. ACT consisted of T cells engineered with tumor-specific TCRs. Immunogenic consequences were analyzed by Real-Time PCR, and flow cytometry (FACS) analyses. Prostate tumor debulking was evaluated by histological analyses. Results We found that local hypofractionated RT and ACT, while individually inefficacious in controlling tumor growth, concurred to the debulking of advanced prostate adenocarcinoma when used in combination in treating TRAMP mice. Mechanistically, exposing isolated tumor cells, or the TRAMP mouse prostate to hypo-fractionated RT regimens induced stronger type-I interferon (IFN-I) responses, when compared to single high dose. Acutely, hypofractionated RT promoted better immune tumor infiltration, among which TCR redirected effector cells. Conclusions Data support feasibility and efficacy of combining hypo-fractionated local RT with ACT in the form of TCR engineered T cells to promote prostate cancer recognition and eradication. Tumor debulking was observed in the absence of treatment-related toxicity. Systemic recirculation of TCR redirected T cells was observed. We are now investigating therapeutic effects at distal (metastatic) sites. Acknowledgements The authors acknowledge the support of the Italian Association for Cancer Research (AIRC) Ethics Approval The studies involving animals were approved by The Institutional Ethical Committee (IACUC#999)

Inter-observer variability in contouring the penile bulb on CT images for prostate cancer treatment planning

Several investigations have recently suggested the existence of a correlation between the dose received by the penile bulb (PB) and the risk of erectile dysfunction (ED) after radical radiotherapy for clinically localized prostate carcinoma