The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer

BACKGROUND: Diabetes mellitus is frequently observed in pancreatic cancer patients and is both a risk factor and an early manifestation of the disease. METHODS: We analysed the prognostic impact of diabetes on the outcome of pancreatic cancer following resection and adjuvant chemotherapy using individual patient data from three European Study Group for Pancreatic Cancer randomised controlled trials. Analyses were carried out to assess the association between clinical characteristics and the presence of preoperative diabetes, as well as the effect of diabetic status on overall survival. RESULTS: In total, 1105 patients were included in the analysis, of whom 257 (23%) had confirmed diabetes and 848 (77%) did not. Median (95% confidence interval (CI)) unadjusted overall survival in non-diabetic patients was 22.3 (20.8–24.1) months compared with 18.8 (16.9–22.1) months for diabetic patients (P=0.24). Diabetic patients were older, had increased weight and more co-morbidities. Following adjustment, multivariable analysis demonstrated that diabetic patients had an increased risk of death (hazard ratio: 1.19 (95% CI 1.01, 1.40), P=0.034). Maximum tumour size of diabetic patients was larger at randomisation (33.6 vs 29.7 mm, P=0.026). CONCLUSIONS: Diabetes mellitus was associated with increased tumour size and reduced survival following pancreatic cancer resection and adjuvant chemotherapy

Development and testing of a model for risk and protective factors for eating disorders and higher weight among emerging adults: A study protocol

© 2019 Research has demonstrated that eating disorders (ED) and higher weight have lifetime co-occurrence suggesting that they may be best considered within a common etiological model. Although we know that body dissatisfaction is likely to be a risk factor for both outcomes, other proposed risk and protective factors for each condition have not been adequately explored. The current paper tests a conceptual model that is based on a review of the existing literature from both areas of scholarship. It considers biological, sociocultural, psychological, and behavioral factors that may contribute to both outcomes. The model will be tested in a longitudinal design with an initial sample of 600 emerging adults (aged 18–30) per country in nine different countries (total sample = 5400 participants). Questionnaires will be completed online on two occasions, 12 months apart. The first full phase of the study commenced in July 2018, the same time Body Image was approached to publish this protocol paper (the final revised paper was submitted in September 2019), and data collection will be finalized in December 2019. Multi-group path analysis will identify the biopsychosocial predictors – both cross-sectionally and longitudinally – of both ED and higher weight, and how these vary across countries and gender

Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic CancerCancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies

Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer

Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells. Investigation of STAT3 involvement.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer-related deaths worldwide. Myoferlin is a protein implicated in membrane fusion and in receptor recycling. It allows the formation of vesicles for the trafficking in cells. In PDAC, myoferlin is overexpressed in high grades in comparison to low grades. We used an innovative small compound (WJ460) to target myoferlin in PDAC cell lines and reported the triggering of an iron-dependent cell death, namely ferroptosis, considered as an alternative to apoptosis in cancer cells. Owing to the role of STAT3 in iron homeostasis, we decided to explore this signaling pathway upon myoferlin depletion and pharmacological targeting

Modulation de la radiosensibilité des cellules pancréatiques cancéreuses par le ciblage pharmacologique de la myoferline.

Pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related deaths by 2030. Myoferlin is a protein involved in membrane fusion and in membrane receptors recycling and is overexpressed in PDAC where it was reported to be required for an optimal cell growth. We used an innovative small compound (WJ460) to target myoferlin in PDAC cell lines and reported the triggering of ferroptosis, involving mitochondrial iron pool. Based on those results, we believe we revealed a pancreatic cell vulnerability that can be exploited in the treatment of patients with PDAC. Indeed, the alteration of the mitochondrial redox balance is a pathway followed to sensitize cancer cells to radiotherapy. Radiotherapy alone or combined with chemotherapy is a therapeutic modality of the PDAC. Our working hypothesis is that inhibition of myoferlin function sensitizes PDAC cancer cells to radiotherapy. A preliminary analysis carried out using the MiaPaCa-2 cell line demonstrated a significative synergy between WJ460 and irradiation for different combinations. With the aim if increasing the clinical relevance of the project, the various selected combinations of WJ460 and irradiation will be applied first to heterotopic spheroids and then PDAC organoids. Besides, to understand the mechanism behind the radiosensitization observed during treatment with WJ460, we analyzed in silico TCGA data obtained from PDAC patients that indicated a frequent and significative co-occurrence of myoferlin gene alteration with the alteration of genes implicated in DNA repair. In addition, RNA sequencing was performed. The bioinformatic analysis of the results revealed the alteration of gene sets linked to the G2/M phase arrest, considered as increasing radiosensitization. Pharmacological manipulation of myoferlin improves radiosensitivity in vitro. Further work is required to fully understand this discovery and translate these findings into clinical practice