This large series of TP for IPMN reported acceptable morbi-mortality rates with no long-term death from diabetes-related complication. Morphologic assessment was imperfectly reliable with 13% of TP done for LMD only. More than half of patients were operated at an invasive carcinoma stage with poor outcome. Conversely, long-term survival was excellent after TP for noninvasive IPMN.
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Pancreatic cancer (PC) is a deadly cancer for which no diagnostic or prevention plan currently exists since this cancer is asymptomatic in its early development. The very specific and complex tumor microenvironment of PC is responsible for the unsuccessful delivery of therapeutics molecules to tumor cells. For high throughput testing of new molecules, there is a crucial need for more accurate preclinical model. For the first time, we integrated in a microfluidic system 5 major features of PC microenvironment: i) type-I collagen (CI), ii) hyaluronic acid (HA), iii) pancreatic stellate cells (SC), iv) interstitial fluid flow and v) nutrient and oxygen gradients. We showed long 3D culture (30 days). Furthermore, we implemented, thanks to the perfusion capability, the actual FOLFIRINOX protocol to assess the IC50 and we showed that dynamic conditions induce increased chemoresistance compared to 3D static.
Introduction. One of the challenges in the management of patients with cancer of the digestive tract is to prevent relapse. Epigenetic modifications (i.e. DNA methylation and histone marks) have been proven to be involved in the generation and maintenance of a subset of cells with stemness properties, that resist to conventional therapies. Our aim is to identify complexes of chromatin modifier enzymes (epienzymes) that are involved in acquired chemoresistance/aggressiveness of colon and pancreatic cancer cells. Experimental procedures/Methods. A meta-analysis performed on public transcriptomics data from colorectal cancer (CRC) patients cross-referenced with our own data including basal-like pancreatic cancer samples identified a limited number of epienzymes associated with aggressive subtypes of digestive cancers. Among them, the demethylase KDM4B, specific of the lysine 9 of Histone 3, and the transcriptional repressor PRDM1 where found correlated to the expression of several typical markers of cancer stemness. To confirm the role of these epienzymes in colon and pancreatic cancer cell chemoresistance, we have developed several in vivo and in vitro 2D and 3D models of acquired resistance to oxaliplatin-based combined chemotherapies, including FOLFIRINOX and FOLFOX. In this work, these models as well as patient samples have been used to study (i) the dynamic expression profile of these epienzymes (RT-qPCR, immunofluorescent multiplex staining, single-cell analysis and spatial transcriptomics), (ii) the gene regulons that are bound by these epienzymes (CUT&RUN-seq) and (iii) the functional role of these epienzymes in cancer stemness (organoid and sphere-forming assays). Results. We have shown that PRDM1 and KDM4B are expressed heterogeneously in cancer cell populations and overexpressed during specific time frames along the acquisition of resistance to oxaliplatin-based combined therapies both in colon and pancreatic cancer cells. Furthermore, we have obtained promising results regarding the binding of PRDM1 and KDM4B to key players of pluripotency/differentiation in chemoresistant colon cancer cells. Conclusions. Altogether, our data indicate that specific expression of chromatin modifier enzymes, most likely acting as epigenetic complexes, are key milestones of acquired resistance to conventional therapies. This work will pave the way for considering epienzyme-epienzyme interactions as potent drug targets that could circumvent cancer cell aggressiveness. Citation Format: Elsa Hadj Bachir, Charles Poiraud, Hugo Claux, Soumaya El Moghrabi, Sonia Paget, Belinda Duchêne, Nicolas Jonckheere, Bernadette Neve, Emmanuelle Leteurtre, Isabelle Van Seuningen, Audrey Vincent. Epigenetic mechanisms involved in acquired resistance to combined chemotherapies in digestive cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2965.
Background. Adjuvant chemotherapy (AC) improve the prognosis after pancreatic duct adenocarcinoma (PDAC) resection. However, previous studies have shown that a large proportion of patients do not receive or complete AC. This national study examined the risk factors for the omission or interruption of AC. Methods. Data of all patients who underwent pancreatic surgery for PDAC in France between January 2012 and December 2017 were extracted from the French National Administrative Database. We considered “omission of adjuvant chemotherapy” (OAC) all patients who failed to receive any course of gemcitabine within 12 postoperative weeks and “interruption of AC” (IAC) was defined as less than 18 courses of AC. Results. A total of 11 599 patients were included in this study. Pancreaticoduodenectomy was the most common procedure (76.3%), and 31% of the patients experienced major postoperative complications. OACs and IACs affected 42% and 68% of the patients, respectively. Ultimately, only 18.6% of the cohort completed adjuvant treatment. Patients who underwent surgery in a high-volume center were less affected by postoperative complications, with no impact on the likelihood of receiving AC. Multivariate analysis showed that age ≥80 years, Charlson comorbidity index (CCI)≥4, and major complications were associated with OAC (OR=2.19 ; CI95%[1.79-2.68] ; OR=1.75 ; CI95%[1.41-2.18] and OR=2.37 ; CI95%[2.15-2.62] respectively). Moreover, age ≥80 years and CCI 2-3 or ≥4 were also independent risk factors for IAC (OR=1.54, CI95%[1.1–2.15]; OR=1.43, CI95%[1.21-1.68]; OR=1.47, CI95%[1.02-2.12], respectively). Conclusion. Sequence surgery followed by chemotherapy is associated with a high dropout rate, especially in octogenarian and comorbid patients.
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