Omics deciphering of pancreatic ductal adenocarcinoma heterogeneity : from bench to bedside

L'hétérogénéité de l'adénocarcinome canalaire pancréatique (ADCP) est l'obstacle majeur au traitement efficace des patients. En effet, les caractéristiques cliniques et la sensibilité aux traitements sont associés à un phénotype donné et sont plutôt régis à un niveau transcriptomique. Nous avons donc analysé le transcriptome de xénogreffes provenant des patients (Patients Derived Xenografts : PDX) lors des biopsies de tumeurs ou de pièces chirurgicales. Après extraction d’ARN, nous avons trouvé une signature moléculaire capable de diviser les patients en deux groupes, en fonction de leur survie. Nous avons également montré que la réponse autraitement pouvait être prédite par l‘analyse transcriptomique. Nous avons ensuite analysé les tumeurs et leurs stromas, et mis en évidence deux soustypesde stromas et deux sous-types de tumeurs, définis par la transcriptomique basée sur l'ARN, ou la méthylation de l'ADN. Nous avons étudié la réponse aux traitements administrés seuls ou en combinaison avec des chimiothérapies de routine. Nous avons mis en évidence des sous-groupes de patients plus chimiosensibles à certains traitements. Tous ces résultats sont encourageants,mais pas encore applicables en pratique clinique. Nous développons maintenant les organoïdes, véritable représentation de la tumeur en 3dimensions. Contrairement aux PDX, les organoïdes nous permettent d'obtenir des résultats rapidement exploitables. Nous pensons que dans un avenir proche, le traitement des cancers du pancréas sera précédé d'une caractérisation moléculaire étendue afin de sélectionner les traitements les plus appropriés et de pouvoir enfin proposer une médecine personnalisée.Heterogeneity of Pancreatic Ductal AdenoCarcinoma (PDAC) has become the majorimpediment to the effective treatment of patients. Clinical outcome and sensitivity to treatments are associated with a given phenotype and associated at a transcriptomic level. Recent data indicate that studying the expressionof a selected gene set could inform selection of the most appropriate treatments.We areoptimizing this approach by analysing transcriptome of Patient-Derived Xenografts (PDX)from surgical as well as endoscopic ultrasound-guided fine needle aspiration (EUS-FNA)biopsies of tumors, as a source of RNA. We have found a molecularsignature capable of dividing patients into two groups, function of theirsurvival.Independently, we have shown that treatment response pattern can also be foundat a transcriptomic level. We thenanalysed tumors and their stromas, and have found two sub-types of stromas and two sub-types of tumors. These wereindinstinctly defined by RNAseq-based transcriptomics, or DNA methylation. We also studied response to treatments administered alone or incombination to routine chemotherapies. All these results are encouraging, but not yetapplicable in clinical pratice. We are now developing the PDAC Biopsy DerivedPancreatic Cancer Organoids (BDPCO): BDPCO culture represents an excellent source of “exvivo” material. Unlike PDX, which take many months to grow, BDPCO allow us to obtainexploitable material rapidly useful for clinical application. We are convinced that in the near future, the treatment ofpancreatic cancers will be preceded by an extensive molecular characterization of cancercells in order to select the most appropriate treatments

A pancreatic zone at higher risk of fistula after enucleation

Abstract Background To determine predictive factors of postoperative pancreatic fistula (POPF) in patients undergoing enucleation (EN). Methods From 2005 to 2017, 47 patients underwent EN and had magnetic resonance imaging available for precise analysis of tumor location. Three pancreatic zones were delimited by the right side of the portal vein and the main pancreatic head duct (zone #3 comprising the lower head parenchyma and the uncinate process). Results The mortality and morbidity rates were 0% and 62%, respectively. POPF occurred in 23 patients (49%) and was graded as B or C (severe) in 15 patients (32%). Four patients (8.5%) developed a postoperative hemorrhage, and 5 patients (11%) needed a reintervention. In univariate and multivariate analyses, the pancreatic zone was the unique predictive factor of overall (P = .048) or severe POPF (P = .05). We did not observe any difference in postoperative courses when comparing the EN achieved in zones #1 and #2. We noted a longer operative duration (P = .016), higher overall (P = .017) and severe POPF (P = .01) rates, and longer hospital stays (P = .04) when comparing the EN achieved in zone #3 versus that in zones #1 and #2. Patients who underwent EN in zone #3 had a relative risk of developing a severe POPF of 3.22 compared with patients who underwent EN in the two other pancreatic zones. Conclusion Our study identifies the lower head parenchyma and the uncinate process as a high-risk zone of severe POPF after EN. Patients with planned EN in this zone could be selected and benefit from preoperative and/or intraoperative techniques to reduce the severe POPF rate

Surgery of small bowel melanoma metastases in the era of efficient medical therapies

International audienc