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Several scoring systems predict risks of clinically relevant postoperative pancreatic fistula after pancreatectomy, but none have emerged as the gold standard. This study aimed to evaluate the accuracy of postoperative day 1 drain amylase and serum C-reactive protein levels in predicting clinically relevant postoperative pancreatic fistula compared with intraoperative pancreatic characteristics.Patients who underwent pancreatectomy between 2017 and 2019 were included prospectively. Cutoff values were determined using receiver operating characteristic curves, and a score combining postoperative day 1 drain amylase and serum C-reactive protein was tested in a multivariate logistic regression model to evaluate clinically relevant postoperative pancreatic fistula risk.A total of 274 pancreatic resections (182 pancreaticoduodenectomies and 92 distal pancreatectomies) were included. The pancreatic gland texture was "soft" in 47.8% (n = 131), and 55.8% (n = 153) had a small size main pancreatic duct (≤3 mm). Clinically relevant postoperative pancreatic fistula occurred in 58 patients (21.2%). Drain amylase ≥1,000 UI/L and serum C-reactive protein ≥90 mg/L were identified as the optimal cutoffs to predict clinically relevant postoperative pancreatic fistula. On multivariate analysis these cutoffs were independent predictors of clinically relevant postoperative pancreatic fistula after both pancreaticoduodenectomies (drain amylase: P.001, serum C-reactive protein: P = .006) and distal pancreatectomies (drain amylase: P = .009, serum C-reactive protein: P = .001). The postoperative day 1 "90-1000" model, a 2-value score relying on these cutoffs, significantly (P.001) outperformed intraoperative pancreatic parenchymal characteristics in predicting clinically relevant postoperative pancreatic fistula after both pancreaticoduodenectomies and distal pancreatectomies. A postoperative day 1 "90-1000" score = 0 had a negative predictive value of 97% and 94%, respectively, after pancreaticoduodenectomy and distal pancreatectomies.A combined score relying on postoperative day 1 values of drain amylase and serum C-reactive protein levels was accurate in predicting risks of clinically relevant postoperative pancreatic fistula after pancreatectomy.

Delayed post-pancreatectomy hemorrhage (PPH) is still one of the most dreaded complications after pancreatic surgery. Its management is now focused on percutaneous endovascular treatments (PETs). Between 2013 and 2019, 307 patients underwent pancreatic resection. The first endpoint of this study was to determine predictive factors of delayed PPH. The second endpoint was to describe the management of intra-abdominal abscesses (IAA). The third endpoint was to identify risk factors of bleeding recurrence after PET. Patients were divided into two cohorts: A retrospective analysis was performed (“cohort 1,” “learning set”) to highlight predictive factors of delayed PPH. Then, we validated it on a prospective maintained cohort, analyzed retrospectively (“cohort 2,” “validation set”). Second and third endpoints studies were made on the entire cohort. In cohort 1, including 180 patients, 24 experienced delayed PPH. Multivariate analysis revealed that POPF diagnosis on postoperative day (POD) 3 (p=0.004) and IAA (p=0.001) were independent predictive factors of delayed PPH. In cohort 2, association of POPF diagnosis on POD 3 and IAA was strongly associated with delayed PPH (area under the curve [AUC] 0.80; 95% confidence interval [CI] [0.59–0.94]; p=0.003). Concerning our second endpoint, delayed PPH occurred less frequently in patients who underwent postoperative drainage procedure than in patients without IAA drainage (p=0.002). Concerning our third endpoint, a higher body mass index (BMI) (p=0.027), occurrence of postoperative IAA (p=0.030), and undrained IAA (p=0.011) were associated with bleeding recurrence after the first PET procedure. POPF diagnosis on POD 3 and intra-abdominal abscesses are independent predictive factors of delayed PPH. Therefore, patients presenting an insufficiently drained POPF leading to intra-abdominal abscess after pancreatic surgery should be considered as a high-risk situation of delayed PPH. High BMI, occurrence of postoperative IAA, and undrained IAA were associated with recurrence of bleeding after PET.

The aim of the study was to compare histological features, postoperative outcomes, and long-term prognostic factors after pancreaticoduodenectomy for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma. From 2005 to 2017, 188 pancreaticoduodenectomies (pancreatic ductal adenocarcinoma n = 151, distal cholangiocarcinoma n = 37) were included. Postoperative outcomes were compared after matching on pancreatic gland texture and main pancreatic duct size. Matching according to tumor size, lymph node invasion and resection margin was used to compare overall and disease-free survival. Distal cholangiocarcinoma patients had more often “soft” pancreatic gland (P = 0.002) and small size main pancreatic duct (P = 0.001). Pancreatic ductal adenocarcinoma patients had larger tumors (P = 0.009), and higher lymph node ratio (P = 0.017). Severe morbidity (P = 0.023) and clinically relevant pancreatic fistula (P = 0.018) were higher in distal cholangiocarcinoma patients. After matching on gland texture and main pancreatic duct diameter, clinically relevant postoperative pancreatic fistula was still more frequent in distal cholangiocarcinoma patients (P = 0.007). Tumor size > 20 mm was predictive of impaired overall survival (P = 0.024) and disease-free survival (P = 0.003), tumor differentiation (P = 0.027) was predictive of impaired overall survival. Survival outcomes for distal cholangiocarcinoma and pancreatic ductal cholangiocarcinoma were similar after matching patients according to tumor size, lymph node invasion and resection margin. Long-term outcomes after pancreaticoduodenectomy for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma patients are similar. Postoperative course is more complicated after pancreaticoduodenectomy for distal cholangiocarcinoma than pancreatic ductal adenocarcinoma. After pancreaticoduodenectomy, patients with distal cholangiocarcinoma and pancreatic ductal adenocarcinoma have similar long-term oncological outcomes.

Resume Objectifs Evaluation de la valeur du PET scanner au 18F-FDG dans la differenciation des formes benignes et malignes des tumeurs intracanalaires papillaire et mucineuse du pancreas. Introduction Les TIPMP malignes ou de haut risque necessitent une resection chirurgicale mais cette chirurgie devrait etre evitee en cas de TIPMP a faible risque de malignite. Le PET scanner au 18F-FDG a ete etudie dans de nombreuses series retrospectives monocentriques. Methode Il s’agit d’une etude multicentrique francaise prospective non comparative. L’objectif principal de cette etude etait d’analyser la specificite du PET scanner au 18F-FDG pour l’identification des formes malignes des TIPMP (carcinome invasif ou in situ). Le diagnostic final etait obtenu sur l’analyse anatomopathologique de la piece d’exerese. Resultat Sur 120 patients analyses, 99 presentaient une confirmation de TIPMP, incluant 24 lesions malignes, 9 carcinomes in situ et 15 cancers invasifs. Le PET scanner au 18F-FDG etait positif dans 44 et 31 cas respectivement dans l’ensemble de la serie et sur la population de TIPMP. Chez les 99 patients presentant une TIPMP les resultats du PET scanner retrouvaient 13 vrais positifs, 18 faux positif, 57 vrais negatifs et 11 faux negatifs. La sensibilite, specificite, valeur predictive negative et valeur predictive positive etait respectivement de 54,2 %, 76 %, 83,8 % et 41,9 %. Nous n’avons pu identifier une valeur de cut-off de SUVmax permettant la distinction entre une lesion benigne maligne. Les imageries conventionnelles comportaient un scanner abdominal, une imagerie par resonance magnetique nucleaire et une echo-endoscopie. Dans le groupe des patients presentant une TIPMP qui avaient recu les trois techniques d’imagerie, la sensibilite, specificite, valeur predictive positive et negative etaient respectivement de 66,7 %, 84,4 %, 84,4 %, et 66,7 %. Conclusion Dans cette etude, le PET scanner au 18F-FDG n’ameliorait pas la distinction entre les formes benignes et malignes des TIPMP par rapport aux examens d’imagerie conventionnelle.

We evaluated the intuition of expert pancreatic surgeons, in predicting the associated risk of pancreatic resection and compared this “intuition” to actual operative follow-up. The objective was to avoid major complications following pancreatic resection, which remains a challenge. From January 2015 to February 2018, all patients who were 18 years old or more undergoing a pancreatic resection (pancreaticoduodenectomy [PD], distal pancreatectomy [DP], or central pancreatectomy [CP]) for pancreatic lesions were included. Preoperatively and postoperatively, all surgeons completed a form assessing the expected potential occurrence of clinically relevant postoperative pancreatic fistula (CR-POPF: grade B or C), postoperative hemorrhage, and length of stay. Preoperative intuition was assessed for 101 patients for 52 PD, 44 DP, and 5 CP cases. Overall mortality and morbidity rates were 6.9% (n = 7) and 67.3% (n = 68), respectively, and 38 patients (37.6%) developed a POPF, including 27 (26.7%) CR-POPF. Concordance between preoperative intuition of CR-POPF occurrence and reality was minimal, with a Cohen’s kappa coefficient (κ) of 0.175 (P value = 0.009), and the same result was obtained between postoperative intuition and reality (κ = 0.351; P

Surgery of small bowel melanoma metastases has to be reconsidered in the era of targeted treatments and immunotherapy. To retrospectively assess context and outcomes of small bowel melanoma metastases resections. All consecutive melanoma patients who underwent resection of small bowel metastases between 2011 and 2017, in a single referral center, were retrospectively analyzed through melanoma-specific survival (MSS). A total of 20 patients were included with a 47.8 months median follow-up. Before small bowel surgery, eight patients (40%) were asymptomatic while seven had anemia and five patients had abdominal pain. All resections were decided on tumor boards except for three surgeries performed in the emergency setting. In the whole cohort, MSS was 89.5 months with 50% of patients alive at the study endpoint. We classified surgical indications in three groups: (1) surgery as a pivotal treatment for mono- or oligo-metastases limited to the small bowel (n = 6); (2) salvage surgery for symptomatic patients in order to preserve their chances to switch to an active line of medical treatment (n = 8); and (3) surgery of small bowel dissociated metastatic progression for patients otherwise controlled (n = 6), aiming at keeping patients with the same treatment or active follow-up. In these three situations, the objective of surgery was usually met, and most patients had a long median MSS after surgery: 70.3 months, 89.5 months and 72.4 months, respectively. Although medical treatments have dramatically improved survival in metastatic melanoma, surgical control of life-threatening localization like small bowel metastases is often a condition for long survival.

Splenic vessel involvement occurs frequently in pancreatic ductal adenocarcinoma (PDAC) of the body and the tail (B/T) but the impact on survival is unknown. We assessed the influence of radiological and pathologic involvement of splenic artery (p-SA +) and vein (p-SV +) on patient outcomes after distal pancreatectomy (DP) for PDAC. From 2013 to 2019, all DP for PDAC in five centers were included. Factors associated with overall (OS) and disease-free (DFS) survival were identified. Among the 76 patients included, 5 (6.6%) had p-SA + only, 11 (14.5%) had p-SV + only, and 24 (31.6%) had both p-SA + and p-SV + . The preoperative CT-scan accuracy to predict p-SV + and p-SA + was high (sensitivity: 91.4% and 82.8%, respectively; negative predictive value: 89.7% and 88.3%, respectively). The 5-year OS and DFS rates were 3.9% and 8.3%, respectively. Multivariate analysis identified splenic vessel involvement (i.e., p-SA + or p-SV + , or both p-SA + and p-SV +) as the only independent factor influencing DFS (HR 4.04; 95% CI [1.22–13.44], p = 0.023). Tumor size ≥ 30 mm was the only independent factor influencing OS (HR 4.04; 95% CI [1.26–12.95], p = 0.019) and was associated with a high risk of p-SA + (p = 0.001) and p-SV + (p

The prognosis of patients with pancreatic cancer remains poor and novel therapeutic targets are required urgently. Treatment resistance could be due to the tumour microenvironment, a desmoplastic stroma consisting of cancer-associated fibroblasts and tumour-infiltrating lymphocytes (TILs). The aim of the study was to evaluate the prognostic value of TILs and cancer-associated fibroblasts (CAFs) in pancreatic cancer of the body and tail.Using tissue microarray from resected left-sided pancreatic cancer specimens, the immunohistochemistry of TILs (cluster of differentiation (CD) 45, CD3, CD4, FoxP3 and CD8), CAFs (vimentin and α-smooth muscle actin (αSMA)) and functional markers (PD-L1 and Ki-67) was examined, and the association with disease-free (DFS) and overall (OS) survival investigated using a computer-assisted quantitative analysis. Patients were classified into two groups, with low or high levels or ratios, using the 75th percentile value as the cut-off.Forty-three patients were included in the study. Their median DFS and OS were 9 and 27 months respectively. A high CD4/CD3 lymphocyte ratio was associated with poorer DFS (8 months versus 11 months for a low ratio) (hazard ratio (HR) 2·23, 95 per cent c.i. 1·04 to 4·61; P = 0·041) and OS (13 versus 27 months respectively) (HR 2·62, 1·11 to 5·88; P = 0·028). A low αSMA/vimentin ratio together with a high CD4/CD3 ratio was correlated with poorer outcomes. No significant association was found between Ki-67, PD-L1 and survival.In patients with resected left-sided pancreatic cancer, a tumour microenvironment characterized by a high CD4/CD3 lymphocyte ratio along with a low αSMA/vimentin ratio is correlated with poorer survival.El pronóstico del cáncer de páncreas sigue siendo malo y se requieren nuevas dianas terapéuticas de forma urgente. La resistencia al tratamiento podría ser atribuida al microambiente tumoral, un estroma desmoplásico compuesto por fibroblastos asociados al cáncer y linfocitos infiltrantes de tumor. El objetivo del estudio fue evaluar el valor pronóstico de los linfocitos infiltrantes de tumor y de los fibroblastos asociados al cáncer en el cáncer de cuerpo y cola de páncreas. MÉTODOS: Utilizando microarray para el análisis de muestras de tejido obtenidas tras la resección de cáncer de páncreas del lado izquierdo, se realizó inmunohistoquímica de linfocitos infiltrantes de tumor (CD45, CD3, CD4, FoxP3 y CD8), fibroblastos asociados al cáncer (vimentina y actina del músculo liso alfa (αSMA)) y marcadores funcionales (PD-L1 y Ki67), y se investigó la asociación con la supervivencia libre de enfermedad y la supervivencia global. Los resultados se obtuvieron tras un análisis cuantitativo asistido por ordenador. Los pacientes se clasificaron en dos grupos, de bajo y alto riesgo, utilizando el valor del percentil 75 como punto de corte.Se incluyeron 43 pacientes en el estudio. En esta población, la mediana de supervivencia libre de enfermedad y de supervivencia global fueron 9 meses y 27 meses, respectivamente. Una alta proporción de linfocitos CD4/CD3 se asoció a peor supervivencia libre de enfermedad (8 meses versus 11 meses; cociente de riesgos instantáneos, hazard ratio, HR 2,2; i.c. del 95% 1,0-4,6; P = 0,041) y supervivencia global (13 meses versus 27 meses; HR 2,6; i.c. del 95% 1,1-5,9; P = 0.028). Una baja proporción αSMA/vimentina junto con una alta proporción CD4/CD3 se correlacionó con peores resultados. No se encontró asociación significativa entre Ki67, PD-L1 y la supervivencia. CONCLUSIÓN: En pacientes con cáncer de páncreas izquierdo resecado, un microambiente tumoral caracterizado por una alta proporción de linfocitos CD4/CD3 junto con una baja proporción de αSMA/vimentina se correlaciona con una peor supervivencia.

Summary Objective To assess the value of 18F-FDG PET/CT in differentiating between benign and malignant intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Summary background data Malignant or high-risk IPMN require surgical resection but surgery should be avoided in patients with IPMN carrying a low risk of malignancy. 18F-FDG PET has been studied mostly in small, single center, retrospective series. Methods Prospective, non-comparative, multicenter French study. The primary endpoint was the specificity of PET/CT for identifying malignant IPMN (in situ or invasive carcinoma). Final diagnosis was obtained from pathological examination of the resected specimen. Results Among 120 patients analyzed, 99 had confirmed IPMN, including 24 with malignant lesions, namely 9 with carcinoma in situ and 15 with invasive carcinoma. The 18F-FDG PET/CT was positive in 44 and 31 patients in the overall and IPMN populations respectively. In the 99 IPMN patients, PET/CT showed 13 true positive, 18 false positive, 57 true negative and 11 false negative results. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for the diagnosis of malignancy were 54.2%, 76.0%, 83.8% and 41.9% respectively, versus 64.9%, 75.9%, 82.9% and 54.5% in the overall population. We could not identify a cut-off value for SUVmax to distinguish benign from malignant lesions. Conventional imaging included computed tomography, magnetic resonance cholangiopancreatography and endoscopic ultrasound. In IPMN patients who underwent the 3 techniques, sensitivity, specificity, NPV and PPV were 66.7%, 84.4%, 84.4% and 66.7% respectively. Conclusions In this study, 18F-FDG PET/CT did not perform better than conventional imaging to differentiate malignant from benign IPMN.

International audience; HVEM (Herpes Virus Entry Mediator) engagement of BTLA (B and T Lymphocyte Attenuator) triggers inhibitory signals in T cells and could play a role in evading antitumor immunity. Here, HVEM expression levels in melanoma metastases were analyzed by immunohistochemistry, correlated with overall survival (OS) in 116 patients, and validated by TCGA transcriptomic data. Coincident expression of HVEM and its ligand BTLA was studied in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry (n = 21) and immunofluorescence (n = 5). Candidate genes controlling HVEM expression in melanoma were defined by bioinformatics studies and validated by siRNA gene silencing. We found that in patients with AJCC stage III and IV melanoma, OS was poorer in those with high HVEM expression on melanoma cells, than in those with a low expression, by immunohistochemistry (p = .0160) or TCGA transcriptomics (p = .0282). We showed a coincident expression of HVEM at the surface of melanoma cells and of BTLA on TILs. HVEM was more widely expressed than PD-L1 in melanoma cells. From a mechanistic perspective, in contrast to PDL1, HVEM expression did not correlate with an IFNγ signature but with an aggressive gene signature. Interestingly, this signature contained MITF, a key player in melanoma biology, whose expression correlated strongly with HVEM. Finally, siRNA gene silencing validated MITF control of HVEM expression. In conclusion, HVEM expression seems to be a prognosis marker and targeting this axis by checkpoint-inhibitors may be of interest in metastatic melanoma.

Resume La prise en charge des consequences fonctionnelles apres exerese pancreatique est devenue un nouvel enjeu therapeutique. L’objectif de notre etude est d’evaluer l’ensemble des facteurs de risques d’insuffisance pancreatique exocrine (IPExo) et d’insuffisance pancreatique endocrine (IPEndo) apres chirurgie pancreatique et d’etablir un modele predictif de survenue de ces insuffisances. Materiel et methode Entre le 1/01/14 et le 19/06/15, 91 malades consecutifs et suivis de maniere prospective ont eu une duodeno-pancreatectomie cephalique (DPC) et une pancreatectomie gauche (PGauche) dans 72 % et 28 % des cas respectivement. L’IPExo etait definie par une concentration en elastase fecale 1,26 g/L ou l’aggravation d’un diabete existant. Les volumetries pancreatiques etaient mesurees selon les memes principes que les techniques de mesure de volumetrie hepatique. Resultats Le taux d’IPExo et IPEndo a 6 mois postoperatoire etait de 75,9 %, et de 30,8 % respectivement. Le taux d’IPExo apres DPC etait significativement plus eleve qu’apres PGauche (98 % vs 21 % ; p Conclusion L’IPExo est quasi-systematique apres DPC quel que soit le vecteur digestif utilise. L’IPEndo n’est pas differente entre la DPC et la PGauche.

Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets., Pancreatic ductal adenocarcinoma (PDAC) is a complex disease and its underlying epigenomic heterogeneity is not fully understood. Here, the authors utilize patient-derived PDAC xenografts to define the epigenomic landscape of PDAC, highlighting chromatin states linked to differing disease aggressiveness and survival.

During Roux-en-Y-gastric Bypass, the limb lengths are preoperatively determined regardless of individual small bowel length (SBL), which presents a great variability. Few studies highlighted anthropometric factors associated with SBL, and none attempted to predict SBL preoperatively. The aim of this study is to evaluate factors correlated to SBL (anthropometric and radiologic) and to establish a preoperative SBL prediction. In this single-center prospective study, 30 adult patients who underwent laparotomy with a preoperative CT scan were included. Intraoperative SBL measurement was performed with an umbilical tape. Anthropometric parameters were age, gender, height, and BMI. 2D radiological measurements consisted of subcutaneous thickness, abdominal diameters, waist circumference, and mesenteric root length. 3D radiological volumetric reconstructions consisted of whole small bowel and mesentery (WSBM), lean small bowel and mesentery (LSBM), and fat small bowel and mesentery (FSBM). Mean intraoperative measurement of SBL was 531 ± 105 cm. Among the clinical and radiological measurements, the FSBM volume presented the greatest dispersion. Height (p

Resume But Evaluer la presence et l’impact de la mutation K-ras dans une marge de resection histologiquement negative (R0) d’une piece de duodenopancreatectomie cephalique (DPC) pour adenocarcinome resecable de la tete du pancreas. Methode De 2007 a 2010, 22 patients ont eu une DPC en marge saine (R0) pour un ADK resecable d’emblee. Tous les specimens etaient encres et le lit de la veine porte (VP) etait repere par de l’encre bleu ; un echantillon de 2 mm3, incluant de l’encre bleue, etait preleve dans une zone ne comportant pas de tumeur apres verification microscopique. L’ADN de cet echantillon etait extrait et la mutation du gene K-ras etait recherchee : 12 echantillons (55 % ; groupe kras+) presentaient une mutation K-ras dans la marge veineuse et 10 echantillons (45 % ; groupe kras−) n’avaient pas de mutation K-ras dans cette meme marge. Resultats Les 2 groupes etaient comparables. Les survies globales a 3 ans des patients des groupes kras+ versus kras− etaient de 0 % versus 17 % (p = 0,03), respectivement. Les medianes de survies des patients des groupes kras+ versus kras− etaient de 16 mois versus 25 mois (p = 0,04 ; intervalle de confiance a 95 % [1,11–1,88]), respectivement. Conclusion La mutation K-ras dans une marge histologiquement negative (R0) etait presente dans plus de la moitie des specimens avec un impact negatif sur la survie.

Background Delayed gastric emptying (DGE) is the most frequent pancreatic specific complication (PSC) after pancreaticoduodenectomy (PD). Several gastric decompression systems exist to manage DGE. Patients with a pancreatic tumor require prolonged nutrition; however, controversies exist concerning nutrition protocol after PD. The aim of the study was to assess the safety and efficacy of nasogastric (NG), gastrostomy (GT), and gastrojejunostomy (GJ) tubes with different feeding systems on postoperative courses. Methods Between January 2013 and March 2016, 86 patients underwent PD with pancreaticogastrostomy. Patients were divided into three groups: GJ group with enteral nutrition (EN, n = 12, 14%), NG (n = 31, 36%) and GT groups (n = 43, 50%), both with total parenteral nutrition (TPN). Results Patients in the GJ (n = 9, 75%) and GT (n = 18, 42%) groups had an American Society of Anesthesiologists (ASA) score of 3 more often than those in the NG group (n = 5, 16%, p ≤ 0.01). Multivariate analysis identified the GT tube with TPN as an independent risk factor of severe morbidity (p = 0.02) and DGE (p

BACKGROUND The occurrence of post-operative pancreatic fistula (POPF) after pancreaticoduodenectomy is a challenging issue. The aim was to identify variables on preoperative computed tomography (CT) scan, useful to predict clinically significant POPF (grades B-C) after pancreaticoduodenectomy. METHODS Patients presented POPF after pancreaticoduodenectomy were included from two tertiary referral centres. B/W ratio was defined by ratio of pancreas body thickness (B) to main pancreatic duct (W). The predictive parameters of POPF on CT scan were assessed with a receiving operator characteristics (ROC) curve and intrinsic characteristics. RESULTS Between 2010 and 2013, 186 patients who underwent pancreaticoduodenectomy were included. POPF occurred in 25% of them, and was clinically significant in 13%. After univariate analysis, endocrine tumours (P = 0.03), main pancreatic duct size (P 3.8 increased the rates of post-operative haemorrhage (odds ratio = 4.3 (1.4-13.2), P = 0.01), and reintervention (odds ratio = 3.4 (1.2-9.6), P = 0.02). CONCLUSIONS B/W ratio superior to 3.8 assessed on preoperative CT scan may be an easy tool to predict clinically significant POPF after pancreaticoduodenectomy.

International audience; Pancreatic cancer is one of the most aggressive human cancers. PD1/PDL1-inhibitors recently showed promising results in different cancers with correlation between PDL1 tumor expression and responses. Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in pancreatic cancer. In this retrospective study, we analyzed PDL1 mRNA expression in 453 clinical pancreatic cancer samples profiled using DNA microarrays and RNASeq. Compared to normal pancreatic samples, PDL1 expression was upregulated in 19% of cancer samples. Upregulation was not associated with clinicopathological features such as patients' age and sex, pathological type, tumor size, lymph node status, and grade, but was associated with shorter disease-free survival and overall survival in multivariate analyses. Analysis of correlations with biological parameters showed that PDL1 upregulation was associated with some degree of lymphocyte infiltration and signs of anti-tumor T-cell response, but to a lesser extent than what has been reported in breast cancer and GIST. PDL1-up pancreatic cancers displayed profiles of lymphocyte exhaustion, were more enriched in inhibitory molecules and pro-tumor populations (Tregs with upregulation of FOXP3 and IL10, myeloid-derived suppressor cells with upregulation of CD33 and S100A8/A9), and demonstrated a down-modulation of most MHC class I members (HLA-A/B/C, HLA-E/F/G) suggestive of a defect in antigen processing and presentation. In conclusion, our results suggest that PDL1 expression might refine the prediction of metastatic relapse in operated pancreatic cancer, and that PD1/PDL1 inhibitors might reactivate inhibited T-cells to increase the anti-tumor immune response in PDL1-upregulated tumors.

Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.

Introduction et objectifs L’hemorragie post-pancreatectomie (HPP) tardive est toujours actuellement une des complications les plus redoutees apres chirurgie pancreatique. Sa prise en charge est de nos jours dominee par les traitements endovasculaires percutanes (TEP). Notre objectif principal etait de determiner des facteurs predictifs d’HPP tardive. Notre objectif secondaire etait d’identifier des facteurs de risque d’echec du TEP. Methodes Trois cent sept patients ont beneficie d’une resection pancreatique entre 2013 et 2019. Les patients etaient divises en 2 cohortes : une analyse retrospective a ete conduite sur la periode 1 pour mettre en evidence des facteurs predictifs d’HPP tardive. Puis, nous avons elabore un score predictif d’HPP tardive et l’avons valide de facon prospective sur la periode 2. Resultats Pendant la periode 1, 87,5 % (n = 21) des patients du groupe HPP tardive ont presente une fistule pancreatique postoperatoire (FPPO) et l’analyse multivariee a montre que le sexe masculin (p = 0,044) et les abces intra-abdominaux (p = 0,009) etaient des facteurs predictifs independants d’HPP tardive. Pendant la periode 2, le score elabore etait fiable en ce qui concerne la prediction d’HPP tardive (aire sous la courbe [AUC] 0,78 ; indice de confiance a 95 % [0,69–0,85] ; p Conclusion Le sexe masculin, les abces intra-abdominaux et la FPPO sont des facteurs predictifs independants d’HPP tardive. Un IMC eleve est correle a l’echec du TEP.

SUMMARY Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC., In Brief Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.

Background According to knowledge, patients with resectable pancreatic adenocarcinoma (PA) should receive adjuvant gemcitabine-based chemotherapy. Thus, the tumour node metastasis (TNM) classification is not used to determine post-operative treatment but rather only to establish patient prognosis. However, the TNM classification does not include strong factors influencing survival, such as perineural invasion or margin status. This study compared the survival of patients with very similar tumours. Methods From 1997 to 2007, 118 patients underwent pancreatectomy for PA. Twenty-six patients (22%) had long-term survival (>5 years; LTS group). According to the major prognostic factors of PA, we matched (1:1) patients in the LTS group with patients who did not have long-term survival (

Objective To assess the accuracy of pre‐operative staging in patients with peripheral pancreatic cystic neoplasms (pPCNs). Methods From 2005 to 2011, 148 patients underwent a pancreatectomy for pPCNs. The pre‐operative examination methods of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) were compared for their ability to predict the suggested diagnosis accurately, and the definitive diagnosis was affirmed by pathological examination. Results A mural nodule was detected in 34 patients (23%): only 1 patient (3%) had an invasive pPCN at the final histological examination. A biopsy was performed in 79 patients (53%) during EUS: in 55 patients (70%), the biopsy could not conclude a diagnosis; the biopsy provided the correct and wrong diagnosis in 19 patients (24%) and 5 patients (6%), respectively. A correct diagnosis was affirmed by CT, EUS and pancreatic MRI in 60 (41%), 103 (74%) and 80 (86%) patients (when comparing EUS and MRI; P = 0.03), respectively. The positive predictive values (PPVs) of CT, EUS and MRI were 70%, 75% and 87%, respectively. Conclusions Pancreatic MRI appears to be the most appropriate examination to diagnose pPCNs accurately. EUS alone had a poor PPV. Mural nodules in a PCN should not be considered an indisputable sign of pPCN invasiveness.

Predictors of survival following pancreaticoduodenectomy (PD) are well described for pancreatic cancers but are less detailed in ampullary (AC), bile duct (BDC) and duodenal cancers (DC). We therefore sought to evaluate the long-term results of PD for AC, BDC and DC, and to determine for each tumour the predictive factors of survival. Medical charts of patients operated on between 2001 and 2011 were retrospectively reviewed. Univariate and multivariate analyses were performed to determine predictors of survival. One hundred thirty-five patients were identified. Mean follow-up was 47 ± 33 months. Median survival was not reached for DC and was 66 and 24 months for AC and BDC, respectively. Two-year and five-year survival rates were 80 and 51 % for DC and 69 and 51 % for AC, respectively. BDC had a significantly poorer prognosis, with two-year and five-year survival rates of 51 and 34 %, respectively. Predictors of survival were weight loss, N stage and International Union Against Cancer (UICC) stage for AC, T stage and resection margin status for BDC and N stage for DC. AC, BDC and DC display distinctive predictors of survival related to the biological aggressiveness. Preoperative malnutrition worsens the prognosis. The effect of adapted nutritional management on the survival improvement has to be studied.

A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound–guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.

// Odile Gayet 1 , Celine Loncle 1 , Pauline Duconseil 1 , Marine Gilabert 1 , Maria Belen Lopez 1 , Vincent Moutardier 1, 2 , Olivier Turrini 1, 3 , Ezequiel Calvo 4 , Jacques Ewald 3 , Marc Giovannini 3 , Mohamed Gasmi 5 , Erwan Bories 3 , Marc Barthet 5 , Mehdi Ouaissi 6 , Anthony Goncalves 3 , Flora Poizat 3 , Jean Luc Raoul 3 , Veronique Secq 1, 2 , Stephane Garcia 1, 2 , Patrice Viens 3 , Nelson Dusetti 1 , Juan Iovanna 1 1 Centre de Recherche en Cancerologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Universite and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France 2 Hopital Nord, Marseille, France 3 Institut Paoli-Calmettes, Marseille, France 4 Centre Genomique du Centre de recherche du CHUL Research Center, Quebec, Canada 5 Hopital Nord, Departement de Gastroenterologie, Marseille, France 6 Hopital de la Timone, Marseille, France Correspondence to: Nelson Dusetti, e-mail: nelson.dusetti@inserm.fr Juan Iovanna, e-mail: juan.iovanna@inserm.fr Received: August 05, 2014 Accepted: November 02, 2014 Published: December 03, 2014 ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is a disease with a great heterogeneity in the response to treatments. To improve the responsiveness to treatments there are two different approaches, the first one consist to develop new and more efficient drugs that intent to cure all patients and the second one is to use already-approved drugs, alone or in combination, but selecting beforehand the most sensitive patients. In this work we explored the efficiency of the second possibility. We developed a collection of 17 PDAC samples collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved as xenografts and as primary cultures. This collection was characterized at molecular level by a transcriptomic analysis using an Affymetrix approach. In this paper we present data demonstrating that a subgroup of PDAC responds to low doses of 5-aza-dC. These tumors show a specific RNA expression profile that could serve as a marker, but there is no correlation with Dnmt1 , Dnmt3A or Dnmt3B expression. Responder tumors corresponded to well-differentiated samples and longer survival patients. In conclusion, we present data obtained with the well-known drug 5-aza-dC as a proof of concept that a drug that seems to be inefficient in solid tumors in general could be applicable to a particular subgroup of patients with PDAC.

Postoperative pancreatic fistula and pancreas-specific complications have a significant influence on patient management and outcomes after pancreatoduodenectomy. The aim of the study was to assess the value of serum C-reactive protein on the postoperative day 1 as early predictor of pancreatic fistula and pancreas-specific complications. Between 2013 and 2016, 110 patients underwent pancreaticoduodenectomy. Clinical, biological, intraoperative, and pathological characteristics were prospectively recorded. Pancreatic fistula was graded according to the International Study Group on Pancreatic Fistula classification. A composite endpoint was defined as pancreas-specific complications including pancreatic fistula, intra-abdominal abscess, postoperative hemorrhage, and bile leak. The diagnostic accuracy of serum C-reactive protein on postoperative day 1 in predicting adverse postoperative outcomes was assessed by ROC curve analysis. Six patients (5%) died and 87 (79%) experienced postoperative complications (pancreatic-specific complications: n = 58 (53%); pancreatic fistula: n = 48 (44%)). A soft pancreatic gland texture, a main pancreatic duct diameter

Background Postoperative outcomes following pancreaticoduodenectomy are well described for pancreatic cancers. Due to a lower incidence rate, complication rates and relative predictive factors are less detailed for ampullary, bile duct and duodenal cancers. Methods Medical charts of patients operated on between 2001 and 2011 for an ampullary, bile duct or duodenal cancer were reviewed. Data were retrospectively studied with respect to demographics, surgical management, postoperative complications and histological findings. Specific complication rates were reported, and predictive factors for severe morbidity and mortality were determined by multivariate analysis. Results 135 patients were identified: 55 ampullary, 55 bile duct and 25 duodenal cancers. Twelve patients (8.9%) deceased postoperatively, and 36 others (26.7%) presented severe complications. Sixty-seven percent of the pancreas was soft, and pancreatic hardness was found to be the main protective factor against severe morbidity (HR = 0.36, 95% CI = 0.14–0.94, P = 0.037). Age and postpancreatectomy haemorrhage were independent predictors for death (HR = 14.63, 95% CI = 1.57–135.77, P = 0.018, and HR = 14.71, 95% CI = 2.86–75.62, P = 0.001, respectively). Only the use of an external transanastomotic duct stent significantly reduced both the morbidity (HR = 0.37, 95% CI = 0.16–0.83, P = 0.016), and the mortality (HR = 0.12, 95% CI = 0.02–0.69, P = 0.017). Conclusions Pancreaticoduodenectomy for ampullary, bile duct and duodenal cancers is a high-risk procedure. The systematic use of transanastomotic duct stents would significantly decrease the complication rate. Older patients should beneficiate from specific preoperative evaluation using an adapted index. Omental flap techniques to prevent a postpancreatectomy haemorrhage should be efficient. Effects of preoperative octreotid to harden the pancreas should be clarified.

Background Pancreatic carcinoma is one of the most lethal human cancers. In patients with resectable tumors, surgery followed by adjuvant chemotherapy is the only curative treatment. However, the 5-year survival is 20%. Because of a strong metastatic propensity, neoadjuvant chemotherapy is being tested in randomized clinical trials. In this context, improving the selection of patients for immediate surgery or neoadjuvant chemotherapy is crucial, and high-throughput molecular analyses may help; the present study aims to address this. Methods Clinicopathological and gene expression data of 695 pancreatic carcinoma samples were collected from nine datasets and supervised analysis was applied to search for a gene expression signature predictive for overall survival (OS) in the 601 informative operated patients. The signature was identified in a learning set of patients and tested for its robustness in a large independent validation set. Results Supervised analysis identified 1400 genes differentially expressed between two selected patient groups in the learning set, namely 17 long-term survivors (LTS; ≥ 36 months after surgery) and 22 short-term survivors (STS; dead of disease between 2 and 6 months after surgery). From these, a 25-gene prognostic classifier was developed, which identified two classes (“STS-like” and “LTS-like”) in the independent validation set (n = 562), with a 25% (95% CI 18–33) and 48% (95% CI 42–54) 2-year OS (P = 4.33 × 10–9), respectively. Importantly, the prognostic value of this classifier was independent from both clinicopathological prognostic features and molecular subtypes in multivariate analysis, and existed in each of the nine datasets separately. The generation of 100,000 random gene signatures by a resampling scheme showed the non-random nature of our prognostic classifier. Conclusion This study, the largest prognostic study of gene expression profiles in pancreatic carcinoma, reports a 25-gene signature associated with post-operative OS independently of classical factors and molecular subtypes. This classifier may help select patients with resectable disease for either immediate surgery (the LTS-like class) or neoadjuvant chemotherapy (the STS-like class). Its assessment in the current prospective trials of adjuvant and neoadjuvant chemotherapy trials is warranted, as well as the functional analysis of the classifier genes, which may provide new therapeutic targets. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0936-z) contains supplementary material, which is available to authorized users.

International audience; BACKGROUND:Predictors of recurrence following pancreaticoduodenectomy are well described for ductal periampullary cancers but lack reliability for non-ductal tumors. The purpose of this study is to analyze the disease-free survival (DFS) and to define the predictors of recurrence following resection for ampullary (AC), bile duct (BDC) and duodenal cancers (DC).MATERIALS AND METHODS:Clinico-pathological data of patients operated on between 2001 and 2011 were retrospectively reviewed. The effect of lymphatic invasion was specified using the lymph node ratio (LNR) and the number of positive nodes (NPN), with thresholds calculated with the likelihood ratio. Kaplan-Meier disease-free survival (DFS) curves were compared for all covariates by a log-rank test. Multivariate logistic regression analyses were performed to identify predictors of recurrence.RESULTS:135 patients were identified. Mean follow-up was 49 ± 35 months. Median DFS was not reached for AC and was 36 and 18 months for DC and BDC, respectively. Five-year DFS was 52%, 43% and 32% for AC, DC and BDC, respectively. Predictors of recurrence were T4 tumors, neural invasion and preoperative biliary drainage for DC, ≥3 positive nodes and ≥4% loss of BMI for AC, and T3-T4 tumors for BDC.CONCLUSION:Loss of BMI ≥4% is a strong predictor of recurrence in AC, and the recurrence risk increases with the total number of lymph nodes invaded (0; 1-3; ≥4). Only T stage influences recurrence for BDC. Considering DC, the adverse effect of preoperative biliary drainage should be validated in randomized series.

// Amira Mohamed 1, 2 , David Romano 1 , Alexandru Saveanu 1, 2 , Catherine Roche 2 , Manuela Albertelli 3 , Federica Barbieri 3 , Thierry Brue 1, 4 , Patricia Niccoli 5 , Jean-Robert Delpero 6 , Stephane Garcia 8 , Diego Ferone 3 , Tullio Florio 3 , Vincent Moutardier 9 , Flora Poizat 7, * , Anne Barlier 1, 2, * and Corinne Gerard 1 1 Aix Marseille Univ, CNRS, CRN2M, Marseille, France 2 APHM, Conception Hospital, Molecular Biology Laboratory, Marseille, France 3 Department of Internal Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy 4 APHM, Conception Hospital, Endocrinology Department, Marseille, France 5 Paoli Calmettes Cancer Institute, Oncology Department, IPC CoE-ENETS, Marseille, France 6 Paoli Calmettes Cancer Institute, Surgery Department, IPC CoE-ENETS, Marseille, France 7 Paoli Calmettes Cancer Institute, Biopathology Department, IPC CoE-ENETS, Marseille, France 8 APHM, North Hospital, Pathology Laboratory, Marseille, France 9 APHM, North Hospital, Surgery Department, Marseille, France * These authors have contributed equally to this work Correspondence to: Corinne Gerard, email: corinne.gerard@univ-amu.fr Keywords: everolimus, somatostatin analogs, human pancreatic neuroendocrine tumors, primary culture, co-treatment Received: July 26, 2016 Accepted: March 22, 2017 Published: April 10, 2017 ABSTRACT Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Background Duodenal GISTs represent 3–5% of all GISTs with limited understanding of patient outcomes. We conducted a retrospective analysis of primary localized duodenal GISTs. Methods Patients were identified via a survey from 16 FSG centers ( n = 105), and a group of 9 patients enrolled in the BFR14 trial. Data were collected from the original database and patient files, in agreement with French legislation. Results 114 patients were included, with a median age of 57. Tumors originated mainly in D2 (33%), or D3 (24%), with a median size of 5 cm. 109 patients had resection of the primary tumor; with a Local Resection (LR, n = 82), a pancreaticoduodenectomy (PD, n = 23), and data were missing for 4 patients. Resections were R0 ( n = 87, 79%), R1 ( n = 8, 7%), R2 ( n = 6). Tumor characteristics were: KIT+ ( n = 104), CD34+ ( n = 58). Miettinen risk was low ( n = 43), and high ( n = 52). Imatinib was administered preoperatively ( n = 11) and post-operatively ( n = 20). With a median follow-up of 36 months (2–250), 98 patients are alive, and 33 relapsed. The 5-year OS and EFS rates are 86.5% and 54.5%. EFS was similar for patients in the LR and the PD groups ( P > 0.05 ). In multivariate analysis, ECOG PS, and CD34 expression are independent prognostic factors on OS. Miettinen risk and spindle cell type are independent predictive factors for relapse. Conclusions Patients with resected duodenal GIST have a reasonably favorable prognosis. This study favors a preservation of pancreas when there are no anatomical constraints. LR exhibit similar survival and smaller morbidity then PD.

According to knowledge, patients with resectable pancreatic adenocarcinoma (PA) should receive adjuvant gemcitabine-based chemotherapy. Thus, the tumour node metastasis (TNM) classification is not used to determine post-operative treatment but rather only to establish patient prognosis. However, the TNM classification does not include strong factors influencing survival, such as perineural invasion or margin status. This study compared the survival of patients with very similar tumours.From 1997 to 2007, 118 patients underwent pancreatectomy for PA. Twenty-six patients (22%) had long-term survival (5 years; LTS group). According to the major prognostic factors of PA, we matched (1:1) patients in the LTS group with patients who did not have long-term survival (5 years; control group).Surprisingly, we did not have any difficulty identifying patients to include in the control group. Consequently, no differences were noted between patients of the LTS group when compared with patients of the control group according to major prognostic factors and the TNM classification. Three patients (12%) in the LTS group had positive margin status, and two patients (8%) had positive lymph node status. Unsurprisingly, the median survival for the control group versus the LTS group was 16 months versus not reached (P0.01).The lack of difficulty in matching the two groups confirmed that patients of the LTS group did not have an exclusive tumour pattern. TNM classification is outdated because it did not influence adjuvant therapies and did not include two crucial factors: tumour biology and tumour response to chemo/radio therapies.

Five patients with pancreatic tumors and chronic portal vein (PV) thrombosis underwent PV stent placement before surgery. The patients either had resectable tumors or locally advanced tumors with stable, partial, or complete response to neoadjuvant therapy. PV stent placement removed periportal collaterals in all cases, with no complications, in a mean time of 150 minutes. Patients received a daily dose of subcutaneous low-molecular-weight heparin until 12 hours before surgery, and low-molecular-weight heparin was resumed for 30 days after surgery. Surgery was performed 1 day to 3 months after PV stent placement, with no complications related to periportal collaterals.

Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily lethal disease, which, despite a more or less efficient chemotherapeutic treatment, systematically displays a rapid and uncontrolled progression towards a fatal recurrence. Determining which cells give rise to such tumor recurrence is thus crucial before an improved therapeutics outcome can be envisaged for patients with PDAC. In this regard, we recently reported that following a standard chemotherapy for PDAC, a heterogeneous subpopulation of CD44+ cells proliferates and is responsible for tumor recurrence, as shown by almost all recurrent tumor cells becoming CD44+. We designed a strategy to eliminate these cells based on a weekly administration of an anti-CD44 monoclonal antibody to human PDAC-derived xenografts in mice. We demonstrate that xenografts, which were unresponsive to gemcitabine treatment, are however sensitive to this strategy. In conclusion, CD44 represents an efficient therapeutic target in patients with recurrent PDAC.

Patient-derived xenografts (PDX) are appearing as a prime approach for preclinical studies despite being insufficiently characterized as a model of the human disease and its diversity. In this work, 29 PDX were obtained from either surgery or endoscopic ultrasound-guided fine needle aspirate of pancreatic adenocarcinoma. The extensive genomic profiling of these pancreatic PDX, revealed two clinically-relevant subtypes having broad similarities with human primary tumors. These subtypes are defined by highly specific DNA methylation and transcriptomic profiles (mRNA, miRNA or lncRNA) but are not distinguishable by exonic mutations or copy number aberrations. Moreover, by specifically analyzing the stroma transcriptome, as defined by the expression of murine transcripts, we found that it is able to stratify the patients with the same efficiency than the analysis of grafted human tumor cells. This finding suggest that transformed pancreatic cells drive the composition of their own stroma. Finally, the multiomics analysis pinpoints novel therapeutic targets, one of which we demonstrate to be an efficient method for treating pancreatic cancer. Overall, we show that PDX are trustworthy pre-clinical models of pancreatic adenocarcinoma including of unresectable tumors. Their multiomics profiling allow the independent analysis of the uncontaminated cancer or stromal compartments and discloses several original therapeutics targets. Citation Format: Remy Nicolle, Yuna Blum, Laetitia Marisa, Celine Loncle, Odile Gayet, Vincent Moutardier, Olivier Turrini, Marc Giovannini, Benjamin Bian, Martin Bigonnet, Marion Rubis, Nabila Elarouci, Lucile Armenoult, Mira Ayadi, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Aurélie Maignan, Gwen Lomberk, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Jonathan Garnier, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Julie Roques, Ezequiel Calvo, Fabienne Guillaumond, Sophie Vasseur, Raul Urrutia, Aurélien de Reyniès, Nelson Dusetti, Juan Iovanna. Multiomics assessment of the cancer and stromal compartments of patient-derived pancreatic xenografts reveals clinically-relevant subtypes and novel targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4396. doi:10.1158/1538-7445.AM2017-4396