The falciform/round ligament "flooring," an effective method to reduce life-threatening post-pancreatectomy hemorrhage occurrence.

PURPOSE: Late post-pancreatectomy hemorrhage (PPH) represents the most severe complication after pancreatic surgery. We have measured the efficacy of major vessels "flooring" with falciform/round ligament to prevent life-threatening grade C late PPH after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: All consecutive patients who underwent PD and DP between 2013 and 2021 were retrospectively reviewed on a prospectively maintained database. The cohort was divided in two groups: "flooring" vs. "no flooring" method group. The "no flooring" group had omental flap interposition. Patient characteristics and operative and postoperative data including clinically relevant postoperative pancreatic fistula (CR-POPF), late PPH (grade B and C), and 90-day mortality were compared between the two groups. RESULTS: Two hundred and forty patients underwent pancreatic resections, including 143 PD and 97 DP. The "flooring" method was performed in 61 patients (39 PD and 22 DP). No difference was found between the two groups concerning severe morbidity, CR-POPF, delayed PPH, and mortality rate. The rate of patients requiring postoperative intensive care unit was lower in the "flooring" than in the "no flooring" method group (11.5% vs. 25.1%, p = 0.030). Among patients with grade B/C late PPH (n = 30), the rate of life-threatening grade C late PPH was lower in the "flooring" than in the "no flooring" method group (28.6% (n = 2/7) vs. 82.6% (n = 19/24), p = 0.014). Risk factor analysis showed that the "flooring" method was the only protective factor against grade C late PPH occurrence (p = 0.013). CONCLUSION: The "flooring" method using the falciform/round ligament should be considered during pancreatectomies to reduce the occurrence of life-threatening grade C late PPH.

Prognostic impact of splenic vessel involvement and tumor size in distal pancreatectomy for adenocarcinoma: a retrospective multicentric cohort study.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001). CONCLUSION: Tumor size ≥ 30 mm and splenic vessel involvement occurred in more than half of the patients who underwent DP for PDAC and had negative impact on long-term survival. Preoperative CT-scan was reliable to identify splenic vessel involvement in B/T PDAC. Large tumor size and radiological splenic vessel involvement could be taken into account to propose a neoadjuvant treatment.

Postoperative day 1 combination of serum C-reactive protein and drain amylase values predicts risks of clinically relevant pancreatic fistula. The "90-1000" score.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Surgery of small bowel melanoma metastases in the era of efficient medical therapies: a retrospective cohort study.

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.

Delayed post-pancreatectomy hemorrhage and bleeding recurrence after percutaneous endovascular treatment: risk factors from a bi-centric study of 307 consecutive patients.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Intra-pancreatic distal cholangiocarcinoma and pancreatic ductal adenocarcinoma: a common short and long-term prognosis?

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.

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer.

BACKGROUND: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment. METHODS: Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours. FINDINGS: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001). INTERPRETATION: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient. FUNDING: Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.

Prospective study on predictability of complications by pancreatic surgeons.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001). When the pancreatic parenchyma was hard, surgeons predicted the absence of CR-POPF with a negative predictive value of 91.3%. However, they were not able to predict the occurrence of CR-POPF when the pancreas was soft (positive predictive value 48%). CONCLUSIONS: This study assessed for the first time the surgeon's intuition in pancreatic surgery, and demonstrated that pancreatic surgeons cannot accurately assess outcomes except when the pancreatic parenchyma is hard.

HVEM has a broader expression than PD-L1 and constitutes a negative prognostic marker and potential treatment target for melanoma.

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.

Preoperative Biliary Stenting and Major Morbidity After Pancreatoduodenectomy: Does Elapsed Time Matter?: The FRAGERITA Study Group.

OBJECTIVE: To analyze possible associations between the duration of stent placement before surgery and the occurrence and severity of postoperative complications after pancreatoduodenectomy (PD). BACKGROUND: The effect of preoperative stent duration on postoperative outcomes after PD has not been investigated. METHODS: From 2013 to 2016, patients who underwent PD for any reasons after biliary stent placement at 5 European academic centers were analyzed from prospectively maintained databases. The primary aim was to investigate the association between the duration of preoperative biliary stenting and postoperative morbidity. Patients were stratified by stent duration into 3 groups: short (<4 weeks), intermediate (4-8 weeks), and long (≥8 weeks). RESULTS: In all, 312 patients were analyzed. The median time from stent placement to surgery was 37 days (2-559 days), and most operations were performed for pancreatic cancer (67.6%). Morbidity and mortality rates were 56.0% and 2.6%, respectively. Patients in the short group (n = 106) experienced a higher rate of major morbidity (43.4% vs 20.0% vs 24.2%; P < 0.001), biliary fistulae (13.2% vs 4.3% vs 5.5%; P = 0.031), and length of hospital stay [16 (10-52) days vs 12 (8-35) days vs 12 (8-43) days; P = 0.025]. A multivariate adjusted model identified the short stent duration as an independent risk factor for major complications (odds ratio 2.64, 95% confidence interval 1.23-5.67, P = 0.013). CONCLUSIONS: When jaundice treatment cannot be avoided, delaying surgery up to 1 month after biliary stenting may reduce major morbidity, procedure-related complications, and length of hospital stay.

Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes.

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.

Preoperative Prediction of Small Bowel Length Using CT Scan and Tridimensional Reconstructions: a New Tool in Bariatric Surgery?

PURPOSE: 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. OBJECTIVE: The aim of this study is to evaluate factors correlated to SBL (anthropometric and radiologic) and to establish a preoperative SBL prediction. MATERIAL AND METHODS: 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). RESULTS: Mean intraoperative measurement of SBL was 531 ± 105 cm. Among the clinical and radiological measurements, the FSBM volume presented the greatest dispersion. Height (p < 0.02) and LSBM volume (p < 0.01) were significantly correlated to the SBL in univariate analysis. LSBM volume was the only measurement significantly associated with SBL in multivariate analysis (p < 0.006). From the multivariate model, a formula was created to predict SBL. The mean percentage difference between predicted and intraoperative SBL measurements for all patients was 13.7%, and 8.4% for obese patients. CONCLUSION: LSBM volume is significantly correlated to the SBL. A preoperative SBL prediction with low percentage error could be performed with LSBM volume.

C-Reactive Protein on Postoperative Day 1 Is a Reliable Predictor of Pancreas-Specific Complications After Pancreaticoduodenectomy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 3 mm and serum C-reactive protein ≥ 100 mg/L on postoperative day 1 were independent predictors of pancreas-specific complications (p < 0.01) and pancreatic fistula (p < 0.01). ROC analysis showed that serum C-reactive protein ≥ 100 mg/L on postoperative day 1 was a significant predictor of pancreatic fistula (AUC: 0.70; 95%CI: 0.60-0.79, p < 0.01) and pancreas-specific complications (AUC: 0.72; 95%CI: 0.62-0.82, p < 0.01). ROC analysis showed that serum C-reactive protein ≥ 50 mg/L at discharge was a significant predictor of 90-day hospital readmission (AUC: 0.70; 95%CI: 0.60-0.79, p < 0.01). CONCLUSIONS: C-reactive protein levels reliably predict risks of pancreatic fistula, pancreas-specific complications, and hospital readmission, and should be inserted in risk-stratified management algorithms after pancreaticoduodenectomy.

Predict pancreatic fistula after pancreaticoduodenectomy: ratio body thickness/main duct.

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 < 0.01) and B/W ratio (P = 0.04) were significantly associated with POPF. ROC curve showed a greater area under curve for B/W ratio (0.68) than for main pancreatic duct size (0.33). A 3.8 threshold displayed 80 and 51% for sensibility and specificity, respectively, and a negative predictive value of 94%. A B/W ratio >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.

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

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.

A 25-gene classifier predicts overall survival in resectable pancreatic cancer.

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.

Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.

Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer.

Comparison of different feeding regimes after pancreatoduodenectomy - a retrospective cohort analysis.

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 < 0.01). An ASA score of 3, jaundice, common pancreatic duct size ≤3 mm and soft pancreatic gland texture (p < 0.05) were found as independent risk factors of PSCs. Use of a GJ tube with EN, GT tube with TPN, jaundice, and PSCs were identified as independent risk factors for greater postoperative length of hospital stay (p < 0.01). Mean global hospitalization cost did not differ between groups. CONCLUSION: GT tube insertion with TPN was associated with increased severe postoperative morbidity and DGE and should not be recommended. EN through a GJ tube after PD is feasible but does not have clear advantages on postoperative courses compared to an NG tube.

Venous Resection in Pancreatic Ductal Adenocarcinoma: Impact of Surgical Experience on Early Postoperative Courses.

BACKGROUND/AIM: The aim of this study was to determine the effects of surgical experience on early postoperative courses after pancreaticoduodenectomy (PD) with venous resection. PATIENTS AND METHODS: From 2005 to 2014, 134 patients were analyzed, 62 and 72 patients were resected in periods 1 (2005-2009) and 2 (2010-2014) respectively; 115 and 19 patients underwent PD with venous resection in high- and low-volume center groups respectively. RESULTS: Of the entire cohort, mortality rate was 4%. There were no significant differences between the two periods. In the low-volume center group, the mortality rate was increased (21% vs. 2%, p<0.01) and the mean length of hospital stay was longer (25 (±27) days vs. 17 (±8) days, p=0.04). The high-volume center group was the only independent protective factor regarding death (OR=0.04, 95%CI (0.01-0.38), p<0.01) and length of hospital stay (OR<0.01, 95%CI (0.00-0.43), p=0.03). CONCLUSION: Patients who present isolated venous invasion must be referred to high-volume centers for surgery.

Disease-free survival following resection in non-ductal periampullary cancers: A retrospective multicenter analysis.

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.