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PURPOSE The double purse-string telescoped pancreaticogastrostomy (PG) technique has been suggested as an alternative approach to reduce the risk of postoperative pancreatic fistula (POPF). Its efficacity in high-risk situations has not yet been explored. This study compared the incidence of clinically relevant POPF (CR-POPF) between patients with high-risk anastomosis undergoing PG and those undergoing pancreaticojejunostomy (PJ). METHODS From 2013 to 2019, 198 consecutive patients with high-risk anastomosis, an updated alternative fistula risk score > 20%, and who underwent pancreatoduodenectomy with the PJ (165) or PG (33) technique were included. Optimal mitigation strategy (external stenting/octreotide omission) was applied for all patients. The primary endpoint was the incidence of CR-POPF. RESULTS The mean ua-FRS was 33%. CR-POPF (grade B/C) was found in 42 patients (21%) and postoperative hemorrhage in 30 (15%); the mortality rate was 4%. CR-POPF rates were comparable between the PJ (19%) and PG (33%) groups (P = 0.062). The PG group had a higher rate of POPF grade C (24% vs. 10%; P = 0.036), longer operative time (P = 0.019), and a higher transfusion rate (P

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.

Background Emergency completion pancreatectomy (CP) after pancreatoduodenectomy (PD) is a technically demanding procedure. We report our experiences with a four-step standardized technique used at our center since 2012. Methods In the first step, the gastrojejunostomy is divided with a stapler to quickly access the pancreatic anastomosis and permit adequate exposure, especially in cases of active bleeding. Second, the bowel loops connected to the pancreatic anastomosis is divided in cases of pancreaticojejunostomy. Third, the pancreatectomy is completed with or without the splenic vessels and spleen conservation according to the local conditions. Finally, the fourth step reconstructs in a Roux-en-Y fashion and ensures drainage. Results From January 2012 to December 2019, 450 patients underwent PD at our center. Reintervention for grade C postoperative pancreatic fistula was decided for 30 patients, and CP was performed in 21 patients. The mean intraoperative blood loss and operative duration were relatively low (600 ml and 240 min, respectively). During the perioperative period, three patients died from multiple organ failure, and two patients died intraoperatively from a cataclysmic hemorrhage originating from the superior mesenteric artery. Discussion Our standardized procedure appears to be relatively safe, reproducible, and could be particularly useful for young surgeons.

International audience; Background: Experienced pancreatic surgeons, for whom complexity is not an issue, must decide at the end of neoadjuvant therapy whether to continue or discontinue surgery, when pancreatectomy with vascular resection is planned in patients with pancreatic ductal adenocarcinoma (PDAC). Objective: Our study aimed to determine preoperative factors that can predict short postoperative survival in such situations. Methods: Overall, 105 patients with borderline or locally advanced PDAC received neoadjuvant FOLFIRINOX (followed by chemoradiation in 22% of patients) and underwent pancreatectomy with segmental venous and/or arterial resection at two high-volume centers. The primary endpoint was overall survival (OS) of < 1 year after surgery for patients who did not die from the surgery. Results: Tumors were classified as borderline in 78% of cases and locally advanced in 22% of cases. Mean CA19-9 at diagnosis was 934 U/mL, which significantly decreased to 213 U/mL (p < 0.01) after a median of six cycles of FOLFIRINOX. Pancreaticoduodenectomy was performed most often (76%). The vast majority of patients underwent venous resection (92%), and a simultaneous arterial resection was performed in 16 patients (15%). The severe morbidity rate and 30- and 90-day mortality rates were 21%, 8.5%, and 10.4%, respectively. The median OS after surgery was 23 months. In the multivariate analysis, preoperative CA19-9 ≥ 450 U/mL was the only preoperative factor independently associated with OS of < 1 year (p = 0.044). Conclusion: The preoperative CA19-9 value should be considered in the clinical decision-making process when complex vascular resection is required. © 2021, Society of Surgical Oncology.

This study aimed to determine the impact of FOLFIRINOX neoadjuvant therapy on patients with non-metastatic borderline/locally advanced (BL/LA) pancreatic ductal adenocarcinoma (PDAC), in current practice.From 2010 to 2017, 258 patients with BL/LA PDAC from a single high-volume institution received FOLFIRINOX neoadjuvant treatment.The 258 patients received a median number of 6 cycles of FOLFIRINOX (range, 3-16); 98 (38%) patients underwent curative surgery, and 160 (62%) continued medical treatment. A venous resection was performed in 57 patients (58%), and an arterial resection in 12 (12%). The postoperative 30- and 90-day mortality rates were 6.1% and 8.2%, respectively. Adjuvant chemotherapy was performed in 57 patients (59%). The median overall survival (OS) in patients who did (n = 98) or did not (n = 160) undergo surgical resection were 39 months and 19 months, respectively (P 0.001). In resected patients, the ASA 3 score (P 0.01), venous resection (P 0.01), hemorrhage (P 0.01), and R1 margin status (P = 0.03) were found to negatively influence the OS. The median OS was significantly higher in patients who did not require a venous resection (not reached vs. 26.5 months, P 0.001).Neoadjuvant FOLFIRINOX provided a survival benefit in BL/LA PDAC patients, particularly in those who did not ultimately require venous resection.

Background Pancreatic neuroendocrine tumors (PNET) are rare, with a significant malignant potential. This study aimed to determine outcomes of patients with resected PNETs according to the cystic component and confirm the accuracy of preoperative staging. Methods From 1997 to 2016, 106 patients underwent resection of PNETs, including 73 purely solid (S-PNETs, 69%), 21 mixed (M-PNETs, 20%), and 12 purely cystic lesions (C-PNETs, 11%). To ensure consistent comparisons of overall (OS) and disease-free (DFS) survival outcomes between the 3 groups, the patients were matched according to the World Health Organization (WHO) grade and tumor height. Results Overall, the rate of correlation between the preoperative and pathological diagnoses was low in the C-PNET group (33%, P = 0.03). None of the 24 patients (23%) with metastatic disease at the time of surgery were in the C-PNET group. Furthermore, significantly more parenchyma-sparing resections (P = 0.039) and fewer enlarged resections (P = 0.019) were achieved in the C-PNET group. C-PNET group had a significantly lower node invasion rate than the S-PNET and M-PNET groups (8% vs. 41% and 24%, P = 0.004). Although median OS was comparable in all 3 groups before (P = 0.3) and after (P = 0.18) matching, higher median DFS was observed in the C-PNET group than in the other groups after matching (P = 0.038). Conclusion C-PNET was associated with a better prognosis than PNET with a solid component. The results support a wait-and-see policy in cases wherein a reliable preoperative diagnosis remains challenging.

Purpose To determine if improvement in imaging reduces the non-resection rate (NRR) among patients with pancreatic ductal adenocarcinoma (PDAC). Methods From 2000 to 2019, 751 consecutive patients with PDAC were considered eligible for a intention-to-treat pancreatectomy and entered the operating room. In April 2011, our institution acquired a dual energy spectral computed tomography (CT) scanner and liver diffusion weighted magnetic resonance imaging (DW-MRI) was included in the imaging workup. We consequently considered 2 periods of inclusion: period #1 (February 2000–March 2011) and period #2 (April 2011–August 2019). Results All patients underwent a preoperative CT scan with a median delay to surgery of 18 days. Liver DW-MRI was performed among 407 patients (54%). Median delay between CT and surgery decreased (21 days to 16 days, P P P P P P Conclusions Due to changes in our therapeutic strategies, the NRR did not decrease during two decades despite imaging improvement.

We evaluated the usefulness of the 2017 definition of borderline pancreatic ductal adenocarcinoma (BR-PDAC) in fit patients (performance status 0-1) based on anatomical (A) and biological dimensions (B).From 2011 to 2018, 139 resected patients with BR-PDAC according to the 2017 definition were included: 18 patients underwent upfront pancreatectomy (CA 19-9 500 U/mL and/or regional lymph node metastasis; BR-B group), and 121 received FOLFIRINOX (FX) induction chemotherapy and were divided into BR-A (CA 19-9 500 U/mL, no regional lymph node metastasis; n = 68) and BR-AB (CA 19-9 500 U/mL and/or regional lymph node metastasis; n = 53) groups.The 3 groups were comparable according to patient characteristics (except for back pain (P .01) and CA 19-9 (P .01)), intraoperative data, and postoperative courses. BR-AB patients required more venous resections (P .01). The 3 groups were comparable on pathologic findings, except that BR-B patients had more lymph node invasions (P = .02). Median overall survival (OS) of the 121 patients was 45 months. In multivariate analysis, venous resection (P = .039) and R1 resection (P = .012) were poorly linked with OS, whereas BR-A classification (P .01) independently favored OS. Median survival times of BR-A, BR-AB, and BR-B groups were undetermined, 27 months, and 20 months (P.001), respectively.The 2017 definition was relevant for sub-classifying patients with BR-PDAC. The anatomical dimension (BR-A) was a favorable prognostic factor, whereas the biological dimension (BR-AB and BR-B) poorly impacted survival.

International audience

Purpose: Using a standardized specimen protocol analysis, this study aimed to evaluate the resection margin status of patients who underwent resection for either distal cholangiocarcinoma (DC) or pancreatic ductal adenocarcinoma (PDAC). This allowed a precise millimetric analysis of each inked margin. Methods: From 2010 to 2018, 355 consecutively inked specimens from patients with PDAC (n = 288) or DC (n = 67) were prospectively assessed. We assessed relationships between the tumor and the following margins: transection of the pancreatic neck, bile duct, posterior surface, margin toward superior mesenteric artery, and the surface of superior mesenteric vein/portal vein groove. Resection margins were evaluated using a predefined cut-off value of 1 mm, however, clearances of 0 and 1.5 mm were also evaluated. Results: Patients with DC were mostly men (64% vs. 49%, p = 0.028), of older age (68 yo vs. 65, p = 0.033), required biliary stenting more frequently (93% vs. 77%, p &lt, 0.01), and received less neoadjuvant treatment (p &lt, 0.001) than patients with PDAC. The venous resection rate was higher among patients with PDAC (p = 0.028). Postoperative and 90-day mortality rates were comparable. Patients with PDAC had greater tumor size (28.6 vs. 24 mm, p = 0.01) than those with DC. The R1 resection rate was comparable between the two groups, regardless of the clearance margin. Among the three types of resection margins, a venous groove was the most frequent in both entities. In multivariate analysis, the R1 resection margin did not influence patient survival in either PDAC or DC. Conclusion: Our standardized specimen protocol analysis showed that the R1 resection rate was comparable in PDAC and DC.

Postoperative aspiration pneumonitis (POAP) is a rare (1%) but worrying complication with a high mortality rate (up to 30%). 1 , 2 , 3 General anesthesia combined with gastrointestinal surgery induces digestive tract paralysis with the risk of delayed gastric emptying and consequent POAP. In the last two decades, efforts to decrease perioperative opioid use, 4 together with the rise of minimally invasive surgery, have reduced the surgical impact on digestive motility. In contrast, enhanced recovery after digestive surgery leads to decreased routine gastric tube feeding and increased early postoperative feeding, 5 , 6 , 7 , 8 which may induce gastric emptying and increase the risk of POAP, which remains a constant risk after digestive surgery, with various effects ranging from isolated radiologic signs to severe pneumonitis with multiorgan failure. To date, there have been no definitions or grading schemes for POAP, and it is difficult to draw realistic comparisons among perioperative drugs or procedures that could be effective in reducing POAP. Therefore, the present study seeks to develop a simple and reliable POAP classification that could facilitate relevant comparisons of preventive measures and postoperative courses.

Two-stage hepatectomy (TSH) strategy is used to treat patients with bilobar colorectal liver metastasis (CLM). However, many patients do not undergo the second hepatectomy owing to disease progression in the future liver remnant (FLR) after portal vein embolization (PVE). This study aimed to assess the impact of disease progression in the FLRs of patients who completed the first hepatectomy.68 consecutive patients underwent the first hepatectomy followed by PVE. Six patients (9%) dropped out after the PVE (two-stage failed [TSF] group) because of unresectable hepatic or general disease progression. Seventeen patients (25%) completed their second hepatectomy despite disease progression in the FLR (new CLM [nCLM] group) as it was considered resectable, while 45 patients (66%) underwent the second hepatectomy (control group).The 5-year overall survival rates in the TSF, nCLM, and control groups were 0%, 7%, and 60%, respectively (P 0.001). The median overall survival times between the TSF and nCLM groups were 26 months and 42 months (P = 0.005). Patients in the nCLM group whose hepatic disease progression was detected preoperatively versus intraoperatively had comparable survival rates.Resectable hepatic disease progression in the FLR after PVE should not be considered a contraindication for the second hepatectomy.

Positive para-aortic lymph nodes (PALN) (station 16) are commonly detected in the final pathologic examination (ranging from 15 to 26%) among patients who undergo upfront pancreatoduodenectomy for resectable pancreatic ductal adenocarcinoma. However, after neoadjuvant treatment (NAT) the role of positive PALN as a watershed for surgical resection remains unclear. We aimed to determine the incidence of intraoperative detection of PALN after NAT with FOLFIRINOX for pancreatic head adenocarcinoma and its impact on survival, as our policy was to not resect the tumor in such situations. From January 2014 to December 2020, 136 patients with non-metastatic cancer who received neoadjuvant FOLFIRINOX and underwent explorative laparotomy were included. Intraoperative positive PALN were observed in 7 patients (5%). Patients had resectable (n = 5) or locally advanced (n = 2) disease at the time of surgery, but none of them underwent surgical resection. Positive PALN were significantly associated with a lower median number of FOLFIRINOX cycles (4 vs. 6, P = 0.05). There was no significant difference in overall survival between patients with positive loco-regional lymph nodes after resection and patients with non-resection owing to positive PALN (22 versus 16 months, P = 0.16), Overall survival with positive PALN, carcinomatosis, and liver metastasis was 16, 14, and 10 months, respectively (P > 0.05). Our results suggest that NAT may lower PALN involvement. We have modified our policy, positive PALN after NAT are no longer a contraindication to resection, rather a holistic picture of the disease guides management.

International audience; [No abstract available]

Background This study aimed to investigate the short- and long-terms outcomes of patients undergoing major hepatectomy (MH) with inferior vena cava (IVC) resection for intrahepatic cholangiocarcinoma (ICC). Methods Data from all patients who underwent MH for ICC with or without IVC resection between 2010 and 2018 were analysed retrospectively. Postoperative outcomes, overall survival (OS), and recurrence-free survival (RFS) were compared in the whole population. A propensity score matching (PSM) analysis and an inverse probability weighting analysis (IPW) were performed to assess the influence of IVC resection on short- and long-terms outcomes. Results Among the 78 patients who underwent MH, 20 had IVC resection (IVC patients). Overall, the mortality and severe complication rate were 8% and 20%, respectively. IVC patients required more extended hepatectomies (p = 0.001) and had increased rates of transfusions (p = 0.001), however they did not experience increased postoperative morbidity, even after PSM. The 1-, 3- and 5-years OS and DFS were 78%, 45%, and 32% and 48%, 20%, and 16%, respectively. IVC was not associated with decreased OS (p = 0.52) and/or RFS (p = 0.85), even after IPW. Conclusion MH with IVC resection for ICC seems to provide acceptable short- and long-term results in a selected population of patients.

Background Sacrificing a replaced right hepatic artery (rRHA) from the superior mesenteric artery is occasionally necessary to obtain an R0 resection after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA). Preoperative embolization (PEA) of the rRHA has been proposed to avoid the onset of postoperative biliary and ischemic liver complications. Methods Eighteen patients with cephalic PA with an rRHA underwent PEA of the rRHA from 2013 to 2019. The monitoring after embolization and PD was systematic and included a clinical-biological evaluation and a computed tomography scan. This study aimed to determine the feasibility of PEA of the rRHA, postoperative morbidity at 90 days, and quality of oncologic resection after PD. Results Feasibility of PEA was 100% without complications. A PD was performed in 16/18 patients. Mortality was 2/16 with one death after septic shock with hepatic ischemia without an arterial obstruction. Overall morbidity was 44% including one hepatic abscess after hepatic ischemia (6%). Two resections were R1 ( Conclusion PEA of the rRHA before PD was safe and reproducible. PEA of the rRHA followed by en bloc PD resection seems to limit the risk of bilio-hepatic ischemia and could facilitate oncologic resection.

Backgrounds/Aims Surgical resection remains the gold standard in the treatment of colorectal liver metastasis. However, when a patient presents with a deep solitary colorectal liver metastasis (S-CLM), the balance between the hepatic volume sacrificed and the S-CLM volume is sometimes clearly unappropriated. Thus, alternatives to surgery, such as operative and percutaneous radiofrequency ablation (RFA) and microwave ablation (MWA), have been developed. This study aimed to identify the prognostic factors affecting survival of patients with S-CLM who undergo curative-intent liver resection or local destruction (RFA or MWA). Methods We retrospectively identified 211 patients with synchronous or metachronous S-CLM who underwent either surgical resection (n=182) or local destruction (RFA or MWA; n=29) according to the S-CLM size, location, and surrounding Glissonian structures. Results Patients who underwent RFA or MWA had S-CLM of a smaller size than those who underwent resection (mean 19.7 vs. 37.3 mm, p

Background The current study aimed to evaluate the outcomes of patients with unresectable non-metastatic locally advanced pancreatic adenocarcinoma (LAPA) who did not benefit from resection considering the treatment strategy in the clinical settings. Methods Between 2010 and 2017, a total of 234 patients underwent induction chemotherapy for LAPA that could not be treated with surgery. After oncologic restaging, continuous chemotherapy or chemoradiation (CRT) was decided for patients without metastatic disease. The Kaplan–Meier method was used to determine overall survival (OS), and the Wilcoxon test to compare survival curves. Multivariate analysis was performed using the stepwise logistic regression method. Results FOLFIRINOX was the most common induction regimen (168 patients, 72%), with a median of 6 chemotherapy cycles and resulted in higher OS, compared to gemcitabine (19 vs. 16 months, hazard ratio (HR) = 1.2, 95% confidence interval: 0.86–1.6, P = .03). However, no difference was observed after adjusting for age (≤75 years) and performance status score (0–1). At restaging, 187 patients (80%) had non-metastatic disease: CRT was administered to 126 patients (67%) while chemotherapy was continued in 61 (33%). Patients who received CRT had characteristics comparable to those who continued with chemotherapy, with similar OS. They also had longer progression-free survival (median 13.3 vs. 9.6 months, HR = 1.38, 95% confidence interval: 1–1.9, P Conclusions The median survival of patients who could not undergo surgery was 19 months. Hence, CRT should not be eliminated as a treatment option and may be useful as a part of optimised sequential chemotherapy for both local and metastatic disease.

Objective To determine the effect of clinical status (weight variation and performance status [PS]) at diagnosis and during induction treatment on resectability and overall survival (OS) rates in patients with borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC). Methods From 2005 to 2017, 454 consecutive patients were diagnosed with LAPC or BRPC. We evaluated the PS (0–1 or 2–3), body mass index at diagnosis, and weight loss (WL) > 5% at initial staging and after induction treatment and separated continuous weight loss (CWL) from weight stabilization. Results A total of 294 patients (64.8%) presented with WL, and 57 patients (12.6%) presented with a PS of 2–3. At restaging, 60 patients (13.2%) presented with CWL. Independent factors that poorly influenced the OS were a PS of 2–3 at diagnosis (P < .01), CWL at restaging (P < .01), and absence of resection (P < .01). Factors independently impeding resection were LAPC (P < .01), PS > 1 at diagnosis (P < .01), and CWL (P = .01). In total, 142 patients (31.3%) underwent pancreatectomy. Independent factors that poorly influenced the OS in the resected group were PS > 0 at diagnosis (P = .01) and obesity (P < .01). For the 312 unresected cancer patients (68.7%), CWL (P < .01) was identified as an independent factor that poorly influenced the OS. Conclusion Clinical parameters that are easy to measure and monitor are independent factors of poor prognosis. The variation of weight during the induction treatment, more than WL at diagnosis, significantly precluded resection and was an independent factor of shorter OS in unresected patients.

A new neoadjuvant regimen, together with more aggressive surgeries, appears to have increased the resectability rate in patients with pancreatic ductal adenocarcinoma (PDAC). Our study aimed to evaluate the outcomes of patients who underwent venous resection (VR) during pancreatectomies for PDAC.Between 2005 and 2017, 130 patients underwent pancreatectomies with type 3 or 4 (i.e., segmental resection without or with graft interposition, respectively) VR for PDAC. Patients' characteristics, surgical techniques, perioperative management, pathological findings, and outcomes were recorded and compared during 2 inclusion periods: the landmark year for the introduction of the FOLFIRINOX regimen and the hyperspecialization of our pancreatic-surgery team was 2010.Performance of pancreatectomies with VR steadily increased through the 2 inclusion periods. In the overall series (n = 130), the median overall survival time and the 5-year survival proportion were 26.3 months and 21%, respectively. Upon multivariate analysis, ASA score 3 (P = 0.01) and R1 resection margins (P 0.01) were found to be negative independent factors influencing survival. Patients who underwent upfront VR (n = 47) had survival rates similar to those of patients who received neoadjuvant treatment (n = 83). After 2010, more complex VR were performed; however, no difference was found between the 2 periods with respect to postoperative courses, pathologic findings, or survival after a matching process based on patients' characteristics and tumor stages.Over the last 2 decades, VR during pancreatectomy has been confirmed as a safe procedure despite the increase in technical complexity. Disappointingly, we did not observe any dramatic survival improvement.

Purpose This study proposes and details a simple and inexpensive protective technique of wrapping the hepatic and gastroduodenal artery stumps with a peritoneal patch during pancreatoduodenectomy (PD) in order to decrease post-pancreatectomy hemorrhage (PPH). Methods Among the 85 patients who underwent PD between July 2020 and March 2021, 16 patients with high-risk pancreatic anastomosis received a peritoneal patch. The Updated Alternative Fistula Risk Score (ua-FRS) was calculated. Post-operative pancreatic fistula (POPF) and PPH were diagnosed and graded according to the International Study Group of Pancreatic Surgery. The mortality rate was calculated up to 90 days after PD. Results The mean ua-FRS of the 16 patients was 43% (range: 21-63%). Among them, 6 (38%) experienced clinically relevant-POPF, and a PPH was observed in two patients (13%). In these two patients who required re-intervention, the peritoneal patch was remarkably intact, and neither the gastroduodenal stump nor hepatic artery was involved. None of the patients experienced 90-day mortality. Conclusion Although the outcomes are encouraging, the evaluation of a larger series to assess the effectiveness of the peritoneal protective patch for arteries in a high-risk pancreatic anastomosis is ongoing.

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.

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 Acute kidney injury (AKI) following major hepatectomy (MH) remains inadequately investigated. This retrospective study aimed to assess the risk factors and prognostic value of AKI on short-term outcomes following MH without portal pedicle clamping. Methods From January 2014 through June 2017, 111 consecutive patients underwent MH without portal pedicle clamping, but with intraoperative low-crystalloid infusion. Kidney Disease Improving Global Outcomes stages II and III were classified as severe AKI. Results A total of 102 patients did not develop AKI or only AKI stage I (92%, control group), whereas 9 patients developed severe AKI (8%, severe AKI group). Hepatectomy (P = 0.002) and surgery (P = 0.011) durations were longer in the severe AKI group. Clavien-Dindo grades 3 to 5 morbidity (55% versus 9%, P = 0.001), liver failure (P = 0.017), and 90-day mortality (33% versus 2%, P = 0.003) were significantly higher in the severe AKI group. After a multivariate analysis, the duration of hepatectomy (cut-off: 250 min; P = 0.029) and urea serum levels on postoperative day 3 (P = 0.006) were identified as independent predictors of severe AKI. Discussion Severe AKI, is common with increased duration of hepatectomy, was associated with poor short-term outcomes, and can be predicted by operative duration greater than 250 minutes.

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

Genome-wide molecular profiles have been proven to be beneficial for the identification of clinically relevant tumor subtypes in many neoplastic diseases. While pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death, very few genomic and transcriptomic studies have been conducted. This is mainly due to the difficulty to obtain a suitable cohort of PDAC tumor samples. The major obstacle is the usually high proportion of non-transformed stromal cells, which can greatly hinder the analysis of carcinogenic-specific processes. Moreover, tumor cohorts requiring resection samples can be biased by the exclusion of inoperable patients, representing 85% of all patients presenting PDAC. In this study, we generated Patient Derived Xenografts (PDX) with samples collected from 29 patients using either Endoscopic Ultrasound-Guided Fine-Needle Aspirates or, for operable patients, resections. The transcriptomic profiles, of both mRNA and miRNA, and the epigenetic landscape of early PDX passages consistently identified two tumor-specific molecular subtypes: a well differentiated group often referred to as classical, and an undifferentiated group previously recognized as Basal, Quasi-Mesenchymal or Squamous. Of all the genetic alterations determined by Copy Number analysis and exome sequencing, none were specific to any of the two subtypes, which therefore could not be discriminated solely on genetic basis. These two PDAC subtypes are characterized by distinct epigenetic and transcriptomic profiles of which the analysis revealed the deregulation of several pathways previously imputed in PDAC development and carcinogenesis in general. In particular, we showed that the Wnt pathway as well as several metabolic pathways, including cytochrome P450 genes recently implicated in drug resistance, are both epigenetically and transcriptionally deregulated. Altogether, our results provide new insights on pancreatic carcinogenesis and suggest that PDAC phenotypical heterogeneity is mainly driven by epigenetic rather than genetic events. Citation Format: Remy Nicolle, Yuna Blum, Laetitia Marisa, Jonathan Garnier, Benjamin Bian, Celine Loncle, Martin Bigonnet, Odile Gayet, Vincent Moutardier, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Olivier Turrini, Marc Giovannini, Aurélie Maignan, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Marc Barthet, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Ezequiel Calvo, Aurélien de Reyniès, Nelson Dusetti, Juan Iovanna.{Authors}. Multi-omics characterization of PDAC subtypes using PDX reveals that epigenetic but not genetic analysis permit a clinically relevant classification. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A48.

The extensive desmoplasia in pancreatic ductal adenocarcinoma (PDAC) has raised major interrogations on its role and function in the carcinogenic process. Patient-derived xenograft (PDX) offers an ideal setting to distinguish and to study the interactions between the cancerous epithelial cells and its stroma. Indeed, sequencing profiles of a mix of cancerous/Human and stroma/Mouse cells can be analyzed separately in silico by unambiguously assigning each sequence to the human or mouse genome. Using RNA sequencing, we profiled 30 pancreatic tumor PDXs and extracted the transcriptome profiles of epithelial cancerous cells as well as their corresponding stroma. On average, 70% of RNA sequencing reads were specifically attributed to a human origin, and therefore an epithelial origin, while 22% of RNA sequencing reads were mouse-specific. Using the rate of mouse sequences as a surrogate of the proportion of non-transformed cells, we observe a high variability in the infiltration level from 7% to 60%. The estimation was also consistent in whole exome sequencing (using the same sequencing process) and with the histological quantification of fibrotic tissue. By specifically analyzing the gene expression in mouse-stromal cells, we show that their transcriptomic profile is consistent with the recent description of human PDAC in situ tumors with high levels of genes of the reported activated-stroma and normal-stroma signatures. We also show that stromal cells over-express genes involved in the SLIT/ROBO axon guidance signalling pathway, in angiogenesis as well as a large number of collagens, cytokines and ligands associated with growth and developmental pathways. Recent studies identified two major subtypes of PDAC from transcriptomic analysis: a well differentiated, often referred as classical, and an undifferentiated, previously recognized as Basal, Quasi-Mesenchymal or Squamous. The stroma characterized in this work broadly reflects this heterogeneity with stromal gene expression signatures predictive of each subtype. For instance, collagens are significantly over-expressed in the stroma of squamous tumors. The concomitant analysis of transcriptomic profiles of both subtypes shows potential cross-talks between cancerous and stromal cells. Particularly in Squamous tumors, genes implicated in the axon-guidance and Wnt pathways are significantly upregulated in both, stroma and transformed cells. On the other hand, the stroma and transformed cells of Classical tumors shows an upregulation of complementary genes associated with several metabolic pathways. Taken together, our transcriptomic analysis reveals that human transformed pancreatic cells determine the composition, quantitatively and qualitatively, of stroma mouse cells in a PDX model. This model also reveals a broad variability of PDAC stromas and highlights potential cross-talks between them through known and novel pathways. Citation Format: Rémy Nicolle, Yuna Blum, Laetitia Marisa, Jonathan Garnier, Benjamin Bian, Celine Loncle, Martin Bigonnet, Odile Gayet, Vincent Moutardier, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Olivier Turrini, Marc Giovannini, Aurélie Maignan, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Marc Barthet, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Ezequiel Calvo, Aurélien de Reyniès, Juan Iovanna, Nelson Dusetti.{Authors}. Pancreatic cancer cell drives stroma composition. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B72.