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Predicting R status before surgery for pancreatic cancer (PDAC) patients with upfront surgery and neoadjuvant therapy.Negative surgical margins (R0) are a key predictor of long-term outcomes in PDAC.Patients undergoing pancreatic resection with curative intent for PDAC were identified. Using the CT scans from the time of diagnosis, the 2019 NCCN borderline resectability criteria were compared to novel criteria: presence of any alteration of the superior mesenteric-portal vein (SMPV) and perivascular stranding of the superior mesenteric artery (SMA). Accuracy of predicting R status was evaluated for both criteria. Patient baseline characteristics, surgical, histopathological parameters, and long-term overall survival (OS) after resection were evaluated.A total of 593 patients undergoing pancreatic resections for PDAC between 2010 and 2018 were identified. Three hundred and twenty-five (54.8%) patients underwent upfront surgery, whereas 268 (45.2%) received neoadjuvant therapy. In upfront resected patients, positive SMA stranding was associated with 56% margin positive resection rates, whereas positive SMA stranding and SMPV alterations together showed a margin positive resection rate of 75%. In contrast to these criteria, the 2019 NCCN borderline criteria failed to predict margin status. In patients undergoing neoadjuvant therapy, only perivascular SMA stranding remained a predictor of margin positive resection, leading to a rate of 33% R+ resections. Perivascular SMA stranding was related to higher clinical T stage (P = 0.003) and clinical N stage (P = 0.043) as well as perineural invasion (P = 0.022). SMA stranding was associated with worse survival in both patients undergoing upfront surgery (36 vs 22 months, P = 0.002) and neoadjuvant therapy (47 vs 34 months, P = 0.050).The novel criteria were accurate predictors of R status in PDAC patients undergoing upfront resection. After neoadjuvant treatment, likelihood of positive resection margins is approximately halved, and only perivascular SMA stranding remained a predictive factor.

Purpose Postoperative pancreatic fistulae (POPF) present a serious and life-threatening complication after pancreatic head resections (PD). Therefore, reliable risk stratification to identify those at risk is urgently needed. The aim of this study was to identify postoperative laboratory parameters for the prediction of POPF in the early postoperative period. Methods One hundred eighty-two patients who underwent PD from 2012 until 2017 were retrospectively analyzed. Multivariate logistic regression was performed using the GLM (general linear model) method for model building. Two nomograms were created based on the GLM models of postoperative day one and postoperative day one to five. A cohort of 48 patients operated between 2018 and 2019 served as internal validation. Results Clinically relevant pancreatic fistulae (CR-POPF) were present in 16% (n = 29) of patients. Patients with CR-POPF experienced significantly more insufficiencies of gastroenterostomies, delayed gastric emptying, and more extraluminal bleeding than patients without CR-POPF. Multivariate analysis revealed multiple postoperative predictive models, the best one including ASA, main pancreatic duct diameter, operation time, and serum lipase as well as leucocytes on day one. This model was able to predict CR-POPF with an accuracy of 90% and an AUC of 0.903. Two nomograms were created for easier use. Conclusion Clinically relevant fistula can be predicted using simple laboratory and clinical parameters. Not serum amylase, but serum lipase is an independent predictor of CR-POPF. Our simple nomograms may help in the identification of patients for early postoperative interventions.

Objectives The postoperative quality of life (QoL) after pancreatic surgery is frequently impaired. The aim of this study was to evaluate the QoL after pancreatic surgery and its influencing risk factors. Furthermore, an age-adjusted comparison with the normal population of Germany was performed. Methods A total of 94 patients were surveyed. The Short Form-36 questionnaire was sent to all patients undergoing pancreatic surgery between 2013 and 2017. All pathologies and types of pancreatic resections were included. Statistical analyses were performed, and an analysis by the Robert Koch-Institute to determine the health-related age-adjusted QoL in Germany served as control group. Results Response rate was 29%. Median time of survey was 28 months. As compared with a normative population, QoL after pancreaticoduodenectomy was significantly impaired. Distal pancreatic resection showed no significant differences. Univariate and Lasso analyses showed that the following factors had a negative impact: coronary artery disease, chronic pancreatitis, and open access. Postoperative enzyme supplementation seemed to have a positive impact. Conclusions Pancreatic surgery leads to long-lasting negative effect on QoL. Distal pancreatic resections and laparoscopic access seemed to be the best tolerated. Complications seems to have less impact, whereas maintaining exocrine and endocrine function seems to have a positive effect.

Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal malignancy characterized by early loco-regional invasion. Portal vein resection (PVR) during pancreatoduodenectomy (PD) for PDAC is performed if tumor cell invasion to the venous wall (PVI) is suspected. The aim of this study is to evaluate radiological criteria for predicting PVR and PVI. Methods Patients undergoing PD for PDAC were identified from a prospectively maintained database. On the basis of CT- and MRI-based imaging portal vein tumor contact (PV), stranding of the superior mesenteric artery (SMA) and any alterations of the superior mesenterico-portal vein (SMPV) were evaluated. The accuracy of PVI and PVR prediction based on the radiological parameters was calculated. Results 143 patients were included in the study. 48 patients underwent PVR (34%), PVI was diagnosed in 23 patients (16%). Median overall survival was 22 months. Prediction of PVR (sensitivity 79%, negative predictive value 88%, p = 0.010) and PVI (sensitivity 95%, negative predictive value 99%, p = 0.002) was most accurate for any SMPV alterations as compared to the other radiological parameters. SMPV alterations qualified as an independent prognostic parameter (26.5 months vs. 33.5months, p = 0.034). Conclusion Radiological evaluation of any SMPV alterations is a simple preoperative method to accurately predict PVI. Assessing SMPV alterations may help to identify candidates for neoadjuvant therapy.

Background Patient-derived xenograft (PDX) mouse models of cancer have been recognized as better mouse models that recapitulate the characteristics of original malignancies including preserved tumor heterogeneity, lineage hierarchy, and tumor microenvironment. However, common challenges of PDX models are the significant time required for tumor expansion, reduced tumor take rates, and higher costs. Here, we describe a fast, simple, and cost-effective method of expanding PDX of pancreatic ductal adenocarcinoma (PDAC) in mice. Methods We used two established frozen PDAC PDX tissues (derived from two different patients) and implanted them subcutaneously into SCID mice. After tissues reached 10–20 mm in diameter, we performed survival surgery on each mouse to harvest 90–95% of subcutaneous PDX (incomplete resection), allowing the remaining 5–10% of PDX to continue growing in the same mouse. Results We expanded three consecutive passages (P1, P2, and P3) of PDX in the same mouse. Comparing the times required for in vivo expansion, P2 and P3 (expanded through incomplete resection) grew 26-60% faster than P1. Moreover, such expanded PDX tissues were successfully implanted orthotopically into mouse pancreases. Within 20 weeks using only 14 mice, we generated sufficient PDX tissue for future implantation of 200 mice. Our histology study confirmed that the morphologies of cancer cells and stromal structures were similar across all three passages of subcutaneous PDX and the orthotopic PDX and were reflective of the original patient tumors. Conclusions Taking advantage of incomplete resection of tumors associated with high local recurrence, we established a fast method of PDAC PDX expansion in mice.

The benefit of adjuvant therapy in ampullary cancer (AMPAC) patients following pancreatoduodenectomy (PD) is debated. The aim of this study was to determine the role of adjuvant therapy after pancreatoduodenectomy (PD) in histological subtypes of AMPAC.Patients undergoing PD for AMPAC at 5 high-volume European surgical centers from 1996 to 2017 were identified. Patient baseline characteristics, surgical and histopathological parameters, and long-term overall survival (OS) after resection were evaluated.214 patients undergoing PD for AMPAC were included. ASA score (ASA1-2 149 vs. ASA 3-4 82 months median OS, p = 0.002), preoperative serum CEA (CEA0.5 ng/ml 128 vs. CEA0.5 ng/ml 62 months, p = 0.013), preoperative serum CA19-9 (CA19-9 40 IU/ml 147 vs. CA19-940IU/ml 111 months, p = 0.042), T stage (T1-2 163 vs. T3-4 98 months, p 0.001), N stage (N0 159 vs. N+ 110 months, p 0.001), grading (G1-2 145 vs. G3-4 113 months, p = 0.026), R status (R0 136 vs. R+ 38 months, p = 0.031), and histological subtype (intestinal subtype 156 vs. PB/M subtype 118 months, p = 0.003) qualified as prognostic parameters. In multivariable analysis, ASA score (HR 1.784, 95%CI 0.997-3.193, p = 0.050) and N stage (HR 1.831, 95%CI 0.904-3.707, p = 0.033) remained independent prognostic factors. In PB/M subtype AMPAC, patients undergoing adjuvant therapy showed an improved median overall survival (adjuvant therapy 85 months vs. no adjuvant therapy 65 months, p = 0.005), and adjuvant therapy remained an independent prognostic parameter in multivariate analysis (HR 0.351, 95%CI 0.151-0.851, p = 0.015). There was no significant benefit of adjuvant therapy in intestinal subtype AMPAC patients.Adjuvant treatment seems indicated in pancreatobiliary or mixed type AMPAC.

Whether the presence of bacteria in the bile or postoperative infections sustained by microorganisms with different levels of drug-resistance are associated with changes in the oncologic prognosis of patients undergoing surgery for pancreatic cancer has not been thoroughly investigated. The aim was to study the association of bile contamination, postoperative infections, and multi-level resistance with long-term outcome.Prospectively maintained databases were queried for patients who underwent pancreatoduodenectomy (PD). Patients who underwent preoperative biliary stenting prior to PD and an intraoperative bile culture were included. The levels of bacterial resistance of intraoperative bile cultures and of specimens of postoperative infections were stratified into multidrug sensitive (MDS), multidrug-resistant (MDR), and extensive drug-resistant (XDR).A total of 267 patients met the inclusion criteria. The Kaplan-Meier survival curves for overall survival (OS) of patients having no bacteriobilia or positive cultures with MDS versus MDR/XDR bacteria were not statistically different (log-rank=0.9). OS of patients stratified for no postoperative infection or infections by MDS was significantly better than those having MRD/XDR isolates (log-rank=0.04). A Cox multivariate model showed that having MRD/XDR postoperative infections was and independent variable for worse OS (HR=1.227; 95%CI=1.189-1.1918; p=0.036).Postoperative drug resistant infections are a significant risk factor for poor OS after pancreatoduodenectomy for ductal adenocarcinoma.

To describe PNI and to evaluate its impact on disease-free (DFS) and overall survival (OS) in patients with resected pancreatic ductal adenocarcinoma (PDAC).Although PNI is a prognostic factor for survival in many GI cancers, there is limited knowledge regarding its impact on tumor recurrence, especially in ''early stage disease'' (PDAC ≤20 mm, R0/ N0 PDAC).This multicenter retrospective study included patients undergoing PDAC resection between 2009 and 2014. The association of PNI with DFS and OS was analyzed using Cox proportional-hazards models.PNI was found in 87% of 778 patients included in the study, with lower rates in PDAC ≤20 mm (78.7%) and in R0/N0 tumors (70.6%). PNI rate did not differ between patients who underwent neoadjuvant therapy and upfront surgery (88% vs 84%, P = 0.08). Although not significant at multivariate analysis ( P = 0.07), patients with PNI had worse DFS at univariate analysis (median DFS: 20 vs 15 months, P0.01). PNI was the only independent predictor of DFS in R0/N0 tumors (hazard ratio [HR]: 2.2) and in PDAC ≤ 20 mm (HR: 1.8). PNI was an independent predictor of OS in the entire cohort (27 vs 50 months, P = 0.01), together with G3 tumors, pN1 status, carbohydrate antigen (CA) 19.937 and pain.PNI represents a major determinant of tumor recurrence and patients' survival in pancreatic cancer. The role of PNI is particularly relevant in early stages, supporting the hypothesis that invasion of nerves by cancer cells has a driving role in pancreatic cancer progression.

Background: Evidence on the optimal pancreatic anastomosis during pancreatoduodenectomy is inconclusive. Large multicenter and nationwide registries may provide additional insights. The study compared the practice and outcome of different pancreatic anastomoses during pancreatoduodenectomy, focusing on the rate of postoperative pancreatic fistula, in two large audits of pancreatic surgery.Methods: Posthoc analysis of patients after pancreatoduodenectomy in the Dutch Pancreatic Cancer Audit and the German DGAV StuDoQ vertical bar Pancreas registries (January 2014 to December 2017). Postoperative pancreatic fistula (International Study Group of Pancreatic Surgery B/C), postpancreatectomy hemorrhage (International Study Group of Pancreatic Surgery B/C) and Clavien-Dindo >= 3 complications rates were compared for the three most common anastomoses: duct-to-mucosa pancreatojejunostomy, non-duct-to-mucosa pancreatojejunostomy, and non-duct-to-mucosa pancreatogastrostomy. Multivariable adjustment for potential confounders was performed.Results: Overall, 6,149 patients were included. The most common anastomosis was duct-to-mucosa pancreatojejunostomy (duct-to-mucosa pancreatojejunostomy 59.8%, non-duct-to-mucosa pancreatojejunostomy 21.1%, non-duct-to-mucosa pancreatogastrostomy 12.4%). The overall postoperative pancreatic fistula rate was 14%: duct-to-mucosa pancreatojejunostomy 12.9%, non-duct-to-mucosa pancreatojejunostomy 14.4% (P = .162), non-duct-to-mucosa pancreatogastrostomy 18.3% (P < .001). The rate of postpancreatectomy hemorrhage was the lowest after duct-to-mucosa pancreatojejunostomy: duct-to-mucosa pancreatojejunostomy 6.9%, non-duct-to-mucosa pancreatojejunostomy 10% (P < .001), non-duct-to-mucosa pancreatogastrostomy 17.9% (P < .001). The rate of Clavien-Dindo >= 3 complications was the lowest after duct-to-mucosa pancreatojejunostomy: duct-to-mucosa pancreatojejunostomy 28%, non-duct-to-mucosa pancreatojejunostomy 32.7% (P = .002), non-duct-to-mucosa pancreatogastrostomy 43.1% (P < .001). In the multivariable analysis, the risk of postoperative pancreatic fistula did not differ significantly between the three anastomoses. The risk of hemorrhage (odds ratio 2.4, 95% confidence interval 1.6-3.5, P < .001) and Clavien-Dindo >= 3 (odds ratio 1.6, 95% confidence interval 1.2-2.1, P = .001) remained significantly higher only for non-duct-to-mucosa pancreatogastrostomy.Conclusion: Data from two national audits showed no difference in the risk-adjusted postoperative pancreatic fistula rate among the three most used pancreatic anastomoses during pancreatoduodenectomy. Pancreatogastrostomy was inferior to pancreatojejunostomy regarding bleeding and overall major complications. (C) 2021 Elsevier Inc. All rights reserved.

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.SignificancePancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with no effective therapies. PDA aggressiveness partly stems from its ability to grow within a uniquely dense stroma restricting nutrient access. This study demonstrates that PDA clones that survive chronic nutrient deprivation acquire reversible non-genetic adaptations allowing them to switch between metabolic states optimal for growth under nutrient-replete or nutrient-deprived conditions. One contributing factor to this adaptation mTORC1 activation, which stabilizes glutamine synthetase (GS) necessary for glutamine generation in nutrient-deprived cancer cells. Our findings imply that although total GS levels may not be a prognostic marker for aggressive disease, GS inhibition is of high therapeutic value, as it targets specific cell clusters adapted to nutrient starvation, thus mitigating tumor growth.

Realistic preclinical models of primary pancreatic cancer and metastasis are urgently needed to test the therapy response ex vivo and facilitate personalized patient treatment. However, the absence of tumor-specific microenvironment in currently used models, e.g., patient-derived cell lines and xenografts, only allows limited predictive insights. Organotypic slice cultures (OTSCs) comprise intact multicellular tissue, which can be rapidly used for the spatially resolved drug response testing. This protocol describes the generation and cultivation of viable tumor slices of pancreatic cancer and its metastasis. Briefly, tissue is casted in low melt agarose and stored in cold isotonic buffer. Next, tissue slices of 300 µm thickness are generated with a vibratome. After preparation, slices are cultured at an air-liquid interface using cell culture inserts and an appropriate cultivation medium. During cultivation, changes in cell differentiation and viability can be monitored. Additionally, this technique enables the application of treatment to viable human tumor tissue ex vivo and subsequent downstream analyses, such as transcriptome and proteome profiling. OTSCs provide a unique opportunity to test the individual treatment response ex vivo and identify individual transcriptomic and proteomic profiles associated with the respective response of distinct slices of a tumor. OTSCs can be further explored to identify therapeutic strategies to personalize treatment of primary pancreatic cancer and metastasis.

Background Postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) can be associated with severe postoperative morbidity. This study aims to develop a preoperative POPF risk calculator that can be easily implemented in clinical routine. Methods Patients undergoing PD were identified from a prospectively-maintained database. A total of 11 preoperative baseline and CT-based radiological parameters were used in a binominal logistic regression model. Parameters remaining predictive for grade B/C POPF were entered into the risk calculator and diagnostic accuracy measures and ROC curves were calculated for a training and a test patient cohort. The risk calculator was transformed into a simple nomogram. Results A total of 242 patients undergoing PD in the period from 2012 to 2018 were included. CT-imaging-based maximum main pancreatic duct (MPD) diameter (p = 0.047), CT-imaging-based pancreatic gland diameter at the anticipated resection margin (p = 0.002) and gender (p = 0.058) were the parameters most predictive for grade B/C POPF. Based on these parameters, a risk calculator was developed to identify patients at high risk of developing grade B/C POPF. In a training cohort of PD patients this risk calculator was associated with an AUC of 0.808 (95%CI 0.726–0.874) and an AUC of 0.756 (95%CI 0.669-0-830) in the independent test cohort. A nomogram applicable as a visual risk scale for quick assessment of POPF grade B/C risk was developed. Conclusion The preoperative POPF risk calculator provides a simple tool to stratify patients planned for PD according to the risk of developing postoperative grade B/C POPF. The nomogram visual risk scale can be easily integrated into clinical routine and may be a valuable model to select patients for POPF-preventive therapy or as a stratification tool for clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer–stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. In vitro cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer–CAF cross-talk. Disrupting this cross-talk in vivo resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival. Implications: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor–stroma cross-talk as a potential therapeutic avenue.

In view of the limited capacities in intensive care units and the increasing economic burden, identification of risk factors could allow better and more efficient planning. Therefore, the aim of this study was to assess independent risk factors for the duration of intensive care unit stay after pancreatoduodenectomy (PD).147 patients who underwent pancreatoduodenectomy in the time period from 2013 to 2015 were identified from a prospective database and a retrospective analysis was performed. The primary endpoint was length of time spent in the ICU. A retrograde analysis was performed using univariate and multivariate regression analysis. All pre-, intra- and postoperative parameters were considered in the analysis.The median time spent in the intensive care unit (ICU) is one day. The univariate analysis demonstrated increased pack years, cerebrovascular events, anticoagulation, elevated creatinine and CA 19-9 as preoperative risk factors. In multivariate analysis, antihypertensive medication (AHT; OR 2.46; 95% CI 1.57 - 3.87; p = 0.05), operation time (OR 1.01; 95% CI 1.00 - 1.01; p = 0.03), extended LAD (OR 5.46; 95% CI 2.77 - 10.75; p = 0.01) and severe PPH (OR 4.01; 95% CI 2.07 - 7.76; p = 0.04) are significant risk factors for longer ICU stay.Patients with cardiovascular risk factors and elevated preoperative creatinine level are at greater risk for a prolonged ICU stay. Risk and benefit of an extended LAD should be weighed during the operation. Median duration on ICU/IMC after PD is one day or less for patients without risk factors. Whether routine monitoring in the ICU/IMC after PD is necessary must be clarified in further studies.Angesichts der begrenzten intensivmedizinischen Kapazitäten und der zunehmenden wirtschaftlichen Belastung könnte die Ermittlung von Risikofaktoren für intensivmedizinische Nachbetreuung eine bessere und effizientere Planung ermöglichen. Ziel dieser Studie war es daher, unabhängige Risikofaktoren für die Dauer des Aufenthaltes auf der Intensivstation nach der Pankreatoduodenektomie (PD) zu ermitteln.147 Patienten, die sich im Zeitraum 2013 – 2015 einer PD unterzogen hatten, wurden aus einer prospektiven Datenbank identifiziert und eine retrospektive Analyse wurde durchgeführt. Der primäre Endpunkt war die Dauer der Zeit, die auf der Intensivstation verbracht wurde. Eine uni- und multivariate Regressionsanalyse wurden durchgeführt, um prä-, intra- und postoperative Risikofaktoren zu ermitteln. Alle erhobenen prä-, intra- und postoperativen Parameter wurden in der Analyse berücksichtigt.Die durchschnittliche Liegezeit auf der Intensivstation nach PD beträgt 1 Tag. Die univariate Analyse zeigte bei den präoperativen Risikofaktoren vermehrte Pack Years, zerebrovaskuläre Ereignisse, Antikoagulation, erhöhtes Kreatinin und CA 19-9 als präoperative Risikofaktoren. In der multivariaten Analyse waren antihypertensive Medikamente (OR 2,46; 95%-KI 1,57 – 3,87; p = 0,05), Operationszeit (OR 1,01; 95%-KI 1,00 – 1,01; p = 0,03), erweiterte Lymphadenektomie (OR 5,46; 95%-KI 2,77 – 10,75; p = 0,01) und die schwere pankreasspezifische Nachblutung (PPH Grad B/C; OR 4,01; 95%-KI 2,07 – 7,76; p = 0,04) signifikante Risikofaktoren für einen verlängerten Intensivaufenthalt.Patienten mit kardiovaskulären Risikofaktoren und erhöhten präoperativen Kreatininwerten haben ein höheres Risiko für einen längeren Aufenthalt auf der Intensivstation. Risiko und Nutzen einer erweiterten Lymphadenektomie sollten während der Operation abgewogen werden. Patienten ohne Risikofaktoren liegen im Median ≤ 1 Tag auf der ITS/IMC. Ob daher eine routinemäßige Überwachung auf der ITS/IMC nach PD nötig ist, muss in weiteren Studien geklärt werden.

OBJECTIVE Our aim was to evaluate recurrence patterns of surgically resected PDAC patients with negative (pN0) or positive (pN1) lymph nodes. SUMMARY BACKGROUND DATA Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer death by 2030. This is mostly due to early local and distant metastasis, even after surgical resection. Knowledge about patterns of recurrence in different patient populations could offer new therapeutic avenues. METHODS Clinicopathologic data were collected for 546 patients who underwent resection of their PDAC between 2005 and 2016 from 2 tertiary university centers. Patients were divided into an upfront resection group (n = 394) and a neoadjuvant group (n = 152). RESULTS Tumor recurrence was significantly less common in pN0 patients as compared with pN1 patients, (upfront surgery: 55% vs. 77%, P < 0.001 and 64% vs. 78%, P = 0.040 in the neoadjuvant group). In addition, time to recurrence was significantly longer in pN0 versus pN1 patients in the upfront resected patients (median 16 mo pN0 vs. 10 mo pN1 P < 0.001), and the neoadjuvant group (pN0 21 mo vs. 11 mo pN1, P < 0.001). Of the patients who recurred, 62% presented with distant metastases (63% of pN0 and 62% of pN1, P = 0.553), 24% with local disease (27% of pN0 and 23% of pN1, P = 0.672) and 14% with synchronous local and distant disease (10% of pN0 and 15% of pN1, P = 0.292). Similarly, there was no difference in recurrence patterns between pN0 and pN1 in the neoadjuvant group, in which 68% recurred with distant metastases (76% of pN0 and 64% of pN1, P = 0.326) and 18% recurred with local disease (pN0: 22% and pN1: 15%, P = 0.435). CONCLUSION Time to recurrence was significantly longer for pN0 patients. However, patterns of recurrence for pN0 vs. pN1 patients were identical. Lymph node status was predictive of time to recurrence, but not location of recurrence.

Laparoscopic pancreatoduodenectomy is a highly challenging procedure. The aim of this study was to analyse post-operative morbidity and mortality as well as long term overall survival in patients undergoing hybrid LPD, as compared to open pancreaticoduodenecomy (OPD) in a single surgeon series.Patients undergoing pancreatoduodenectomy (PD) in the period from 2000 to 2015 were identified from a prospectively maintained database. All LPD procedures were performed by one specialised pancreatic surgeon (TK). Patients were matched 1 : 1 for age, sex, BMI, ASA, histological diagnosis, pancreatic texture and portal venous resection (PVR). All LPD procedures were performed as hybrid LPD - combining laparoscopic resection and open reconstruction via mini laparotomy.A total of 549 patients were identified, including 489 patients in the OPD group and 60 patients in the LPD group. 60 patients were identified who underwent LPD between 2010 and 2015 versus 60 OPD patients operated in the same period. Median overall operation time was shorter in the LPD group than with OPD patients (LPD 352 vs. OPD 397 min; p = 0.002). Overall transfusion units were lower in the LPD group (LPD range 0 - 4 vs. OPD range 0 - 11; p = 0.032). Intensive care unit stay (LPD 1 vs. OPD 6 d; p = 0.008) and overall hospital stay (OHS: LPD 14 vs. OPD 18 d; p = 0.012) were shorter in the LPD groups than in the OPD group. As regards postoperative complications, LPD was associated with reduced rates of clinically relevant grade B/C postoperative pancreatic fistula (LPD 15 vs. OPD 36%; p = 0.036) and grade B/C delayed gastric emptying (LPD 8 vs. OPD 20%; p = 0.049). A total of 56 patients were diagnosed with malignant disease. The number of harvested lymph nodes and R0-resection rates were equal for LPD and OPD patients. LPD patients showed a trend to improved median overall survival (LPD mean 56 months vs. OPD mean 48 months; p = 0.056).Hybrid LPD is a safe procedure associated with a reduction in clinically relevant postoperative complications and allows faster recovery. Long term oncological outcome of hybrid LPD for malignant disease is equal to that with the standard open approach.Ziel dieser Studie war es, die postoperative Morbidität und Mortalität sowie Langzeit-Gesamtüberlebensraten bei Patienten nach laparoskopischer Pankreatoduodenektomie (LPD) in Hybridtechnik im Vergleich zur offenen Pankreatoduodenektomie (OPD) anhand der Serie eines LPD-spezialisierten Pankreaschirurgen zu analysieren.Daten von Patienten, die im Zeitraum 2000 – 2015 eine Pankreatoduodenektomie (PD) erhalten haben, wurden einer prospektiv geführten Datenbank entnommen. Alle LPD-Resektionen wurden von einem Chirurgen (TK) durchgeführt. Es erfolgte ein 1 : 1 Matching der Patienten anhand der Parameter Alter, Geschlecht, BMI, ASA, Histologie, Textur des Pankreasparenchyms und Durchführung einer Pfortaderresektion. Alle LPD-Resektionen wurden in Hybridtechnik mit laparoskopischer Resektion und anschließender Rekonstruktion mittels Minilaparotomie durchgeführt.Insgesamt konnten 549 Patienten anhand der Datenbank identifiziert werden, 489 Patienten in der OPD-Gruppe und 60 Patienten in der LPD-Gruppe. 60 LPD-Patienten aus dem Zeitraum 2010 – 2015 und 60 OPD-Patienten aus dem Zeitraum 2000 – 2015 wurden in die Studie eingeschlossen. Die mediane Operationszeit in der LPD-Gruppe war verkürzt im Vergleich zur OPD-Gruppe (LPD 352 vs. OPD 397 min; p = 0,002). Die Anzahl perioperativ benötigter Erythrozytenkonzentrate war geringer in der LPD-Gruppe (LPD 0 – 4 vs. OPD 0 – 11; p = 0,032). Die mediane Dauer der intensivmedizinischen Therapie (LPD 1 vs. OPD 6 d; p = 0,008) und die mediane Gesamtdauer des Krankenhausaufenthalts (LPD 14 vs. OPD 18 d; p = 0,012) waren kürzer in der LPD-Gruppe im Vergleich zur offenen Resektion. Die LPD war mit einer geringeren Rate klinisch relevanter Grad-B/C-Pankreasfisteln (LPD 15 vs. OPD 36%; p = 0,036) und verzögerter Magenentleerung Grad B/C assoziiert (LPD 8 vs. OPD 20%; p = 0,049). 56 der eingeschlossenen Patienten wiesen eine maligne Raumforderung auf. Die Anzahl resezierter Lymphknoten und die Rate an R0-Resektionen waren vergleichbar in der LPD- und der OPD-Gruppe. Bei LPD-Patienten zeigte sich der Trend einer verbesserten medianen Gesamtüberlebensrate (LPD 56 vs. OPD 48 Monate; p = 0,056).Die LPD in Hybridtechnik ist eine sichere Technik, die mit der Reduktion klinisch relevanter postoperativer Komplikationen assoziiert ist und eine schnelle postoperative Erholung erlaubt. Die onkologischen Langzeitergebnisse nach LPD in Hybridtechnik bei malignen Befunden sind gleichwertig zur offenen Technik.

Surgically assessed pancreatic texture has been identified as the strongest predictor of postoperative pancreatic fistula. However, texture is a subjective parameter with no proven reliability or validity. Therefore, a more objective parameter is needed. In this study, we evaluated the fibrosis level at the pancreatic neck resection margin and correlated fibrosis and all clinico-pathologic parameters collected over the course of the Pancreatogastrostomy vs Pancreatojejunostomy for RECOnstruction (RECOPANC) study.The RECOPANC trial was a multicenter randomized prospective trial of patients undergoing pancreatoduodenectomy. There were 261 hematoxylin and eosin-stained slides allocated for histopathologic analyses. Pancreatic fibrosis was scored from 0 to III (no fibrosis up to severe fibrosis) by 2 blinded independent pathologists. All variables possibly associated with POPF were entered into a generalized linear model for multivariable analysis.The fibrosis grade and pancreatic texture were scored in all 261 patients. In POPF B/C (postoperative pancreatic fistula grade B or C) patients, 71% had a soft pancreas, and fibrosis grades were distributed as follows: 48% with score 0, 28% with score I, 20% with score II, and 7% with score III, respectively. Fibrosis grading showed substantial inter-rater reliability (kappa = 0.74) and correlated positively with hard pancreatic texture (p0.05). In univariable analysis, area under the curve (AUC) for POPF B/C prediction was higher for fibrosis grade than for pancreatic texture (0.71 vs 0.59). In multivariate analysis, the following predictors were selected: sex, surgeon volume, pancreatic texture, and fibrosis grade. However, the addition of pancreatic texture only led to an incremental improvement (AUC 0.794 vs 0.819).Histologically evaluated pancreatic fibrosis is an easily applicable and highly reproducible POPF predictor and superior to surgically evaluated pancreatic texture. Future studies might use fibrosis grade for risk stratification in pancreatoduodenectomy.

Background: Biliary stenting leads to antimicrobial-resistant (AMR) microorganism retrievement in bile cultures. However, the impact of intraoperative bile colonizations on post-pancreaticoduodenectomy complications remains unclear. Aims of our study were to characterize the bile flora of stented patients in comparison with postoperative cultures and to analyze whether patterns of drug resistance affected postoperative outcomes. Methods: We analyzed records from stent-bearing pancreaticoduodenectomy patients at 3 European centers. Intra- and postoperative cultures were compared and classified as multidrug sensitive (MDS), multidrug resistant (MDR), and extensively drug resistant (XDR). Thirty-day complications were graded according to international standards. Results: Out of 270 patients, intraoperative cultures were positive in 219 (81.1%) cases. In 36.7%, MDS species were isolated; in 35.9%, MDR; and in 8.5%, XDR species. A solid correspondence between the species isolated intra- and postoperatively (p< 0.001) was observed. Intraoperative MDR/XDR isolation was associated with an increased rate of surgical (p= 0.043) and infectious complications (p= 0.030), but not severe complication rate (p = 0.973). Postoperative MDR/XDR isolation was associated with higher risk of major complications (45.6% vs. 15.8%, p< 0.001), postoperative pancreatic fistula (p< 0.001), and post-pancreatectomy hemorrhage (p= 0.002). By multivariate analysis, intraoperative AMR isolation was associated with high likelihood of postoperative AMR infections. However, only in 43/121 cases, intraoperative MDR/XDR microorganisms turned into the occurrence of postoperative infections. Conclusion: Intraoperative AMR isolates do not translate into severe outcomes, despite being significantly associated with surgical and infectious complications.

Pancreatic cancer is one of the most aggressive cancers with a 5-year patient survival rate of 8.2% and limited availability of therapeutic agents to target metastatic disease. Pancreatic cancer is characterized by a dense stromal cell population with unknown contribution to the progression or suppression of tumor growth. In this study, we describe a microengineered tumor stromal assay of patient-derived pancreatic cancer cells to study the heterotypic interactions of patient pancreatic cancer cells with different types of stromal fibroblasts under basal and drug-treated conditions. The population dynamics of tumor cells in terms of migration and viability were visualized as a functional end point. Coculture with cancer-associated fibroblasts increased the migration of cancer cells when compared to dermal fibroblasts. Finally, we imaged the response of a bromodomain and extraterminal inhibitor on the viability of pancreatic cancer clusters surrounding by stroma in microengineered tumor stromal assay. We visualized a codynamic reduction in both cancer and stromal cells with bromodomain and extraterminal treatment compared to the dimethyl sulfoxide-treated group. This study demonstrates the ability to engineer tumor–stromal assays with patient-derived cells, study the role of diverse types of stromal cells on cancer progression, and precisely visualize a coculture during the screening of therapeutic compounds.

IMPORTANCE: Sarcopenia and sarcopenic obesity have been associated with poor outcomes in unresectable pancreatic cancer (PC). Neoadjuvant treatment (NT) is used increasingly to improve resectability; however, its effects on fat and muscle body composition have not been characterized. OBJECTIVES: To evaluate whether NT affects muscle mass and adipose tissue in patients with borderline resectable PC (BRPC) and locally advanced PC (LAPC) and determine whether there were potential differences between patients who ultimately underwent resection and those who did not. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study conducted at 4 academic medical centers, 193 patients with BRPC and LAPC undergoing surgical exploration after NT who had available computed tomographic scans (both at diagnosis and preoperatively) and confirmed pancreatic ductal adenocarcinoma were evaluated. The study was conducted from January 2013 to December 2015. Data analysis was performed from September 2016 to May 2017. Measurement of body compartments was evaluated with volume assessment software before and after NT. A radiologist blinded to the patient outcome assessed the areas of skeletal muscle, total adipose tissue, and visceral adipose tissue through a standardized protocol. EXPOSURES: Receipt of NT. MAIN OUTCOMES AND MEASURES: Achievement of pancreatic resection at surgical exploration after the receipt of NT. RESULTS: Of the 193 patients with complete radiologic imaging available after NT, 96 (49.7%) were women; mean (SD) age at diagnosis was 64 (11) years. Most patients received combined therapy with fluorouracil, irinotecan, oxaliplatin, leucovorin, and folic acid (124 [64.2%]) and 86 (44.6%) received chemoradiotherapy as well. The median interval between pre-NT and post-NT imaging was 6 months (interquartile range [IQR], 4-7 months). All body compartments significantly changed. The adipose compound decreased (median total adipose tissue area from 284.0 cm(2); IQR, 171.0-414.0 to 250.0 cm(2); IQR, 139.0-363.0; P

The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients.Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging.Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected.Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR: 49%, LA: 51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9100 U/mL and8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index1, preoperative CA 19-9100 U/mL and tumor size (3.0 cm on CT or2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS: 29.1 vs 13.7, P0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01).BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.

The incidence of cystic neoplasms of the pancreas (CNP) is steadily increasing, most likely due to the commonly increased use of cross-sectional abdominal imaging. Most of these lesions are benign at the time of initial presentation, but some harbor malignant potential that either requires constant surveillance or surgical resection. However, it is still unclear when resection is mandated and when observation is sufficient. Moreover, the extent of resection and the technique used are also a matter of debate since limited resection and minimally invasive procedures are becoming more popular. Therefore, the aim of this review was to assess the role of surgery for the management of CNPs with an emphasis on novel procedures.

Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (

The purpose of this study is to evaluate long-term mortality and quality of life (QoL) of intensive care patients with pneumonia and/or sepsis 1 year after discharge and to identify potential predictors for these outcome measures.This retrospective cohort study analyzed all patients admitted to the intensive care unit (ICU) of a German university hospital with diagnosis of pneumonia and/or sepsis between 2008 and 2009. Quality of life was assessed by telephone interview or mail using the standardized EuroQol 5-dimension questionaire.Of 1406 patients treated in the ICU within the observational period, 217 met the inclusion criteria. Whereas in-hospital mortality differed significantly between pneumonia (17%) and sepsis (46%) (P.001), 1-year mortality was not statistically significant (51% and 65%, P = .057). A high Simplified Acute Physiology Score (SAPS) II value was associated with high in-hospital mortality but failed to predict 1-year mortality. Quality of life, measured 1 year after discharge by visual analog scale (VAS), was 50% ± 25%, which was significantly lower than in a matched control group (70% ± 20%; P.001). A high SAPS II score on admission did not correlate with VAS but was an independent predictor of a low EuroQol 5-dimension index.The high post-ICU mortality of patients with pneumonia and sepsis emphasizes the need to focus on long-term follow-up in ICU studies and demonstrates that even when sepsis signs are missing, critically ill patients due to pneumonia have high 1-year mortality. Simplified Acute Physiology Score II does not predict long-term mortality, but a low SAPS II on admission might be useful to identify patients with good physical status after 1 year.Hospital mortality of patients treated for pneumonia and/or sepsis is high and increases significantly within the first year after discharge. The SAPS II predicts in-hospital mortality and the physical components of QoL but not long-term mortality.One-year mortality of ICU pneumonia patients is equally high as in sepsis patients. Simplified Acute Physiology Score II cannot predict long-term mortality but can predict QoL.