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Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3–5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.

The impact of neoadjuvant chemotherapy on tumor cells is largely unknown with resistance to therapy remaining a significant challenge. We analyzed 171 chemo-naïve and post-chemotherapy resected patient samples (chemoradiotherapy excluded) using RNAseq and multiplexed immunofluorescence. Neoadjuvant chemotherapy enriched for distinct neoplastic persister phenotypes expressing Classical and Basal-like biomarkers GATA6 and KRT17. The enrichment of GATA6HiClassical-like and KRT17Hi Basal-like cells in post-chemotherapy patient samples was associated with poor survival after mFOLFIRINOX, but not gemcitabine. CYP3A subfamily enzymes (CYP3A4 and CYP3A5) were expressed in GATA6Hi and KRT17Hi persister cells and can degrade mFOLFIRINOX constituent irinotecan. Taken together these data support a model in which pre-existing subpopulations of GATA6Hi (Classical) and/or KRT17Hi (Basal) neoplastic cells emerge after mFOLFIRINOX treatment by expressing CYP3A. The identification of CYP3A-enabled persister cell phenotypes is an important step in the design of effective therapies to overcome drug-tolerance and prevent recurrence after neoadjuvant therapy. Citation Format: Xu Zhou, Roma Kurilov, John P. Neoptolemos, Benedikt Brors, Kai Hu, Teresa Peccerella, Jing-Yu An, Stephanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Ulrike Heger, Oliver Strobel, Simon T Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus Büchler, Thilo Hackert, Franco Fortunato, Peter Bailey. Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A010.

Tumor-associated autoreactive antibodies could represent a moderately sensitive but highly specific type of biomarker. While autoantibodies in the blood of patients with pancreatic cancer have been reported, the consensus among studies is low and data validation is lacking. We profiled the abundance of circulating autoantibodies in patients with pancreatic ductal adenocarcinoma (PDAC) in a multi-step approach. For this purpose, microarrays with in situ expressed proteins were produced that contained 3060 non-mutated human proteins; one emphasis was on cell surface proteins. The microarrays were utilized for autoantibody screening of sera collected from patients of PDAC stages I, IIA, IIB/III and IV. In addition, samples were studied that represented the different grades of the precursor lesion intraductal pupillary mucinous neoplasm (IPMN) – low-grade, high-grade dysplasia and IPMN with associated carcinoma. Third, sera from patients diseased with the PDAC risk factor chronic pancreatitis (CP) as well as healthy donors served as control groups. The analysis revealed a significant increase in the overall proportion of immunoreactive proteins in late grades of IPMN and stages of PDAC; within each group, some sera displayed higher reactivity than others. The screening phase led to the identification of about 100 proteins, which showed a relatively high immunoreactivity associated with PDAC in comparison to an age- and sex-matched healthy control group. The characteristics of PDAC-associated autoantibodies were confirmed for the 100 proteins by analyzing sera from a total of 1200 PDAC, IPMN and CP patients as well as healthy donors. The patient groups were age- and sex-matched among each other. This confirmation phase validated the PDAC-related immunoreactivity of 17 proteins, showing high specificity of samples from PDAC patients in comparison to the healthy control group but low sensitivity of less than 10%. The clinically defined PDAC stages displayed different autoantibody profiles. However, no stage-related autoantibodies could be identified. Further, these PDAC-related antigens were also immunoreactive in smaller proportions of CP and IPMN patients, demonstrating the biological relation between PDAC and its precursors CP and IPMN. The majority of the other antigens showed a high immunoreactivity without correlation of autoantibody abundance and PDAC diagnosis, highlighting the importance of validation in large cohorts. The presence of autoantibodies specific for the 17 identified PDAC-related proteins is currently technically cross-validated by Luminex multiplex serology. In conclusion, the study has identified novel PDAC-related autoantibodies towards non-modified human proteins. While the specificity of some detected autoantibodies was high, the low sensitivity and the immunoreactivity of related precursor lesions make the definition of a broad applicable biomarker panel unlikely or too complex. However, the antigens that are specific for PDAC indicate target molecules, which could offer new therapeutic options in a personalized approach. Citation Format: Henning Boekhoff, Laura Hendricks, Elena Cairo, Andrea Bauer, Mari Hambardzumyan, Markus W. Büchler, Silvia Calderazzo, Vivienn Weru, Anette Kopp-Schneider, Hermann Brenner, Thilo Hackert, Oliver Strobel, Tim Waterboer, Nathalia Giese, Joerg D. Hoheisel. Profiling of circulating autoreactive antibodies in some 1200 patients with pancreatic ductal adenocarcinoma and progressive precursor lesions [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A035.

____________________________________________________________________________________________ABSTRAC Background - The incidence of Grade C postoperative pancreatic fistula ranges from 2 to 11% depending on the type of pancreatic resection. This complication may frequently require early relaparotomy and the surgical approach remains technically challenging and is still associated with a high mortality. Infectious complications and post-operative hemorrhage are the two most common causes of reoperation. Summary - The best management of grade C pancreatic fistulas remains controversial and ranges from conservative approaches up to completion pancreatectomy. The choice of the technique depends on the patient’s conditions, intraoperative findings, and surgeon’s discretion. A pancreas-preserving strategy appears to be attractive, including from simple to more complex procedures such as debridement and drainage, and external wirsungostomy. Completion pancreatectomy should be reserved for selected cases, including stable patients with severe infection complication or hemorrhage after pancreatic fistula who do not respond to pancreas-preserving procedures. Key Messages - This review describes the current options for management of grade C pancreatic fistula after pancreatoduodenectomy with regard to indication, choice of procedure and outcomes of the different approaches.

In the treatment of pancreatic ductal adenocarcinoma (PDAC) the best chance at long term survival or cure has to date always included the complete surgical removal of the tumor. However, locally advanced pancreatic cancer (LAPC), about 25% of all newly diagnosed PDAC, is defined by its primary technical unresectability due to infiltration of visceral arteries and absence of metastasis. Induction therapies, especially FOLFIRINOX treatment, together with technical surgical advancement have increased the numbers for conversion to secondary resectability. Recent data on resections after induction therapy show promising, almost doubled survival compared to palliative treatment. Yet, around 70% of LAPC remain unresectable after induction therapy, often due to persistent local invasion. As locally ablative techniques are becoming more widely available this review examines their possible applicability to substitute for surgery in these cases which we propose to group under the new term "Inconvertible LAPC". The need for defining this novel subgroup who might benefit from ablative treatment is based on the findings in our review that high-level evidence on ablative techniques for PDAC is largely lacking and the latest effective, harmonized treatment guidelines for LAPC are not often incorporated in these studies. The "inconvertible LAPC" label requires persistent unresectability after staging and induction therapy of LAPC according to current guidelines followed by liberal indication for aggressive surgical exploration at a center equipped for extended pancreatic resections. Ideally, this specification of a new, distinct patient group will also put it in the spotlight more, hopefully prompt more trials designed to generate robust evidence and optimize transferability of study results.

Pancreatic ductal adenocarcinoma (PDAC) is an oligosymptomatic disease, that is usually diagnosed in an advanced tumor stage. Traditionally, only the small subset of patients with tumors that showed no signs of vascular infiltration and distant metastases proceeded to surgery-still the only curative therapeutic modality to date. The remaining majority of patients received palliative chemotherapy or chemoradiation, usually with gemcitabine monotherapy. While gemcitabine monotherapy results in improved survival compared to best supportive care, most patients still succumb to the disease under therapy in a relatively short amount of time. Over the last years and decades, paradigms have shifted in PDAC treatment and potent multidrug chemotherapy protocols, including gemcitabine plus nab-paclitaxel and FOLFIRINOX, result in sufficient downstaging of advanced tumors in many patients. In this context, more and more patients are eligible for exploration and often resection. In this review we discuss the current state of the art in the clinical management and surgical treatment of patients with locally advanced pancreatic cancer, including classifications of locally advanced and borderline disease and surgical strategies for extended resections. An emphasis is put on arterial and venous resections and their outcome. In the end, we discuss current gaps in the literature and propose directions future research endeavors should focus on.

Background The d evelopment of surgical techniques and specialization and specifically complication management in pancreatic surgery have improved surgical outcomes as well as oncological results in pancreatic surgery in recent decades. Historical morbidity and especially mortality rates of up to 80% have decreased to below 5% today. This review summarizes the current state of the art in pancreatic cancer surgery. Methods The present literature and clinical experience are summarized to give an overview of the present best practice in pancreatic surgery as one of the most advanced surgical disciplines today. Results Based on the available literature, three important aspects contribute to best patient care in pancreatic surgery, namely, surgical progress, interdisciplinary complication management, and multimodal oncological treatment in case of pancreatic cancer. In addition, minimally invasive and robotic procedures are currently fields of development and specific topics of research. Conclusion In experienced hands, pancreatic surgery—despite being one of the most challenging fields of surgery—is a safe domain today. The impact of multimodal, especially adjuvant, therapy for oncological indications is well established and evidence-based. New technologies are evolving and will be evaluated with high-evidence studies in the near future.

Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine, median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm, 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine, 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

Intraductal papillary mucinous neoplasm (IPMN)-associated carcinoma is a subtype of pancreatic cancer for which prognostic factors, the validity of the AJCC/UICC staging system and the role of adjuvant chemotherapy remain unknown.Clinicopathological, treatment and follow-up data of patients with IPMN-associated carcinoma undergoing resection between 2002 and 2018 were analyzed. Uni- and multivariable survival analyses were performed to identify prognostic factors.Of 424 patients undergoing resection for IPMN-associated carcinoma, 77% patients had pancreatic ductal adenocarcinoma (IPMN-PDAC) and 23% had colloid carcinoma (IPMN-CC). Compared to IPMN-CC, IPMN-PDAC was diagnosed at more advanced tumor stages, more frequently involved lymph nodes, more frequently showed poor differentiation and were associated with higher rates of R1 resections. Resected IPMN-PDAC showed markedly shorter median overall survival than IPMN-CC (26.7 months vs. 91.3 months). The current AJCC/UICC staging system was validated for IPMN-associated carcinoma and for both of its subtypes. In multivariable analysis age ≥70 years, diabetes mellitus, high levels of Ca 19-9, IPMN-PDAC subtype, G3 tumors and higher AJCC/UICC stage were independently associated with shorter survival. Adjuvant therapy was not associated with improved survival in IPMN-associated carcinoma. Overall survival was comparable in patients receiving vs. not receiving adjuvant therapy.Survival after resection of IPMN-associated carcinoma depends on tumor stage, on histologic tumor subtype, grading, and Ca 19-9 levels. The current 8th edition of the AJCC/UICC staging system is applicable for IPMN-associated carcinoma and for both of its subtypes IPMN-PDAC and IPMN-CC. The role of adjuvant therapy for IPMN-associated carcinoma remains unclear.

ObjectiveGATA6 is a master regulator of pancreatic differentiation and a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression is associated with poor patient outcome.GATA4is the second most expressed GATA factor in the pancreas. The aim was to assess whether, and how, GATA4 contributes to PDAC phenotype and to analyze the association of expression with clinical outcome.DesignWe analyzed PDAC transcriptomic data, stratifying cases according toGATA4andGATA6expression, and identified differentially expressed genes and pathways. A multicenter TMA study to assess GATA4 and GATA6 expression in PDAC samples (n=745) from patients undergoing tumour resection was performed using immunohistochemistry with antibodies of validated specificity. GATA4 and GATA6 levels were dichotomized into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.ResultsSubtype classification using transcriptomic data revealed thatGATA4mRNA is enriched in classical, compared to basal-like tumours. We classified samples in 4 groups as high/low forGATA4andGATA6. Reduced expression ofGATA4did not have a major transcriptional impact. However, concomitant low expression ofGATA4enhanced the transcriptomic effects ofGATA6low expression. Reduced expression of both proteins in tumours was associated with the worst patient survival.GATA4andGATA6expression significantly decreased in metastases and negatively correlated with basal markers.ConclusionsOur analyses uncover a cooperative interaction betweenGATA4andGATA6to maintain the classical PDAC phenotype and provide compelling clinical rationale for assessing their expression as biomarkers of poor prognosis.SUMMARY BOXWhat is already known about this subject?-Patients with classical-type PDAC have a better outcome-Retrospective analyses suggest that classical-type PDAC is more sensitive to 5-FU-based chemotherapy-GATA6 is a surrogate biomarker of classical tumours and its expression is associated with better survival-GATA4 and GATA6 have overlapping and unique functions during pancreatic and gastrointestinal developmentWhat are the new findings?-Tumours displaying only low GATA4 expression have a transcriptomic profile similar to those with preserved expression of both transcription factors-Combined low expression of GATA4 and GATA6 has the highest transcriptomic impact-In a large multicenter tissue microarray study, patients with tumours showing low expression of both GATA4 and GATA6 have the worst overall survival-Low expression of GATA4 and GATA6 is an independent predictor of survival in patients with resectable PDAC-GATA4 levels are down-regulated in liver metastases and are negatively correlated with basal markers such as KRT5/6, KRT14, and TP63How might it impact on clinical practice in the foreseeable future?-The combined assessment of GATA4 and GATA6 expression may improve prognostic stratification of patients with PDAC-Prospective studies should confirm whether GATA4 and GATA6 expression is also predictive of response to chemotherapy in PDAC patients

Objective To propose a noninvasive diagnostic approach, which allows reliable distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMNs). Background IPMNs are identifiable precursor lesions of pancreatic cancer, of which surgical resection is warranted prior to the development of invasive carcinoma, but low-grade IPMNs should not be unnecessarily resected. However, diagnostic tools that preoperatively enable accurate risk stratification of IPMNs are missing. Methods This single-center, retrospective cohort study included 56 patients who underwent surgical resection for IPMN including 18 low-risk (low-grade) and 38 high-risk (high-grade/invasive carcinoma) IPMNs, from whom clinical features and serum samples were prospectively obtained. An antibody microarray platform was used to analyze the serum proteome. Based on serum markers and selected clinical characteristics support vector machine models were constructed to predict the risk of IPMN malignancy. Results A serum protein signature discriminating low- and high-risk IPMN patients was identified. Combinations of established clinical features and the newly identified serum biomarkers correctly distinguished low- and high-risk IPMNs in 93% on 1000-fold cross-validation. Conclusions This study highlights the synergistic predictive value of combining a novel serum protein signature with conventional clinical characteristics to risk-stratify IPMN patients. If these findings are supported by larger validation studies, they might enable more rational decision-making in clinical management of IPMN patients in conjunction with clinical guidelines.

To compare perioperative outcomes of laparoscopic pancreaticoduodenectomy (LPD) to open pancreaticoduodenectomy (OPD) using evidence from randomized controlled trials (RCTs).LPD is used more commonly, but this surge is mostly based on observational data.We searched CENTRAL, Medline and Web of Science for RCTs comparing minimally invasive to OPD for adults with benign or malignant disease requiring elective pancreaticoduodenectomy. Main outcomes were 90-day mortality, Clavien-Dindo ≥3 complications, and length of hospital stay (LOS). Secondary outcomes were postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), bile leak, blood loss, reoperation, readmission, oncologic outcomes (R0-resection, lymph nodes harvested), and operative times. Data were pooled as odds ratio (OR) or mean difference (MD) with a random-effects model. Risk of bias was assessed using the Cochrane Tool and the GRADE approach (Prospero registration ID: CRD42019120363).Three RCTs with a total of 224 patients were included. Meta-analysis showed there were no significant differences regarding 90-day mortality, Clavien-Dindo ≥3 complications, LOS, POPF, DGE, PPH, bile leak, reoperation, readmission, or oncologic outcomes between LPD and OPD. Operative times were significantly longer for LPD {MD [95% confidence interval (CI)] 95.44 minutes (24.06-166.81 minutes)}, whereas blood loss was lower for LPD [MD (CI) -150.99 mL (-168.54 to -133.44 mL)]. Certainty of evidence was moderate to very low.At current level of evidence, LPD shows no advantage over OPD. Limitations include high risk of bias and moderate to very low certainty of evidence. Further studies should focus on patient safety during LPD learning curves and the potential role of robotic surgery.

Background: The progression and response to systemic treatment of cancer is substantially dependent on the balance between cancer cell death (apoptosis and necroptosis) and cancer cell survival (autophagy). Although well characterized in experimental systems, the status of cancer cell survival and cell death in human pancreatic ductal adenocarcinoma (PDAC), especially in response to chemotherapy and different types of chemotherapy is poorly described. Results: The median (95% confidence interval) survival was 31.6 (24.5–44.5) months after FOLFIRINOX versus 15.8 (2.0–20.5) months after gemcitabine-based therapy (p = 0.039). PDAC tissue autophagy was reduced compared to normal pancreata based on reduced BECLIN-1 expression and LC3-Lamp-2 colocalization, whilst necroptosis (RIP-1) was increased. Neoadjuvant therapy was associated with further reduced autophagy based on p62/SQSTM-1 accumulation, and increased necroptosis (RIP3 and pMLKL) and apoptosis (BAX, cleaved CASPASE-9 and CASPASE-3) markers, increased nuclear p65 (NF-κB) and extracellular HMGB1 expression, with greater CD8+ lymphocyte infiltration. Survival was associated with reduced autophagy and increased apoptosis. Necroptosis (RIP-3, pMLKL) and apoptosis (BAX and cleaved CASPASE-9) markers were higher after FOLFIRINOX than gemcitabine-based treatment. Patients and methods: Cancer cell autophagy, apoptosis, and necroptosis marker expression was compared in pancreatic tissue samples from 51 subjects, comprising four groups: (1) surgical resection for PDAC after FOLFIRINOX (n = 11), or (2) after gemcitabine-based (n = 14) neoadjuvant therapy, (3) patients undergoing PDAC resection without prior chemotherapy (n = 13), and (4) normal pancreata from 13 organ donors. Marker expression was undertaken using semi-automated immunofluorescence-FACS-like analysis, defining PDAC cells by CK-7+ expression.

Pancreatic cancer is associated with high recurrence rates, and any surgery should aim to prevent local recurrence. However, systematic resection of putatively tumor-infiltrated soft tissue adjacent to the celiac branches and superior mesenteric artery has not regularly been applied in pancreatic head resection. We describe a technique of vessel-oriented pancreatic head resection, allowing for extended removal of lymphatic and neural tissue that is situated in the TRIANGLE in between the celiac trunk, the superior mesenteric artery, and the portal vein. Vessel-oriented dissection or vascular resection facilitates complete removal of putatively tumor-infiltrated soft tissue, thus potentially reducing the risk of isolated local recurrence in pancreatic cancer.

Introduction: The present study evaluated the potential benefit of adding cetuximab to neoadjuvant, adjuvant, or palliative standard therapy for pancreatic cancer. Methods: A systematic literature search was performed in MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL). Only randomised controlled trials (RCTs) investigating the effect of adding cetuximab to standard chemotherapy in pancreatic cancer were included. Evaluated outcomes were overall survival, progression-free survival, objective response, and toxicity. For overall survival and progression-free survival, hazard ratios (HR) with 95% confidence intervals (CI) were chosen as effect measure. For objective response, odds ratios (OR) with 95% CI were used. Analysis was based on a random effects model. Results: After screening 568 publications, a total of 4 RCTs with 924 patients were included. In all trials, patients were adequately randomised with balanced intervention and control groups. There was no significant difference in overall survival (HR 1.04; 95% CI: 0.90–1.19; p = 0.60), progression-free survival (HR 1.06; 95% CI: 0.93–1.22; p = 0.36), or objective response (OR 0.99; 95% CI: 0.66 –1.49; p = 0.96) when adding cetuximab to a standard therapy. Toxicity was the same or higher in each of the included trials. According to GRADE, the certainty of the evidence is high. Therefore, adding cetuximab to pancreatic cancer therapy has no clinically relevant benefit. Conclusion: In the presence of no survival benefit, increased toxicity, and higher costs, a decreased cost-benefit ratio compared to the standard care must be suggested. Conducting further RCTs in unselected pancreatic cancer populations is unlikely to change this conclusion.

Background Effective chemotherapy protocols are currently changing the treatment options for metastasized pancreatic cancer. Survival benefits after synchronous metastasectomy have been reported for selected patients. We set out to assess predictive factors of resectability for synchronous metastases after FOLFIRINOX. Methods Consecutive patients with metastatic pancreatic cancer undergoing surgery after FOLFIRINOX between 2011 and 2017 were identified from a prospectively collected database. Surgery following chemotherapy was indicated in patients with no more than six metastatic lesions, no progression detected on CT, and technically resectable disease. Patients who received synchronous metastasectomy were compared with patients who received explorative laparotomy or palliative surgery in terms of predictors of resectability and overall survival. In patients undergoing resection, prognostic factors were examined. Results Of 101 patients scheduled for surgery after FOLFIRINOX, synchronous metastasectomy was performed in 43 cases (43%) and non-resection surgery in 58 cases (57%). The shrinkage rate of the primary tumor on CT (P = 0.04) and the postchemotherapy serum CA19-9 concentration (P = 0.02) were associated with resectability. The median overall survival of the patients undergoing metastasectomy was longer than that of the patients without resection (21.9 months vs 16.4 months, P = 0.006). Postchemotherapy serum CA19-9 value (P = 0.04) and lymph node ratio (P = 0.01) were prognostic factors in the patients undergoing metastasectomy. Conclusions In selected patients who satisfied our surgical criteria, shrinkage rate of primary tumor and postchemotherapy serum CA19-9 level, which predict resectability of metastasized pancreatic cancer, should be considered in decision making to avoid unnecessary surgery.

The benefit of preoperative biliary stenting in the treatment of pancreatic ductal adenocarcinoma is controversially debated. Data from recent meta-analyses favor primary surgery for the majority of resectable pancreatic cancers. Regardless of this evidence, preoperative biliary stenting via endoscopy (EBS) is commonly performed, often before involvement of a surgeon. The goal of this study was to elucidate the association of bile duct stenting, microbiological dislocation of gut flora to the biliary compartment, and major postoperative complications. Patient data was derived from a prospectively maintained database including all pancreatic resections between January 2006 and December 2014. Patients receiving pancreaticoduodenectomy for malignant disease in the head of the pancreas with prior EBS were included. Microbiological data were obtained through conventional culture from intraoperative bile duct swabs. Two hundred ninety-eight patients were enrolled in this study. Severe postoperative complications were associated with stent colonization: Postoperative pancreatic fistula type C occurred more frequently in E. coli–colonized patients (sample estimated odds ratio (OR) = 4.07), and the rate of lymphatic fistula was elevated in Enterococcus-colonized patients (OR = 3.25). Longer stenting duration (> 16 days) was associated with the prevalence of these bacteria. Major surgical complications following pancreaticoduodenectomy, including severe pancreatic fistula, are associated with bacterobilia after EBS. The indication for bile duct stenting should be evaluated in a multidisciplinary setting.

Solid pseudopapillary neoplasms (SPN) are rare and represent approximately 4% of all cystic pancreatic tumors. The prognosis is excellent, although 10-15% of SPN patients show metastasis at the time of surgery or tumor recurrence during follow-up after pancreatectomy. Aim of the study was to analyze surgical management, risk factors for malignancy as well as long-term outcome and prognosis of this distinct tumor entity.All patients with pancreatic resection for SPN between 10/2001 and 07/2018 in the authors' institution were identified from a prospective database. Clinicopathologic details, perioperative data and long-term follow-up results were retrospectively analyzed.Fifty-two patients were identified, 44 (85%) of them were female and the median age was 29 years (IQR 9-71). Seven (13%) patients showed a malignant behaviour of SPN with N1 (n = 2) or M1 (n = 1) disease at resection; 5 patients developed tumor recurrence, after a median of 21 months. During follow-up time (median 54 months) all patients were alive, the 5- and 10-year rates for disease-free survival were 89.0% and 81.6%, respectively. Significant risk factors for recurrence were age18 years (p = 0.0087) and parenchyma-preserving surgical approaches (p = 0.0006). The postoperative long-term outcome showed ECOG = 0-1 in all patients, with resection related exocrine insufficiency in 20 (41%) and diabetes mellitus in 2 (4%) patients.Age 18 years is a significant risk factor for malignancy in SPN, and parenchyma preserving resections harbor a significant risk for tumor recurrence. As recurrence may occur late, a systematic life-long follow-up should be performed.

Background/Aims: Many aspects of the biology of pancreatic neuroendocrine tumors (PanNETs), including determinants of proliferative, invasive, and metastatic potential, remain poorly understood. Placenta-specific 8 (PLAC8), a gene with unknown molecular function, has been reported to have tumor-promoting roles in different human malignancies, including exocrine pancreatic cancer. Since preliminary data suggested deregulation of PLAC8 expression in PanNET, we have performed detailed analyses of PLAC8 expression and function in human PanNET. Methods: Primary tissue from PanNET patients was immunohistochemically stained for PLAC8, and expression was correlated with clinicopathological data. In vitro, PLAC8 expression was inhibited by siRNA transfection in PanNET cell lines and effects were analyzed by qRT-PCR, Western blot, and proliferation assays. Results: We report that PLAC8 is expressed in the majority of well-differentiated human PanNETs, predominantly in early-stage and low-grade tumors. SiRNA-mediated knockdown of PLAC8 in PanNET cells resulted in decreased proliferation and viability, while apoptosis was not induced. Mechanistically, these effects were mediated by attenuation of cell cycle progression, as Western blot analyses demonstrated upregulation of the tumor suppressor p21/CDKN2A and downregulation of the cell cycle regulator Cyclin D1 as well as reduced levels of phosphorylated ribosomal protein s6 and retinoblastoma protein. Conclusion: Our findings establish PLAC8 as a central mediator of cell growth in a subset of human PanNET, providing evidence for the existence of distinct molecular subtypes within this class of tumors.

Pancreatic cancer (PC) remains a disease characterized by an extremely poor prognosis, which is often limited by advanced tumor stage at diagnosis. As surgery remains the only option for long-term survival, indications for resection to achieve a complete tumor removal have been extended in recent years, including locally advanced as well as metastatic disease. Here, we provide a literature overview of modern multimodal treatment concepts of metastatic PC focused on surgery and local interventions including neoadjuvant concepts, stratification of patients, prognostic parameters, and oncological outcomes. The current literature lacks level I evidence studies on surgery in stage IV PC. The available observational studies show that resection for liver metastasis has been increasingly performed in recent years, outcomes improve after neoadjuvant therapy, and certain prognostic parameters can identify patients who benefit from this approach. In addition, interventional or radio-oncological liver-directed therapies have been evaluated showing the possibility of some disease control. Resection of pulmonary metastases is rarely performed, although this patient subgroup may have a more favorable prognosis than patients with stage IV liver cancer. Surgery in the setting of peritoneal carcinomatosis remains experimental without any valid supporting data. There are promising data to support resection of metastatic PC, presuming this approach is embedded in a multimodal oncological concept with modern and effective multi-agent chemotherapies and proper patient selection. Based on this, future studies should specify distinct groups of patients who benefit from extended surgical approaches including synchronous or staged metastasectomy.

Pancreatic cancer is the third leading cause of cancer-related death in the Western world and is projected to soon become the second commonest cause of cancer mortality. During the past two decades, there have been important clinical developments in the fight against this aggressive disease. The aim of this review article is to summarize the evolution of the multidisciplinary oncological and surgical management of pancreatic cancer. The centralization of pancreatic surgery into specialized institutions has led to improvements in surgical techniques, with reduced surgical mortality rates of

A considerable number of reports have been published on the feasibility, techniques, and early postoperative results of robotic-assisted oesophageal surgery. However, these are mostly smaller case series, suggesting that the robot-assisted Ivor Lewis procedure is still in the implementation phase and far from being standardised. Oesophageal surgeons from seven robotic university centres in Germany, experienced in both minimally invasive and robot-assisted minimally invasive surgery, took part in a workshop on robot-assisted surgery. An intensive exchange of opinions and experiences, followed by a step-by-step re-enactment of the operation in a cadaver lab, enabled us to develop a standardised robot-assisted Ivor Lewis surgical workflow, which is presented here. Systematic and objective comparison of experiences and results using a robot-assisted Ivor Lewis procedure has made it possible to develop a standardised surgical workflow that is now clinically applied in our centres. It is hoped that standardisation of this procedure will help to maintain patient safety, prevent medical errors, and facilitate the learning curve, while introducing robotic surgery into a centre.

Objective To evaluate the impact of clinical and pathological parameters, including resection margin (R) status, on survival in patients undergoing pancreatic surgery after neoadjuvant treatment for initially unresectable pancreatic ductal adenocarcinoma (PDAC). Background Prognostic factors are well documented for patients with resectable PDAC, but have not been described in detail for patients with initially unresectable PDAC undergoing resection after neoadjuvant therapy. Methods Prospectively collected data of consecutive patients with initially unresectable pancreatic cancer treated by neoadjuvant treatment and resection were analyzed. The R status was categorized as R0 (tumor-free margin >1 mm), R1 ≤1 mm (tumor-free margin ≤1 mm), and R1 direct (microscopic tumor infiltration at margin). Clinicopathological characteristics and outcomes were compared among these groups and tested for survival prediction. Results Between January, 2006 and February, 2017, 280 patients with borderline resectable (n = 18), locally advanced (n = 190), or oligometastatic (n = 72) disease underwent tumor resection after neoadjuvant treatment. Median overall survival from the time of surgery was 25.1 months for R0 (n = 82), 15.3 months for R1 ≤1 mm (n = 99), and 16.1 months for R1 direct (n = 99), with 3-year overall survival rates of 35.0%, 20.7%, and 18.5%, respectively (P = 0.0076). The median duration of the neoadjuvant treatment period was 5.1 months. In multivariable analysis, preoperative CA 19-9 levels, lymph node status, metastasis category, and vascular involvement were all significant prognostic factors for overall survival. The R status was not an independent prognostic factor. Conclusions In patients undergoing resection after neoadjuvant therapy for initially unresectable PDAC, preoperative CA 19-9 levels, lymph node involvement, metastasis category, and vascular involvement, but not the R status, were independent prognostic factors of overall survival.

Chemotherapy is an important part of multimodality pancreatic cancer treatment. After curative resection, adjuvant chemotherapy can significantly improve disease free survival and overall survival. The current standard of care is six months adjuvant chemotherapy with modified folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) in patients fit enough for this protocol, otherwise six months of gemcitabine and capecitabine based on the European Study Group for Pancreatic Cancer (ESPAC)-4 study. In patients with metastatic disease, combination chemotherapy according to the FOLFIRINOX protocol or with gemcitabine plus nab-paclitaxel is an important improvement to gemcitabine monotherapy that was the standard for many years. Patients not fit for combination chemotherapy however may still benefit from gemcitabine. Patients with good performance status may benefit from second-line chemotherapy. Chemoradiation has long been used in locally advanced pancreatic cancer but is now tempered following the LAP07 study. This trial showed no difference in overall survival in those patients with stable disease after four months of gemcitabine (with or without erlotinib) randomized to either continuation of gemcitabine therapy or chemoradiation (54Gy with capecitabine). As an alternative to radiation, other forms local therapies including radiofrequency ablation, irreversible electroporation, high-intensity focused ultrasound, microwave ablation and local anti-KRAS therapy (using siG12D-LODER) are currently under investigation. Given the systemic nature of pancreas cancer from an early stage, the success of any local approach other than complete surgical resection (with adjuvant systemic therapy) is likely to be very limited. In patients with locally advanced, irresectable cancer, chemotherapy may offer the chance for secondary resection with a survival similar to patients with primary resectable disease. Downstaging regimens need to be evaluated in prospective randomized trials in order to make firm recommendations. Selection of patient groups for specific therapy including cytotoxics is becoming a reality using assays based on drug cellular transport and metabolism, and molecular signatures. Going forward, high throughput screening of different chemotherapy agents using molecular signatures based on patients' derived organoids holds considerable promise.

Die abdominelle Sepsis ist die schwerste Verlaufsform einer abdominellen Infektion, bei der es aufgrund einer Fehlregulation der Antwort des Wirtsorganismus auf die Infektion zu einem lebensbedrohlichen Organversagen bis hin zu einem septischen Schock kommt, der eine Letalitat von >40 % hat. Der vorliegende Artikel gibt eine Ubersicht uber die Evidenz zum strategischen Vorgehen bei der Behandlung von Patienten mit abdomineller Sepsis und septischem Schock. Der Fokus liegt dabei auf den zeitkritischen Elementen Diagnose, antiinfektive Therapie und hamodynamische Stabilisierung.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

IntroductionPancreatic resections are an important field of surgery worldwide to treat a variety of benign and malignant diseases. Postoperative pancreatic fistula (POPF) remains a frequent and critical complication after partial pancreatectomy and affects up to 50% of patients. POPF increases mortality, prolongs the postoperative hospital stay and is associated with a significant economic burden. Despite various scientific approaches and clinical strategies, it has not yet been possible to develop an effective preventive tool. The SmartPAN indicator is the first surgery-ready medical device for direct visualisation of pancreatic leakage already during the operation. Applied to the surface of pancreatic tissue, it detects sites of biochemical leak via colour reaction, thereby guiding effective closure and potentially mitigating POPF development.Methods and analysisThe ViP trial is a prospective single-arm, single-centre first in human study to collect data on usability and confirm safety of SmartPAN. A total of 35 patients with planned partial pancreatectomy will be included in the trial with a follow-up of 30 days after the index surgery. Usability endpoints such as adherence to protocol and evaluation by the operating surgeon as well as safety parameters including major intraoperative and postoperative complications, especially POPF development, will be analysed.Ethics and disseminationFollowing the IDEAL-D (Idea, Development, Exploration, Assessment, and Long term study of Device development and surgical innovation) framework of medical device development preclinical in vitro, porcine in vivo, and human ex vivo studies have proven feasibility, efficacy and safety of SmartPAN. After market approval, the ViP trial is the IDEAL Stage I trial to investigate SmartPAN in a clinical setting. The study has been approved by the local ethics committee as the device is used exclusively within its intended purpose. Results will be published in a peer-reviewed journal. The study will provide a basis for a future randomised controlled interventional trial to confirm clinical efficacy of SmartPAN.Trial registration numberGerman Clinical Trial Register DRKS00027559, registered on 4 March 2022.

BackgroundPancreatic surgery is regarded as the only curative treatment for pancreatic cancer (PC). As the neoadjuvant therapy is applied widely nowadays, the proportion of patients with PC undergoing surgery also with locally advanced tumour findings has increased accordingly. Especially in these situations, a radical resection of all tumour tissues is challenging. A novel surgical strategy has been introduced recently to achieve this aim, namely the TRIANGLE operation which comprises the radical resection of all nerve and lymphatic tissue between coeliac artery, superior mesenteric artery and mesenteric–portal axis without including extended lymphadenectomy outside this area. Due to currently published studies, Triangle Operation is a safe and feasible procedure. However, this has not been systematically analysed to date. This systematic review and meta-analysis aim to evaluate surgical and postoperative outcomes of Triangle Operation in pancreatic surgery.Methods and analysisPubmed, Web of Science and Cochrane Central Register of Controlled Trials in the Cochrane Library will be searched from inception until 31 December 2022. This study will include all articles comparing Triangle Operation versus non-Triangle Operation in pancreatic surgery to assess outcomes. The primary endpoints will be R0 resection rate and 1-year overall survival. The secondary endpoints will be delayed gastric emptying, postoperative pancreatic fistula, post pancreatectomy haemorrhages and reoperation incidence, overall complications, mortality and 3-year overall survival. The study selection, study quality assessment, data extraction and critical appraisal will be carried out by two reviewers. Inter-reviewer disagreements will be evaluated by discussion with a third reviewer. Besides, a subgroup analysis will be conducted focused on robotic surgery, laparoscopic surgery and open surgery in detail. Additionally, the Grading of Recommendations, Assessment, Development and Evaluations framework will be performed to evaluate the strength of evidence.Ethics and disseminationThis systematic review and meta-analysis will not require ethical approval. Results will be published in a peer-reviewed scientific journal.PROSPERO registration numberCRD42021234721.

Purpose Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long-term experience with everolimus and give a thorough review of the therapeutic strategies used so far. Patients and methods Four patients (mean age 46 years, range 37-55) with progressing thymic NEN (t-NEN) (two well-differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5-56) after the first diagnosis. The follow-up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. Results We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t-NEN (Ki-67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well-differentiated t-NEN (Ki-67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longest compared to the other nonsurgical therapies used. Conclusion Comparing the sparse data available everolimus is a promising treatment for t-NEN at least in second-line therapy. A low Ki-67 index was associated with a better outcome.

Pancreatic cancer is a very aggressive malignant disease with an extremely poor prognosis; however, the survival of patients at all tumor stages is highly variable. Standard therapies, which are based predominantly on the TNM classification, patient's general condition and comorbidities, are highly variable in their effectiveness. In recent years, new technologies with multi-omics tumor characterizations have revealed the molecular heterogeneity of pancreatic cancer; however, in routine clinical practice, pancreatic cancer is usually considered as a uniform disease without paying attention to the individual tumor biology. Recent clinical studies have shown that molecular analyses can identify pharmacological targets and prognosis-relevant or treatment-relevant subtypes. Better methods for prognosis prediction and stratification based on clinical and molecular parameters could help to create more effective personalized multimodal therapy concepts and replace uniform standard therapies.Das Pankreaskarzinom ist eine sehr aggressive Krebserkrankung mit einer äußerst schlechten Prognose. Das Überleben der Patienten in sämtlichen Tumorstadien ist jedoch sehr unterschiedlich. Standardtherapien, die sich überwiegend an TNM-Klassifikation, Allgemeinzustand und Komorbidität orientieren, sind in ihrer Effektivität sehr variabel. Neue Technologien mit Multi-omics-Tumorcharakterisierungen haben in den letzten Jahren die molekulare Heterogenität des Pankreaskarzinoms aufgezeigt. In der klinischen Routine wird das Pankreaskarzinom allerdings meist als uniforme Erkrankung betrachtet ohne Beachtung der individuellen Tumorbiologie. Aktuelle klinische Studien haben gezeigt, dass molekulare Analysen pharmakologische Zielstrukturen und prognose- bzw. therapierelevante Subtypen identifizieren können. Bessere Methoden zur Prognoseprädiktion und Stratifizierung anhand klinischer und molekularer Parameter könnten dazu beitragen, effektivere, personalisierte multimodale Therapiekonzepte zu erstellen und werden einheitliche Standardtherapien ablösen.

The resection of retropancreatic nerve plexuses for pancreatic head cancer became standard of care during open pancreatoduodenectomy to minimize local recurrences. Since more surgical centers are progressing on the learning curve, robotically-assisted pancreatoduodenectomy is now increasingly performed with decreasing anatomic exclusion criteria. To achieve comparable and favorable oncologic outcomes, advanced surgical techniques should be transferred and implemented when performing robotic resections.The nomenclature and anatomic principles of retropancreatic nerve plexuses and three different levels of dissections are utilized based on established definitions.The en bloc dissection in the "TRIANGLE" area (triangular-shaped retropancreatic space enclosed by the common hepatic artery, superior mesenteric artery, and superior mesenteric vein/portal vein) and the periadventitial dissection of arteries for non-tunica media-invading tumors were executed robotically. Both can be utilized to achieve a radical dorsal and medial margin. Video recordings are provided to illustrate varying TRIANGLE dissections.To accomplish oncologic non-inferiority, established principles from open pancreatic resections can be incorporated precisely and safely, overcoming the lack of haptic feedback while exploiting the technological advantages of the robotically-assisted platform.

Objective Evaluation of the outcome after resection for distal bile duct cancer (DBC) with focus on the impact of microscopic histopathological resection status R0 (>1 mm) vs R1 (≤1 mm) vs R1 (direct). Summary background data DBC is a rare disease for which oncologic resection offers the only chance of cure. Methods Prospectively collected data of consecutive patients undergoing pancreaticoduodenectomy for DBC were analyzed. Histopathological resection status was classified according to the Leeds protocol for pancreatic cancer (PDAC; R0 >1 mm margin clearance vs. R1 ≤1 mm vs. R1 direct margin involvement). Results A total of 196 patients underwent pancreaticoduodenectomy for DBC. Microscopic complete tumor clearance (R0>1 mm) was achieved in 113 patients (58%). Median overall survival (OS) of the entire cohort was 37 months (5- and 10-year OS rate: 40% and 31%, respectively). After R0 resection, median OS increased to 78 months with a 5-year OS rate of 52%. Negative prognostic factors were age >70 years (p 1000 ml (p=0.0009, HR 1.99), pN1 and pN2 status (p=0.0052 and p=0.0006, HR2.14 and 2.62, respectively) and American Society of Anesthesiologists score >II (p=0.0259, HR 1.61). Conclusions This is the largest European single-center study of surgical treatment for DBC and the first to investigate the prognostic impact of the revised PDAC resection status definition in DBC. The results show that this definition is valid in DBC and that "true" R0 resection (>1 mm) is a key factor for excellent survival. In contrast to PDAC, there was no survival difference between R1 (≤1 mm) and R1 (direct).

The natural connection between the duodenum and the pancreatic duct enables a minimally invasive access to the pancreas. Endoscopically this access is already regularly used, mainly for diagnostic and even for certain therapeutic purposes. With per-oral pancreatoscopy the endopancreatic approach allows the direct visualization of the pancreatic duct system potentially improving the diagnostic work-up of pancreatic cystic neoplasms, intrapancreatic strictures and removal of pancreatic duct stones. However, the endopancreatic access can equally be applied for surgical interventions. The objective of this review is to summarize endoscopic and surgical interventions using the endopancreatic access. Endopancreatic surgery stands for a further development of the endoscopic technique: a rigid endoscope is transabdominally introduced over the duodenum and the papilla to enable resections of strictures and inflamed tissue from inside the pancreas under visual control. While the orientation and localization of target structures using this minimally invasive approach is difficult, the development of an accurate image guidance system will play a key role for the clinical implementation and widespread use of endoscopic and surgical endopancreatic interventions.

Septic shock substantially alters the pharmacokinetic properties of β-lactams with a subsequently high risk of insufficiently low serum concentrations and treatment failure. Considering their pharmacokinetic (PK)/pharmacodynamic (PD) index, prolonged infusions (PI) of β-lactams extend the time that the unbound fraction of the drug remains above the minimal inhibitory concentration MIC (ft &gt, MIC) and may improve patient survival. The present study is a monocentric, retrospective before-and-after analysis of septic shock patients treated with β-lactams. Patients of the years 2015-2017 received intermittent bolus application whereas patients of 2017–2020 received PI of β-lactams. The primary outcome was mortality at day 30 and 90 after diagnosis of septic shock. Mortality rates in the PI group were significantly lower on day 30 (PI: 41%, n = 119/290 vs. IB: 54.8%, n = 68/114, p = 0.0097) and day 90 (PI: 47.9%, n = 139/290 vs. IB: 62.9%, n = 78/124, p = 0.005). After propensity-score matching, 30- and 90-day mortality remained lower for the PI group (−10%, p = 0.14). PI was further associated with a reduction in the duration of invasive ventilation and a stronger decrease in SOFA scores within a 14d-observation period. PI of β-lactams was associated with a significant reduction of mortality in patients with septic shock and may have beneficial effects on invasive ventilation and recovery from sepsis-related organ failure.

Background Acute pancreatitis (AP) is defined as an acute inflammatory attack of the pancreas of sudden onset. Around 25% of patients have either moderately severe or severe disease with a mortality rate of 15–20%. Purpose The aim of this article was to summarize the advances being made in the understanding of this disease and the important role of surgery. Results and conclusions An accurate diagnosis should be made a soon as possible, initiating resuscitation with large volume intravenous fluids and oxygen by mask. Predicted severe disease will require intensive monitoring. Most deaths within the first week are due to multi-organ failure; thus, these patients will require intensive therapy unit management. During the second phase of the disease, death is due to local complications arising from the pancreatic inflammation, requiring accurate identification to determine the correct form of treatment. Acute peripancreatic fluid collections arise 4 weeks and largely resolve on conservative management. Necrotizing pancreatitis causing acute necrotic collections and later walled-off necrosis will require treatment if symptomatic or infected. Initial endoscopic transgastric or percutaneous drainage will resolve less serious collections but necrosectomy using minimally invasive approaches will be needed for more serious collections. To prevent recurrent attacks of AP, causative factors need to be removed where possible such as cholecystectomy and cessation of alcohol. Future progress requires improved management of multi-organ failure and more effective minimally invasive techniques for the removal of necrosis.

The aim of this study was to develop and validate a pretreatment prognostic score in pancreatic cancer (PDAC).Pretreatment prognostication in PDAC is important for treatment decisions but remains challenging. Available prognostic tools are derived from selected cohorts of patients who underwent resection, excluding up to 20% of patients with exploration only, and do not adequately reflect the pretreatment scenario.Patients undergoing surgery for PDAC in Heidelberg from July 2006 to June 2014 were identified from a prospective database. Pretreatment parameters were extracted from the database and the laboratory information system. Parameters independently associated with overall survival by uni- and multivariable analyses were used to build a prognostic score. A contemporary cohort from Verona was used for external validation.In 1197 patients, multiple pretreatment parameters were associated with overall survival by univariable analyses. American Society of Anesthesiology classification, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen, C-reactive protein, albumin, and platelet count were independently associated with survival and were used to create the Heidelberg Prognostic Pancreatic Cancer (HELPP)-score. The HELPP-score was closely associated with overall survival (median survival between 31.3 and 4.8 months; 5-year survival rates between 35% and 0%) and was able to stratify survival in subgroups with or without resection as well as in CA19-9 nonsecretors. In the resected subgroup the HELPP-score stratified survival independently of pathological prognostic factors. The HELPP-score was externally validated and was superior to CA19-9 in both the development and validation cohorts.The HELPP-score is a readily available prognostic tool based on pretreatment routine parameters to stratify survival in PDAC independently of resection status and pathological tumor stage.

OBJECTIVE The aim of this study was to determine the role of gastric venous congestion (GVC) in mortality after total pancreatectomy (TP). BACKGROUND Data from a nationwide administrative database revealed that TP is associated with a 23% mortality rate in Germany. METHODS A total of 585 consecutive patients who had undergone TP (n = 514) or elective completion pancreatectomy (n = 71) between January 2015 and December 2019 were analyzed. Univariable and multivariable analyses were performed to identify risk factors for GVC and 90-day mortality. RESULTS GVC was observed in 163 patients (27.9%) requiring partial or total gastrectomy. Splenectomy (OR 2.14, 95% CI 1.25-3.80, p = 0.007) and coronary vein resection (OR 5.49, 95% CI 3.19-9.64, p < 0.001) were independently associated with GVC. The overall 90-day mortality after TP was 4.1% (24 of 585 patients), 7.4% in patients with GVC and 2.8% in those without GVC (p = 0.014). Of the 24 patients who died after TP, 12 (50%) had GVC. CONCLUSION GVC is a frequent albeit not well-known finding after TP, especially when splenectomy and resection of the coronary vein are performed. Adequate decision making for partial gastrectomy during TP is crucial. Insufficient gastric venous drainage after TP is life-threatening.

Objective: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD). Summary Background Data: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking. Methods: A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort. Results: Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively (P < 0.001). Conclusion: For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Objectives Acinar cell carcinoma of the pancreas (pACC) forms a rare subgroup of pancreatic tumors. We report on our institutional experience with systemic first- and further-line therapy in patients with metastatic pACC and embed our findings in a review of the literature. Methods Patients with stage IV pACC who started systemic treatment between 2008 and 2019 at our institution were identified via our institutional database. Clinical data were extracted from the patients' electronic data records. Survival times were calculated by the Kaplan-Meier method. Results Six patients received a fluoropyrimidine- and oxaliplatin-containing first-line treatment, and 4 patients were started on gemcitabine-based protocols. Median progression-free survival was 4.8 months [95% confidence interval (CI), 3.3 to not available (n.a.)], and median overall survival was 15.3 months (95% CI, 10.1 to n.a.). Residual survival for second-line treatment was 2.1 months (95% CI, 1.3 to n.a.), although 1 patient experienced almost complete remission under targeted therapy. Conclusions The most encouraging and deep responses result from poly-chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), which seems to be the appropriate choice in fit patients. Gemcitabine monotherapy seems without substantial activity in pACC. Whenever possible, patients with pACC should be screened for targetable mutations.

Simple Summary Surgery is the only potential cure for pancreatic ductal adenocarcinoma and should always be combined with adjuvant chemotherapy or other multimodal treatment. Besides the advances in such multimodal approaches, there has been substantial progress in surgical techniques to especially address advanced resections. These techniques include specific operative steps, such as ‘artery first’ or ‘uncinate first’ approaches as well as techniques that allow safe vascular resection and reconstruction to achieve radical tumor removal. Most recently, also minimally-invasive and robotic approaches have been adopted for pancreatic cancer surgery; however, there is no high-level evidence on these evolving techniques especially with regards to long-term results compared to conventional surgical techniques. Abstract Pancreatic ductal adenocarcinoma (PDAC) represents an aggressive tumor of the digestive system with still low five-year survival of less than 10%. Although there are improvements for multimodal therapy of PDAC, surgery still remains the effective way to treat the disease. Combined with adjuvant and/or neoadjuvant treatment, pancreatic surgery is able to enhance the five-year survival up to around 20%. However, pancreatic resection is always associated with a high risk of complications and regarded as one of the most complex fields in abdominal surgery. This review gives a summary on the surgical treatment for PDAC based on the current literature with a special focus on resection techniques.

Background/objectives Irreversible electroporation (IRE) is an emerging treatment for locally advanced pancreatic cancer (LAPC) which in some cohorts has been associated with severe complications. Additionally, re-resection of isolated local recurrence (ILR) after pancreatic ductal adenocarcinoma (PDAC) can improve survival. We investigated safety, feasibility and oncologic outcomes in the first report on open IRE for unresectable ILR of PDAC in a staged surgical approach. Methods Records of the prospectively documented institutional database were screened for patients undergoing laparotomy in IRE-standby due to questionable resectability. Endpoints were morbidity, mortality and overall (OS) and progression free survival (PFS). Data of LAPC and ILR were compared statistically for safety and feasibility analysis. Results Intraoperative IRE was performed in 11 ILR and 14 LAPC. Six (54.5%) ILR and 10 (71.4%) LAPC patients had postoperative complications, type and frequency did not differ significantly. Major complications occurred in one ILR and two LAPC patients. Median OS was 20.0 months (95% CI: 2.7–37.3) after IRE for ILR and 28 (17.4–38.6) for LAPC. Median PFS after IRE was seven months for both ILR (4.1–9.9; n = 9) and LAPC (2.3–11.7; n = 13). Conclusion Open IRE for unresectable ILR was associated with acceptable perioperative risk. In this small, highly selected subset of patients with limited therapeutic options ancillary treatment with IRE might improve survival. Randomized treatment studies are required to establish the definitive role of IRE as compared to palliative standards of care in unresectable recurrence of PDAC and inconvertible LAPC.

Induction of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDA) is an unresolved challenge. Systematic investigation of the microenvironment of primary pancreatic tumors revealed a role of endocrine Langerhans islets in the coordination of immune activation. We found that intratumoral β-cells, regulated via STAT3, secrete C-C motif chemokine ligand 27 (CCL27) and thereby promote a TH1 phenotype in the microenvironment resulting in an enhanced T cell infiltration and prolonged patient survival. The local effect can be abrogated in a patient-based human explant model by inhibition of the CCL27 receptor CCR10. This defense mechanism is paralleled by an impaired metabolic function of Langerhans islets with reduced insulin levels resulting in a dysregulation of glycemic control in patients. Based on these findings, screening of PDA cases (n= 2264) led to the identification of type 2 diabetes mellitus (T2DM) and extractable glycated haemoglobin (HbA1c) levels as response markers for neoadjuvant chemotherapy with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Collectively these data provide insights into the interconnection of T2DM and PDA, and link declining glycemic control to therapeutic efficacy, which can be utilized as a tool for clinical decision-making and improve patient management.

Background & Aims3D-Bioprinting of an endocrine pancreas is a promising future curative treatment for selected patients with insulin secretion deficiency. In this study we present an end-to-end integrative, scalable concept extending from the molecular to the macroscopic level.MethodsA hybrid scaffold device was manufactured by 3D-(bio)printing. INS-1 cells with/without endothelial cells were bioprinted in gelatin methacrylate blend hydrogel. Polycaprolactone was 3D-printed and heparin-functionalized as structural scaffold component. In vitro evaluation was performed by viability and growth assays, total mRNA sequencing, and glucose-stimulated insulin secretion. In vivo, xenotransplantation to fertilized chicken eggs was used to investigate vascularization and function, and finite element analysis modeling served to detect boundary conditions and applicability for human islets of Langerhans.ResultsInsulin-secreting pseudoislets were formed and resulted in a viable and proliferative experimental model. Transcriptomics revealed upregulation of proliferative and β-cell-specific signaling cascades, downregulation of apoptotic pathways, and overexpression of extracellular matrix proteins and VEGF induced by pseudoislet formation and 3D culture. Co-culture with human endothelial cells created a natural cellular niche resulting in enhanced insulin response after glucose stimulation. Survival and function of the pseudoislets after explantation and extensive scaffold vascularization of both the hydrogel and heparinized polycaprolactone components were demonstrated in ovo. Computer simulations of oxygen, glucose, and insulin flows were used to evaluate scaffold architectures and Langerhans islets at a future transplantation site along neurovascular structures.ConclusionA defined end-to-end process for multidisciplinary bioconvergence research on a bioartificial endocrine pancreas was developed. A modular, patient-specific device architecture is proposed for future research studies.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylationlow tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylationlow/IFNsignhigh and Methylationhigh/IFNsignlow PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived KrasG12D/Trp53−/− mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylationlow/IFNsignhigh subtype potentially targetable by agents blocking intrinsic IFN signaling. Significance: The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity. This article is highlighted in the In This Issue feature, p. 521