BACKGROUND:NAD(P)H quinone dehydrogenase 1 (NQO1), a detoxification enzyme regulated by the Nrf2 cytoprotective pathway, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). NQO1 levels are also influenced by the C609T single-nucleotide polymorphism (SNP). We hypothesized that elevated NQO1 would confer chemoresistance in PDAC and predict poor patient outcome. METHODS:NQO1 tumor levels and germline C609T SNP status were assessed in archival samples from the European Study Group for Pancreatic Cancer (ESPAC) trials. NQO1 expression (H-score) was treated as continuous for survival regression analyses and dichotomized for visual summaries. Nrf2 or downstream gene induction was assessed in Nrf2 reporter mice or in PDAC cells following exposure to gemcitabine (Gem), 5-fluorouracil (5-FU), or the capecitabine (Cap) metabolite 5-fluoro-5'-deoxyuridine (5'-DFUR). Colony formation following NQO1 depletion was assessed. RESULTS:NQO1 tumor levels correlated with germline C609T SNP status (P < .001). Contrary to our hypothesis, high NQO1 expression was associated with improved survival in ESPAC-4 patients randomized to GemCap (HR = 0.87 [95% CI = 0.751 to 0.999]; P = .049), and had no association to outcome in the Gem-only treated arm (HR = 0.98 [95% CI = 0.78 to 1.23]; P = .867). Including genotype data did not improve predictive model performance. Neither Gem nor 5-FU induced Nrf2 in vivo. At high concentrations, they suppressed Nrf2/NQO1 in PDAC cells, an effect not mitigated by co-treatment with 5'-DFUR. NQO1 depletion experiments revealed that NQO1 inhibits colony formation. The strongest inhibition was observed when NQO1-positive cells were co-treated with Gem and 5'-DFUR, supporting our clinical data from ESPAC. CONCLUSION:High tumor NQO1 predicts better outcome following GemCap therapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, due to its aggressive invasiveness and resistance to therapy. The dense, stiff extracellular matrix, composed primarily of collagen I and basement membrane components such as collagen IV and laminin, acts as a mechanical barrier that constrains PDAC invasion. We investigated whether the actin-related protein (Arp) 2/3 complex, a key actin nucleator, is essential for PDAC cells to overcome extracellular matrix stiffness and facilitate migration. CRISPR/Cas9 knockout of the Arpc4 gene in murine PDAC cell lines derived from KrasG12D-driven transgenic mice resulted in substantially downregulated all Arp2/3 complex members. Inactivation of Arp2/3 significantly impaired PDAC cell migration, disrupted branched tubular structure formation in collagen I, and inhibited invasive front formation in organoid culture together with tumor-associated macrophages and fibroblasts. Mechanistically, β1 integrin signaling emerged as a key regulator of Arp2/3-dependent migration through collagen-rich matrices. Clinically, elevated expression of Arp2/3 complex components correlates with poor patient survival and basal-like differentiation subtypes, underscoring its role in disease progression. This study identifies the Arp2/3 complex and β1 integrin signaling as critical mediators of PDAC invasiveness and suggests them as potential therapeutic targets for mitigating PDAC progression.

Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, characterized by late diagnosis, aggressive biology and limited therapeutic success. Advances in multiagent chemotherapy have improved outcomes across disease stages, whereas precision medicine approaches are reshaping treatment paradigms. Personalized RNA vaccines and oncogenic KRAS-directed agents represent emerging immunological and molecular frontiers. Multimodal treatment regimens and surgical innovations, including vessel-oriented and minimally invasive techniques, have enhanced complete resection rates and enabled conversion of initially unresectable locally advanced pancreatic cancer into resectable disease. Increasingly, multidisciplinary, biology-guided strategies define resectability and the sequence of systemic and local therapies. The tumour microenvironment’s complex stromal and immune ecology remains central to therapeutic resistance but also offers opportunities for rational combination therapy. Early detection and risk-adapted surveillance for high-risk individuals are advancing, as are artificial intelligence-assisted imaging and liquid biopsy approaches. Despite persistent challenges, the convergence of mechanistic insights, precision therapeutics and supportive care provides a framework for transforming pancreatic ductal adenocarcinoma from an inevitably lethal disease towards a better manageable condition. In this Primer, Roth et al. discuss the epidemiology, current knowledge of pathophysiology, diagnosis, management and quality of life of individuals with pancreatic ductal adenocarcinoma, which remains one of the deadliest malignancies globally.

Robotic liver resection (RLR) has emerged as a minimally invasive alternative to open liver resection (OLR) for selected primary liver tumors, but its application for major hepatectomies remains limited. This retrospective study included patients who underwent hepatectomy for hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (iCC) at Ulm University Hospital (Nov 2020–Sep 2023) and Klinikum Nuremberg (Dec 2023–Jun 2025). Patients underwent RLR (n = 65) or OLR (n = 35). Demographics, operative data (including IWATE score), and postoperative outcomes—length of stay (LOS), blood loss, complications (Clavien–Dindo), and 90-day mortality—were compared using Fisher’s exact and Mann–Whitney U tests (p < 0.05). A total of 100 patients were analyzed. Median age was 68.0 years (IQR 63.0–74.0) in RLR vs. 70.05 years (IQR 63.5–78.3) in OLR. LOS was significantly shorter after RLR (5 days [IQR 4–7] vs. 11 days [IQR 7–20.5], p < 0.001). Operative time tended to be lower with RLR (173 min [IQR 135–237] vs. 219 min [IQR 177–287], p = 0.072), and blood loss was significantly reduced (300 ml [IQR 100–625] vs. 750 ml [IQR 400–1450], p = 0.001). Bile leakage occurred in 4.6

Abstract Recent evidence suggests that the gut microbiome plays a role in the development and treatment response of pancreatic ductal adenocarcinoma (PDAC). However, the functional impact of tumor location and preoperative biliary stenting (PBS) on microbial composition and metabolism remains poorly understood. In this prospective study, preoperative stool specimens were collected from patients undergoing surgery for PDAC at Heidelberg University Hospital, Germany, between March 2020 and July 2021. Whole-genome shotgun metagenomic sequencing was performed to characterize microbial composition and functional pathways. A total of 63 preoperative stool samples were analyzed, including 40 patients with pancreatic head tumors (63.5%) and 23 with body/tail tumors (36.5%). Microbial community composition differed significantly according to tumor location (Bray–Curtis, p=0.005), with enrichment of Ruminococcus bromii in body/tail tumors. Among patients with pancreatic head tumors, PBS was associated with reduced alpha diversity (Shannon index, p=0.04), depletion of taxa including members of the Eubacteriales and Clostridiales orders as well as the genera Raoultella and Prevotella, and reduced abundance of selected genes involved in secondary bile acid metabolism. PBS was also associated with a higher rate of major postoperative complications according to Clavien–Dindo >3a (28.6% vs 3.8%; p=0.04). These findings suggest that biliary intervention may induce functional dysbiosis characterized by reduced microbial diversity and impaired bile acid metabolism, potentially disrupting host– microbiome crosstalk and contributing to adverse postoperative outcomes in pancreatic cancer.

Robot-assisted pancreatoduodenectomy (RPD) is increasingly performed for cancer in the pancreatic head. Randomised evidence confirming its oncological safety and efficacy is lacking. The DIPLOMA-2x2 trial aims to compare the oncological safety of RPD versus OPD in terms of radicality (microscopically radical resection [R0] resection). We hypothesise that RPD is non-inferior to OPD in terms of radicality and superior regarding time to functional recovery. The DIPLOMA-2x2 trial is an investigator-initiated, international, multicentre, patient- and assessor-blinded randomised non-inferiority trial. The trial was conducted as a roll-over of the DIPLOMA-2 trial and includes 20 high-volume tertiary referral hospitals in 7 countries. Minimum surgeon’s experience is 60 RPD and 60 OPD, with a minimum annual centre volume of 30 RPD prior to trial initiation. Eligible patients are adults (≥18 years) with suspected or proven upfront resectable pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (DCC) without any vascular involvement. Participants are randomised in a 2:1 ratio to RPD or OPD, respectively, stratified by tumour indication (proven PDAC versus other) and preoperative pancreatic fistula risk (high versus low). In total, 413 patients will be included, of which 137 previously randomised in DIPLOMA-2 and 276 newly recruited in DIPLOMA-2x2. Patients are blinded up to postoperative day 5. Primary outcome is pathological R0-resection rate (pR0; >1 mm tumour clearance at surgical resection margins and anatomical surfaces, 0 mm clearance at anterior surface), tested for non-inferiority with a −7

ABSTRACT Background Pancreatic cancer remains one of the most lethal cancers despite extensive efforts and research conducted over the past decades. To effectuate groundbreaking improvements in pancreatic cancer treatment, interdisciplinary and international collaboration is essential. Evidence‐based guidelines, including state‐of‐the‐art evidence and expert opinion, are crucial to guide medical specialists, researchers, and patients, especially on issues where consensus is still lacking. This article describes the methodological protocol for the development of the European Multidisciplinary Evidence‐Based Guideline on Pancreatic Cancer. The guideline aims to identify current knowledge gaps on pancreatic cancer management, develop questions based on these knowledge gaps, and answer these questions with evidence‐based recommendations supplemented, when evidence is lacking, with expert advice for treatment and future research. Methods This guideline development protocol is developed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The process is structured into six stages: First, 13 theme‐based multidisciplinary working groups are established, comprising representatives from 30 European medical and patient societies. Second, these working groups identify the most relevant current knowledge gaps on pancreatic cancer within their theme and formulate key questions. Third, the available evidence to answer these key questions is obtained through systematic reviews and the certainty of evidence is assessed using the GRADE approach. Fourth, recommendations are developed based on the available evidence. Fifth, all participants reach consensus on the recommendations through a modified Delphi process. Sixth, the recommendations are discussed during an open conference, including an external validation committee. Discussion This methodological protocol of the European Multidisciplinary Evidence‐Based Guideline on Pancreatic Cancer is designed to identify key knowledge gaps across 13 themes and formulate evidence‐based recommendations. This guideline initiative unites 30 European medical and patient societies for pancreatic cancer.

Background: Recent evidence suggests that gut microbiome plays a role in the development of pancreatic ductal adenocarcinoma (PDAC) and influences treatment response. However, the association of tumor location and preoperative biliary stenting (PBS) with gut microbial composition and diversity remains poorly understood. Methods: Preoperative stool specimens were prospectively collected from patients with PDAC undergoing surgery between March 2020 and July 2021 at the Department of Surgery, Heidelberg University Hospital, Germany. Whole-genome shotgun metagenomic sequencing was performed. Microbial diversity was assessed using the Shannon index and Bray-Curtis dissimilarity with principal coordinates analysis. Results: A total of 63 preoperative stool samples were analyzed from 40 patients with pancreatic head (63.5%) and 23 with body/tail tumors (36.5%). Baseline characteristics were comparable between groups. Microbial community composition differed significantly between tumor locations (Bray-Curtis, p = 0.005), with enrichment of Ruminococcus bromii in body/tail tumors. Among patients with pancreatic head tumors, PBS was associated with reduced alpha diversity (Shannon index, p = 0.04) and depletion of taxa including Eubacteriales and Clostridiales taxa, and members of the genera Raoultella and Prevotella. PBS was associated with a higher rate of major complications > 3a according to the Clavien-Dindo classification (28.6% vs. 3.8%; p = 0.04). Conclusions: PBS was associated with reduced microbial diversity and distinct taxonomic alterations of the gut microbiome. These findings suggest that biliary stenting is associated with microbiome alterations that may be relevant for perioperative risk stratification and warrant further investigation.

Esophageal resections are associated with significant postoperative morbidity and mortality. The standard surgical approach is minimally invasive, with a high proportion of robotic resections. The aim of this study was to evaluate the learning curve (LC) in the context of establishing a structured training program. As part of the retrospective analysis, all consecutive hybrid robot-assisted Ivor-Lewis esophageal resections performed by a defined team between May 2023 and October 2025 were evaluated. The LCs for the frequency of postoperative complications Clavien-Dindo (CD) ≥ III, in particular anastomotic leakage, and the textbook outcome rate were analyzed. The LCs for these target variables were evaluated using the cumulative sum (CUSUM) analysis. Between May 2023 and October 2025, a total of 71 patients underwent hybrid robot-assisted Ivor-Lewis esophagectomy. In-hospital mortality in the study population was 1.4

Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, characterized by late diagnosis, aggressive biology and limited therapeutic success. Advances in multiagent chemotherapy have improved outcomes across disease stages, whereas precision medicine approaches are reshaping treatment paradigms. Personalized RNA vaccines and oncogenic KRAS-directed agents represent emerging immunological and molecular frontiers. Multimodal treatment regimens and surgical innovations, including vessel-oriented and minimally invasive techniques, have enhanced complete resection rates and enabled conversion of initially unresectable locally advanced pancreatic cancer into resectable disease. Increasingly, multidisciplinary, biology-guided strategies define resectability and the sequence of systemic and local therapies. The tumour microenvironment's complex stromal and immune ecology remains central to therapeutic resistance but also offers opportunities for rational combination therapy. Early detection and risk-adapted surveillance for high-risk individuals are advancing, as are artificial intelligence-assisted imaging and liquid biopsy approaches. Despite persistent challenges, the convergence of mechanistic insights, precision therapeutics and supportive care provides a framework for transforming pancreatic ductal adenocarcinoma from an inevitably lethal disease towards a better manageable condition.

Introduction Surgical site infections (SSI) impose a substantial clinical and economic burden on healthcare systems, accounting for approximately 15% of nosocomial infections. While intraoperative lavage is predominantly performed with isotonic solutions, its efficacy in preventing SSI remains unproven. Hypochlorous acid (HOCl) has emerged as a promising antimicrobial agent due to its potent microbicidal properties and high biocompatibility. The primary objective of this study is to evaluate whether the systematic introduction of a standardised intraoperative lavage with HOCl reduces the incidence of SSI in patients undergoing elective visceral surgery compared with conventional irrigation with isotonic saline. It is hypothesised that the implementation of HOCl-based lavage will lead to a significant reduction in the composite rate of superficial, deep and organ/space SSIs during the immediate postoperative hospitalisation period.Methods This is a single-centre, prospective, sequential, quasi-experimental trial conducted at Heidelberg University Hospital. A prospective cohort of approximately 500 adult patients undergoing elective visceral surgery with HOCl-based lavage (Granudacyn) will be compared with a sequential retrospective control cohort of 500 patients treated with isotonic solution. The primary outcome is the incidence of SSI (superficial, deep or organ/space) according to Centres for Disease Control and Prevention criteria, assessed until hospital discharge or postoperative day 10 (+/- 2 days). Secondary outcomes include length of stay in the intensive care unit and hospital, duration of antibiotic therapy and the Comprehensive Complication Index (CCI).Ethics and dissemination The study protocol has been approved by the Ethics Committee of the Medical Faculty of Heidelberg University (S-522/2025). Findings will be disseminated through peer-reviewed publications and presentations at international surgical congresses to inform clinical practice and future SSI prevention guidelines.Trial registration number DRKS00038635

BackgroundLiver tumors in childhood are rare and associated with high treatment demands. Over the past decades substantial progress has been achieved through effective chemotherapies and improved surgical techniques as well as international collaborations. Nevertheless, the challenges for the surgical treatment remain high. In Germany additional specific difficulties arise in this context. ObjectiveTo summarize the current evidence on the surgical management of pediatric liver tumors, to analyze the care structures in Germany and to develop perspectives for optimizing treatment. Material and methodsNarrative review of the current evidence, systematic analysis of the surgical results of previous hepatoblastoma studies, and evaluation of German care pathways in order to identify problems and perspectives. ResultsThe improved prognosis of children with liver tumors (particularly hepatoblastoma) is mainly due to multimodal, risk-adapted treatment concepts and advances in surgical strategies. Because of the rarity of pediatric liver resections, pediatric liver tumor surgery in Germany is positioned at the intersection of pediatric, visceral and transplantation surgery. Surgically, strategies adapted to children are crucial to increase resection rates and avoid postoperative complications. A direct transfer of concepts from adult liver surgery carries substantial risks. In Germany the basic prerequisites are good but care can be further improved through better communication with reference structures, intelligent centralization approaches and investment in surgical training. DiscussionPediatric liver tumor surgery is associated with specific challenges due to the rarity and high demands. In Germany, strengthening multidisciplinary structures and communication as well as efficient centralization of treatment planning, can further improve patient safety and outcomes for children with liver tumors.

BACKGROUND:Interpretation of recurrence following resection of intraductal papillary mucinous neoplasms (IPMNs) is hindered by inconsistent terminology and outcome reporting. A distinction between metachronous/de novo IPMN development, progression of residual disease, and true recurrence of invasive entities is rarely considered. METHODS:A systematic review and meta-analysis were conducted following PRISMA and Cochrane guidelines (PROSPERO-ID: 1009399). The primary endpoint was postoperative recurrence of non-invasive IPMN and IPMN-derived pancreatic cancer (PC). Recurrence following resection of non-invasive IPMN was reclassified as progression of persistent cysts or de novo metachronous IPMN. Secondary endpoints comprised risk-factors for recurrence. RESULTS:Sixty-six articles with 11 464 patients were included. After a median follow-up of 26 (interquartile range (i.q.r.) 18.0-53.0) to 72 (i.q.r. 5-318) months, the recurrence rate of IPMN-derived PC was 41.9% (1646/3925 patients), with a 5-year pooled recurrence-free survival of 46.6%. Systemic recurrence was most common (1034/1646; 62.8%), followed by locoregional (430/1646; 26.1%). Secondary treatments were administered in 655/1646 patients (39.8%) presenting with recurrence and included chemotherapy (65.5%), surgery (22.1%) and radiation (5.8%). Lymph node involvement (hazard ratio 2.87, 95% confidence interval 1.51 to 5.43) and tubular subtype (hazard ratio 1.68, 1.16 to 2.43) were identified as independent predictors of recurrence-free survival. The overall recurrence rate following pancreatic resection of non-invasive IPMN was 11.2% (831/7446), after median follow-up of 28 (i.q.r. 1-153) to 114 (i.q.r. 12-204) months. Among these, 408 (49.1%) developed as de novo lesions in the remnant pancreas and 174 (20.9%) as progression of pre-existing cyst detected at the time of index surgery; the remaining 249 patients (30.0%) could not be reclassified. Non-invasive recurrence was more common (308; 37.1%) than IPMN-derived PC (118; 14.2%), whereas the type of recurrence was unspecified in 405 patients (48.7%). Secondary treatment data were available for 265 patients, of whom 131 (49.4%) underwent reoperation. CONCLUSION:The recurrence rate of IPMN-derived PC is high and warrants close surveillance policies. The majority of 'recurring' non-invasive IPMNs are de novo lesions. Standardized reporting, distinguishing true recurrence from de novo development and progression of residual disease, is essential to stratify recurrence risk and optimize surveillance protocols accurately.

Background:With the recent publication of the first randomized controlled trials (RCTs) comparing robotic partial pancreatoduodenectomy (RPD) versus open partial pancreaticoduodenectomy (OPD) now providing high-level evidence, this study aims to analyze the short-term outcomes of RPD versus OPD to answer the ongoing clinical debate regarding the advantages and limitations of RPD, particularly in terms of perioperative safety. Methods:We searched Medline, Web of Science, and CENTRAL accessed last on 26th of November 2025 for prospective studies. The main outcome was 90-day mortality; secondary outcomes included complications, and short-term oncological outcomes (R0 resection rate), among others. A random-effects model was employed. Risk of bias was assessed using the Cochrane risk-of-bias-tool (RoB 2) for randomized controlled trials (RCTs), and the ROBINS-I-tool for comparative cohort trials (CCTs). The certainty of evidence was graded according to GRADE. (PROSPERO registration ID: CRD42024523577). Findings:Out of a total of 7388 screened studies, 358 studies underwent full-text screening leading to inclusion of 7 studies (3 RCTs and 4 CCTs). No significant difference was observed between RPD and OPD for 90-day mortality [OR (95% CI) 1.07 (0.04, 29.40)], clinically relevant complications including postoperative pancreatic fistula (POPF), or reoperation rates [OR (95% CI) 1.10 (0.47, 2.59)]. Lymph node yield, R0 resection rate, operative time and length of hospital stay were also not significantly different. However, readmission rates favored OPD [OR (95% CI) 1.22 (1.15, 1.28)], while there was a lower amount of intraoperative blood loss in RPD [SMD (95% CI) -0.98 (-1.65, -0.32)]. Interpretation:In this systematic review and meta-analysis, mortality following RPD was comparable to OPD. RPD has demonstrated similar rates for major complications and short-term oncological outcomes and can thus be equally recommended as OPD but this recommendation is limited to experienced, high-volume centers. Funding:This systematic review and meta-analysis was investigator-initiated and did not receive additional funding.

Introduction Surgical site infections (SSIs) impose a significant clinical and economic burden on the healthcare systems. To date, traditional preventive strategies have frequently failed to demonstrate definitive efficacy. Hypochlorous acid (HOCl) has emerged as a compelling antimicrobial alternative, characterised by potent microbicidal properties and excellent biocompatibility. Hypoclates:Peritonitis investigates the clinical impact of an HOCl-based lavage strategy in patients undergoing surgical treatment for secondary peritonitis. The trial evaluates the primary endpoint of postoperative SSI incidence up to day 10 (±2 days), hypothesising that the antimicrobial and biocompatible properties of HOCl significantly lower infection rates compared with standard isotonic lavage.Methods Using a sequential, quasi-experimental design, this mono-centric study assesses the clinical impact of adopting an intensified, multi-day HOCl-lavage protocol (Granudacyn) for patients with secondary peritonitis. We will compare a prospective intervention group (n≈100) against a preceding cohort of equal size that received standard isotonic irrigation. The primary endpoint is defined as the frequency of SSIs—inclusive of superficial, deep and organ/space infections according to Centers for Disease Control and Prevention criteria—monitored through hospital discharge or up to postoperative day 10 (±2 days). Secondary evaluative measures include the length of intensive care unit and total hospital stay, the duration of postoperative antibiotic therapy and the cumulative morbidity burden as calculated by the Comprehensive Complication Index.Ethics and dissemination Ethical clearance for this trial was provided by the Institutional Review Board of the Medical Faculty of Heidelberg University (S-523/2025). To facilitate knowledge transfer and evidence-based practice, the study results will be presented at international scientific meetings and published in peer-reviewed journals, thereby contributing to the refinement of SSI prevention protocols in emergency visceral surgery.Trial registration number German Clinical Trials Register (DRKS), DRKS00038630.

Optimization of perioperative hemodynamic management during major pancreatic surgery can reduce postoperative complications. In this study, we aimed to investigate the effect of intraoperative hemodynamic management, in consideration of both anesthesiologic and surgery-related aspects on major short-term complications following partial pancreatoduodenectomy (PD). Data of 525 patients undergoing PD between January 2017 and December 2018 at the Heidelberg University Hospital were retrospectively analyzed. Primary outcome was a composite of 90-day mortality, pancreatic fistula and completion pancreatectomy. Logistic regression was performed to estimate the impact of anesthesiologic and surgical factors. Furthermore, patients were stratified by the amount of fluid administered intraoperatively and the maximum catecholamine dose to examine the impact on the primary endpoint. Using logistic regression analysis we demonstrated that epidural anesthesia was associated with a reduction in the occurrence of the combined endpoint (OR 0.568; CI 0.331–0.973), this effect was primarily driven by a lower rate of completion pancreatectomy. The intraoperative administration of fresh frozen plasma (FFP) doubled the odds of the occurrence of the primary endpoint (OR 2.238; CI 1.290–3.882). The comparison of patients with and without FFP transfusion showed that all components of the primary endpoint were more frequent in the FFP group. Complication rates in the stratified fluid groups showed a U-shaped curve with the least amount of complications in patients who received 6.5 to 8 ml/kg/h of intraoperative fluid. The comparison of maximum norepinephrine doses revealed the same pattern with the least complication rate in the low-intermediate dose range (0.05–0.08 µg/kg/min and 0.08–0.11 µg/kg/min). Epidural anesthesia had a beneficial effect on the rate of major surgical complications following PD, whereas intraoperative FFP transfusion showed a negative association. Intraoperative hemodynamic management appears to have a major impact on perioperative mortality and morbidity with a U-shaped relation for both fluid and vasopressor dose.