Background Chen's U-suture technique was presented with a low incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) in 2014. This study aimed to compare the outcomes of Chen's U-suture technique with those of duct-to-mucosa and traditional invagination pancreaticojejunostomy. Methods The data of patients who underwent pancreaticoduodenectomy across 21 hospitals between 2014 and 2019 were analyzed and categorized into Chen's group, the duct-to-mucosa (DTM) group, and the traditional invagination (TIG) group. Propensity score matching (PSM) analysis was performed to balance the baseline differences among three groups. Subsequently, the surgical outcomes were compared across the groups. Results After PSM, 1060 patients in each group were matched, resulting in balanced baseline characteristics. The CR-POPF rate was 5.19 % in Chen's group, compared to 8.02 % in the TIG group and 7.45 % in the DTM group (P=0.025). A statistically significant difference was identified between Chen's group and the TIG group (P = 0.034), whereas no significant difference was observed when comparing Chen's group to the DTM group (P = 0.060). In the subgroup with a small pancreatic duct (≤3 mm), the CR-POPF rate in Chen's group was significantly lower than that in the DTM group (4.6 % vs 7.4 %, P = 0.019). The incidences of intra-abdominal infection and abscess in Chen's group were 7.45 % and 0.47 % respectively, compared to 10.28 % and 2.26 % in the TIG group, and 10.19 % and 1.51 % in DTM group (all P < 0.05). No significant differences were observed in the rates of severe complications or mortality among the three groups. Conclusions Chen's U-suture technique was a better invagination pancreaticojejunostomy with decreased CR-POPF and POPF-related infection. Furthermore, it was superior to the duct-to-mucosa method for the patients with a small pancreatic duct.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with limited therapeutic options. Dysregulated transcriptional networks are key drivers of its aggressive biology. Here, by integrating clinical datasets with mechanistic studies, we performed a family wide systematic analysis of E2F transcription factors and identified E2F3 as a key oncogenic driver with prognostic significance comparable to E2F1. Functional studies showed that E2F3 accelerates PDAC proliferation and xenograft growth. Mechanistically, E2F3 transcriptionally activates the E3 ligase TRIM26, which binds TAB1, promotes K11-linked polyubiquitination, and facilitates TAB1-TAK1 complex formation to engage canonical NF-κB signaling. The SPRY and RING domains of TRIM26 mediate TAB1 interaction and ubiquitination, respectively. TRIM26 depletion attenuated E2F3 induced NF-κB activation and tumor growth, whereas its restoration rescued these effects. Clinically, E2F3, TRIM26, and phosphorylated p65 levels were positively correlated in PDAC tissues, and therapeutic delivery of siTRIM26 recapitulated NF-κB inhibition. These findings uncover an unrecognized E2F3-TRIM26-TAB1/TAK1-NF-κB signaling axis that links cell cycle regulation with inflammatory activation in PDAC and nominate TRIM26 as a druggable vulnerability to therapeutically decouple this oncogenic crosstalk.

RNF43 is frequently inactivated by mutations in pancreatic ductal adenocarcinoma (PDAC), but the molecular mechanisms and therapeutic vulnerabilities associated with RNF43 loss remain poorly defined. Here, we demonstrate that RNF43 functions as an E3 ubiquitin ligase targeting YBX1 for degradation, thereby suppressing mitochondrial oxidative phosphorylation (OXPHOS). In RNF43-deficient PDAC models, stabilized YBX1 activates MYC through dual mechanisms-enhancing MYC mRNA stability via IGF2BP1 and physically interacting with c-Myc protein-leading to transcriptional upregulation of IDH2 and IDH3A and subsequent OXPHOS activation. Importantly, RNF43 loss conferred sensitivity to OXPHOS inhibition both in vitro and in vivo. Treatment with the OXPHOS inhibitor IACS-010759 suppressed the proliferation, migration, invasion, and metastasis of RNF43-mutant tumors. Our findings identify a RNF43-YBX1-MYC signaling axis associated with metabolic reprogramming in pancreatic cancer and suggest that OXPHOS inhibition may represent a potential therapeutic vulnerability in tumors with RNF43-inactivating mutations.

The full text of this preprint has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

Epidermal growth factor receptor (EGFR) is a pivotal therapeutic target in pancreatic ductal adenocarcinoma (PDAC); however, the clinical efficacy of tyrosine kinase inhibitors (TKIs) such as erlotinib is frequently curtailed by acquired resistance. This study identifies histone deacetylase 1 (HDAC1) as a critical epigenetic driver of this resistance. HDAC1 is markedly upregulated in erlotinib-resistant PDAC cells, where it directly suppresses the transcriptional activity of TFCP2 through site-specific deacetylation at lysine 256 (K256). This modification attenuates TFCP2 function, leading to transcriptional repression of the metastasis suppressor NDRG1 and increased expression of EGFR, thereby activating EGFR-TKI resistance signaling pathways. Furthermore, EGFR-mediated tyrosine phosphorylation protects HDAC1 from ubiquitin-proteasome system (UPS)-dependent degradation, stabilizing HDAC1 and establishing a self-reinforcing feedback loop that sustains its elevated expression in the resistant state. To counter this mechanism, we designed a bioactive peptide derived from TFCP2 that competitively inhibits K256 deacetylation, thereby restoring TFCP2 transcriptional activity. In vitro and in vivo studies demonstrate that pharmacological inhibition of HDAC1 or restoration of TFCP2 acetylation reverses erlotinib resistance in PDAC. These findings unveil a previously unrecognized mechanism of EGFR-TKI resistance and suggest a promising strategy to enhance therapeutic efficacy in PDAC.

Prophylactic abdominal drainage during pancreaticoduodenectomy (PD) is a common treatment strategy for pancreatic fistula. However, its benefits and safety have been the subject of debate. The objective of this meta-analysis and system review is to assess the effects of prophylactic drainage, various types of drainage (active and passive), and the timing of drainage removal (early and late) on the postoperative outcomes of PD. A systematic literature search was conducted in the PubMed, Web of Science, and Cochrane Library databases as of April 28, 2024. Randomized controlled trials (RCTs) comparing prophylactic abdominal drainage, different drainage patterns, and the timing of drainage removal after PD were included, and the postoperative outcomes were evaluated. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to aggregate dichotomous outcomes. Meta-analysis was performed using the Mantel-Haenszel fixed- and random-effects models. Nine RCTs, including a total of 1638 patients, were incorporated in our study. The meta-analysis showed no statistically significant differences in postoperative outcomes between the closed-suction drain (CSD) group and the passive drain to gravity (PDG) group. Compared to the late drain removal (LDR) group, the early drain removal (EDR) group had a significant reduction in the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) (OR = 0.39, 95% CI = 0.20-0.79; P = .009), morbidity (OR = 0.41, 95% CI = 0.20-0.84; P = .01), and intra-abdominal infection (OR = 0.40, 95% CI = 0.22-0.75; P = .004). For the group of present of drainage and the group of absent of drainage, the patient inclusion criteria of the included studies were too heterogeneous, making meta-analysis inappropriate. The existing evidence is insufficient to negate the necessity of prophylactic drainage after PD. The meta-analysis did not show superiority of any specific approaches of drainage tube. However, this study did indicate that patients benefit from EDR in terms of CR-POPF, morbidity, and intra-abdominal infection. EDR was recommended for low/intermediate-risk patients.

Rationale: Loss of histone deacetylase 5 (HDAC5) is frequently observed in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC), and is associated with poor patient survival. Although HDAC5 has been implicated in DNA damage repair, the molecular mechanisms by which it regulates DNA double-strand break (DSB) repair pathway choice remain unclear. Methods: Using PDAC cell lines, genetically engineered mouse models, patient-derived organoids, and biochemical assays, we investigated the role of HDAC5 in DNA end resection and homologous recombination (HR). Protein interactions, post-translational modifications, DNA repair pathway activity, and cellular responses to DNA damage and PARP inhibition were systematically analyzed. Results: We identify HDAC5 as a critical regulator of DNA end resection and HR through deacetylation of Ku70. DNA damage induces casein kinase 2 (CK2)-mediated phosphorylation of HDAC5, promoting its nuclear translocation. Nuclear HDAC5 directly deacetylates Ku70 at lysine 287, facilitating Ku70 dissociation from DSB sites, thereby enabling DNA end resection and HR repair. In contrast, HDAC5 loss or CK2 inhibition results in Ku70 K287 hyperacetylation, prolonged retention of the Ku heterodimer at DSBs, impaired DNA end resection, and suppression of HR. Consequently, HDAC5-deficient PDAC cells exhibit increased sensitivity to PARP inhibitors, while pharmacological CK2 inhibition sensitizes HDAC5-proficient tumors to PARP inhibition. Conclusions: These findings uncover a previously unrecognized CK2-HDAC5-Ku70 signaling axis that governs DNA repair pathway choice by regulating DNA end resection. Targeting this axis provides a mechanistic rationale for enhancing PARP inhibitor sensitivity in PDAC, including tumors without classical homologous recombination deficiency.

e16446 Background: Neoadjuvant therapy has become standard practice for selected patients with pancreatic cancer, with proven benefits in improving R0 resection rates and survival outcomes; nevertheless, optimal regimen selection remains poorly defined due to a lack of high-quality evidence. This study evaluated the efficacy and safety of the NASOX regimen—liposomal irinotecan, oxaliplatin, and S-1—as neoadjuvant therapy in patients with high-risk resectable, borderline resectable (BRPC), or locally advanced pancreatic cancer (LAPC). Methods: This ongoing prospective multicenter study enrolled patients with cytologically confirmed pancreatic cancer, an ECOG performance status of 0–2, adequate organ function, and no prior anticancer therapy. Patients received 4-6 cycles of neoadjuvant NASOX (liposomal irinotecan 50 mg/m², oxaliplatin 60 mg/m 2 , S-1 40 mg/m 2 , every 2 weeks), with each cycle defined as 4 weeks and consisting of two administrations. Tumor response was assessed every 2 cycles according to RECIST v1.1, and serum CA19-9 levels were monitored biweekly. The primary endpoint was surgical conversion rate. Secondary end points included R0 resection rate, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 2023 and December 2025, 26 patients were enrolled (median age 58 years (range: 35–75); 34.6% females (n = 9)), including 1 (3.8%) high-risk resectable, 4 (15.4%) BRPC, and 21 (80.8%) LAPC. Among 18 patients with efficacy evaluation result, 8 achieved partial response (PR), 8 had stable disease (SD), and 2 had progressive disease (PD), yielding an ORR of 44.4% (8/18) and a DCR of 88.8% (16/18). Following multidisciplinary team (MDT) discussion, 7 patients were deemed suitable for surgical exploration; 2 declined surgery for non-medical reasons. 5 patients (25.0%) underwent resection, all achieving R0 resection. Median PFS and OS have not yet been reached. Among 16 patients completing planned therapy, median CA19-9 levels decreased from 580.9 U/mL at baseline to 213.5 U/mL; nine patients achieved > 50% reduction, and three normalized CA19-9 levels. Grade ≥3 treatment-related adverse events occurred in 38.5% of patients, most commonly neutropenia (19.2%) and vomiting (11.5%). No treatment-related deaths were observed. Conclusions: Neoadjuvant NASOX demonstrates promising antitumor activity with a manageable safety profile in patients with pancreatic cancer, supporting further prospective evaluation.

Abstract Background: PDAC is a highly lethal malignancy, with approximately 80% of patients presenting with unresectable locally advanced or metastatic disease at diagnosis. Prognosis for advanced PDAC remains poor, with limited treatment options. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, has shown convincing efficacy with favorable safety profile in Phase 3 trials in gastric cancer and cervical cancer. Herein, we report preliminary efficacy and safety results of cadonilimab plus AG (gemcitabine combined with nab-paclitaxel) as the first-line treatment in patients (pts) with advanced PDAC in a phase 2 study (NCT05859750). Methods: Pts with unresectable advanced or metastatic PDAC and no prior systemic therapy were enrolled. Eligible pts received cadonilimab (6 mg/kg or 10 mg/kg, Q2W) + chemo (AG, Q4W). The primary endpoint was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Results: As of 20 Oct 2025, 59 pts were enrolled (median age 63.1 years, 61.0% male, 74.6% ECOG PS 1, 59.3% with distant metastasis). The median follow-up time was 24.7 months (range: 3.0+, 27.4). 56 patients (95%) had at least one post-baseline tumor evaluation. The ORR and disease control rate (DCR) were 33.9% (19/56) and 96.4% (54/56), respectively, with no significant difference between locally advanced or metastatic pts. Longer DoR and survival was observed in the pts with locally advanced diseases. The median DoR was 7.46 months (95%CI: 4.07, NE) vs 4.80 months (95%CI: 1.87, 11.01). The median PFS was 11.1 months (95%CI: 8.7, 15.9) vs 7.2 months (95%CI: 5.5, 7.7). The median OS was 23.4 months (95%CI: 14.9, NE) vs 10.5 months (95%CI: 8.5, 12.8). Treatment-related adverse events (TRAEs) occurred in 100.0% of pts, and the most frequent were neutrophil count decreased (96.6%), anemia (89.8%), white blood cell count decreased (84.7%), platelet count decreased (76.3%), rash (52.5%), alanine aminotransferase increased (49.2%), aspartate aminotransferase increased (47.5%), alopecia (45.8%), lymphocyte count decreased (35.6%), pyrexia (35.6%), asthenia (32.2%), and pruritus (32.2%). No new safety signals were identified. Conclusions: AK104 in combination with AG showed encouraging efficacy and manageable safety in previously untreated pts with advanced PDAC. Table 1. OS and PFS based on RECIST 1.1 by disease status Locally advanced(N = 24) Metastatic(N = 35) Total (N=59) Median PFS (months), (95% CI) 11.1 (8.7, 15.9) 7.2 (5.5, 7.7) 8.5 (7.2, 10.4) 6-month PFS Rate (%), (95% CI) 89.9 (65.3, 97.4) 54.2 (34.2, 70.5) 69.2 (54.0, 80.2) Median OS (months), (95% CI) 23.4 (14.9, NE) 10.5 (8.5, 12.8) 13.8 (11.5, 17.7) 12-month OS Rate (%), (95% CI) 91.7 (70.6, 97.8) 40.0 (24.0, 55.5) 61.0 (47.4, 72.1) 24-month OS Rate (%), (95% CI) 44.1 (23.5, 62.8) 14.3 (5.2, 27.7) 26.2 (15.6, 38.1) Citation Format: Wenming Wu, Xiafei Hong, Qi Xu, Gang Jin, Zhihua Li, He Tian, Heshui Wu, Yiping Mou, Baocai Xing, Dianrong Xiu, Zhifang Yao, Zhongmin Maxwell Wang, Baiyong Li, Yu Xia. A phase II, multicenter, open-label study (COMPASSION-26) of cadonilimab, a PD-1/CTLA-4 bispecific antibody,combined with chemotherapy (chemo) as first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT145.

4192 Background: Spevatamig is an IgG1-based bispecific antibody targeting CLDN18.2 and CD47 with an optimized anti-CD47 arm designed to bind to CD47 more highly on cancer cells than on human red blood cells. We have previously described its monotherapy safety data and preliminary combination efficacy data in 1L mPDAC (Saeed et al., J Clin Oncol. 2026). Herein, we provide updated data from patients in the 1L mPDAC cohort, including additional efficacy data from the 2 mg/kg QW spevatamig + GnP dose level and new safety data from the 3 mg/kg QW spevatamig + GnP dose level. Methods: TWINPEAK is a multi-cohort Phase 1/2 dose escalation and expansion study (US: NCT05482893; China: CTR20252758) of spevatamig as monotherapy or combination therapy (with chemotherapy and/or an immune-checkpoint inhibitor) in patients with select gastrointestinal (GI) cancers. Here we report data from the Phase 2 cohort of spevatamig + GnP in 1L mPDAC at 2 dose levels: 2 mg/kg QW (N=22) and 3 mg/kg QW (N=22). Key endpoints include safety and tolerability, objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS). Results: As of January 15, 2026, 151 patients have been treated with spevatamig collectively in monotherapy and combination settings. In the 2 mg/kg QW spevatamig + GnP dose level (N=22), spevatamig continues to demonstrate tolerability when combined with chemotherapy, with cytopenia rates not exceeding those anticipated with GnP and no grade ≥ 3 nausea or vomiting events. The ORR is 48%, DCR is 90%, mPFS is 7.3 months (95% confidence interval: 5.6 months - not yet reached) and mOS is > 13 months (still maturing), with a median follow-up duration of 8.9 months. Antitumor activity was demonstrated irrespective of tumor CLDN18.2 expression levels and RAS mutational status. In the 3 mg/kg QW spevatamig + GnP dose level (N=22), no significant additive toxicity was noted when compared to the adverse event profile anticipated with GnP alone among patients with available safety data. No grade ≥ 3 nausea or vomiting events occurred. Updated safety data will be provided at the meeting for patients in this dose level. Conclusions: Overall, spevatamig 2 mg/kg QW or 3 mg/kg QW + GnP is well tolerated, with no significant additive toxicity compared to the adverse event profile anticipated with GnP alone. The additional efficacy data from patients treated at the 2 mg/kg QW spevatamig + GnP dose level continues to demonstrate promise when compared to pivotal trials of GnP in 1L mPDAC; enrollment into the 3 mg/kg QW spevatamig + GnP dose level is ongoing with maturing efficacy data. These two dose levels exhibit good combinability with chemotherapy and can be assessed in future combination studies with novel targeted therapies such as KRAS inhibitors. Clinical trial information: NCT05482893 .

In this phase 2 study (NCT05047991), patients with unresectable metastatic pancreatic adenocarcinoma were randomized to receive NALIRIFOX (liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin) or gemcitabine plus nab-paclitaxel. The primary endpoint was progression free survival (PFS). Secondary endpoints included other efficacy outcomes (overall survival, objective response rate, disease control rate, and duration of response), as well as safety, pharmacokinetic parameters, and evaluation of the relationship between UGT1A1*6 and UGT1A1*28 polymorphisms and safety. A total of 117 patients were enrolled and randomly assigned to NALIRIFOX (n = 78) or gemcitabine plus nab-paclitaxel (n = 39). At a median follow-up of 18.7 months (interquartile range [IQR], 7.5–22.1) for NALIRIFOX and 12.1 months (IQR: 6.4–14.8) for the gemcitabine plus nab-paclitaxel, median PFS was 7.6 months (95

Purpose:Optimal neoadjuvant therapy for borderline resectable pancreatic cancer/locally advanced pancreatic cancer (BRPC/LAPC) remains undefined. This study evaluated the efficacy and safety of neoadjuvant nab-paclitaxel and gemcitabine plus camrelizumab, with or without early stereotactic body radiation therapy (SBRT), among patients with BRPC/LAPC. Methods and Materials:This single-center, prospective trial enrolled adults with previously untreated BRPC/LAPC. Patients were assigned to an SBRT cohort, receiving early SBRT (25 Gy in 5 fractions) followed by nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 with camrelizumab (200 mg every 3 weeks), or to a non-SBRT cohort treated with the same chemoimmunotherapy alone. A multidisciplinary team determined whether patients underwent surgery or continued first-line therapy. The objective response rate served as the primary endpoint. Results:A total of 22 patients were enrolled (11 in each cohort). The objective response rate was 36.4% (8/22), and disease-control rate was 100% (22/22). Six patients (27.3%) underwent surgery, and all achieved clinical-to-pathologic downstaging and R0 margins (6/6). With a median follow-up of 30.0 months (95% CI, 23.3-36.7), median progression-free survival was 12.5 months (95% CI, 9.6 to not available) in the SBRT cohort and 6.6 months (95% CI, 6.4 to not available) in the non-SBRT cohort in an exploratory between-cohort analysis (P = .003). Median overall survival was 20.8 and 13.9 months in the SBRT and non-SBRT cohorts, respectively (P = .261). Toxicity profiles were similar across cohorts, with grade ≥3 treatment-related adverse events occurring in 36.4% of patients. Conclusions:Neoadjuvant nab-paclitaxel and gemcitabine plus camrelizumab, with or without early SBRT, showed encouraging efficacy and acceptable tolerability for BRPC/LAPC. The potential benefit of early SBRT warrants further investigation.

KRAS G12D mutations occur in approximately 2–4% of patients with non-small cell lung cancer (NSCLC). GFH375, a compound that targets both “ON” (GTP-bound) and “OFF” (GDP-bound) states of the KRAS G12D proteins, was evaluated in a phase 1/2 study among patients with advanced solid tumors harboring KRAS G12D mutations. The objectives were to evaluate safety and tolerability, characterize pharmacokinetics, and evaluate preliminary efficacy. A total of 86 patients with KRAS G12D -mutant advanced solid tumors, including 28 with advanced NSCLC, were treated with the single agent GFH375 administered orally once or twice daily. Overall, GFH375 was well tolerated and had a manageable safety profile. Treatment-related adverse events occurred in 97.7% of the patients: 37.2% experienced grade ≥3 adverse events, and 1 patient (1.2%) experienced a grade 5 adverse event. Encouraging antitumor activity was demonstrated in patients with previously treated NSCLC, with objective response rates of 57.7% (90% CI: 39.8–74.2) at all dose levels and 68.8% (90% CI: 45.2–86.8) at 600 mg once daily; the 6-month progression-free survival rates were 60.4% (90% CI: 46.2–78.8) and 77.4% (90% CI: 60.6–98.9), respectively. Co-occurring alterations were analyzed with circulating tumor DNA (ctDNA) collected at baseline and at the end of treatment. The study is ongoing (ClinicalTrials.gov identifier: NCT06500676).

Since being reported in 2014 with a low clinically relevant postoperative pancreatic fistula (CR-POPF) rate, Chen’s U-suture technique has undergone multiple modifications. This study aims to compare the surgical outcomes of the modified Chen’s U-suture technique with duct-to-mucosa anastomosis in laparoscopic pancreaticoduodenectomy (LPD). Data on 669 consecutive patients treated with LPD in 8 tertiary medical centers from January 2021 to December 2024 were retrospectively collected and classified into Chen’s group (n = 276) and duct-to-mucosa group (n = 393) according to different pancreaticojejunostomy. Propensity score matching (PSM) analysis was performed to balance the baseline differences. The surgical outcomes were compared. After PSM, 208 patients in each group with balanced baseline characteristics were matched. The mean duration of pancreaticojejunostomy was 16.87 ± 6.20 min in Chen’s group compared to 21.74 ± 13.82 min in the duct-to-mucosa group (p < 0.001). The mean length of postoperative hospital stay was shorter in Chen’s group (10.07 ± 8.17 days vs. 13.19 ± 11.42 days, p = 0.002). There were 14 patients (6.73

The biological significance of forkhead box A1 (FOXA1) in non-steroid-driven malignancies, such as pancreatic ductal adenocarcinoma (PDAC), has garnered increasing recognition. It assumes a pivotal role in regulating critical processes such as PDAC cell lineage, metabolism, and metastasis. However, its regulatory mechanisms remain elusive. Here, we demonstrate that histone deacetylase 5 (HDAC5) mediates the deacetylation of FOXA1 at lysine residue 270 (K270), leading to repression of FOXA1's global chromatin occupancy. In HDAC5-loss PDAC, K270 hyper-acetylated FOXA1 is reprogrammed to the transcription start sites (TSSs) of HIF1α-targeted genes, functioning as a pioneer factor of HIF1α signaling. Additionally, we show that HDAC5 antagonizes LSD1-mediated FOXA1 activation by converging on the dynamic equilibrium of acetylation-methylation transition at K270. Pharmacological inhibition of HIF1α/LSD1 suppresses the growth and progression of HDAC5-deficient PDAC in in vivo and in vitro models. Our study reveals the role of FOXA1 as a pioneer factor of HIF1α in PDAC, providing potential therapeutic strategies for HDAC5-deficient PDAC.

The impact of advanced age on pancreaticoduodenectomy (PD) remains controversial, partly due to inconsistent definitions of “elderly”. To determine the optimal age cut-off for risk stratification and evaluate the safety of different surgical approaches and anastomotic techniques in elderly patients, this study retrospectively analyzed clinical data of 7,028 patients who underwent PD between 2014 and 2019 at 21 centers. Logistic regression analysis demonstrated that advancing age was significantly associated with increased risks of clinically relevant postoperative pancreatic fistula (CR-POPF), bile leakage, pulmonary infection, intra-abdominal infection, and mortality. The optimal age cut-off for predicting CR-POPF was determined as 65 years using receiver operating characteristic curve analysis and the Youden index. Patients were stratified into younger and elderly groups based on this threshold. Both before and after propensity score matching, the elderly group continued to demonstrate significantly higher rates of CR-POPF (before matching: 9.02

BackgroundThe incidence of postoperative pancreatic fistula following distal pancreatectomy is as high as 30%-50%. Postoperative pancreatic fistula can be a major cause of perioperative morbidity, resulting in prolonged hospital stays and increased health care costs. The management of the pancreatic stump is one of the key factors influencing the occurrence of postoperative pancreatic fistula after distal pancreatectomy, but the optimal management approach remains debatable. The main methods for pancreatic stump closure include manual suturing and stapler closure. However, both methods are associated with a high risk of postoperative pancreatic fistula, which may be related to the balance between providing sufficient pancreatic duct burst pressure and ensuring blood supply to the stump. Ligation of the pancreatic stump has been attempted to reduce the risk of postoperative pancreatic fistula following distal pancreatectomy, but its efficacy remains limited by the challenge of achieving the optimal ligation force. ObjectiveThis study aims to investigate whether ligation of the pancreatic stump with a quantified force can decrease the risk of postoperative pancreatic fistula following distal pancreatectomy. MethodsIn this nonrandomized controlled clinical study at a tertiary center in China, the major eligibility criterion is the presence of lesions planned for distal pancreatectomy. Sixty patients will be allocated to the experimental or control group according to their choice. Recruitment for either group will be discontinued upon reaching the predefined sample size of 30 participants. In the experimental group, the pancreas will be ligated 5 mm from the pancreatic stump with a quantified force to provide a pancreatic duct burst pressure of approximately 40-70 mm Hg. The ligation force will be provided by a 3.2-mm-diameter silicone ring. During pancreatic stump ligation, this silicone ring will be stretched to 15 mm, generating an applied force of 1.3 N. The pancreas will be severed using energy-based devices before or after the ligation. In the control group, the pancreatic stump will be managed by manual suturing or stapling closure according to the surgeon’s clinical judgment and preference. Postoperative regular follow-up examinations will be conducted. The primary outcomes include postoperative pancreatic fistula and postoperative hospital stay, and the secondary outcomes include intra-abdominal infection, incision infection, and postoperative treatment costs. The primary and secondary outcomes of patients in this cohort will be statistically compared using appropriate tests. ResultsThis study started in February 2025, and the recruitment period is from February to September 2025. ConclusionsThis protocol proposes a novel approach for pancreatic stump management aimed at preventing postoperative pancreatic fistula following distal pancreatectomy. The research team established the optimal ligation force for the pancreatic stump to ensure adequate burst pressure for the pancreatic duct while preventing acute stump necrosis, thereby theoretically reducing the risk of postoperative pancreatic fistula. Trial RegistrationChinese Clinical Trial Register ChiCTR2500097781; https://www.chictr.org.cn/showproj.html?proj=247008 International Registered Report Identifier (IRRID)DERR1-10.2196/74018