OBJECTIVE:To determine whether robotic pancreatoduodenectomy (RPD) is non-inferior to open pancreatoduodenectomy (OPD) in terms of postoperative functional recovery, without compromising safety or oncological quality. DESIGN:Multicentre, single masked, phase 3, non-inferiority randomised controlled trial. SETTING:Seven tertiary high volume pancreatic centres in China, 15 June 2020 to 28 November 2024. PARTICIPANTS:268 adults with resectable pancreatic or periampullary disease. INTERVENTIONS:Participants were randomised to receive standardised RPD (n=142) or OPD (n=126), with enhanced recovery pathways. MAIN OUTCOME MEASURES:The primary outcome was time from surgery to postoperative functional recovery, defined as adequate pain control without parenteral analgesia, ≥50% oral intake without intravenous fluids, independent mobilisation, and absence of active intra-abdominal infection. The restricted mean event time (RMET) within 40 days was a summary for time from surgery to postoperative functional recovery. Secondary outcomes included operative metrics, disease related outcomes, length of stay, postoperative morbidity, including complications of Clavien-Dindo grade II or higher (defined as complications requiring drug treatment or more intensive intervention), and hospital admission costs. RESULTS:Overall, 254 of 268 randomly assigned participants (mean age 62 years; 172 (64.2%) men) underwent surgery, completed follow-up, and were included in the modified intention-to-treat population; 14 did not undergo surgery. In the modified intention-to-treat population, the RMET was 12.1 days (95% confidence interval (CI) 11.2 to 13.1) in the RPD group and 16.0 days (14.5 to 17.5) in the OPD group (difference -3.9 days, 95% CI -5.6 to -2.2; P<0.001). Operative time was longer in the RPD group (300 minutes (interquartile range (IQR) 240-360 minutes) versus 270 (210-300) minutes in the OPD group, P<0.001) but postoperative length of stay was shorter in the RPD group (13 (IQR 11-16) days v 16 (13-20) days, P<0.001). Overall postoperative morbidity was 31.1% (41/132) in the RPD group versus 36.1% (44/122) in the OPD group and incidence of any complications of Clavien-Dindo grade II or higher was 23.5% (31/132) versus 34.4% (42/122), respectively. 90 day mortality was 0.8% (1) in the RPD group and 2.5% (3) in the OPD group. Median total costs of hospital admission (including readmission cost) were higher in the RPD group than in the OPD group (¥130 905 (£14 369; $19 351; €16 628) (IQR ¥114 853-¥152 547) v ¥108 071 (¥92 134-¥128 035), difference ¥22 834 (95% CI ¥16 744 to ¥30 522); P<0.001). CONCLUSIONS:In high volume centres with credentialled surgeons, RPD met the non-inferiority margin for time from surgery to postoperative functional recovery, with comparable disease related outcomes and overall burden from postoperative complications. To generate wider system level efficiency gains, the implementation of RPD should take account of institutional expertise, procedural volume, acquisition of robotic surgical platforms and maintenance costs, and the potential for shorter hospital stay. TRIAL REGISTRATION:ClinicalTrials.gov NCT04400357.

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.

BACKGROUND:Implementation of remote robotic-assisted surgery (rRAS) has the potential to significantly improve access to high-quality surgical care for patients worldwide. Advances in robotic systems and telecommunications now enable highly reliable, low latency, and cybersecure connectivity. These technological developments, together with the broader adoption of telemedicine, have driven an increasing interest in the implementation of rRAS. METHODS:The Clinical Robotic Surgery Association (CRSA) convened a conference to develop international clinical recommendations for rRAS using the Danish Model of Consensus. The society identified five key issue categories and invited a panel of experts to address specific questions for each. Panel members and a jury of 10 unbiased, non-expert in rRAS professionals participated in a day-long conference on November 19, 2025 (Los Angeles, USA). During the conference, participants presented, discussed, and reached consensus on specific guidelines relevant to each category. Immediately after the conference, the jury reviewed and approved the recommended guidelines. RESULTS:Multiple recommendations were approved for each of the following categories: Operating Models, Roles and Responsibilities (2 recommendations), Clinical Pathway (2 recommendations), Emergency Management (8 recommendations), Technical Considerations (5 recommendations), and Medico-legal and Ethical Considerations (4 recommendations). CONCLUSIONS:There was consensus that with recent advances in telecommunication and robotic technologies, rRAS can be offered safely and effectively if the identified safeguards are realized. Adoption of rRAS is expected to continue advancing rapidly.

To evaluate the clinical applicability of previously established transcriptomic signatures (molecular subtypes, components and GemPred status) in metastatic pancreatic cancer, we conducted a retrospective pooled analysis of 178 patients from three phase 2 trials (PRODIGE35/37, AFUGEM; 2013-2016) testing first-line regimens (FOLFIRINOX, GemNab, FuNab, FOLFIRI3). RNA sequencing was performed on primary/metastatic tumors across French centers, with blinded assessment of subtypes (immune classical, pure basal-like, stroma-activated), quantitative components, and GemPred status. Primary endpoint: progression-free survival (PFS). Immune classical subtype showed superior median PFS (9.03 months) and OS (11.27 months) versus basal-like and stroma-activated subtypes (PFS: p = 0.015; OS: p = 0.010). Higher classical component correlated with improved OS (HR = 0.737, p = 0.005) but not PFS (HR = 0.90, p = 0.339). Inactive stroma predicted better PFS (HR = 0.66, p = 0.003) and OS (HR = 0.697, p = 0.013). GemPred-negative patients treated with FOLFIRINOX versus GemNab had higher ORR (46.9% vs. 19.1%, p = 0.046), longer PFS (8.2 vs. 2.3 months; HR = 2.28, p = 0.008), and OS (11.6 vs. 5.0 months; HR = 2.04, p = 0.021). No differences occurred in GemPred-positive patients. In a formal treatment-by-GemPred interaction analysis (FOLFIRINOX vs. GemNab), the interaction was significant for OS (adjusted p-interaction = 0.050) but not for PFS (adjusted p-interaction = 0.51). Transcriptomic signatures retain prognostic and predictive utility in metastatic pancreatic cancer, with GemPred representing a hypothesis-generating predictive signal for OS (e.g., a FOLFIRINOX OS benefit in GemPred-negative). Prospective validation is warranted for clinical implementation.

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and largely refractory to current therapies, underscoring the need to uncover the molecular drivers of progression to identify targetable vulnerabilities. In this study, we found that fibronectin type III domain-containing 4 (FNDC4), known for its role in macrophage polarization and metabolic regulation, was elevated in metastatic PDAC cells and correlated with poor patient outcomes. FNDC4 knockdown reduced tumor growth and metastasis in a diverse set of aggressive PDAC models. Mechanistically, FNDC4 enhanced cell cycle and apoptosis regulator 1 (CCAR1) stability, thereby sustaining CCAR1/β-catenin signaling. FNDC4 deficiency led to reduced CCAR1 and β-catenin expression and consequently impaired invasion and colony formation. Moreover, FNDC4 promoted immune evasion by driving macrophage polarization toward a protumorigenic M2 phenotype. FNDC4 loss shifted macrophage polarization toward an antitumor profile and increased CD4+ and CD8+ T-cell infiltration. Together, the effects of FNDC4 targeting resulted in reduced tumor burden, suppression of metastasis, and improved survival in immunocompetent murine PDAC models. Unexpectedly, FNDC4 localized to the nucleus, pointing to potential intranuclear activity. Transcriptomic and functional analyses further identified CCL5 as a critical downstream effector, required for recruiting CCR5+ T cells and mediating the immune effects of FNDC4 inhibition. Upstream, BHLHE40 directly activated FNDC4 transcription, which was stimulated by induction of epithelial-mesenchymal transition. Importantly, combining FNDC4 inhibition with claudin 18.2 chimeric antigen receptor T cells or chemotherapy resulted in enhanced tumor control compared with monotherapy. Together, these findings underscore the role of FNDC4 in promoting PDAC progression and the potential of FNDC4 as a target for innovative multimodal treatment strategies. SIGNIFICANCE:FNDC4 is a key driver of pancreatic cancer invasiveness and immunosuppression that can be targeted to reprogram the pancreatic tumor microenvironment and suppress tumor metastasis, offering a promising therapeutic strategy.

BACKGROUND:Adjuvant chemotherapy (AC) provides an improved long-term survival chance for those with R0/R1 resection, following limited survival improvement space, as well as intolerable side effects. There is currently a gap in the use of macromolecule-targeted drugs (nimotuzumab) added to AC, so we developed this study. MATERIALS AND METHODS:Resectable pancreatic cancers (RPC) were treated with surgery and postoperative chemotherapy with or without nimotuzumab. Demographic and clinical data were collected from the electronic medical records of Ruijin Hospital from May 2016 to July 2022. The primary efficacy endpoint was OS. Additional endpoints included disease-free survival (DFS) and adverse reactions (safety). RESULTS:Thirty-six RPC patients who had received AC with nimotuzumab (study arm) or 55 patients who had conducted AC alone (control arm) treatment out of the 795 patients screened. The median age was 61 years. The Barthel score was 99. The study arm demonstrated a prolonged median overall survival (mOS) and median disease-free survival (mDFS) trend compared with the control arm (mOS, 45.1 mo vs. 28.1 mo; mDFS, 20.0 mo vs. 13.0 mo). In the further exploratory analyses of KRAS mutation and KRASG12D types, the study arm also showed a survival benefit trend (mOS, 44.6 mo vs. 25.0 mo, mDFS, 30.9 mo vs. 10.3 mo in KRAS mutation; mOS, 36.2 mo vs. 19.6 mo in KRASG12D type). R0 patients with KRASG12D, the survival benefit on DFS was significantly different (mDFS, 16.0 mo vs. 9.9 mo; P =0.022). For adverse events grade 3 or higher calculated, the highest incidence of adverse reactions was slightly hematologic abnormalities, such as anemia, leukopenia, etc., in both groups. No grade 4 or above adverse reactions were observed. CONCLUSIONS:By adding nimotuzumab to existing gemcitabine-based AC regimens, RPC patients would show a survival benefit trend with a satisfactory safety profile.

2509 Background: Pancreatic cancer has a high postoperative recurrence rate. Although adjuvant chemotherapy is standard of care, many patients are unable to tolerate it, highlighting an unmet need for alternative adjuvant strategies. Personalized neoantigen mRNA vaccines can induce tumor-specific T-cell responses and may synergize with PD-1 blockade. This study evaluated the safety, tolerability, and preliminary clinical activity of XP-004 combined with a PD-1 inhibitor as adjuvant therapy in resected pancreatic cancer patients intolerant to chemotherapy. Methods: This open-label, single-arm, investigator-initiated phase I trial (2024PCV004; NCT06496373) initiated in May 2024 plans to enroll 16-20 patients with resected pancreatic cancer intolerant to chemotherapy. Patients received XP-004 intramuscularly (1.0 mg Q3W for 13 cycles), including a KRAS-targeted single-neoantigen vaccine for 4 cycles followed by a personalized multi-neoantigen vaccine for 9 cycles, combined with toripalimab (PD-1 inhibitor). Each personalized vaccine encoded 10–20 personalized neoantigens selected using next-generation sequencing and bioinformatic prediction. The primary endpoint was safety and tolerability; secondary endpoints included neoantigen-specific CD4⁺ and CD8⁺ T-cell responses, recurrence-free survival (RFS), and overall survival (OS). Results: As of December 15, 2025, 16 patients were enrolled. XP-004 mRNA vaccine was well tolerated. Treatment-related AEs included fever (100%), injection-site pain (87.5%), nausea (43.8%), vomiting (37.5%), pruritus (50.0%), rash (25.0%), and fatigue (37.5%). Grade ≥3 AEs were observed in 12.5% patients, including fever (12.5%) and pruritus (6.3%), the latter attributed to toripalimab. No other immune-related AEs were observed. Transient cytokine increases (IFN-γ, IL-5, IL-6, IL-8, IL-10) were observed without organ dysfunction. At a median postoperative follow-up of 43.9 weeks (range of 6.1–72.0 weeks), and a median follow-up of 37.6 weeks (range of 0.9–63.7 weeks) after first vaccination, all patients remained recurrence-free, with no clinical or molecular evidence of recurrence, including no tumor-informed MRD relapse. Among the 13 patients evaluable for immunogenicity, 13 (100.0%) developed neoantigen-specific T-cell responses; 53 of 165 neoantigens (32.1%) were immunogenic. Conclusions: XP-004 combined with PD-1 inhibitor demonstrated favorable safety and tolerability and induced robust neoantigen-specific T-cell responses in resected pancreatic cancer patients intolerant to chemotherapy. Early follow-up suggests potential RFS benefit, supporting further investigation of this adjuvant immunotherapy strategy. Clinical trial information: NCT06496373 .

Abstract Objective: The China Pancreas Data Center (CPDC) was established in 2015 with the support of the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association and initiated prospective data collection in 2017. This article reports contemporary real-world evidence on surgical outcomes during 2020–2021, with the objective of assessing and refining clinical practice in pancreatic cancer care in China. Methods: Patients who underwent surgical treatment recorded in CPDC between January 2020 and December 2021 were retrospectively reviewed. Systematic analysis of real-world data encompassing demographics, medical history, comorbidities, symptoms, perioperative assessment and management, surgical interventions, postoperative complications, pathological findings, and overall survival was performed. Results: A total of 6297 pancreatic cancer patients who underwent surgical treatment from 65 centers across China were enrolled for analysis during 2020–2021. The median age was 64 years, and the male-to-female ratio was 1.2:1. Abdominal pain and jaundice were the most common symptoms. Approximately 62.6% of patients presented with pancreatic head/neck tumors, and the distribution of disease stage (I–IV) was 32.5%, 44.7%, 18.7%, and 4.1%, respectively. Minimally invasive surgery was performed in 30.4% of patients, with a conversion rate of 24.9%. Postoperative complication rates by Clavien–Dindo (I–V) were 52.6%, 33.2%, 12.7%, 1.0%, and 0.6%, respectively. The predominant neoadjuvant and adjuvant chemotherapy regimen was nab-paclitaxel plus gemcitabine (AG). The cohort’s in-hospital, 30-, and 90-day mortality rates were 0.6%, 1.2%, and 3.1%, respectively. And 1-year, 2-year, and 3-year postoperative overall survival rates were 75.8%, 53.3%, and 42.0%, respectively. Conclusions: Surgical management of pancreatic cancer in China exhibited regional and center-based concentration. The adoption of minimally invasive pancreatic surgery, surgical safety metrics, and outcomes reported herein align with established benchmarks from international high-volume pancreatic centers. Establishment and promotion of nationwide benchmarks and standardized protocols for pancreatic surgery are warranted.

The prevalence of type 2 diabetes mellitus (T2DM) is rising rapidly in China and is linked to increased cancer risk, but causality remains unclear due to biases. We examined the causal effect of T2DM on cancer risk using bias-minimizing methods. We conducted a matched cohort study within China Kadoorie Biobank (median follow-up 49 months in men and 53 months in women). To minimize bias, we included only new-onset T2DM, applied sequential longitudinal matching, used pre-diagnosis BMI, and accounted for detection time bias. Stratified Cox models estimated sex-specific time-split hazard ratios (tsHRs). Results were triangulated with two-sample Mendelian Randomization (MR) in East Asians. After 1:3 matching, 8657 men and 13,680 women with T2DM were matched to unexposed individuals. T2DM was associated with increased risk of total cancers in men (tsHR 1.57, 95% CI 1.38-1.78) and women (tsHR 1.29, 95% CI 1.14-1.46). Site-specifically, T2DM was associated with liver cancer (men: 68 cases, tsHR 2.12, 95% CI 1.42-3.15; women: 43 cases, tsHR 2.39, 95% CI 1.42-4.04) and pancreatic cancer (men: 36 cases, tsHR 2.57, 95% CI 1.35-4.92; women: 33 cases, tsHR 3.95, 95% CI 1.92-8.13). No significant associations were observed for colorectal, lung, stomach, or breast cancers. In multivariable MR, genetic liability to T2DM was associated with pancreatic cancer after adjusting for BMI (OR 1.07, 95% CI 1.01-1.14, p = 0.03). In this large Chinese population, we found evidence for causal associations between T2DM and pancreatic cancer only, whereas evidence for other cancers was weak or discordant.

ABSTRACT Objective We aimed to, for the first time, assess the value of modified textbook outcome (mTO) in robot‐assisted middle pancreatectomy (RMP) procedures. Summary Background Data Pancreatic fistula remains to be the major complication after RMP. Textbook outcome (TO) is introduced to capture the most desirable surgical outcomes. The value of TO in RMP surgery remains unknown. Methods All patients who underwent RMP in our center from 2010 to 2023 were enrolled in the study. Baseline characteristics, operative outcomes, and oncological outcomes were collected and analyzed. Textbook outcome was calculated separately for each patient and analyzed. Results The mTO was defined by the absence of modified post‐operative pancreatic fistula (mPOPF), postpancreatectomy hemorrhage (PPH), severe complications (Clavien–Dindo ≥ III), readmission, and in‐hospital mortality (IHM). The overall mTO rate and mPOPF rate of 209 patients were 73.68% and 15.79%, respectively. Patients who achieved modified textbook outcomes have shorter post‐operative hospitalization days (median (IQR), 17 (9) vs. 34 (26), p < 0.001). Passing the learning curve leads to a reduction of the mPOPF rate and an increase of the mTO rate. Conclusions Modified textbook outcome is a practical metric for evaluating ideal surgical outcomes in RMP surgery. Follow‐up multi‐center clinical research is necessary to evaluate this indicator even further.

The development of pancreatic surgery in China has progressed remarkably over 7 decades.China initiated its pancreatic surgery journey in the 1950s,marked by the first pancreaticoduodenectomy performed by Zeng Xianjiu in 1951.Early progress was hindered by techno-logical limitations and fragmented practices,but the establishment of academic platforms such as the National Pancreatic Disease Sym-posia in the 1980s catalyzed standardized research and interdisciplinary collaboration.In 2006,Zhang Shengdao spearheaded China's first Guidelines for the Diagnosis and Treatment of Severe Acute Pancreatitis.The 21st century has seen remarkable progress in pancreatic surgery,marked by the China-specific treatment guidelines,technological breakthroughs in laparoscopic and robotic surgical systems,and the increasing centralization of pancreatic surgery in high-volume medical centers.These synergistic advancements have collectively propelled a paradigm shift in contemporary cancer care.By 2022,China Pancreas Data Center reported a postoperative mortality rate of 0.4%and 3-year survival rates of 43%for resected pancreatic cancer,rivaling global benchmarks.China has also emerged as a leader in minimally invasive pancreatic surgery,with advancements in laparoscopic and robotic pancreatic surgery.Academic growth paralleled clinical progress:the Chinese Pancreatic Association,established in 2022,fosters global collaboration,evidenced by its 2024 annual con-ference attracting over 10,000 participants.Through technological innovation,centralized care models,and international partnerships,China continues to redefine its role in advancing pancreatic surgery.

Objective:The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers.Background:RDP is an emerging minimally invasive approach; however, only limited, mostly single-center data are available on its safe implementation, including the learning curve.Methods:Consecutive patients undergoing elective RDP from 16 expert centers across 3 continents were included to assess the learning curve. Based on the first 100 RDPs at each center, 3 cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade >= III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared.Results:The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P = 0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P = 0.012), and mastery was associated with a higher proportion of patients with textbook outcomes (71% vs 63%; P = 0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications.Conclusions:Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP.

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

Abstract Targeting KRAS is promising in KRAS-mutant cancers. However, primary and acquired resistance to KRAS inhibitors impedes their clinical use. We conducted a Phase IIa clinical trial enrolling 7 patients with resectable PDAC bearing KRAS^G12D mutations, who received standard neoadjuvant chemotherapy plus KRAS inhibitors. Genomic analyses revealed acquired mutations in KRAS and other cancer-related. Single-cell transcriptomic profiling showed significant differences in cancer-associated fibroblast (CAF) populations between responders and non-responders. Kinome CRISPR library screening and FDA-approved compound library screening nominated the JAK-STAT pathway as critical for response to KRAS inhibition. Cell lines resistant to KRAS inhibitors have activated JAK-STAT pathway. In vitro and in vivo, STAT3 inhibition synergized with KRAS inhibition, altered cytokine secretion by cancer cells, and modulated CAF status. These findings demonstrate that activation of the JAK-STAT pathway is a common mechanism of resistance to KRAS inhibitors in diverse KRAS-mutant cancers and suggest that dual targeting of KRAS and STAT3 may enhance therapeutic efficacy. Citation Format: Yi Zhao, Yizhi Cao, Yu Bao, Baiyong Shen. Targeting the JAK-STAT pathway sensitizes KRAS-mutant cancer to KRAS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6771.

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

Background:Nutritional problems are common in patients with pancreatic cancer. However, the relationship between nutritional risk screening and the survival of patients after pancreaticoduodenectomy remains inconclusive. This study aimed to examine the association between preoperative nutritional risk and survival time among adult Chinese patients with pancreatic cancer after pancreaticoduodenectomy. Methods:This study was conducted at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine in China. Patients aged 18 years or more who received pancreaticoduodenectomy for pancreatic cancer in our center between December 2019 and June 2022 from the follow-up database were included in the study. We retrospectively collected data on the demographics, disease, treatment, nutritional risk score, and survival time of the patients with pancreatic cancer. A Cox regression model was used to analyze the association between nutritional risk and survival time in different covariate models. Results:A total of 656 patients were included in the study, and the median survival time was 24.0 months (95% CI:21.6-26.3). In total, 29.1% of patients had nutritional risk on admission. At the end of the follow-up, a total of 364 (55.5%) patients had died. The overall 1-, 2-, and 3-year survival rate of the 656 patients with pancreatic cancer after pancreaticoduodenectomy was 72.7%, 49.8%, and 34.4%, respectively. In the Cox regression model adjusted for age, education level, carbohydrate antigen 199 levels, neutrophil-lymphocyte ratio, tumor diameter, lymph node metastasis, distant organ metastasis, differentiation, nerve invasion, surgical margins, surgical time, intraoperative blood loss, postoperative complications, and chemotherapy, patients with nutritional risk score greater than 3 had a lower survival time compared with those without nutritional risk (HR = 1.33, 95% CI:1.06-1.67; P = 0.015). Conclusions:Preoperative nutritional risk has a detrimental impact on survival in patients with pancreatic cancer who undergo pancreaticoduodenectomy, and this relationship is stable. Nursing staff should screen early for nutritional risk using the Nutritional Risk Screening-2002 tool in patients with pancreatic cancer at diagnosis and, in conjunction with their doctors, develop and implement a timely nutritional treatment plan for those at risk to improve the poor survival time.

Background The prevalence of type 2 diabetes mellitus (T2DM) is increasing in China, and T2DM is linked to higher risk of several cancers, particularly obesity-related cancers (ORCs). Whether these associations are causal remains unclear due to potential biases. Methods We conducted a matched cohort study within the China Kadoorie Biobank (512,724 participants recruited 2004-08) to examine causal associations between new-onset T2DM and cancer incidence. To minimise bias, we: (i) included only incident T2DM cases, (ii) applied sex-specific sequential longitudinal matching, (iii) restricted analysis to pre-diagnosis body mass index (BMI), and (iv) accounted for detection time bias. Cox models stratified on the matched set estimated sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs). Results were triangulated with two-sample Mendelian randomisation (MR). Findings After 1:3 matching, 8,657 men and 13,680 women with new-onset T2DM were retained, matched to 25,852 and 40,938 unexposed individuals, respectively. During follow-up to 31 Dec 2018, the incidence rate (IR) of total cancer was 1,365.1 per 100,000 person-years (95% CI 1,250.1-1,480.0) in men with T2DM versus 800.2 (749.7-850.7) in unexposed matches, and 864.7 (794.5-935.0) in women with T2DM versus 629.4 (594.7-664.1) in unexposed matches. T2DM was associated with increased risk of total cancer in men (HR 1.57, 95% CI 1.38-1.79) and women (HR 1.30, 95% CI 1.15-1.47). There was evidence of associations with liver (men HR 2.12, 95% CI 1.42-3.15; women HR 2.39, 95% CI 1.42-4.04) and pancreatic cancer (men HR 2.57, 95% CI 1.35-4.92; women HR 3.95, 95% CI 1.92-8.13). In MR, liability to T2DM was causally related with pancreatic cancer (pooled OR 1.08, 95% CI 1.02-1.15, P = 0.01), but not other cancers. Triangulation supported a causal link between T2DM and pancreatic cancer in East Asians. Interpretation These findings provide strong evidence for a causal relationship only between T2DM and pancreatic cancer risk in Chinese, while evidence for other cancer sites was weak or discordant. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by China Scholarship Council and NIHR Manchester Biomedical Research Centre. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Prior to commencement of CKB, ethics approval was obtained from the Oxford University Tropical Research Ethics Committee and the Chinese Centre for Disease Control and Prevention Ethical Review Committee, and all participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Bona fide researchers can apply for open-access CKB dataset by registering and applying at https://www.ckbiobank.org/data-access. Ancestry-specific GWAS summary for T2DM can be obtained from the DIAGRAM consortium (https://www.diagram-consortium.org/downloads.html). Summary-level data for colorectal cancer from BBJ-CRC sub-study and for BMI are publicly available on GWAS Catalog (study accession ID: GCST005591 and GCST90103751, respectively). Summary-level data for pancreatic cancer from the combined Japanese study are publicly available on the website of JaPAN consortium (http://www.aichi-med-u.ac.jp/JaPAN/current_initiatives-e.html). Summary-level data derived from CKB participants for the selected SNPs in the current study are available upon a reasonable request to the corresponding author.

Background Post-pancreatectomy acute pancreatitis (PPAP) is an early acute inflammatory process of the pancreatic remnant that is associated with a series of downstream pancreas-specific complications. This study aimed to investigate the relationship between postoperative serum C-reactive protein (CRP) levels and the occurrence of PPAP after pancreaticoduodenectomy (PD). Methods Consecutive patients who underwent PD between January 1, 2020, and May 31, 2022, were retrospectively analyzed. PPAP was defined according to the International Study Group for Pancreatic Surgery (ISGPS) definitions. A Sankey diagram incorporating Fistula Risk Score (FRS), serum amylase levels, and serum CRP levels was further performed for the early iterative risk stratification of PPAP. Results A total of 601 patients were included in the analysis. Postoperative serum hyperamylasemia (POH) was observed in 268 patients (44.6%), of whom 136 (16.7%) developed PPAP after PD. Patients with serum CRP >100 mg/L on postoperative day (POD) 2 had a significantly higher incidence of PPAP (27.2% vs. 2.3%, p < 0.001). The highest Youden index was achieved with the cut-off value of 100 mg/L, with the area under the curve (AUC) value of 0.754 for predicting PPAP (sensitivity 91.8%, specificity 59.0%). Multivariate analysis revealed that body mass index (BMI) ≥24 (OR 2.09), estimated blood loss >200 mL (OR 1.70), and elevated serum CRP levels (OR 13.01) were independent risk factors for PPAP. Notably, patients with both POH and elevated serum CRP levels on POD 2 were classified as the high-risk group, exhibiting a remarkably high PPAP rate of 41.8%. Conclusions Serum CRP levels on POD 2 are strongly associated with the development of PPAP after PD. This finding has the potential to enable tailored postoperative management and pave the way for the anti-inflammation strategies targeting the early postoperative period.

The gut microbiome is altered after bariatric surgery and is associated with weight loss. However, the commensal bacteria involved and the underlying mechanism remain to be determined. We performed shotgun metagenomic sequencing in obese subjects before and longitudinally after sleeve gastrectomy (SG), and found a significant enrichment in microbial species in Clostridia and bile acid metabolizing genes after SG treatment. Bile acid profiling further revealed decreased primary bile acids (PBAs) and increased conjugated secondary bile acids (C-SBAs) after SG. Specifically, glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) were increased at different follow-ups after SG, and were associated with the increased abundance of Clostridia and body weight reduction. Fecal microbiome transplantation with post-SG feces increased SBA levels, and alleviated body weight gain in the recipient mice. Furthermore, both Clostridia-enriched spore-forming bacteria and GDCA supplementation increased the expression of genes responsible for lipolysis and fatty acid oxidation in adipose tissue and reduced adiposity via Takeda G-protein-coupled receptor 5 (TGR5) signaling. Our findings reveal post-SG gut microbiome and C-SBAs as contributory to SG-induced weight loss, in part via TGR5 signaling, and suggest SBA-producing gut microbes as a potential therapeutic target for obesity intervention.