BACKGROUND:Minimally invasive left-sided pancreatectomy (MIS-LP) is increasingly adopted for resection of grade 1 and 2 pancreatic neuroendocrine tumours (PNETs), but its oncological equivalence to open left-sided pancreatectomy (O-LP) remains to be fully evaluated. METHODS:We conducted a retrospective cohort study using SEER-Medicare data (2010-2019) including all patients who underwent left-sided pancreatectomy (LP) for PNETs. A multilevel Cox regression model was used to to provide adjusted hazard ratios (HR) for overall survival (OS) and cancer-specific survival (CSS) when comparing between MIS-LP and O-LP. A 6-month landmark survival analysis was performed to account for early postoperative deaths. RESULTS:A total of 772 patients were included, with 257 (33.3%) undergoing MIS-LP. Six-hundred-and-seventy-two patients had grade 1, and 100 patients had grade 2 PNETs. MIS-LP was associated with better OS (HR 0.48, 95% CI 0.26-0.86, P=0.014) and CSS (HR 0.35, 95% CI 0.14-0.88, P=0.026). In the 6-month landmark analysis, O-LP was associated with similar OS and CSS to MIS-LP. CONCLUSION:MIS-LP is associated with improved early survival compared to O-LP in patients with low- to intermediate-grade PNETs.

Fig. S5. Identification and characterization of cell niches. (A) Elbow plot used to determine the optimal number of cell niches. (B) Distribution of cell types and identified cell niches across all slides. (C) Niche proportions across all samples. (D) Heatmap shows the enrichment levels of each cell type within the respective cell niches, * indicates p < 0.05, * indicates p < 0.01, * indicates p < 0.001.

Pancreatic colloid carcinoma (CC) is a rare subtype of invasive carcinoma arising from intraductal papillary mucinous neoplasm (IPMN), characterized by abundant extracellular mucin and an intestinal phenotype. Its rarity (1–3

Kaplan–Meier curves for survival outcomes in patients with MSS/pMMR mCRC receiving ICI-based therapies, stratified by liver metastasis status at the time of ICI initiation. A, PFS: Patients without liver metastases had significantly higher 12-month PFS rates (12.8% vs. 1.1%; P = 0.034). The median PFS was 2.1 months (95% CI, 1.59–2.62) in those with liver metastases and 2.5 months (95% CI, 2.22–2.71) in those without liver metastases (HR, 1.68; 95% CI, 1.13–2.5; P = 0.009). B, OS: Median OS was 11.53 months (95% CI, 3.01–20.06) in those without liver metastases and 6.17 months (95% CI, 2.87–9.46) in those with liver metastases (HR, 2.03; 95% CI, 1.35–3.06; P < 0.001).

OBJECTIVE:To determine the rate of malignancy in radiologically classified mixed-type intraductal papillary mucinous neoplasms (IPMNs) undergoing surgical resection compared to main-duct (MD) and branch-duct (BD) IPMNs. BACKGROUND:Mixed-IPMNs are widely perceived as high-risk lesions; however, limited and heterogeneous data available on this category raise uncertainty regarding their true risk profile. METHODS:Retrospective analysis of 836 consecutive resected IPMNs (2000-2025) from a prospectively maintained single-institution database. IPMNs were classified and compared based on preoperative imaging. Malignancy was defined as high-grade dysplasia or invasive carcinoma. RESULTS:Of 773 patients who met inclusion criteria, 305 (39.4%) had a radiologically defined mixed-IPMN, 135 (17.5%) MD-IPMN, and 333 (43.1%) BD-IPMN. Malignancy was observed in 46.5% of mixed-IPMNs (142/305), 79.2% MD-IPMNs (107/135), and 33.9% BD-IPMNs (113/333). The rate of invasive carcinoma was 19.0% (58/305) in mixed-IPMNs and 45.9% (62/135) in MD-IPMNs ( P <0.001). In the absence of high-risk stigmata, the malignancy rate of mixed-IPMNs decreased to 24.7% (46/186), and did not differ from that of BD-IPMNs (51/252, 20.2%; P =0.263). Moreover, when main pancreatic duct (MPD) dilatation was the single worrisome feature, the malignancy rate was 6.3%, with risk increasing significantly only in the presence of multiple worrisome features or when MPD dilatation reached 7-8 mm. Furthermore, in one-third of radiologically defined mixed-IPMNs (103/305), final pathology revealed no MPD involvement. CONCLUSIONS:Mixed-IPMNs are highly heterogeneous and have a lower malignancy rate than previously reported in resected cohorts. In the absence of high-risk stigmata, most lesions are benign, highlighting limitations of current risk stratification and selection for surgery.

Importance Lymph node (LN) metastasis is a strong predictor of tumor recurrence following pancreatectomy for localized pancreatic neuroendocrine tumors (PanNETs). However, most patients lack LN metastasis and many tumors recur. Tools to guide risk-adapted surveillance in this group are lacking. Objective To develop and validate a tumor recurrence and survival risk score for patients with LN-negative PanNETs. Design, Setting, and Participants This retrospective, case-control study of patients with localized PanNETs took place at 5 high-volume US institutions from 2000 to 2023. Inclusion required 8 or more evaluated LNs and negative nodal status. Median follow-up was 50.6 months. These data were analyzed from March 2025 to May 2025. Exposure Surgical resection of localized PanNETs per clinical guidelines. Main Outcomes and Measures The primary outcome was tumor recurrence. Independent predictors were identified using multivariable logistic regression and used to construct a 13-point composite risk score. Performance was assessed using C statistics. Kaplan-Meier and log-rank methods evaluated disease-free survival (DFS). Genomic profiling was conducted in an external validation cohort to identify and validate recurrence-associated mutational risk scores. Results Of 2024 patients, 770 met inclusion criteria. Median age was 58.7 (IQR, 18.4) years; 405 were male (52.6%) and 365 were female (47.4%). Most tumors were sporadic (94.1%), nonfunctional (90.4%), and located in the body/neck (50.9%). Recurrence occurred in 82 patients (10.6%) at a median of 32.4 (IQR, 16.3-82.0) months after surgery. Independent predictors included male sex (odds ratio [OR], 2.2; 95% CI, 1.3-3.9), tumor size 3 cm or larger (OR, 2.64; 95% CI, 1.5-4.6), World Health Organization grade 2 or higher (OR, 3.70; 95% CI, 1.4-10.0), and lymphovascular invasion (OR, 3.84; 95% CI, 2.1-6.9). The risk score showed strong performance (area under the receiver operating characteristic, 0.83 internally; 0.95 externally). Recurrence rates by risk group were 2.4%, 9.0%, and 27.7% ( P < .001), and 10-year DFS rates of 96.1%, 83.6%, and 51.3%, for low-risk, moderate-risk, and high-risk groups, respectively ( P < .001). Genomic analyses revealed higher tumor mutational burden, somatic mutation count, and somatic mutations in CDC42BPB , DAXX , ERI2 , GALNT9 , MTOR , NUMA1 , and TRPC7 genes among recurrent tumors. Conclusions and Relevance Despite LN-negative status, a subset of patients with PanNETs remained at high risk for recurrence. This validated risk score stratifies recurrence and survival risk showing biological relevance. These findings provide a framework for refining postoperative surveillance and risk-adapted therapeutic strategies.

Table S3. Summary of adverse events in study participants.

Objective: To determine the rate of malignancy in radiologically classified mixed-type intraductal papillary mucinous neoplasms (IPMNs) undergoing surgical resection compared to main-duct (MD) and branch-duct (BD) IPMNs. Background: Mixed-IPMNs are widely perceived as high-risk lesions; however, limited and heterogeneous data available on this category raise uncertainty regarding their true risk profile. Methods: Retrospective analysis of 836 consecutive resected IPMNs (2000–2025) from a prospectively maintained single-institution database. IPMNs were classified and compared based on preoperative imaging. Malignancy was defined as high-grade dysplasia or invasive carcinoma. Results: Of 773 patients who met inclusion criteria, 305 (39.4%) had a radiologically defined mixed-IPMN, 135 (17.5%) MD-IPMN, and 333 (43.1%) BD-IPMN. Malignancy was observed in 46.5% of mixed-IPMNs (142/305), 79.2% MD-IPMNs (107/135), and 33.9% BD-IPMNs (113/333). The rate of invasive carcinoma was 19.0% (58/305) in mixed-IPMNs and 45.9% (62/135) in MD-IPMNs ( P <0.001). In the absence of high-risk stigmata, the malignancy rate of mixed-IPMNs decreased to 24.7% (46/186), and did not differ from that of BD-IPMNs (51/252, 20.2%; P =0.263). Moreover, when main pancreatic duct (MPD) dilatation was the single worrisome feature, the malignancy rate was 6.3%, with risk increasing significantly only in the presence of multiple worrisome features or when MPD dilatation reached 7-8 mm. Furthermore, in one-third of radiologically defined mixed-IPMNs (103/305), final pathology revealed no MPD involvement. Conclusions: Mixed-IPMNs are highly heterogeneous and have a lower malignancy rate than previously reported in resected cohorts. In the absence of high-risk stigmata, most lesions are benign, highlighting limitations of current risk stratification and selection for surgery.

BACKGROUND:ASCO recommends extended venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) following cancer surgery. However, these recommendations were based on trials using routine venography, which detects asymptomatic VTEs, and real-life efficacy is not well studied. We aimed to assess the association of extended VTE prophylaxis with the incidence of clinically significant VTE after elective cancer surgery. PATIENTS AND METHODS:In this retrospective, population-based cohort study, we identified patients who underwent surgical resection for lung, breast, esophageal, gastric, pancreas, and colon cancer from 2010 to 2017 using the SEER-Medicare linked dataset. Patients were divided into 1 of 2 main groups for comparative analyses: those who received extended VTE prophylaxis after cancer surgery and those who did not. Patients who received extended VTE prophylaxis after cancer surgery were identified as those prescribed prophylactic doses of LMWH or a DOAC within 7 days of discharge, as captured in Medicare Part D files. RESULTS:A total of 113,739 Medicare beneficiaries were identified, of whom 1,570 (1.4%) received extended VTE prophylaxis. There was a year-over-year increase in the use of extended VTE prophylaxis during the study period, rising from 0.6% in 2010 to 3.3% in 2017. The overall incidence of VTE was 1.6% at 1 month, 4.3% at 6 months, 5.7% at 12 months, with significant differences observed across cancer types (P<.001). However, patients who received extended VTE prophylaxis had a higher 1-year cumulative incidence of postoperative VTE compared with those who did not (11.4% vs 5.3%; P<.001), an association that was consistent across cancer sites. In adjusted analyses, extended VTE prophylaxis was independently associated with an increased risk of VTE (hazard ratio, 1.6; 95% CI, 1.3-2.0; P<.001). Extended prophylaxis was also associated with a higher 1-year incidence of bleeding events compared with patients who did not receive prophylaxis (12.0% vs 8.5%; P<.001). CONCLUSIONS:The utilization of extended VTE prophylaxis after cancer surgery remains low, although it has increased every year. Paradoxically, patients who received extended VTE prophylaxis had higher incidences of clinically significant VTE and bleeding compared with those who did not, likely reflecting patient selection and surveillance bias after surgery. In light of these findings, national guidelines recommending postoperative extended VTE prophylaxis, and its use as a surrogate for quality of care, should continue to be re-examined.

BACKGROUND:The clinico-pathological characteristics and accuracy of the current International Association of Pancreatology guidelines for IPMN in relation to its location within the pancreas has not been investigated. METHODS:751 patients who underwent pancreatic resection for IPMN in two tertiary referral centers were retrospectively categorized into subgroups according to location within the pancreas. Likelihood of worrisome features, high-risk stigmata (HRS), clinico-pathological features and presence of malignancy were compared. RESULTS:480 (64%) patients had IPMN in the ventral pancreas (i.e. head, uncinate process and neck), and 271(36%) in the dorsal gland (i.e. body/tail). Malignancy was present in 54% (n = 259) of patients with ventral IPMN and in 39% (n = 107) of those with dorsal lesions (p < 0.0001). There was a significantly higher proportion of intestinal epithelium in ventral IPMNs when compared to those in the dorsal pancreas, both in the general cohort and in invasive cancer group (27% vs 15%, OR: 1.94 95%CI:1.16-3.24 p = 0.006 and 31% vs 22% OR 1.52 95%CI: 0.77-3, p = 0.24 respectively). Patients with ventral IPMN more frequently presented with HRS (49%vs 37%, p < 0.001), while dorsal IPMN often showed only worrisome features (54%vs 43%, p = 0.06). ROC curve analysis identified optimal cut-off values for main pancreatic duct diameter of 9 mm in ventral IPMNs and 5 mm in dorsal IPMNs for malignancy prediction. CONCLUSIONS:Ventral IPMNs are more commonly resected and show higher rates of intestinal epithelium and malignancy compared with dorsal lesions. A MPD size > 5 mm in IPMNs of the dorsal pancreas is associated with a substantial risk of malignancy.

Demographic and clinical characteristics of patients with MSS/pMMR mCRC by liver metastasis status.

Group 3 innate lymphoid cells (ILC3s) are key sensors of the intestinal environment, integrating dietary and microbial cues to maintain intestinal immunity. We found that intestinal ILC3s were reduced in overweight and obese humans and in high-fat diet (HFD)-fed mice. ILC3 loss occurred independently of caloric excess, weight gain, or glucose intolerance. Instead, impairment arose within hours of HFD consumption and was initiated by microbiota-driven intestinal barrier permeability and concomitant activation of inflammatory mononuclear phagocytes (MNPs). This response to inflammation impaired fatty acid oxidation in lipid-loaded ILC3s, resulting in mitochondrial damage and cell death. Intestinal ILC3 cell death was rescued by removal of excess fats from the diet. ILC3s from individuals with obesity also exhibited impaired fatty acid oxidation. Together, our findings define a malleable mechanism whereby dietary fats and microbial cues drive ILC3 maladaptation and death, with consequences for intestinal homeostasis.

664 Background: Multimodal therapy for pancreatic cancer (PC) may be challenging in older adults with comorbidities or limited performance status (PS). Methods: This is a retrospective review of patients (pts) age 70 and older with localized PC treated with neoadjuvant or definitive radiation (RT) at the Massachusetts General Hospital from 2016-2024. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) calculated from RT start. The Cox model was used to assess predictors of survival: age (>75 vs ≤75), ECOG PS (1+ vs 0), NCCN Stage (resectable vs not), ypT (2+ vs 0/1) and N (1 vs 0), and resection (yes vs no). Results: 366 pts met inclusion criteria with a median follow-up of 13 mo (range 0.2-102.2). Median age was 75 (range 70-95). 339 pts (93%) were deemed medically fit for surgery of whom 153 had resectable, 58 had borderline, and 128 had locally advanced disease. 317 of the 339 pts (94%) received induction chemotherapy (INCT), including: FOLFIRINOX (n=249), gemcitabine/nab-paclitaxel (n=61), and gemcitabine (n=29). 27 pts were deemed medically inoperable, of whom 11 were treated with INCT and RT and 16 with RT alone. RT regimens included: 50.4-58.8 Gy/28 fractions (fx) (n=223), 40 Gy/10 fx (n=2), 30 Gy/10 fx (n=52), 33-40 Gy/5 fx (n=28), or other (n=61). 3 discontinued RT due to toxicity (n=2) or progression (n=1). Of the 339 pts deemed medically fit, 206 (61%) had resection. The R0 resection rate was 86%. Median OS of the entire, medically operable and inoperable cohorts was 18.9 (95% CI 16.2-22.7), 20.3 (95% CI 17-25.4), and 10.1 (95% CI 7.5-17.1) mo. Median PFS of the entire, medically operable and inoperable cohorts was 9.6 (95% CI 8.3-11.5), 10.1 (95% CI 8.8-12.2), and 6.9 (95% CI 4.8-9.1) mo. Table 1 shows PFS and OS by NCCN categories. Univariate predictors of PFS and OS included age (HR 1.31 (p=0.029); HR 1.46 (p<0.01)), PS (HR 1.54 (p<0.001); HR 1.84 (p<0.001)), NCCN stage (HR 0.64 (p<0.001); HR 0.69 (p<0.01)), ypT (HR 1.78 (p<0.01); HR 1.58 (p=0.048)), N stage (HR 2.07 (p<0.001); HR 2.33 (p<0.001)), and resection (HR 0.33 (p<0.001); HR 0.33 (p<0.001)). Conclusions: RT was well tolerated in this elderly population. Among well-selected elderly pts, favorable outcomes can be achieved in those who undergo NT and resection, including borderline and locally advanced patients. For medically inoperable pts, further work is needed to investigate the optimal regimen. Clinical outcomes of elderly patients with PC. Median PFS (months) Median OS (months) Resectable (N=167) Neoadjuvant Therapy (NT) + resection (N=128) NT - no resection (N=25)Medically Inoperable (N=14) 17.3 2.3 6.2 29.8 8.2 10.3 Borderline (N=61) NT + resection (N=37) NT – no resection (N=21)Medically Inoperable (N=3) 20.8 2.4 7 31.3 13 7 Locally Advanced (N=138) NT + resection (N=41) NT – no resection (N=87) Medically Inoperable (N=10) 12.56.77.5 30.2 2.58

Regimens of immune checkpoint inhibitor-based therapies