Abstract Asymptomatic precursor lesions that predate invasive pancreatic ductal adenocarcinoma (PDAC) by years provide a compelling opportunity for cancer interception. One such precursor is the intraductal papillary mucinous neoplasm (IPMN). Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS) imaging and spatial transcriptomics, we discovered long-chain hydroxylated sulfatide species and their biosynthetic enzymes as selectively enriched in IPMN. Genetic ablation of UGT8 and Gal3st1, the key enzymes catalyzing the synthesis of the sulfatide precursor galactosylceramide (GalCer) and sulfatides, respectively, suppressed sulfatide production and triggered mitochondrial ceramide accumulation in mutant Kras;Gnas IPMN cells. These metabolic disruptions led to reduced proliferation and invasiveness, alongside increased caspase-dependent apoptosis. Pharmacologic UGT8 inhibition also caused profound impairments in mitochondrial function and morphology. Integrated lipidomic and proteomic analyses on mitochondrial fractions revealed remodeling of lipid composition and dysregulation of proteins involved in mitochondrial translation, oxidative phosphorylation, mitophagy and sphingolipid metabolism, corroborating the phenotypic changes observed in our functional studies. In vivo, UGT8 inhibition suppressed tumor growth in IPMN allograft models. Collectively, our findings identify enhanced sulfatide metabolism as an early metabolic alteration of cystic pre-cancerous lesions and demonstrate that targeting UGT8 perturbs mitochondrial homeostasis and function, revealing a potential strategy for pancreatic cancer interception. Citation Format: Riccardo Ballarò, Yihui Chen, Marta Sans, Fredrik Ivar Thege, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, Jianjun Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal Rajapakshe, Mark Hurd, Ricardo A. León-Letelier, Jody Vykoukal, Jennifer B. Dennison, Kim-Anh Do, Samir M. Hanash, Robert Wolff, Paola A. Guerrera, Michael Paul Kim, C. Max Schmidt, Anirban Maitra, Johannes Fahrmann. Targeting sulfatide metabolism as a therapeutic vulnerability in pancreatic pre-cancer lesions [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 7316.

BACKGROUND:Surgery for pancreatic cancer is associated with postoperative venous thromboembolism (VTE) rates of 5% to 20%, prompting the routine use of extended VTE chemoprophylaxis. The incidence and predictors of VTE after chronic pancreatitis (CP) surgery remain unclear. METHODS:Retrospective single-institution analysis of postsurgical patients for CP between January 2007 and June 2025. Postoperative VTE rates at 90 days were evaluated, including extremity deep vein thrombosis (DVT), pulmonary embolism (PE), and mesenteric vein thrombosis (MVT). Perioperative definitions aligned with the American College of Surgeons National Surgical Quality Improvement Program and the International Study Group for Pancreatic Surgery. RESULTS:A total of 739 patients underwent surgery for CP. Venous thrombosis developed in 50 (6.8%) patients. Postoperative DVT/PE was diagnosed in 22 (3.0%) patients on postoperative day 23 ± 20. Multivariable regression found higher body mass index, lower serum albumin, and longer operative time to be risk factors for DVT/PE. Major morbidity was higher in patients who developed DVT/PE (86.3% vs 40.2%; P <.001); however, mortality was similar between groups (0% vs 0.6%; P =.7). Postoperative MVT was diagnosed in 33 (4.5%) patients on postoperative day 23±18. Multivariable regression found organ-space infection and postpancreatectomy hemorrhage to be risk factors for MVT. Major morbidity (81.8% vs 39.7%; P <.001) and mortality (6.1% vs 0.4%; P =.0001) were higher in patients who developed MVT. CONCLUSIONS:Extremity DVT, PE, and/or MVT occurred in 6.8% of patients who underwent surgery for CP and impacted postoperative morbidity and mortality. Given this high-risk population, prospective studies optimizing strategies for postoperative chemoprophylaxis are warranted and should consider extended chemoprophylaxis and weight-based dosing.

Abstract Background Intraductal papillary mucinous neoplasms (IPMNs) are recognized as precursor lesions to pancreatic ductal adenocarcinoma (PDAC). However, the molecular programs underlying progression from low-grade dysplasia to advanced disease remain incompletely characterized. Herein, we performed an integrated plasma and tissue–proteomic analyses coupled with spatial and single-cell transcriptomics to identify biologically coherent remodeling programs reflected in circulation that distinguish IPMN by dysplasia grade and invasive disease. Methods Using the O-link proximity extension assay platform, a panel of 1,104 proteins were quantified in plasma samples collected from patients with low-grade (LG) IPMN (n=30), high-grade (HG) IPMN with or without associated PDAC (IPMN/PDAC; n=40) and PDAC without IPMN (n=8). Predictive performance of individual biomarkers were assessed; likelihood ratio testing was performed to identify protein biomarkers that were complementarity with CA19-9 for risk of malignancy of IPMN. Findings were intersected with available spatial (N= 13) and single-cell (N= 6) transcriptomic datasets of IPMN tissues as well as mass spectrometry-based proteomic profiles of an independent set of resected human IPMN tissues (N= 9). Results A total of 28, 43, and 35 circulating proteins were found to be differential in HG, IPMN/PDAC, and HG + IPMN/PDAC cases compared to LG IPMN. Among differential proteins were known PDAC-associated markers CEACAM5, CTRC, and REG3A as well as several biomarkers reflecting cytoskeletal and extracellular matrix remodeling and inflammatory processes. Focusing on cytoskeletal and ECM-related proteins and using likelihood ratio testing, an “OR” rule considering CA19-9, BGN, and ITGB1BP1 achieved overall sensitivity of 48.7% for HG + IPMN/PDAC, including 38.1% sensitivity for HG IPMN, at an overall specificity of 90%, which was improved compared to that of CA19-9 alone (overall sensitivity of 28.2%; McNemar Exact test 1-sided p-value: 0.011). Integrated proteomic and spatial transcriptomic datasets of IPMN tissues revealed coordinated alterations cytoskeletal and ECM remodeling and elevated matrix stiffness as prominent features associated with IPMN/PDAC, which paralleled concordant increases in BGN and ITGB1BP1. Cell-type of origin analyses based on spatial and single-cell data further revealed fibroblasts and myeloid cells as primary contributors to expression levels of BGN whereas ITGB1BP1 was primarily expressed in neoplastic epithelium. Conclusion Advanced IPMN dysplasia and invasive disease are characterized by coordinated tissue remodeling programs that are systemically reflected in circulating proteomic profiles. Blood-based biomarkers identified through our study, such as BGN and ITB1BP1, have potential to improve upon CA19-9 for risk stratification of IPMN to better guide clinical management.

Historical pediatric data recommend surgical resection for type I choledochal cysts because of the risk of malignant progression over time (up to 60

The operative management of duodenal tumors remains controversial with outcomes comparing pancreatoduodenectomy (PD) versus duodenectomy arising from small, noncontemporary cohorts. The aim of this study is to examine perioperative outcomes between PD and duodenectomy for duodenal masses. It is hypothesized that the morbidity profile of a duodenectomy lies between that of a PD and that of an enterectomy for a distal small bowel tumor. A single-institution retrospective review was performed of patients with non-ampullary duodenal tumors who underwent PD or duodenectomy between 2006 and 2025. Duodenectomy was classified as proximal (D1/D2) versus distal (D3/D4) duodenectomy based on tumor location. Patients who underwent enterectomy for jejunal/ileal tumors were identified as another comparison group. The primary outcome was 30-day major morbidity, defined as a composite of core complications (delayed oral feeding autonomy, abscess, anastomotic leak, bleeding requiring intervention, reoperation) and was evaluated across four cohorts: PD vs. proximal duodenectomy vs. distal duodenectomy vs. enterectomy. The analytic cohort consisted of 235 patients: PD = 86 (36.6

BACKGROUND The current retrospective study aimed to assess the interaction between surgeon-volume and hospital-volume on outcomes after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). METHODS Patients with PDAC undergoing PD from 2008 to 2023 were identified using the National Cancer Database. Operative volumes of ≥20 cases/year defined high-volume hospitals (HVH) and ≥12 cases/year defined high-volume surgeons (HVS). Those below those thresholds were low-volume surgeons (LVS) and low-volume hospitals (LVH). Multivariable logistic regression was used to assess associations between surgeon/hospital volume and outcomes, relative to HVS/HVH. RESULTS The inclusion cohort consisted of 50,519 patients treated by 3,155 surgeons operating at 976 hospitals. 90-day mortality declined with increasing volume: LVS/LVH = 6.4%, HVS/LVH = 5.7%, LVS/HVH = 4.0%, HVS/HVH = 3.5% (p<0.001). Patients undergoing surgery by HVS/LVH [Odds Ratio (OR): 1.58, 95% Confidence Interval (95%CI): (1.12, 2.24), p=0.009] and LVS/LVH [OR: 1.59, 95%CI: (1.24, 2.04), p<0.001] had a higher adjusted likelihood of mortality. LVS/HVH was not associated with mortality compared with HVS/HVH. Both HVS/LVH [OR: 1.93, 95%CI: (1.27, 2.92), p=0.002] and LVS/LVH [OR: 1.60, 95% CI: (1.15, 2.23), p=0.006] had a higher likelihood of readmission. CONCLUSION Outcomes after PD for PDAC remain more greatly influenced by hospital-volume rather than surgeon-volume.

BACKGROUND:Postpancreatectomy acute pancreatitis (PPAP) is an increasingly recognized but still disputed clinical entity. Defined by the International Study Group for Pancreatic Surgery in 2022 as a 48-hour postoperative elevation of serum amylase level and radiographic confirmation of pancreatitis. PPAP is graded as postoperative hyperamylasemia (POH), grade B, and grade C. The 2023 National Surgical Quality Improvement Program's (NSQIP) pancreatectomy-targeted Participant Use Data File included for the first time PPAP variables. This study aimed to determine whether the NSQIP data will reflect the incidence of PPAP in a national sample. METHODS:Patients who underwent a pancreatectomy at 168 participating institutions between January 1, 2023, and December 31, 2023, were included in the NSQIP pancreatectomy-targeted dataset. Cases were identified using Current Procedural Terminology codes. The variables were captured retrospectively. Data were amassed and managed by the American College of Surgeons NSQIP. RESULTS:Of 8015 patients included in the analysis, 1273 (17%) had amylase values. Among these patients, 782 (61%) had normal serum amylase level, 430 (34%) had POH, 53 (4.1%) had grade B PPAP, and 8 (0.01%) had grade C PPAP. Multivariable logistic regression found a small pancreatic duct and soft pancreatic texture to be significantly associated with POH and clinically relevant PPAP (CR-PPAP) for head resections. Patients with POH and CR-PPAP were significantly more likely to have any-cause morbidity and complications, such as Clavien-Dindo grade ≥ 3 (P <.05 and P <.05, respectively). CONCLUSION:This is the first national survey of patients who underwent pancreatectomy that confirmed a high incidence of POH and PPAP. The low rate of amylase level measurement suggests that general education about this disease process will be important. Normal pancreatic texture is the most significant risk factor for developing POH/PPAP, and mitigation strategies and more liberal use of early postoperative imaging should be considered for patients.

Additional details of the Lunaphore COMET protocol and assay information.

Patient and clinical information for the IPMN samples included in the COMET cohort.

Background We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC). Objective We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC. Design Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition. Results MALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8 , Gal3St1 , and FA2H , to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice. Conclusion Our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.

Predicted NKX6-2 targets and transcription factors associated with NKX6-2 expression evaluated by GENIE3.

Differentially expressed genes between LG, HG, and PDAC samples per region.

Protein panel used for the COMET protocol for cyclic immunofluorescent staining.

OBJECTIVE:To evaluate perioperative morbidity and mortality outcomes in a large, contemporary series of patients undergoing pancreas head resection for chronic pancreatitis. SUMMARY BACKGROUND DATA:Select chronic pancreatitis (CP) patients benefit from pancreatic head resection, but contemporary data are sparse. Anatomy dictates selection of duodenum-preserving pancreatic head resection (DPPHR) or pancreatoduodenectomy (PD). We hypothesized that both DPPHR and PD are safe in select patients. METHODS:CP patients undergoing pancreas head resection from 2007-2023 at a high-volume institution were analyzed. Patient comorbidities, operative data, and postoperative 30-day outcomes were defined according to National Surgical Quality Improvement Program (NSQIP) and International Study Group on Pancreatic Surgery (ISGPS). Preoperative and intraoperative variables between groups were compared. Continuous data are presented as median [interquartile range]. RESULTS:Among 338 patients (50% female), 252 underwent PD and 86 DPPHR (69 Frey, 11 Beger, 4 Izbicki, 2 Bern). Median age was 52[17] years (PD 53.1[17], DPPHR 50.1[20], P=0.036). Preoperative tobacco use (57%) and diabetes (27%) were common. The PD group had longer operative times (282[131] vs. 207.5[91] minutes, P<0.001) and higher intraoperative blood loss (307.5[400] vs. 100[200] milliliters, P<0.001). Median length of stay was 8[6] days (PD 8[6.3], DPPHR 7[4]). Major morbidity occurred in 22% of patients (PD 23%, DPPHR 21%). At 30 days, the readmission rate was 17% (PD 17%, DPPHR 17%) and mortality occurred in 1.2% (PD 1.6%, DPPHR 0%). CONCLUSIONS:This large, contemporary analysis demonstrated safety of pancreatic head resection in select CP patients.

Markers per clusters generated from ST analyses of two pancreas specimens collected from Kras;Gnas mice.

Differentially expressed genes between Nkx6-2 positive and negative spots in the Kras;Gnas STepithelial spots.