Faculty Bibliography

BACKGROUND:Accurate preoperative malignancy risk assessment in intraductal papillary mucinous neoplasm (IPMN) is essential to balance timely intervention for high-grade dysplasia or invasive cancer (HGD/IC) against avoiding unnecessary or premature surgery in low-grade IPMN. This study aimed to externally validate the 2023 International Association of Pancreatology (IAP)/Kyoto guidelines and develop a combined prediction model incorporating routinely collected clinical data and laboratory parameters. METHODS:We conducted a retrospective cohort study of 194 patients who underwent resection for IPMN between 2012 and 2024. We evaluated the predictive performance of the current IAP/Kyoto criteria ("Kyoto model"), developed a clinical model using routinely available laboratory and clinical variables, and integrated both into a combined model. Model performance was assessed using discrimination and calibration metrics, with internal validation via bootstrapping and five-fold cross-validation. RESULTS:The Kyoto model demonstrated modest discrimination (AUC 0.62). The clinical model, incorporating neutrophil-to-lymphocyte ratio (NLR), smoking history, blood glucose, CA19-9, and alkaline phosphatase, achieved an optimism-corrected AUC of 0.76. Compared to the Kyoto model, the combined model (AUC 0.77) significantly improved discrimination and calibration (p < 0.001). At a predicted probability threshold of >0.75, the combined model achieved a 90% specificity and 91% positive predictive value for HGD/IC, identifying a high-risk subgroup suitable for surgical intervention. CONCLUSIONS:Integrating routinely collected clinical and laboratory parameters with guideline-based imaging features shows promise to enhance preoperative identification of high-risk IPMN in patients already being considered for surgical resection. The combined model offers a practical, high-specificity tool to support surgical decision-making in this selected population, though its performance metrics should not be extrapolated to unselected surveillance cohorts. External validation is required before broader clinical implementation.

BACKGROUND:Risk calculators (RCs) support clinicians estimating the likelihood that a pancreatic intraductal papillary mucinous neoplasm (IPMN) would progress so that surveillance might be discontinued for low-risk lesions. We tested the effect of an RC on clinicians' judgment and decision-making and identified their cancer risk threshold for changing their decision. PATIENTS AND METHODS/METHODS:We presented clinicians with three vignettes (V1, V2, and V3) of patients with low-risk IPMNs and asked them to assess the likelihood that the IPMN would progress to develop high-risk features and whether they would recommend continuing surveillance imaging. Clinicians were randomly assigned to the clinical vignettes alone (n = 35) or supplemented by data from the Dutch-American Risk Stratification Tool (DART-1 RC: n = 37). We compared clinicians' judgments and decisions between groups and assessed their cancer risk threshold (level of risk at which recommendation would change). RESULTS:Across all vignettes, the RC resulted in no change in clinicians' judged likelihood of IPMN progression (V1 8.49 vs. 8.41%, p = 0.09; V2 4.39 vs. 6.75%, p = 0.99; V3 13.61 vs. 13.29%, p = 0.27) or recommendation to continue surveillance (V1 57 vs. 41%, p = 0.78; V2 41 vs. 59%, p = 0.55; V3 66 vs. 34%, p = 0.31). Clinicians varied in their reported risk threshold (V1 9%, interquartile range [IQR] 2, 13%; V2 9% [IQR 1, 15%], V3 8% [IQR 3, 20%]). CONCLUSIONS:An RC did not significantly influence clinicians' risk perception or decision to continue surveillance, although the study was limited by low sample size. The cancer risk threshold at which clinicians would change their recommendation varies widely. Future work is needed to understand why RCs do not appear to alter decision-making.

IMPORTANCE/UNASSIGNED:Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the US. Although early detection improves survival, the rarity of the disease has rendered population screening a difficult approach. OBJECTIVE/UNASSIGNED:To develop and validate a parsimonious, interpretable, and generalizable model predicting incident PDAC-termed PRIME (PDAC Risk Model for Earlier Detection)-using routinely available electronic health record (EHR) data. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used the Optum Labs Data Warehouse, a longitudinal, deidentified US EHR and claims database. Adults 40 years or older with an outpatient clinical encounter between 2016 and 2018 were included. Participants from 23 health systems (n = 4 859 833) comprised the training cohort; 31 additional systems (n = 5 619 091) served as validation. International validation was conducted in the UK Biobank (n = 498 754). Data analysis occurred July 2025 to January 2026. EXPOSURES/UNASSIGNED:Demographics, diagnosis codes, and routinely measured laboratory values were evaluated. Elastic-net regularization with 10-fold cross-validation selected the predictor set. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Incident PDAC was identified by International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes. Model performance was assessed using time-dependent area under the curve (AUC) and calibration metrics. RESULTS/UNASSIGNED:Overall, the study included more than 11 million adults (2.1% Asian individuals, 8.4% Black individuals, 4.3% Hispanic/Latino individuals, 82.7% White individuals, and 2.4% other race/ethnicity by EHR reporting). In the training cohort (mean [SD] age, 60.4 [11] years), 14 405 individuals were diagnosed with PDAC (incidence 55 per 100 000 person-years) over a mean (SD) of 5.4 (2.5) years; in the validation cohort, 11 693 individuals were diagnosed with PDAC (54 per 100 000 person-years) over a mean (SD) of 3.9 (2.5) years. PRIME retained 19 predictors including history of pancreatitis, gastrointestinal disorders, prior cancers, type 2 diabetes, elevated aspartate aminotransferase levels, smoking, non-type-O blood, and male sex. Discrimination was strong at the 36-month time horizon (AUC = 0.75 in both the training and validation cohorts) with good calibration. In the validation cohort, patients in the top 1% of predicted risk had substantially higher PDAC risk (HR, 7.63; 95% CI, 6.85-8.49) compared with average-risk patients. In the UK Biobank, PRIME achieved a 36-month AUC of 0.71 with good calibration. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this validation cohort study, PRIME was a transparent EHR-based model that effectively stratified PDAC risk across diverse US health systems and generalized internationally. Prospective studies should evaluate for EHR-guided PDAC case-finding and integration with blood-based early-detection assays.

BACKGROUND:Epigenetic regulators represent a novel strategy to modulate the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). In preclinical models, DNA hypomethylating agents enhance cytotoxic T-cell infiltration, synergize with PD-1 blockade, and improve survival when combined with immune checkpoint blockade. This single-institution, phase II study evaluated the safety, efficacy, and biomarkers of azacitidine plus pembrolizumab in patients with previously treated PDAC. METHODS:Patients with locally advanced or metastatic PDAC after one prior regimen received 50 mg/m2 subcutaneous azacitidine on days 1-5 of a 28-day cycle, starting week 1, and pembrolizumab 200 mg intravenously every 3 weeks starting week 3. Baseline and on-treatment blood and tumor was collected for exploratory biomarker analysis. RESULTS:Thirty-six patients enrolled between October 2017 and September 2021 (median age: 62.5 years); 34 were evaluable for safety; 31 for efficacy. Treatment was generally well-tolerated, with Grade 1-2 fatigue and diarrhea most common AEs. Three patients (9.7%) had a partial response, and the disease control rate was 35.5%. Median progression-free and overall survival was 1.51 and 4.83 months, respectively. Exploratory analysis suggested higher baseline CD8+ T cells and lower tumor Ki-67 was associated with response, whereas low baseline CD8+ T cell and Granzyme B infiltration correlated with higher exponential tumor growth rate. PD-L1 and CD68 expression were not predictive of benefit. CONCLUSION/CONCLUSIONS:Azacitidine plus pembrolizumab demonstrated limited clinical activity in second line, locally advanced or metastatic PDAC. Biomarker analysis suggests higher baseline CD8+ T-cell infiltration and lower proliferative index may identify patients more likely to benefit. (NCT03264404).

INTRODUCTION/BACKGROUND:Accurate preoperative evaluation of pancreatic cysts is essential. However, cytology and biochemical analysis are often limited by low cellularity, and risk stratification is critical for management. PancreaSeq Genomic Classifier (GC) analyzes cyst fluid for molecular alterations to aid diagnosis and risk assessment. MATERIALS AND METHODS/METHODS:We retrospectively analyzed 219 pancreatic cysts from 206 patients using PancreaSeq GC, integrating molecular findings with cytology, biochemical, imaging, surgical pathology, and follow-up. RESULTS:PancreaSeq GC successfully analyzed 216/219 cysts (99%) and detected alterations in 182 (83%). Among cases with both cytology and molecular data (n = 201), concordance was high in cytologically mucinous neoplasms (94%) and atypical cases (95%). Notably, among cases reported as negative for malignancy or nondiagnostic on cytology (n = 128), PancreaSeq GC identified mucinous neoplasms in 82 cases (64%), demonstrating added value in limited samples. Surgical pathology correlation (n = 24) showed excellent performance for distinguishing mucinous from nonmucinous cysts (area under the curve [AUC] = 0.94, P < 0.001). Risk stratification for detection of any dysplasia yielded an AUC of 0.78 (P = 0.006), and for high-grade dysplasia an AUC of 0.74 (P = 0.046). PancreaSeq GC reliably predicted neuroendocrine tumors, but the sensitivity for focal high-grade dysplasia in mucinous neoplasms and serous cystadenoma was limited. Compared with carcinoembryonic antigen (CEA), cyst fluid glucose showed higher sensitivity but lower specificity for mucinous cyst detection. CONCLUSIONS:PancreaSeq GC provides significant diagnostic and risk-stratification value that complements cytological evaluation, particularly in indeterminate or nondiagnostic cytology specimens and when biochemical data are unavailable. Integration of molecular findings improves cyst classification and dysplasia risk assessment. Multidisciplinary assessment remains essential, given the assay's limited sensitivity for focal high-grade dysplasia and serous cystadenomas.

OBJECTIVE:To describe the imaging appearances and treatment response patterns of the pancreatic neuroendocrine tumors (panNETs) following radiofrequency ablation (RFA). METHODS:From an internal database, 17 patients (8 male; mean age: 67±14 y) with 18 pathology-proven, localized, nonfunctioning panNETs <3 cm who underwent EUS-RFA for curative intent were included. A total of 32 preablation and 33 postablation scans were included (CT, MRI, or 68Ga-DOTATATE PET). Lesion size and enhancement on CT/MRI were independently assessed by 2 readers, while SUVmax was extracted from the original PET reports by a separate reviewer. The Wilcoxon signed-rank and McNemar tests were performed. Treatment response is defined as a complete response (loss of enhancement and SUVmax), a partial response (decrease in size, enhancement, or SUVmax), or no response (no change). RESULTS:Mean lesion size decreased from 1.4​​​​​​±0.5​ cm preablation to 0.3±0.5 cm postablation (P<0.0001). Mean SUVmax declined from 17.3±11.2 to 3.1±6.0 (P<0.001). Hyperenhancement was present in 15/18 (83.3%) lesions preablation versus 5/18 (27.8%) postablation (P<0.01). Of these 15 hyperenhancing lesions, 11 were solid, 3 were cystic, and 1 was mixed cystic and solid. Complete response occurred in 12/18 (66.7%) lesions, with either complete disappearance 5/12 (41.4%) or bland cavity formation 7/12 (58.5%). Partial response occurred in 5/18 (27.8%) lesions; 4/5 decreased in size (mean±SD: 1.4±0.5 cm preablation vs. 0.6±0.7 cm postablation), and 3/5 demonstrated decreased SUVmax. One patient with partial response underwent 2 repeat ablations with an ultimate decrease in SUVmax from 34.1 to 5.9. One solid, hyperenhancing pancreatic body lesion demonstrated no response (1.3 cm); preablation SUVmax was 10.8, but they did not undergo postablation DOTATATE PET. One patient developed postablation pancreatitis. Mean clinical follow-up was 650 days (423). CONCLUSION/CONCLUSIONS:RFA is an emerging treatment for small, nonfunctioning panNET. Postablation imaging findings most commonly included complete resolution of the tumor, decreased enhancement, decreased SUVmax, and formation of a bland cavity. As interest in this technique continues to grow, radiologists' familiarity with expected post-treatment imaging appearances and their associated response patterns is essential for accurate assessment.

BACKGROUND AND AIMS/OBJECTIVE:Endoscopic full-thickness resection (EFTR) is an established, safe technique for the resection of appendiceal orifice (AO) neoplasms. Post-EFTR appendicitis is a recognised adverse event. There are no systematic reviews and a paucity of literature which has assessed outcomes especially with respect to delayed appendicitis, mucocele, or fistula formation. We aimed to evaluate efficacy of EFTR for AO lesions. PATIENTS AND METHODS/METHODS:Consecutive AO lesions referred for consideration of EFTR were prospectively studied. Multiple data points were recorded including technical success, EFTR histopathological data, adverse events, and follow-up surveillance data by colonoscopy. Surveillance CT was performed due to concern of potential mucocele from the obstructed remnant appendix. RESULTS:Over a 4 year period to July 2023, 37 AO lesions were referred to a tertiary center for consideration of EFTR. EFTR was attempted in 35 (95%) lesions. Most lesions were small [median size 10mm, interquartile range (IQR) 10-15mm], Paris 0-IIa morphology (n=32, 91%) with serrated histopathology (n=17, 49%). R0 resection was achieved in most EFTR cases (n=30/35, 86%). Adverse events included appendicitis (n=4, 11%) and delayed bleeding (n=2, 6%). At 6-month (IQR 4-6 months) surveillance colonoscopy, there was 1 (3%) case of residual lesion. This was successfully treated endoscopically, confirmed on a second surveillance colonoscopy. There was one case of appendicitis of the remnant at 7 months. At surveillance CT abdomen/pelvis (median 15 months, IQR 7-37 months), 2/17 (12%) fistulas were identified. Both of these patients had presumed adhesions due to abdominal surgery prior to EFTR. CONCLUSIONS:In conclusion, EFTR is an effective technique for the curative resection of select, small (<15mm) Paris 0-IIa AO lesions. Appendicitis is a relatively common adverse event but often managed conservatively. The long-term significance post-EFTR fistulas remains unclear. Caution should be exercised when considering EFTR in a patient with prior regional surgery.

IMPORTANCE/UNASSIGNED:The oral microbiota may be involved in the development of pancreatic cancer, yet current evidence is largely limited to bacterial 16S amplicon sequencing and small retrospective case-control studies. OBJECTIVE/UNASSIGNED:To test whether the oral bacterial and fungal microbiome is associated with the subsequent development of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used data from 2 epidemiological cohorts: the American Cancer Society Cancer Prevention Study-II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Among cohort participants who provided oral samples, those who prospectively developed pancreatic cancer were identified during follow-up. Control participants who remained free of cancer were selected by 1:1 frequency matching on cohort, 5-year age band, sex, race and ethnicity, and time since oral sample collection. Data were collected from August 2023 to September 2024, and data were analyzed from August 2023 to January 2025. EXPOSURES/UNASSIGNED:The oral bacterial and fungal microbiome were characterized via whole-genome shotgun sequencing and internal transcribed spacer (ITS) sequencing, respectively. The association of periodontal pathogens of the red complex (Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia) and orange complex (Fusobacterium nucleatum, F periodonticum, Prevotella intermedia, P nigrescens, Parvimonas micra, Eubacterium nodatum, Campylobacter shower, and C gracilis) with pancreatic cancer was tested via logistic regression. The association of the microbiome-wide bacterial and fungal taxa with pancreatic cancer was assessed by Analysis of Compositions of Microbiomes With Bias Correction 2 (ANCOM-BC2). Microbial risk scores (MRS) for pancreatic cancer were calculated from the risk-associated bacterial and fungal species. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Pancreatic cancer incidence. RESULTS/UNASSIGNED:Of 122 000 cohort participants who provided samples, 445 developed pancreatic cancer over a median (IQR) follow-up of 8.8 (4.9-13.4) years and were matched with 445 controls. Of these 890 participants, 474 (53.3%) were male, and the mean (SD) age was 67.2 (7.5) years. Three oral bacterial periodontal pathogens-P gingivalis, E nodatum, and P micra-were associated with increased risk of pancreatic cancer. A bacteriome-wide scan revealed 8 oral bacteria associated with decreased and 13 oral bacteria associated with increased risk of pancreatic cancer (false discovery rate-adjusted Q statistic less than .05). Of the fungi, genus Candida was associated with increased risk of pancreatic cancer. The MRS, based on 27 oral species, was associated with an increase in pancreatic cancer risk (multivariate odds ratio per 1-SD increase in MRS, 3.44; 95% CI, 2.63-4.51). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, oral bacteria and fungi were significant risk factors for pancreatic cancer development. Oral microbiota hold promise as biomarkers to identify individuals at high risk of pancreatic cancer, potentially contributing to personalized prevention.