Faculty Bibliography

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.

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.

Widespread hyperalgesia, characterized by pain sensitivity beyond the primary pain site, is a common yet under-characterized feature across chronic pain conditions, including chronic pancreatitis (CP). In this exploratory study, we identified a candidate neural biosignature of widespread hyperalgesia using high-density electroencephalography (EEG) in patients with chronic low back pain (cLBP). Specifically, stimulus-evoked delta, theta, and alpha oscillatory activity in the bilateral medial orbitofrontal cortex (mOFC) differentiated cLBP patients with widespread hyperalgesia from healthy controls. To examine cross-condition generalizability and advance predictive biomarker development for CP, we applied this mOFC-derived EEG biosignature to an independent cohort of patients with CP. The biosignature distinguished CP patients with widespread hyperalgesia and predicted individual treatment responses to peripherally targeted endoscopic therapy. These preliminary findings provide early support for a shared cortical signature of central sensitization across pain conditions and offer translational potential for developing EEG-based predictive tools for treatment response in CP.

Early detection of pancreatic cancer (PC) remains challenging largely due to the low population incidence and few known risk factors. However, screening in at-risk populations and detection of early cancer has the potential to significantly alter survival. In this study, we aim to develop a predictive model to identify patients at risk for developing new-onset PC at two and a half to three year time frame. We used the Electronic Health Records (EHR) of a large medical system from 2000 to 2021 (N = 537,410). The EHR data analyzed in this work consists of patients' demographic information, diagnosis records, and lab values, which are used to identify patients who were diagnosed with pancreatic cancer and the risk factors used in the machine learning algorithm for prediction. We identified 73 risk factors of pancreatic cancer with the Phenome-wide Association Study (PheWAS) on a matched case-control cohort. Based on them, we built a large-scale machine learning algorithm based on EHR. A temporally stratified validation based on patients not included in any stage of the training of the model was performed. This model showed an AUROC at 0.742 [0.727, 0.757] which was similar in both the general population and in a subset of the population who has had prior cross-sectional imaging. The rate of diagnosis of pancreatic cancer in those in the top 1 percentile of the risk score was 6 folds higher than the general population. Our model leverages data extracted from a 6-month window of time in the electronic health record to identify patients at nearly sixfold higher than baseline risk of developing pancreatic cancer 2.5-3 years from evaluation. This approach offers an opportunity to define an enriched population entirely based on static data, where current screening may be recommended.

BACKGROUND AND AIMS/OBJECTIVE:Fully covered self-expandable metal stents (FCSEMSs) are widely used in benign upper gastrointestinal (GI) conditions, but stent migration remains a limitation. An over-the-scope clip (OTSC) device (Ovesco Endoscopy) for stent anchoring has been recently developed. The aim of this study was to evaluate the effect of OTSC fixation on SEMS migration rate. METHODS:A retrospective review of consecutive patients who underwent FCSEMS placement for benign upper GI conditions between 1/2011 and 10/2022 at 16 centers. The primary outcome was rate of stent migration. The secondary outcomes were clinical success and adverse events. RESULTS:A total of 311 (no fixation 122, OTSC 94, endoscopic suturing 95) patients underwent 316 stenting procedures. Compared to the no fixation (NF) group (n=49, 39%), the rate of stent migration was significantly lower in the OTSC (SF) (n=16, 17%, p=0.001) and endoscopic suturing (ES) group (n=23, 24%, p=0.01). The rate of stent migration was not different between the SF and ES groups (p=0.2). On multivariate analysis, SF (OR 0.34, CI 0.17-0.70, p<0.01) and ES (OR 0.46, CI 0.23-0.91, p=0.02) were independently associated with decreased risk of stent migration. Compared to the NF group (n=64, 52%), there was a higher rate of clinical success in the SF (n=64, 68%; p=0.03) and ES group (n=66, 69%; p = 0.02). There was no significant difference in the rate of adverse events between the three groups. CONCLUSION/CONCLUSIONS:Stent fixation using OTSC is safe and effective at preventing stent migration and may also result in improved clinical response.

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) presents a redoubtable challenge due to late-stage diagnosis and limited treatment options, necessitating innovative therapeutic strategies. METHODS:Here, we report our results investigating the safety and efficacy of talimogene laherparepvec (T-VEC), an FDA-approved oncolytic herpes simplex virus type 1, in patients with advanced PDAC. Nine patients with treatment-refractory advanced PDAC received escalating doses of T-VEC via endoscopic injection. RESULTS:While no objective responses were observed, stable disease was achieved in 44% of patients, with a median overall survival of 7.8 months, including one patient who survived 28 months. Adverse events were manageable, with the maximum tolerated dose determined to be 108 PFU/mL. CONCLUSION/CONCLUSIONS:Our findings underscore the feasibility of intratumoral T-VEC administration in advanced PDAC. Further investigation, particularly in combination with immunotherapies administered systemically is warranted to more optimally assess T-VEC in this challenging malignancy.ClinicalTrials.gov Identifier: NCT03086642.

BACKGROUND AND STUDY AIMS/UNASSIGNED:EUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS. PATIENTS AND METHODS/UNASSIGNED:A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure. RESULTS/UNASSIGNED:<0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not. CONCLUSIONS/UNASSIGNED:EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.