Faculty Bibliography

Pancreatic cystic lesions (PCLs) have become more prevalent over time, particularly in asymptomatic individuals. Current screening guidelines for incidental PCLs offer a unified approach to surveillance and management, predicated on "worrisome features." Although PCLs are common in the general population, their prevalence may be higher in high-risk individuals (HRI, unaffected patients with specific familial and/or genetic risk factors). As more PCLs are diagnosed and more HRI identified, it is important to promote research that bridges data gaps and introduces nuance to risk assessment tools, ensuring tailoring of guidelines to the needs of HRI with varying pancreatic cancer risk factors.

BACKGROUND:Health technology assessments (HTAs) of robotic assisted surgery (RAS) face several challenges in assessing the value of robotic surgical platforms. As a result of using different assessment methods, previous HTAs have reached different conclusions when evaluating RAS. While the number of available systems and surgical procedures is rapidly growing, existing frameworks for assessing MedTech provide a starting point, but specific considerations are needed for HTAs of RAS to ensure consistent results. This work aimed to discuss different approaches and produce guidance on evaluating RAS. METHODS:A consensus conference research methodology was adopted. A panel of 14 experts was assembled with international experience and representing relevant stakeholders: clinicians, health economists, HTA practitioners, policy makers, and industry. A review of previous HTAs was performed and seven key themes were extracted from the literature for consideration. Over five meetings, the panel discussed the key themes and formulated consensus statements. RESULTS:A total of ninety-eight previous HTAs were identified from twenty-five total countries. The seven key themes were evidence inclusion and exclusion, patient- and clinician-reported outcomes, the learning curve, allocation of costs, appropriate time horizons, economic analysis methods, and robotic ecosystem/wider benefits. CONCLUSIONS:Robotic surgical platforms are tools, not therapies. Their value varies according to context and should be considered across therapeutic areas and stakeholders. The principles set out in this paper should help HTA bodies at all levels to evaluate RAS. This work may serve as a case study for rapidly developing areas in MedTech that require particular consideration for HTAs.

UNLABELLED:Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47.2% meeting familial pancreatic cancer criteria without a known pathogenic variant (PV) and the remainder having a pathogenic variant in a PDAC-risk gene (CDKN2A, STK11, PRSS1, BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). Study participants were predominantly from the United States (82.7%), the most common age range at enrollment was 60-69 years (37.4%), and a non-PDAC cancer was present in 32.4%. There were racial/ethnic- and sex-based disparities among enrolled subjects, as the majority of participants were female (65.9%) and self-reported white (87.7%), with only 2.9% having Hispanic ethnicity. While more than 97% of participants consented to utilize imaging data and biosamples for research, there was no difference in rate of consent based on race/ethnicity, sex, or age, thereby demonstrating uniform participation in research activities among all subgroups after enrollment. Ensuring that diversity of HRIs in PDAC surveillance programs mirrors the communities served by participating centers is important. Substantial racial/ethnic- and sex-based disparities persist among recently enrolled HRIs undergoing PDAC surveillance, and therefore reducing these disparities will be a major focus of the PRECEDE Consortium moving forward. PREVENTION RELEVANCE:Pancreatic cancer surveillance is critical to decreasing pancreatic cancer mortality; therefore, it is important that pancreatic cancer surveillance studies enroll diverse patients. We demonstrate that substantial racial/ethnic- and sex-based disparities exist amongst enrollment in the international PRECEDE consortium, highlighting the dire need for future efforts to reduce these disparities. See related Spotlight, p. 305.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.

BACKGROUND:Financial relationships with industry may bias educational content delivered by physicians. SAGES strives to mitigate potential bias, relying on physician self-reporting. Retrospective review of relationships is possible using the Open Payments Database (OPD), a public record of industry-reported payments to US physicians. We aimed to evaluate the effectiveness of the SAGES disclosure process by comparing faculty disclosures to SAGES, faculty disclosures within presentations, and OPD records among speakers at the 2018-2020 SAGES meetings. METHODS:We reviewed all presentations from the SAGES 2018-2020 Annual Meetings. For each invited presentation, all slide-disclosed relationships were recorded. For US physicians, we queried the OPD and recorded relationships ≥ $500 USD in the calendar year prior to presentation. We compared the slide-disclosed relationships with OPD-reported relationships and with those provided to SAGES during the faculty disclosure process. We surveyed a sample of the 2020 annual meeting speakers to analyze potential reasons for discordance. RESULTS:From 2018 to 2020, there were 1,355 invited presentations, of which 1,234 (91%) were available for review. Disclosure slides were present in 1,098 (89%), increasing from 86% in 2018 to 93% in 2020. The proportion of speakers with OPD-reported relationships ≥ $500 increased from 54% in 2018 to 66% in 2020. The total value of OPD relationships decreased from $5.9 million (2018) to $3.3 million (2020) with a concomitant decrease in the proportion with high discordance from 9% in 2018 to 5% in 2020. Among the 2020 speakers with high discordance, the most common explanations for discordance were being unaware of payment or payment outside the 12-month timeframe (55%). CONCLUSIONS:Discordance between financial disclosures reported to SAGES and OPD highlight the need for improvements in the faculty disclosure process. SAGES will continue to streamline this process by incorporating faculty review of their OPD disclosures to ensure all educational programs remain free of commercial bias.

BACKGROUND:Germline BRCA1 and BRCA2 mutations (gBRCAm) can inform pancreatic cancer (PC) risk and treatment but most of the available information is derived from white patients. The ethnic and geographic variability of gBRCAm prevalence and of germline BRCA (gBRCA) testing uptake in PC globally is largely unknown. MATERIALS AND METHODS/METHODS:We carried out a systematic review and prevalence meta-analysis of gBRCA testing and gBRCAm prevalence in PC patients stratified by ethnicity. The main outcome was the distribution of gBRCA testing uptake across diverse populations worldwide. Secondary outcomes included: geographic distribution of gBRCA testing uptake, temporal analysis of gBRCA testing uptake in ethnic groups, and pooled proportion of gBRCAm stratified by ethnicity. The study is listed under PROSPERO registration number #CRD42022311769. RESULTS:A total of 51 studies with 16 621 patients were included. Twelve of the studies (23.5%) enrolled white patients only, 10 Asians only (19.6%), and 29 (56.9%) included mixed populations. The pooled prevalence of white, Asian, African American, and Hispanic patients tested per study was 88.7%, 34.8%, 3.6%, and 5.2%, respectively. The majority of included studies were from high-income countries (HICs) (64; 91.2%). Temporal analysis showed a significant increase only in white and Asians patients tested from 2000 to present (P < 0.001). The pooled prevalence of gBRCAm was: 3.3% in white, 1.7% in Asian, and negligible (<0.3%) in African American and Hispanic patients. CONCLUSIONS:Data on gBRCA testing and gBRCAm in PC derive mostly from white patients and from HICs. This limits the interpretation of gBRCAm for treating PC across diverse populations and implies substantial global and racial disparities in access to BRCA testing in PC.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

PURPOSE/OBJECTIVE:The aim of this study was to evaluate the diagnostic performance of preoperative cross-sectional imaging findings using the SAR-AGA definitions in Crohn's disease (CD) patients who underwent ileocolic resection (ICR) with and without surgically complex ileocolic CD (CIC-CD). METHODS:69 CD patients [38 men; mean (± SD) age: 40.6 (16.2) years] who underwent ICR were retrospectively classified by surgical complexity by a colorectal surgeon using operative findings. CIC-CD was defined as ileal CD, not confined to the distal ileum. Two radiologists retrospectively evaluated the preoperative imaging for the presence and type of penetrating disease, stricture, or probable stricture using the SAR-AGA consensus definitions. The diagnostic performance of preoperative imaging findings was compared for patients with and without CIC-CD. Estimated blood loss (EBL), operative time (OT), conversion to open surgery, diversion, and length of hospital stay (LOS) were compared. RESULTS:60.9% had CIC-CD and 79.7% underwent primary ICR. Penetrating disease was more common in patients with than without CIC-CD (76.2% vs. 40.7%, p = 0.0048) and similar among primary versus redo ICR (p = 0.12). Patients with CIC-CD had more complex fistulas (59.5% vs. 11.1%; p < 0.0001) and fewer simple fistulas (2.4% vs. 18.5%; p = 0.03) than those without. Mesenteric findings (abscess, inflammatory mass) were more frequent in patients with (35.7%) than without (0%) (p = 0.0002) CIC-CD. Stricture and probable stricture were similar (p = 0.59). CIC-CD patients had greater EBL (178 cc vs. 57 cc, p = 0.006), conversion rates (30% vs. 0%, p = 0.0026), and diversion (80% vs. 52%, p = 0.04). CONCLUSION/CONCLUSIONS:Complex fistula, mesenteric abscess, or inflammatory mass defined by the SAR-AGA guidelines suggests CIC-CD. ICR for CIC-CD had greater EBL, conversion to open surgery, and diversion.