Wallace, Michael B.

Abstract Importance and Objective Gastroesophageal reflux disease (GERD) is a chronic condition associated with several risk factors, but little is known about the association between hormone therapy (HT) and GERD in postmenopausal women. Evidence Review We investigated the association between ever or current menopausal HT use and GERD using a systematic review and meta-analysis. Studies published between 2008 and August 31, 2022, were pooled using a DerSimonian and Laird random-effects model, and outcomes were reported as adjusted odds ratios (aOR) with a corresponding 95% CI. Findings The pooled analysis of five studies found a significant direct association between estrogen use and GERD (aOR, 1.41; 95% CI, 1.16-1.66; I 2 = 97.6%), and progestogen use and GERD (two studies: aOR, 1.39; 95% CI, 1.15-1.64; I 2 = 0.0%). The use of combined HT was also associated with GERD (1.16; 95% CI, 1.00-1.33; I 2 = 87.9%). Overall, HT use was associated with 29% higher odds for GERD (aOR, 1.29; 95% CI, 1.17-1.42; I 2 = 94.8%). The large number of pooled participants, differences in study design, geography, patient characteristics, and outcome assessment resulted in significant high heterogeneity. Conclusions and Relevance There is a significant association between ever or current HT use and GERD. However, the results should be interpreted with caution, given the small number of included studies and high heterogeneity. This warrants careful evaluation of GERD risk factors when prescribing HT to reduce the risk of potential GERD complications.

Objective: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. Background and Aims: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. Methods: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA (CEACAM5) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. Results: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41–59%) and lower specificities (56–96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. Conclusions: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment is associated with resistance to therapies and promotes angiogenesis, giving rise to a chaotic and leaky vasculature that is inefficient at shuttling oxygen and nutrients. Hypoxia and its downstream effectors have been implicated in immune resistance and could be contributing to the lack of response to immunotherapy experienced by patients with PDAC. Paradoxically, increasing evidence has shown hypoxia to augment genomic instability and mutagenesis in cancer, suggesting that hypoxic tumor cells could have increased production of neoantigens that can potentially enable their clearance by cytotoxic immune cells. Strategies aimed at relieving this condition have been on the rise, and one such approach opts for normalizing the tumor vasculature to reverse hypoxia and its downstream support of tumor pathogenesis. An important consideration for the successful implementation of such strategies in the clinic is that not all PDACs are equally hypoxic, therefore hypoxia-detection approaches should be integrated to enable optimal patient selection for achieving improved patient outcomes.

688 Background: Guidelines recommend patients with pancreatic ductal adenocarcinoma (PDAC) undergo genetic testing for germline pathogenic variants (PV). The aim of this study was to evaluate compliance with recently updated guidelines (May 2019) and assess subsequent uptake and outcomes of genetic testing in PDAC patients. In addition, social and clinical factors associated with genetic testing were assessed. Methods: A retrospective chart review of patients diagnosed with PDAC between May 2018 and August 2020 was performed. Discussion and subsequent uptake of genetic testing was reviewed and compared between a 12-month period before (pre-guideline) and a 12-month period after (post-guideline) guidelines were updated, accounting for a three-month transition period. Univariate and multivariate logistic regression analysis was used to assess factors predictive of undergoing genetic testing. Results: In total, 534 patients with PDAC were identified; 321 (60.1%) in the pre-guideline period and 213 (39.9%) in the post-guideline period. The mean age at diagnosis was 68 years and 47% were female. Genetic testing was discussed in 34% (109/321) of pre-guideline and in 39% (84/213) of post-guideline patients ( P = .23). Of those, 82% (89/109) of patients in pre-guideline and 75% (63/84) in post-guideline groups underwent subsequent genetic testing ( P = .71). In 26 (17.1%) of 152 tested patients, a PV was identified, of which 17 (11.2%; 17/152) had a PDAC-associated PV. Age, cancer stage at diagnosis, length of survival, and having a first-degree relative with pancreatic cancer were significant predictors of genetic testing on multivariate analysis. Conclusions: Adherence to recently updated guidelines is poor and germline genetic testing in PDAC patients remains insufficient. Efforts to increase awareness of benefits of testing, which include personalized therapies for patients and cascade testing in family members for subsequent enrollment in pancreatic cancer surveillance programs, could improve future uptake.[Table: see text]