Somatic Mutational Analysis in Endoscopic Ultrasound-Guided Biopsy of Pancreatic Adenocarcinoma: Assessing Yield and Impact.

INTRODUCTION: We sought to determine the yield of somatic mutational analysis from endoscopic ultrasound (EUS)-guided biopsies of pancreatic adenocarcinoma compared with that of surgical resection and to assess the impact of these results on oncologic treatment. METHODS: We determined the yield of EUS sampling and surgical resection. We evaluated the potential impact of mutational analysis by identifying actionable mutations and its direct impact by reviewing actual treatment decisions. RESULTS: Yield of EUS sampling was 89.5%, comparable with the 95.8% yield of surgical resection. More than a quarter in the EUS cohort carried actionable mutations, and of these, more than 1 in 6 had treatment impacted by mutational analysis. DISCUSSION: EUS sampling is nearly always adequate for somatic testing and may have substantial potential and real impact on treatment decisions.

Development of American Society for Gastrointestinal Endoscopy standards for training in advanced endoscopy within dedicated advanced endoscopy fellowship programs.

BACKGROUND AND AIMS: Training in interventional endoscopy is offered by nonaccredited advanced endoscopy fellowship programs (AEFPs). The number of these programs has increased dramatically with a concurrent increase in the breadth and complexity of interventional endoscopy procedures. Accreditation is governed by competency-based education, yet what constitutes a "high-quality" nonaccredited AEFP has not been defined. Using an evidence-based consensus process, we aimed to establish standards for AEFPs. METHODS: The RAND UCLA appropriateness method, a well-described modified Delphi process to develop quality indicators, was used. A task force established by the American Society for Gastrointestinal Endoscopy drafted potential quality indicators (structure, process, and outcome) in 6 categories: activity preceding training; structure of AEFPs; training in ERCP, EUS, and EMR; and luminal stent placement. Three rounds of iterative feedback from 20 experts were conducted. Round 0 involved discussion of project details. In round 1, experts independently ranked proposed quality indicators on a 9-point interval scale ranging from highly inappropriate (1) to highly appropriate (9). Next, proposed quality indicators were discussed and reworded in a group meeting followed by round 2, in which experts independently reranked proposed quality indicators and provided benchmarks (when applicable). The median score for each quality indicator was calculated. Mean absolute deviation from the median was calculated, and appropriateness of potential quality indicators was assessed using the BIOMED concerted action on appropriateness definition, P value method, and interpercentile range adjusted for symmetry definition. A quality indicator was deemed appropriate if the median score was ≥7 and met criteria for appropriateness using all 3 defined statistical methods. RESULTS: Of 89 proposed quality indicators, 37 statements met criteria as appropriate for a quality indicator (activity preceding training, 2; structure of AEFPs, 10; training in ERCP, 7; training in EUS, 8; training in EMR, 7; luminal stent placement, 3). Minimum thresholds were defined for 19 relevant quality indicators for number of trainers, procedures during fellowship, and procedures before assessment of competence. Among the final appropriate quality indicators were that all trainees should undergo qualitative and quantitative competence assessments using validated tools at least quarterly with documented feedback throughout the training period and that trainees should track outcomes and relevant quality metrics for specific procedures. CONCLUSIONS: This consensus process using validated methodology established standards for an AEFP in an effort to ensure adequate training in the most commonly taught interventional endoscopic procedures (ERCP, EUS, EMR, and luminal stent placement) during fellowship. An important component of an AEFP is the use of competency-based assessments that are compliant with the Accreditation Council for Graduate Medical Education's Next Accreditation System, with the goal of ensuring that trainees achieve specific milestones in their progression to achieving cognitive and technical competency.

Prognostic Factors for Non-anastomotic Biliary Strictures Following Adult Liver Transplantation: A Systematic Review and Meta-Analysis.

INTRODUCTION: The development of non-anastomotic biliary strictures (NAS) following orthotopic adult liver transplantation (OLT) is associated with significant morbidity. We performed a systematic review and meta-analysis to identify all prognostic factors for the development of NAS. METHODS: A systematic review was conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. We used the Newcastle-Ottawa scale to assess the quality of the included studies. Using the random-effects model, we calculated the weighted pooled odds ratios (OR), mean differences (MD), hazard ratios (HR), and 95% confidence intervals (CI) of the risk factors. RESULTS: Based on 19 international studies that included a total of 8269 adult LT patients, we calculated an 8% overall incidence of NAS. In this study, 7 potential prognostic factors were associated with a statistically significant hazard ratio for NAS in pooled analyses including (1) DCD donors compared to DBD donors (2) PSC as an indication for a liver transplant (3) Roux-en-Y bile duct reconstruction compared to duct-to-duct reconstruction (4) hepatic artery thrombosis (5) longer cold ischemia time (6) longer warm ischemia time (7) and total operative times. CONCLUSION: In this systematic review and meta-analysis, we identified 7 prognostic factors for the development of NAS following OLT. These findings might lay the groundwork for development of diagnostic algorithms to better risk stratify patients at risk for development of NAS.

Standardization of EUS imaging and reporting in high-risk individuals of pancreatic adenocarcinoma: consensus statement of the Pancreatic Cancer Early Detection Consortium.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma is an aggressive disease most often diagnosed after local progression or metastatic dissemination, precluding resection and resulting in a high mortality rate. For individuals with elevated personal risk of the development of pancreatic cancer, EUS is a frequently used advanced imaging and diagnostic modality. However, variability in the expertise and definition of EUS findings exists among gastroenterologists, as well as a lack of standardized reporting of relevant findings at the time of examination. Adoption of standardized EUS reporting, using a universally accepted and agreed on terminology, is needed. METHODS: A consensus statement designed to create a standardized reporting template was authored by a multidisciplinary group of experts in pancreatic diseases that includes gastroenterologists, radiologists, surgeons, oncologists, and geneticists. This statement was developed using a modified Delphi process as part of the Pancreatic Cancer Early Detection Consortium, and >75% agreement was required to reach consensus. RESULTS: We identified reporting elements and present standardized reporting templates for EUS indications, procedural data, EUS image capture, and descriptors of findings, tissue sampling, and postprocedural assessment of adequacy. CONCLUSIONS: Adoption of this standardized EUS reporting template should improve consistency in clinical decision-making for individuals with elevated risk of pancreatic cancer by providing complete and accurate reporting of pancreatic abnormalities. Standardization will also help to facilitate research and clinical trial design by using clearly defined and consistent imaging descriptions, thus allowing for comparison of results across different centers.

Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma.

BACKGROUND: Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. METHODS: We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. RESULTS: Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. CONCLUSION: PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.

Donning a New Approach to the Practice of Gastroenterology: Perspectives From the COVID-19 Pandemic Epicenter.

The COVID-19 pandemic seemingly is peaking now in New York City and has triggered significant changes to the standard management of gastrointestinal diseases. Priorities such as minimizing viral transmission, preserving personal protective equipment, and freeing hospital beds have driven unconventional approaches to managing gastroenterology (GI) patients. Conversion of endoscopy units to COVID units and redeployment of GI fellows and faculty has profoundly changed the profile of most GI services. Meanwhile, consult and procedural volumes have been reduced drastically. In this review, we share our collective experiences regarding how we have changed our practice of medicine in response to the COVID surge. Although we review our management of specific consults and conditions, the overarching theme focuses primarily on noninvasive measures and maximizing medical therapies. Endoscopic procedures have been reserved for those timely interventions that are most likely to be therapeutic. The role of multidisciplinary discussion, although always important, now has become critical. The support of our faculty and trainees remains essential. Local leadership can encourage well-being by frequent team check-ins and by fostering trainee development through remote learning. Advancing a clear vision and a transparent process for how to organize and triage care in the recovery phase will allow for a smooth transition to our new normal.

Low Frequency of Lymph Node Metastases in Patients in the United States With Early-stage Gastric Cancers That Fulfill Japanese Endoscopic Resection Criteria.

BACKGROUND & AIMS: In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US. METHODS: We performed a retrospective study of 176 patients (mean age 68.5 years; 59.1% male; 58.5% white) who underwent surgical resection with lymph node dissection of T1 and Tis gastric adenocarcinomas, staged by pathologists, at 7 tertiary care centers in the US from January 1, 1999, through December 31, 2016. The frequency of lymph node metastases and associated risk factors were determined. RESULTS: The mean size of gastric adenocarcinomas was 23.0 ± 16.6 mm-most were located in the lower-third of the stomach (67.0%), invading the submucosa (55.1%), and moderately differentiated (31.3%). Lymphovascular invasion was observed in 18.2% of lesions. Overall, 20.5% of patients had lymph node metastases. Submucosal invasion (odds ratio, 3.9; 95% CI, 1.4-10.7) and lymphovascular invasion (odds ratio, 4.6; 95% CI, 1.8-12.0) were independently associated with increased risk of metastasis to lymph nodes. The frequency of lymph node metastases among patients fulfilling standard and expanded Japanese criteria for ER were 0 and 7.5%, respectively. CONCLUSIONS: The frequency of lymph node metastases among patients with early gastric cancer in a US population is higher than that of published Asian series. However, early gastric cancer lesions that meet the Japanese standard criteria for ER are associated with negligible risk of metastasis to lymph nodes, so ER can be recommended for definitive therapy. Expanded criteria cancers appear to have a higher risk of metastasis to lymph nodes, so ER may be considered for select cases.

Optical coherence tomography (OCT) prior to peroral endoscopic myotomy (POEM) reduces procedural time and bleeding: a multicenter international collaborative study.

BACKGROUND: Per-oral endoscopic myotomy (POEM) has emerged as an endoscopic treatment of achalasia. There are no pre-procedural imaging modalities to predict the safest and the most efficacious approach. AIM: To evaluate the use of optimal coherence tomography (OCT) in providing a pre-procedural esophageal assessment. METHODS: Patients undergoing POEM from July 2013 to November 2015 were captured in a multicenter, international registry. Patients who underwent OCT pre-POEM ("OCT arm") were compared to patients without pre-POEM OCT ("control arm"). OCT images were assessed for the degree of vascularity and the thickness of the circular muscular layer, and an approach was determined. RESULTS: A total of 84 patients were captured in the registry. Fifty-one patients underwent pre-POEM OCT. Using OCT as a guide, 24 (47 %) of patients underwent anterior POEM while 27 (53 %) underwent posterior POEM. Technical success was achieved in 96 % of patients. Significantly less bleeding occurred in the OCT arm when compared to the control group [4 (8 %) vs. 14 (43 %), p = 0.0001]. As a result, procedural time was significantly lower in the OCT group as compared to the control group (85.8 vs. 121.7 min, p = 0.000097). CONCLUSION: Pre-POEM OCT results in a reduction in procedural bleeding which contributes to a reduction in overall procedural time. CLINICAL TRIAL REGISTRATION: NCT01438385.

The Role of Real Time Endoscopic Ultrasound Guided Elastography for Targeting EUS-FNA of Suspicious Pancreatic Masses: A Review of the Literature and A Single Center Experience.

BACKGROUND: Endoscopic ultrasound guided elastography is an imaging modality that can be used to evaluate tissue stiffness and to assess solid pancreatic lesions. It can also assist in optimizing the diagnostic yield of endoscopic ultrasound guided fine needle aspiration biopsies. AIMS: To review the literature on solid pancreatic lesions, the use of EUS guided fine needle aspiration and endoscopic ultrasound guided elastography and to present a single center experience using elastography to direct fine needle aspiration biopsies of solid pancreatic lesions. METHODS: We present a review of the literature and a single center experience describing the use of EUS guided elastography in directing fine needle aspiration biopsies of solid pancreatic lesions. RESULTS: Thirteen male veterans with an average age of 62.3 (SD±11.8) years were enrolled in the study. The mean pancreatic mass size on EUS was 5.1×5.2 (SD±4.4×4.5) cm. A total of 13 lesions were identified during elastography. The lesions were most commonly found in the body (n=5), followed by multifocal lesions (n=4), pancreatic head (n=3) and tail (n=1). The seven concerning pancreatic lesions were stratified based on color pattern identified on EUS and EUS-elastography. Three lesions were homogenously blue, and four lesions were heterogeneously blue. The remaining six lesions which were less concerning were predominantly green. Of the three lesions, that were homogenously blue, two were diagnosed as adenocarcinoma (n=2) and chronic pancreatitis (n=1) respectively. Of the four heterogeneously blue lesions two were adenocarcinomas, while the other two represented a large B-cell lymphoma and chronic pancreatitis. Patients whose lesions were characterized as homogenous or heterogeneous green were benign and remained disease free after a median of two years of regular follow up. LIMITATIONS: Relatively small number of patients studied. CONCLUSIONS: In our single center experience we found that the use of real time endoscopic ultrasound guided elastography for targeting fine needle aspiration of suspicious pancreatic lesions may be beneficial as an adjunct modality to complement conventional EUS. Larger prospective studies need to be conducted to evaluate the utility of this modality in targeting pancreatic lesions.

BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.

BACKGROUND: Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. METHODS: Patients in a high-risk PDAC prevention and genetics program or those with a personal history of PDAC who were referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. RESULTS: A total of 37 patients without PDAC underwent BRCA1/2 testing at the study institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six patients carried Ashkenazi Jewish founder mutations (3 with BRCA1 and 3 with BRCA2), and 1 patient was found to have a BRCA2 mutation on comprehensive testing. Thirty-two patients with PDAC underwent BRCA1/2 genetic testing. Five patients had Ashkenazi Jewish founder mutations (2 with BRCA1 and 3 with BRCA2), and 2 patients were found to have BRCA2 mutations on comprehensive testing. The diagnostic yield was 7 of 32 patients (21.9%). CONCLUSIONS: BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation-positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer.

Uptake and patterns of use of gemcitabine for metastatic pancreatic cancer: a population-based study.

Gemcitabine was approved for advanced pancreatic cancer in 1996. We investigated uptake and predictors of its use. We identified 3,231 individuals > 65 years in the SEER-Medicare database with stage IV pancreatic adenocarcinoma, diagnosed between 1998-2005, who survived > 30 days. Of these, 54% received chemotherapy, 93% with gemcitabine. Gemcitabine nonreceipt was associated with advanced age and unmarried (OR: 0.65, 95% CI: 0.55-0.76). Diagnosis in 2004-2005 versus 1998-2000 was more likely to receive gemcitabine (OR: 1.51, 95% CI: 1.23-1.84) as were higher SES patients (highest versus lowest quintile, OR: 2.14, 95% CI: 1.60-2.85). Gemcitabine was rapidly adopted among elderly advanced pancreatic cancer patients; several factors are associated with use.

Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting.

BACKGROUND: Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. METHODS: Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum. RESULTS: Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification. CONCLUSION: Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.

Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.

Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.

[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].

Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment.

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.

Management of pancreatic fluid collections.

Pancreatic fluid collections often develop as a complication of acute pancreatitis but can be seen in a variety of conditions including chronic pancreatitis, trauma, malignancy or post-operatively. It is important to classify a pancreatic fluid collection in order to optimize treatment strategies and management. Most interventions are targeted towards the management of delayed complications of pancreatitis, including pancreatic pseudocysts and walled-off necrosis (WON), which often develop days to weeks after the initial episode of pancreatitis. Surgical, percutaneous, and endoscopic interventions are all possible methods for treatment of pancreatic fluid collections, however endoscopic drainage with endoscopic ultrasound has become first-line. Advances within endoscopic drainage strategies have also led to innovative changes in the specific stents used for treatment, with possible options including double pigtail plastic stents, fully covered self-expanding metal stents and lumen-apposing metal stents (LAMS).

Post-transplant biliary complications: advances in pathophysiology, diagnosis, and treatment.

Liver transplantation (LT) is the only curative therapy in patients with end-stage liver disease. Long-term survival is excellent, yet LT recipients are at risk of significant complications. Biliary complications are an important source of morbidity after LT, with an estimated incidence of 5%-32%. Post-LT biliary complications include strictures (anastomotic and non-anastomotic), bile leaks, stones, and sphincter of Oddi dysfunction. Prompt recognition and management is critical as these complications are associated with mortality rates up to 20% and retransplantation rates up to 13%. This review aims to summarise our current understanding of risk factors, natural history, diagnostic testing, and treatment options for post-transplant biliary complications.