Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:As abdominal imaging becomes more sensitive and regularly used, pancreatic cystic lesions (PCLs) are being diagnosed more frequently. A small but clinically significant minority of these lesions have a predisposition to either harbor malignancy or undergo malignant transformation. This review highlights the current state and performance of cystic fluid biomarkers and how they may be incorporated into management. RECENT FINDINGS/RESULTS:Among the major domains of molecular testing for PCLs, DNA based analyses have demonstrated the highest accuracy in identifying cyst type and have the most data to support their clinical use. However, epigenetic and protein biomarker based molecular assessments have emerged with the potential to complement DNA based approaches. In addition, recent studies have increasingly demonstrated the value associated with combinations of mutations and other biomarkers in identifying higher grade mucinous cystic lesions. We present the performance of individual biomarkers in cyst fluid analysis with an emphasis on an algorithmic approach to improve the accurate identification of both cyst type and risk of malignant transformation.

BACKGROUND AND AIMS/OBJECTIVE:Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMN lacking worrisome features (WF) and high-risk stigmata (HRS)), warrant surveillance. However, their optimal duration, especially among cysts with initial five years of size stability, warrants further investigation. We aim to systematically review the surveillance of low-risk BD-IPMNs and investigate incidence of WF/HRS and advanced neoplasia: high-grade dysplasia and pancreatic cancer during the initial (<five-year) and extended surveillance period (≥five-year). METHODS:A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as % patient-years). The meta-analysis relied on time-to-event plots and utilized random-effects model. RESULTS:Forty-one eligible studies underwent systematic review, and eighteen studies were meta-analyzed. Pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance were 2.2% [95%CI:1.0%-3.7%] and 2.9% [95%CI:1.0%-5.7%] patient-years, respectively, whereas incidence of advanced neoplasia were 0.6%[95%CI:0.2%-1.00%] and 1.0%[95%CI:0.6%-1.5%] patient-years, respectively. Pooled incidence of disease-specific mortality during initial and extended surveillance were 0.3% [95%CI:0.1% - 0.6%] and 0.6% [95%CI: 0.0%-1.6%] patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had WF/HRS and advanced neoplasia incidence of 1.9%[95%CI:1.2%-2.8%] and 0.2%[95%CI:0.1%-0.5%] patient-years, respectively. CONCLUSION/CONCLUSIONS:A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs is a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.

INTRODUCTION/BACKGROUND: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/CONCLUSIONS: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.

Since its emergence as a diagnostic modality in the 1980s, endoscopic ultrasound (EUS) has provided the clinician profound access to gastrointestinal organs to aid in the direct visualization, sampling, and subsequent identification of pancreatic pathology. In recent years, advancements in EUS as an interventional technique have promoted the use of local ablative therapies as a minimally invasive alternative to the surgical management of pancreatic neuroendocrine tumors (pNETs) and pancreatic cystic neoplasms (PCNs), especially for those deemed to be poor operative candidates. EUS-guided local therapies have demonstrated promising efficacy in addressing a spectrum of pancreatic neoplasms, while also balancing local adverse effects on healthy parenchyma. This article serves as a review of the current literature detailing the mechanisms, outcomes, complications, and limitations of EUS-guided local ablative therapies such as chemical ablation and radiofrequency ablation (RFA) for the treatment of pNETs and PCNs, as well as a discussion of future applications of EUS-guided techniques to address a broader scope of pancreatic pathology.

Since its emergence as a diagnostic modality in the 1980s, endoscopic ultrasound (EUS) has provided the clinician profound access to gastrointestinal organs to aid in the direct visualization, sampling, and subsequent identification of pancreatic pathology. In recent years, advancements in EUS as an interventional technique have promoted the use of local ablative therapies as a minimally invasive alternative to the surgical management of pancreatic neuroendocrine tumors (pNETs) and pancreatic cystic neoplasms (PCNs), especially for those deemed to be poor operative candidates. EUS-guided local therapies have demonstrated promising efficacy in addressing a spectrum of pancreatic neoplasms, while also balancing local adverse effects on healthy parenchyma. This article serves as a review of the current literature detailing the mechanisms, outcomes, complications, and limitations of EUS-guided local ablative therapies such as chemical ablation and radiofrequency ablation (RFA) for the treatment of pNETs and PCNs, as well as a discussion of future applications of EUS-guided techniques to address a broader scope of pancreatic pathology.

Cholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. We present our diagnostic and theranostic approach to the initial evaluation of cholangiocarcinomas, focusing on extrahepatic cholangiocarcinoma. This involves a multipronged strategy incorporating advanced imaging, endoscopic methods, multiple approaches to tissue sampling, and molecular markers. We also provide an algorithm for the sequential use of these tools.

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.

Introduction: Pancreatic cancer continues to carry a dismal prognosis due to the high failure rates of conventional first line treatments. There is growing interest in the molecular profiling of tumors to guide early initiation of targeted therapies. Nearly all patients undergo endoscopic ultrasound (EUS) fine needle aspiration or biopsy as the initial diagnostic procedure. Therefore, we sought to assess the yield of EUS biopsies in obtaining samples for molecular profiling of pancreatic tumors and investigated the endoscopic factors associated with successful EUS sampling.
Method(s): We performed a search for all EUS-guided needle biopsies done for the indication of suspected pancreatic mass on imaging between January 2017 and January 2022. We then limited our cases to those diagnosed with pancreatic adenocarcinoma and had EUS samples sent for molecular profiling. Molecular profiling was done with next-generation sequencing with either a targeted panel of 648 genes or 324 genes. Differences in tumor size, number of needle passes, and needle gauge size between the successful sampling and non-successful sampling groups were determined by Mann-Whitney U Test using SPSS Statistics.
Result(s): We identified 309 consecutive cases where the diagnosis of pancreatic adenocarcinoma was established by EUS. Fifty-nine EUS biopsies were sent for molecular profiling and of these, fifty-three were sufficient for molecular testing (89.5% success rate). No procedural factors were significantly associated with successful sampling though we observed larger mean tumor sizes (31.3 vs 28 mm) and greater mean number of needle passes (3.4 vs 2.7 mean passes) in the successful sampling group. In Figure, we show the most commonly identified mutations and identify those that at the time had potential clinical impact on therapies. The yield of actionable mutations was 14% in the 53 patients who were successfully tested. (Figure)
Conclusion(s): Our results support that yield of somatic mutation testing is high from standard of care EUS biopsies and no obvious procedural factors were associated with failure of testing. We found that 14% of patients had actionable mutations. As the number of available targeted therapies improve, we expect the impact of this highly technically successful approach to grow (Table)