Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H; Lund, Amanda W; Welling, Theodore H; Dolgalev, Igor; Tsirigos, Aristotelis; Simeone, Diane M
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.
Prognostic Factors for Non-anastomotic Biliary Strictures Following Adult Liver Transplantation: A Systematic Review and Meta-Analysis
Fasullo, Matthew; Ghazaleh, Sami; Sayeh, Wasef; Vachhani, Ravi; Chkhikvadze, Tamta; Gonda, Tamas; Janec, Eileen; Khanna, Lauren; Haber, Gregory; Shah, Tilak
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.
Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies
Wan, Shanshan; Zhao, Ende; Weissinger, Daniel; Krantz, Benjamin A; Werba, Gregor; Freeman, Daniel; Khanna, Lauren G; Siolas, Despina; Oberstein, Paul E; Chattopadhyay, Pratip K; Simeone, Diane M; Welling, Theodore H
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.
Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting
Everett, Jessica N; Dettwyler, Shenin A; Jing, Xiaohong; Stender, Cody; Schmitter, Madeleine; Baptiste, Ariele; Chun, Jennifer; Kawaler, Emily A; Khanna, Lauren G; Gross, Seth A; Gonda, Tamas A; Beri, Nina; Oberstein, Paul E; Simeone, Diane M
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 45â€‰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 (pâ€‰<â€‰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/CONCLUSIONS: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.
Post-transplant biliary complications: advances in pathophysiology, diagnosis, and treatment
Fasullo, Matthew; Patel, Milan; Khanna, Lauren; Shah, Tilak
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.
Standardization of EUS imaging and reporting in high-risk individuals of pancreatic adenocarcinoma: consensus statement of the Pancreatic Cancer Early Detection Consortium (PRECEDE)
Gonda, Tamas A; Farrell, James; Wallace, Michael; Khanna, Lauren; Janec, Eileen; Kwon, Richard; Saunders, Michael; Siddiqui, Uzma; Brand, Randall; Simeone, Diane
BACKGROUND AND AIMS/OBJECTIVE: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, there is variability in the expertise and definition of EUS findings among gastroenterologists, as well as lack of standardized reporting of relevant findings at the time of examination. Adoption of standardized EUS reporting, using a universally accepted and agreed upon 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 (PRECEDE) 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 for 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.
Management of pancreatic fluid collections
Bhakta, Dimpal; de Latour, Rabia; Khanna, Lauren
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).
Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma
Everett, Jessica N; Burgos, Gabriela; Chun, Jennifer; Baptiste, Ariele; Khanna, Lauren G; Oberstein, Paul E; Simeone, Diane M
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/CONCLUSIONS:PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.
Social Determinants of Weight Loss Following Transoral Outlet Reduction (TORe) at a Safety-Net Hospital [Meeting Abstract]
Dornblaser, David W.; Laljee, Saif; Khanna, Lauren; Goodman, Adam; Tzimas, Demetrios; De Latour, Rabia
Donning a new approach to the practice of gastroenterology: perspectives from the COVID-19 pandemic epicenter
Sethi, Amrita; Swaminath, Arun; Latorre, Melissa; Behin, Daniel S; Jodorkovsky, Daniela; Calo, Delia; Aroniadis, Olga; Mone, Anjali; Mendelsohn, Robin B; Sharaiha, Reem Z; Gonda, Tamas A; Khanna, Lauren G; Bucobo, Juan Carlos; Nagula, Satish; Ho, Sammy; Carr-Locke, David L; Robbins, David H
The COVID-19 pandemic is seemingly 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) PPE, and freeing hospital beds have driven unconventional approaches to managing GI patients. Conversion of endoscopy units to COVID units and redeployment of gastroenterology (GI) fellows and faculty has profoundly changed the profile of most GI services. Meanwhile, consult and procedural volumes have been drastically reduced. In this review we share our collective experiences, how we have changed our practice of medicine, in response to the COVID surge. While we will review our management of specific consults and conditions, the overarching theme focuses primarily on non-invasive 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, while always important, has now become critical. And the support of our faculty and trainees remains essential. Local leadership can encourage well-being by frequent team check-ins and foster 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."