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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.
PMID: 36781852
ISSN: 2041-1723
CID: 5427092

Endoscopic Ultrasound Biopsy for Molecular Analysis in Pancreatic Cancer: Findings From a Large Academic Medical Center [Meeting Abstract]

Dong, S; Agarunov, E; Simeone, D; Gonda, T
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)
ISSN: 1572-0241
CID: 5514842

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 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/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.
PMID: 35906821
ISSN: 2045-7634
CID: 5277102

Terbinafine induced pancreatitis in a healthy young adult male [Letter]

Brydges, Hilliard T; Onuh, Ogechukwu C; Nasr, Hani Y; Gonda, Tamas A; Chiu, Ernest S; Caplan, Avrom S
PMID: 35620915
ISSN: 1529-8019
CID: 5248072

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.
PMID: 34736932
ISSN: 1097-6779
CID: 5038412

International external validation of a stratification tool to identify branch-duct intraductal papillary mucinous neoplasms at lowest risk of progression

Overbeek, Kasper A; van Leeuwen, Nikki; Tacelli, Matteo; Anwar, Muhammad S; Yousaf, Muhammad N; Chhoda, Ankit; Arcidiacono, Paolo Giorgio; Gonda, Tamas A; Wallace, Michael B; Capurso, Gabriele; Farrell, James J; Cahen, Djuna L; Bruno, Marco J
BACKGROUND:Identifying branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance. OBJECTIVE:We aimed to externally validate the previously developed Dutch-American Risk stratification Tool (DART-1;, which identifies cysts at low risk of developing worrisome features (WFs) or high-risk stigmata (HRS). METHODS:Three prospective cohorts of individuals under surveillance for BD-IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART-1, a multivariable Cox-proportional logistic regression model with five predictors for the development of WFs or HRS. RESULTS:Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART-1's discriminative ability (C-statistic 0.68) was similar to that in the development cohort (0.64-0.72) and showed moderate calibration. DART-1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3-year risk was 0%-0% versus 0%-3.7% for Q1; 0.3%-0.4% versus 3%-11% for Q2; and 2.6%-3% versus 2.4%-9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%). CONCLUSIONS:The performance of DART-1 to predict the development of WFs or HRS in BD-IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD-IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.
PMID: 35199484
ISSN: 2050-6414
CID: 5172262


Richter, Benjamin I.; Tarabanis, Constantine; Khanna, Lauren G.; Haber, Gregory B.; Sinha, Prashant; Wolfgang, Christopher L.; Gonda, Tamas A.
ISSN: 0016-5085
CID: 5523922

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Gonda, Tamas A; Everett, Jessica N; Wallace, Michael; Simeone, Diane M
PMID: 34454916
ISSN: 1528-0012
CID: 5061112

Hemostatic powder TC-325 treatment of malignancy-related upper gastrointestinal bleeds: International registry outcomes

Hussein, Mohamed; Alzoubaidi, Durayd; O'Donnell, Michael; de la Serna, Alvaro; Bassett, Paul; Varbobitis, Ioannis; Hengehold, Tricia; Ortiz Fernandez-Sordo, Jacobo; Rey, Johannes W; Hayee, Bu'Hussain; Despott, Edward J; Murino, Alberto; Graham, David; Latorre, Melissa; Moreea, Sulleman; Boger, Phillip; Dunn, Jason; Mainie, Inder; Mullady, Daniel; Early, Dayna; Ragunath, Krish; Anderson, John; Bhandari, Pradeep; Goetz, Martin; Kiesslich, Ralf; Coron, Emmanuel; Rodriguez de Santiago, Enrique; Gonda, Tamas; Gross, Seth A; Lovat, Laurence B; Haidry, Rehan
BACKGROUND AND AIM/OBJECTIVE:Upper gastrointestinal tumors account for 5% of upper gastrointestinal bleeds. These patients are challenging to treat due to the diffuse nature of the neoplastic bleeding lesions, high rebleeding rates, and significant transfusion requirements. TC-325 (Cook Medical, North Carolina, USA) is a hemostatic powder for gastrointestinal bleeding. The aim of this study was to examine the outcomes of upper gastrointestinal bleeds secondary to tumors treated with Hemospray therapy. METHODS:Data were prospectively collected on the use of Hemospray from 17 centers. Hemospray was used during emergency endoscopy for upper gastrointestinal bleeds secondary to tumors at the discretion of the endoscopist as a monotherapy, dual therapy with standard hemostatic techniques, or rescue therapy. RESULTS:One hundred and five patients with upper gastrointestinal bleeds secondary to tumors were recruited. The median Blatchford score at baseline was 10 (interquartile range [IQR], 7-12). The median Rockall score was 8 (IQR, 7-9). Immediate hemostasis was achieved in 102/105 (97%) patients, 15% of patients had a 30-day rebleed, 20% of patients died within 30 days (all-cause mortality). There was a significant improvement in transfusion requirements following treatment (P < 0.001) when comparing the number of units transfused 3 weeks before and after treatment. The mean reduction was one unit per patient. CONCLUSIONS:Hemospray achieved high rates of immediate hemostasis, with comparable rebleed rates following treatment of tumor-related upper gastrointestinal bleeds. Hemospray helped in improving transfusion requirements in these patients. This allows for patient stabilization and bridges towards definitive surgery or radiotherapy to treat the underlying tumor.
PMID: 34132412
ISSN: 1440-1746
CID: 4925582

The role of hemospray as a monotherapy treatment of gastrointestinal bleeds [Meeting Abstract]

Hussein, M; Alzoubaidi, D; O'Donnell, M; De, la Serna A; Varbobitis, I; Hengehold, T; Fernandez-Sordo, J O; W, Rey J; Hayee, B; Despott, E; Murino, A; Moreea, S; Boger, P; Dunn, J; Mainie, I; Graham, D; Mullady, D; Early, D; Latorre, M; Ragunath, K; Anderson, J; Bhandari, P; Goetz, M; Keisslich, R; Coron, E; De, Santiago E R; Gonda, T; Gross, S; Lovat, L; Haidry, R
Introduction Dual endoscopic therapy has been considered the standard of care for endoscopic management of GI bleeding. We aimed to look at the outcomes of Hemospray as a monotherapy treatment for GI bleeds. Methods Data was collected on patients with GI bleeds treated with Hemospray monotherapy in 18 centres. Haemostasis was defined as cessation of bleeding within 5 minutes of hemospray application. Results 62 patients with peptic ulcer bleeds were treated. There was an immediate haemostasis of 90% (56/62), re-bleed rate of 16% (7/44) (Table 1). 69% were Forrest 1a/1b ulcers. 72 patients with malignancy related bleeds. There was a haemostasis rate of 100% and a re-bleed rate of 18% (11/63). There was a haemostasis rate of 100% with post endoscopic therapy bleeds. 48% were post endoscopic mucosal resection. 22 patients with lower GI bleeds were treated. 36% secondary to colonic tumours. There was a haemostasis rate of 96% (21/22) and re-bleed of 26% (5/19). A 100% haemostasis was achieved in 5 patients treated for gastric angiodysplasia with one re-bleed. Conclusions Results show high haemostasis and comparable rebleed rates with Hemospray monotherapy treatment. It may play a potential role in actively bleeding peptic ulcers in difficult anatomical positions to help bridge towards definitive therapy. These data may represent the evolution of new treatment paradigms as experience with haemostatic powders increases
ISSN: 1468-3288
CID: 5082952