Publications by authors named "Gregory Cote"

271 Publications

Clinical Utility of Anchored Multiplex Solid Fusion Assay for Diagnosis of Bone and Soft Tissue Tumors.

Am J Surg Pathol 2021 Jun 10. Epub 2021 Jun 10.

James Homer Wright Pathology Laboratories Department of Internal Medicine, Division of Hematology/Oncology Departments of Orthopedic Oncology Surgical Oncology Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Sarcoma diagnosis has become increasingly complex, requiring a combination of morphology, immunohistochemistry, and molecular studies to derive specific diagnoses. We evaluated the role of anchored multiplex polymerase chain reaction-based gene fusion assay in sarcoma diagnostics. Between 2015 and 2018, bone and soft tissue sarcomas with fusion assay results were compared with the histologic diagnosis. Of 143 sarcomas tested for fusions, 43 (30%) had a detectable fusion. In review, they could be classified into 2 main categories: (1) 31 tumors with concordant morphologic and fusion data; and (2) 12 tumors where the fusion panel identified an unexpected rearrangement that played a significant role in classification. The overall concordance of the fusion assay results with morphology/immunohistochemistry or alternate confirmatory molecular studies was 83%. Collectively, anchored multiplex polymerase chain reaction-based solid fusion assay represents a robust means of detecting targeted fusions with known and novel partners. The predictive value of the panel is highest in tumors that show a monomorphic cell population, round cell tumors, as well as tumors rich in inflammatory cells. However, with an increased ability to discover fusions of uncertain significance, it remains essential to emphasize that the diagnosis of bone and soft tissue neoplasms requires the integration of morphology and immunohistochemical profile with these molecular methods, for accurate diagnosis and optimal clinical management of sarcomas.
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http://dx.doi.org/10.1097/PAS.0000000000001745DOI Listing
June 2021

Pancreas Academy: A Conference-Based Approach for Improving Education in Pancreatic Diseases.

Pancreas 2021 May-Jun 01;50(5):645-647

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Abstract: The Collaborative Alliance for Pancreatic Education and Research developed Pancreas Academy as a lecture-based conference with the goal of providing practical guidance in the diagnosis and management of pancreatic diseases for health care providers. Since its inception in 2017, attendance at Pancreas Academy has steadily grown every year, with trainees accounting for the largest proportion of attendees. The proportion of advanced practice providers and pediatric specialists attending the conference, although relatively low, has also risen each year. Despite the growth in the conference, this report highlights the need for continued outreach to primary care providers, nonphysicians, and nongastroenterologists to provide health care providers at all levels pragmatic and essential knowledge in caring for patients with pancreatic diseases.
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http://dx.doi.org/10.1097/MPA.0000000000001820DOI Listing
June 2021

Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; Results of a first-in-human Phase I trial.

Clin Cancer Res 2021 Jun 2. Epub 2021 Jun 2.

Center For Neuro-Oncology, Dana-Farber Cancer Institute.

Purpose: Lower-grade gliomas (LGGs) are malignant tumors in young adults. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.

Experimental Design: We conducted a multicenter, open-label, phase I, dose escalation study of vorasidenib in 93 patients with mutant (m) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154 Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses >100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG (RANO-LGG) in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.

Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0611DOI Listing
June 2021

Direct Endoscopic Necrosectomy With and Without Hydrogen Peroxide for Walled-off Pancreatic Necrosis: A Multicenter Comparative Study.

Am J Gastroenterol 2021 Apr;116(4):700-709

1Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; 2Division Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, Utah, USA; 3Division Gastroenterology and Hepatology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA; 4Borland-Groover Clinic, Jacksonville, Florida, USA; 5Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, USA; 6Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA; 7Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburg, Pennsylvania, USA; 8Division of Gastroenterology, Hepatology and Nutrition, The Ohio state University Wexner Medical Center, Columbus, Ohio, USA; 9Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA; 10Biostatistics & Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA; 11Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Introduction: Endoscopic necrosectomy has emerged as the preferred treatment modality for walled-off pancreatic necrosis. This study was designed to evaluate the safety and efficacy of direct endoscopic necrosectomy with and without hydrogen peroxide (H2O2) lavage.

Methods: Retrospective chart reviews were performed for all patients undergoing endoscopic transmural management of walled-off pancreatic necrosis at 9 major medical centers from November 2011 to August 2018. Clinical success was defined as the resolution of the collection by imaging within 6 months, without requiring non-endoscopic procedures or surgery.

Results: Of 293 patients, 204 met the inclusion criteria. Technical and clinical success rates were 100% (204/204) and 81% (166/189), respectively. For patients, 122 (59.8%) patients had at least one H2O2 necrosectomy (H2O2 group) and 82 (40.2%) patients had standard endoscopic necrosectomy. Clinical success was higher in the H2O2 group: 106/113 (93.8%) vs 60/76 (78.9%), P = 0.002. On a multivariate analysis, the use of H2O2 was associated with higher clinical success rate (odds ratio 3.30, P = 0.033) and earlier resolution (odds ratio 2.27, P < 0.001). During a mean follow-up of 274 days, 27 complications occurred. Comparing procedures performed with and without H2O2 (n = 250 vs 183), there was no difference in post-procedure bleeding (7 vs 9, P = 0.25), perforation (2 vs 3, P = 0.66), infection (1 vs 2, P = 0.58), or overall complication rate (n = 13 [5.2%] vs 14 [7.7%], P = 0.30).

Discussion: H2O2-assisted endoscopic necrosectomy had a higher clinical success rate and a shorter time to resolution with equivalent complication rates relative to standard necrosectomy.See the visual abstract at http://links.lww.com/AJG/B714.(Equation is included in full-text article.).
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http://dx.doi.org/10.14309/ajg.0000000000000987DOI Listing
April 2021

Development of an automated ERCP Quality Report Card using structured data fields.

Tech Innov Gastrointest Endosc 2021 18;23(2):129-138. Epub 2021 Jan 18.

Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA.

Background And Aims: Measuring adherence to ERCP quality indicators (QIs) is confounded by variability in indications, maneuvers, and documentation styles. We hypothesized that incorporation of mandatory, structured data fields within reporting software would permit accurate measurement of QI adherence rates and facilitate generation of a provider ERCP report card.

Methods: At two referral centers, endoscopy documentation software was modified to generate provider alerts prior to finalizing the note. The alerts reminded the provider to document the following components in a standardized manner: indication, altered anatomy, prior interventions, and QIs deemed high priority by society consensus, study authors, or both. Adherence rates for each QI were calculated in aggregate and by provider via data extraction directly from the procedure documentation software. Medical records were reviewed manually to measure the accuracy of automated data extraction. Accuracy of automated measurement for each QI was calculated against results derived by manual review.

Results: During the 9-month study period, 1,376 ERCP procedures were completed by 8 providers. Manual medical record review confirmed high (98-100%) accuracy of automatic extraction of ERCP QIs from the endoscopy report, including cannulation rate of the native papilla and complete extraction of common bile duct stones. An ERCP report card was generated, allowing for individual comparison of adherence to ERCP QIs with colleagues at their institution and others.

Conclusion: In this pilot study, use of mandatory, structured data fields within clinical ERCP reports permit the accurate measurement of high priority ERCP QIs and the subsequent generation of interval report cards.
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http://dx.doi.org/10.1016/j.tige.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078858PMC
January 2021

Expert consensus on endoscopic papillectomy using a Delphi process.

Gastrointest Endosc 2021 Apr 19. Epub 2021 Apr 19.

Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam Gastroenterology Endocrinology & Metabolism, Amsterdam, the Netherlands. Electronic address:

Background And Aims: Consensus regarding an optimal algorithm for endoscopic treatment of papillary adenomas has not been established. We aimed to assess the existing degree of consensus among international experts and develop further concordance by means of a Delphi process.

Methods: A total of 52 international experts in the field of endoscopic papillectomy were invited to participate. Data were collected between August and December 2019 using an online survey platform. A total of 3 rounds were conducted. Consensus was defined as ≥70% agreement.

Results: Sixteen (31%) experts completed the full process, and consensus was achieved on 47 of the final 79 statements (59%). Diagnostic work-up should include at least an upper endoscopy using a duodenoscope (100%) and biopsies (94%). Selected use of additional abdominal imaging (75-81%). Patients with (suspected) papillary malignancy or over 1 cm intraductal extension should be referred for surgical resection (76%). To prevent pancreatitis, rectal nonsteroidal anti-inflammatory drugs should be administered before resection (82%) and a pancreatic stent should be placed (100%). A biliary stent is indicated in case of ongoing bleeding from the papillary region (76%) or concerns for a (micro) perforation after resection (88%). Follow-up should be started 3 to 6 months after initial papillectomy and repeated every 6 to 12 months for at least 5 years (75%).

Conclusions: This is the first step in developing an international consensus-based algorithm for endoscopic management of papillary adenomas. There were surprisingly many areas where consensus could not be achieved. These aspects should be the focus of future studies.
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http://dx.doi.org/10.1016/j.gie.2021.04.009DOI Listing
April 2021

Mortality in acute pancreatitis with persistent organ failure is determined by the number, type, and sequence of organ systems affected.

United European Gastroenterol J 2021 Mar;9(2):139-149

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF.

Objective: We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF.

Methods: We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders.

Results: 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF (p < 0.05). Mortality risk in POF was higher with two (33%, odds ratio [OR] = 10.8, 3.3-34.9) and three (48%, OR = 20.2, 5.9-68.6) organs failing, in comparison to single POF (4%). In subjects with multiple POF, mortality was higher when the cardiovascular and respiratory systems failed first or concurrently as compared to when the renal system failed first or concurrently with other organ (p < 0.05). In multivariate regression model, the number and sequence of organs affected in POF were associated with mortality (p < 0.05). Onset and duration of POF had no impact mortality.

Conclusion: In AP patients with POF, the risk of mortality is influenced by the number, type, and sequence of organs affected. These results are useful for future revisions of AP severity classification systems.
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http://dx.doi.org/10.1002/ueg2.12057DOI Listing
March 2021

Characteristics of patients undergoing ERCP for sphincter of Oddi disorders.

Clin Gastroenterol Hepatol 2021 Mar 11. Epub 2021 Mar 11.

Department of Medicine, Division of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, USA.

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http://dx.doi.org/10.1016/j.cgh.2021.03.008DOI Listing
March 2021

Dynamic changes in the pancreatitis activity scoring system during hospital course in a multicenter, prospective cohort.

J Gastroenterol Hepatol 2021 Feb 18. Epub 2021 Feb 18.

Division of Gastroenterology, Hepatology, and Nutrition, Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.

Background And Aim: The primary aim was to validate the Pancreatitis Activity Scoring System (PASS) in a multicenter prospectively ascertained acute pancreatitis (AP) cohort. Second, we investigated the association of early PASS trajectories with disease severity and length of hospital stay (LOS).

Methods: Data were prospectively collected through the APPRENTICE consortium (2015-2018). AP severity was categorized based on revised Atlanta classification. Delta PASS (ΔPASS) was calculated by subtracting activity score from baseline value. PASS trajectories were compared between severity subsets. Subsequently, the cohort was subdivided into three LOS subgroups as short (S-LOS): 2-3 days; intermediate (I-LOS): 3-7 days; and long (L-LOS): ≥7 days. The generalized estimating equations model was implemented to compare PASS trajectories.

Results: There were 434 subjects analyzed including 322 (74%) mild, 86 (20%) moderately severe, and 26 (6%) severe AP. Severe AP subjects had the highest activity levels and the slowest rate of decline in activity (P = 0.039). Focusing on mild AP, L-LOS subjects (34%) had 28 points per day slower decline; whereas, S-LOS group (13%) showed 34 points per day sharper decrease compared with I-LOS (53%; P < 0.001). We noticed an outlier subset with a median admission-PASS of 466 compared with 140 in the rest. Morphine equivalent dose constituted 80% of the total PASS in the outliers (median morphine equivalent dose score = 392), compared with only 25% in normal-range subjects (score = 33, P value < 0.001).

Conclusions: This study highlighted that PASS can quantify AP activity. Significant differences in PASS trajectories were found both in revised Atlanta classification severity and LOS groups, which can be harnessed in AP monitoring/management (ClincialTrials.gov number, NCT03075618).
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http://dx.doi.org/10.1111/jgh.15430DOI Listing
February 2021

Endoscopic ultrasound-directed transgastric ERCP (EDGE): a systematic review describing the outcomes, adverse events, and knowledge gaps.

Endoscopy 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, USA.

BACKGROUND : Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) has emerged as a viable completely endoscopic method for performing pancreaticobiliary interventions in patients with Roux-en-Y gastric bypass anatomy. The aims of this systematic review were: (1) to describe the indications, outcomes, and complications of EDGE; and (2) to identify deficiencies in our knowledge of important technical approaches and clinical outcomes. METHODS : A systematic review was conducted via comprehensive searches of Medline, Scopus, CINAHL, and Cochrane to identify studies focusing on EDGE outcomes. Simple descriptive statistics were derived from case series only. Case reports were only included to qualitatively describe additional indications, techniques, and adverse events. RESULTS : The initial search identified 2143 abstracts. Nine case series and eight case reports were included. In the nine case series, 169 patients underwent EDGE. The technical success rate was 99 % (168 /169) for gastrogastrostomy/jejunogastrostomy creation and 98 % (166 /169) for subsequent ERCP. Minor adverse events specifically related to EDGE occurred in 18 % (31/169) and included intraprocedural stent migration/malposition (n = 27) and abdominal pain (n = 4). Moderate adverse events specific to EDGE occurred in 5 % (9/169): including bleeding (2 %), persistent fistula (1 %), and perforation (1 %). Severe adverse events occurred in one patient with a perforation requiring surgery. Deficiency in reporting on the clinical significance of adverse events was identified. CONCLUSION : Based on limited observational data, in expert hands, EDGE has a high rate of technical success and an acceptable rate of adverse events. As a novel procedure, many knowledge gaps need to be addressed to inform the design of meaningful comparative studies and guide informed consent.
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http://dx.doi.org/10.1055/a-1376-2394DOI Listing
January 2021

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma.

Nat Med 2021 02 25;27(2):289-300. Epub 2021 Jan 25.

NanoString Technologies, Seattle, WA, USA.

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.
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http://dx.doi.org/10.1038/s41591-020-01212-6DOI Listing
February 2021

Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule.

Cell Rep Med 2020 Dec 22;1(9):100163. Epub 2020 Dec 22.

MacroGenics, Rockville, MD, USA.

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. , MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67CD8 and ICOSCD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.
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http://dx.doi.org/10.1016/j.xcrm.2020.100163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762776PMC
December 2020

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies.

Life Sci Alliance 2021 02 23;4(2). Epub 2020 Dec 23.

Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene to one of three genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.
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http://dx.doi.org/10.26508/lsa.202000808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768195PMC
February 2021

The importance of the "endoscopic oncologist" in the treatment of nonoperable cholangiocarcinoma.

Gastrointest Endosc 2020 12;92(6):1213-1215

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

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http://dx.doi.org/10.1016/j.gie.2020.06.013DOI Listing
December 2020

Introduction and Validation of a Novel Acute Pancreatitis Digital Tool: Interrogating Large Pooled Data From 2 Prospectively Ascertained Cohorts.

Pancreas 2020 Nov/Dec;49(10):1276-1282

Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Ohio State University, Wexner Medical Center, Columbus, OH.

Objectives: Acute pancreatitis (AP) is a sudden onset, rapidly evolving inflammatory response with systemic inflammation and multiorgan failure (MOF) in a subset of patients. New highly accurate clinical decision support tools are needed to allow local doctors to provide expert care.

Methods: Ariel Dynamic Acute Pancreatitis Tracker (ADAPT) is a digital tool to guide physicians in ordering standard tests, evaluate test results and model progression using available data, propose emergent therapies. The accuracy of the severity score calculators was tested using 2 prospectively ascertained Acute Pancreatitis Patient Registry to Examine Novel Therapies in Clinical Experience cohorts (pilot University of Pittsburgh Medical Center, n = 163; international, n = 1544).

Results: The ADAPT and post hoc expert-calculated AP severity scores were 100% concordant in both pilot and international cohorts. High-risk criteria of all 4 severity scores at admission were associated with moderately-severe or severe AP and MOF (both P < 0.0001) and prediction of no MOF was 97.8% to 98.9%. The positive predictive value for MOF was 7.5% to 14.9%.

Conclusions: The ADAPT tool showed 100% accuracy with AP predictive metrics. Prospective evaluation of ADAPT features is needed to determine if additional data can accurately predict and mitigate severe AP and MOF.
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http://dx.doi.org/10.1097/MPA.0000000000001686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128442PMC
October 2020

Review of Duodenoscope Infection Prevention Practices at the Medical University of South Carolina.

Gastroenterol Nurs 2020 Nov/Dec;43(6):E214-E216

Parker L. Ellison Jr., MD, Department of Internal Medicine, Medical University of South Carolina, Charleston.

A rise in duodenoscope-associated infections, especially in regard to multidrug-resistant organisms, has led to an increase in scrutiny regarding duodenoscope reprocessing. Endoscopic retrograde cholangiopancreatography scopes have a specialized elevator wire channel, allowing more flexible duct cannulation; however, this channel can be difficult to reprocess with standard techniques. Although strict adherence to manufacturer reprocessing protocols remains the primary means of infection prevention, periodic microbiological surveillance is a Food and Drug Administration-recommended practice that the Medical University of South Carolina has implemented to further prevent duodenoscope-associated infections. The Medical University of South Carolina obtains 2 separate cultures from 2 duodenoscopes every 2 months, which undergo standard speciation and sensitivity and are returned to use once negative at 48 hours. The initial results of the Medical University of South Carolina's surveillance cultures are negative for any multidrug-resistant organisms; however, other centers should consider implementing surveillance cultures into their reprocessing practices and closely monitoring for future endoscope infection prevention modalities.
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http://dx.doi.org/10.1097/SGA.0000000000000499DOI Listing
October 2020

Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study.

Lancet Oncol 2020 11 6;21(11):1423-1432. Epub 2020 Oct 6.

Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma.

Methods: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing.

Findings: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths.

Interpretation: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941).

Funding: Epizyme.
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http://dx.doi.org/10.1016/S1470-2045(20)30451-4DOI Listing
November 2020

Inhibition of ATR-Chk1 signaling blocks DNA double-strand-break repair and induces cytoplasmic vacuolization in metastatic osteosarcoma.

Ther Adv Med Oncol 2020 14;12:1758835920956900. Epub 2020 Sep 14.

Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. S., Los Angeles, CA 90095, USA.

Background: Ataxia-telangiectasia and Rad3 related protein kinase (ATR) is an essential regulator of the DNA damage response in various cancers; however, its expression and roles in osteosarcoma are unclear. We therefore chose to evaluate the significance and mechanism of ATR in metastatic osteosarcoma, as well as its potential to be a therapeutic target.

Methods: The osteosarcoma tissue microarrays constructed from 70 patient specimens underwent immunohistochemistry to quantify ATR and activated phospho-ATR (pATR) expression and their correlation with clinical outcomes. ATR sublocalization within the metastatic osteosarcoma cells was confirmed by immunofluorescence assay. Cell proliferation, apoptosis, and migration were evaluated following treatment with ATR siRNA or the selective inhibitor Berzosertib. Antitumor effects were determined with three-dimensional (3D) culture models, and the impacts on the DNA damage repair pathways were measured with Western blotting.

Results: Elevated ATR and activated pATR expression correlated with shorter patient survival and less necrosis following neoadjuvant chemotherapy. Intranuclear sublocalization of ATR and pATR suggested a mechanism related to DNA replication. ATR knockdown with siRNA or inhibition with Berzosertib suppressed cell proliferation in a time- and dose-dependent manner and induced apoptosis. In addition, ATR inhibition decreased Chk1 phosphorylation while increasing γHAX expression and PARP cleavage, consistent with the interference of DNA damage repair. The ATR inhibitor Berzosertib also produced the characteristic cytoplasmic vacuolization preceding cell death, and suppressed 3D spheroid formation and cell motility.

Conclusion: The faithful dependence of cells on ATR signaling for survival and progression makes it an emerging therapeutic target in metastatic osteosarcoma.
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http://dx.doi.org/10.1177/1758835920956900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493280PMC
September 2020

Incidence and risk factors of oral feeding intolerance in acute pancreatitis: Results from an international, multicenter, prospective cohort study.

United European Gastroenterol J 2021 Feb 12;9(1):54-62. Epub 2021 Feb 12.

Department of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Background: Inability to advance to an oral diet, or oral feeding intolerance, is a common complication in patients with acute pancreatitis associated with worse clinical outcomes. The factors related to oral feeding intolerance are not well studied.

Objective: We aimed to determine the incidence and risk factors of oral feeding intolerance in acute pancreatitis.

Methods: Patients were prospectively enrolled in the Acute Pancreatitis Patient Registry to Examine Novel Therapies in Clinical Experience, an international acute pancreatitis registry, between 2015 and 2018. Oral feeding intolerance was defined as worsening abdominal pain and/or vomiting after resumption of oral diet. The timing of the initial feeding attempt was stratified based on the day of hospitalization. Multivariable logistic regression was performed to assess for independent risk factors/predictors of oral feeding intolerance.

Results: Of 1233 acute pancreatitis patients included in the study, 160 (13%) experienced oral feeding intolerance. The incidence of oral feeding intolerance was similar irrespective of the timing of the initial feeding attempt relative to hospital admission day (p = 0.41). Patients with oral feeding intolerance were more likely to be younger (45 vs. 50 years of age), men (61% vs. 49%), and active alcohol users (44% vs. 36%). They also had higher blood urea nitrogen (20 vs. 15 mg/dl; p < 0.001) and hematocrit levels (41.7% vs. 40.5%; p = 0.017) on admission; were more likely to have a nonbiliary acute pancreatitis etiology (69% vs. 51%), systemic inflammatory response syndrome of 2 or greater on admission (49% vs. 35%) and at 48 h (50% vs. 26%), develop pancreatic necrosis (29% vs. 13%), moderate to severe acute pancreatitis (41% vs. 24%), and have a longer hospital stay (10 vs. 6 days; all p < 0.04). The adjusted analysis showed that systemic inflammatory response syndrome of 2 or greater at 48 h (odds ratio 3.10; 95% confidence interval 1.83-5.25) and a nonbiliary acute pancreatitis etiology (odds ratio 1.65; 95% confidence interval 1.01-2.69) were independent risk factors for oral feeding intolerance.

Conclusion: Oral feeding intolerance occurs in 13% of acute pancreatitis patients and is independently associated with systemic inflammatory response syndrome at 48 h and a nonbiliary etiology.
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http://dx.doi.org/10.1177/2050640620957243DOI Listing
February 2021

Development and Physical Characterization of α-Glucan Nanoparticles.

Molecules 2020 Aug 21;25(17). Epub 2020 Aug 21.

Mycotoxin Prevention and Applied Microbiology Research Unit, National Center for Agricultural Utilization Research, USDA, 1815 N. University Street, Peoria, IL 61604, USA.

α-Glucans that were enzymatically synthesized from sucrose using glucansucrase cloned from NRRL B-1118 were found to have a glass transition temperature of approximately 80 °C. Using high-pressure homogenization (~70 MPa), the α-glucans were converted into nanoparticles of ~120 nm in diameter with a surface potential of ~-3 mV. Fluorescence measurements using 1,6-diphenyl-1,3,5-hexatriene (DPH) indicate that the α-glucan nanoparticles have a hydrophobic core that remains intact from 10 to 85 °C. α-Glucan nanoparticles were found to be stable for over 220 days and able to form at three pH levels. Accelerated exposure measurements demonstrated that the α-glucan nanoparticles can endure exposure to elevated temperatures up to 60 °C for 6 h intervals.
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http://dx.doi.org/10.3390/molecules25173807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503850PMC
August 2020

Development and initial validation of an instrument for video-based assessment of technical skill in ERCP.

Gastrointest Endosc 2021 04 30;93(4):914-923. Epub 2020 Jul 30.

Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Background And Aims: The accurate measurement of technical skill in ERCP is essential for endoscopic training, quality assurance, and coaching of this procedure. Hypothesizing that technical skill can be measured by analysis of ERCP videos, we aimed to develop and validate a video-based ERCP skill assessment tool.

Methods: Based on review of procedural videos, the task of ERCP was deconstructed into its basic components by an expert panel that developed an initial version of the Bethesda ERCP Skill Assessment Tool (BESAT). Subsequently, 2 modified Delphi panels and 3 validation exercises were conducted with the goal of iteratively refining the tool. Fully crossed generalizability studies investigated the contributions of assessors, ERCP performance, and technical elements to reliability.

Results: Twenty-nine technical elements were initially generated from task deconstruction. Ultimately, after iterative refinement, the tool comprised 6 technical elements and 11 subelements. The developmental process achieved consistent improvements in the performance characteristics of the tool with every iteration. For the most recent version of the tool, BESAT-v4, the generalizability coefficient (a reliability index) was .67. Most variance in BESAT scores (43.55%) was attributed to differences in endoscopists' skill, indicating that the tool can reliably differentiate between endoscopists based on video analysis.

Conclusions: Video-based assessment of ERCP skill appears to be feasible with a novel instrument that demonstrates favorable validity evidence. Future steps include determining whether the tool can discriminate between endoscopists of varying experience levels and predict important outcomes in clinical practice.
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http://dx.doi.org/10.1016/j.gie.2020.07.055DOI Listing
April 2021

Comparison of Urologist- vs Gastroenterologist-Directed Extracorporeal Shock Wave Lithotripsy for Pancreaticolithiasis.

Clin Gastroenterol Hepatol 2021 Jun 23;19(6):1234-1239. Epub 2020 Jul 23.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina. Electronic address:

Background & Aims: Extracorporeal shock wave lithotripsy (ESWL) for pancreaticolithiasis is most commonly performed by urologists. We investigated the effects of transitioning from urologist- to gastroenterologist-directed ESWL on case complexity, process measures, and duct clearance.

Methods: We performed a retrospective study of patients who underwent ESWL for pancreaticolithiasis from 2014 through 2019 at a single center. We collected demographic, clinical, radiographic, and procedural data in duplicate and compared case complexity and process measures between the periods the procedure was performed by urologists (January 2014 through February 2017; 18 patients, 0.47 patients/month) vs gastroenterologists (March 2017 through December 2019; 61 patients; 1.79 patients/month). We also compared data on pancreatic duct stone characteristics and technical success (duct clearance, determined by imaging analysis).

Results: There were no differences in patient demographics, comorbidities, pancreatic stone morphology, or time from referral to ESWL during the period the procedure was performed by urologists vs gastroenterologists. Patients received a higher mean number of ESWL shocks per session during the gastroenterology period (4341) than during the urology period (3117) (P < .001). A higher proportion of patients underwent same-session endoscopic retrograde cholangiopancreatography during the gastroenterology time period (66%) than the urology time period (6%) (P < .001). A higher proportion of patients had partial or complete duct clearance during the gastroenterology period (71%) than during the urology period (44%) (P = .04). During the urology period, a higher proportion of patients were hospitalized following ESWL, although there was no difference in captured adverse events between the periods.

Conclusions: Transition from urologist- to gastroenterologist-directed ESWL did not affect case complexity or wait times for ESWL. However, the transition did result in increased procedure volume, more shocks per ESWL session, and improved duct clearance.
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http://dx.doi.org/10.1016/j.cgh.2020.07.042DOI Listing
June 2021

Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort.

J Gastroenterol 2020 Oct 17;55(10):1000-1009. Epub 2020 Jul 17.

Department of Medicine, University of Pittsburgh, Room 401.4, 3708 Fifth Ave, Pittsburgh, PA, 15213, USA.

Background: Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients.

Study: A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested.

Results: Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p < 2.2 × 10). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes including ROBO2, CTNND2, SGCZ, CNTN5 and BAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2, and CTNND2).

Conclusion: Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted.

Clinical Trials Registration: Clinicaltriasl.gov.# NCT01545167.
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http://dx.doi.org/10.1007/s00535-020-01703-wDOI Listing
October 2020

Advanced techniques for pancreaticobiliary stone extraction.

VideoGIE 2020 Jul 9;5(7):324-325. Epub 2020 Jun 9.

Division of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, South Carolina.

Background And Aims: Pancreaticobiliary stone extraction during endoscopic retrograde cholangiopancreatography can be challenging when working space is limited or the duct is irregular and strictured. We aimed to demonstrate several difficult anatomic scenarios in which stone extraction was accomplished by ductoscopic grasping and retrieval using miniature devices.

Methods: In 2 cases, a miniature retrieval basket and snare are used during cholangioscopy to grasp refractory stones in the intrahepatic and cystic ducts, respectively. In cases 3 and 4, a miniature basket and snare are used during pancreatoscopy to facilitate stone extraction from stenotic and tortuous pancreatic ducts. In case 5, a miniature forceps is used to extract a stone from within a dilated pancreatic side branch.

Results: Stone extraction was successful in all cases without adverse events.

Conclusions: Miniature grasping accessories that fit through the working channel of the cholangioscope/pancreatoscope may allow stone retrieval in difficult anatomic scenarios and thus represent a meaningful addition to our therapeutic armamentarium for the treatment of this condition.
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http://dx.doi.org/10.1016/j.vgie.2020.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332830PMC
July 2020

Ivosidenib in Isocitrate Dehydrogenase 1Mutated Advanced Glioma.

J Clin Oncol 2020 10 12;38(29):3398-3406. Epub 2020 Jun 12.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 () gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.

Methods: We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m solid tumors. Ivosidenib was administered orally daily in 28-day cycles.

Results: In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.

Conclusion: In patients with m advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
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http://dx.doi.org/10.1200/JCO.19.03327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527160PMC
October 2020

Multimodal intervention for avoiding inappropriate cessation of aspirin prior to outpatient endoscopy.

Endosc Int Open 2020 Jun 25;8(6):E708-E716. Epub 2020 May 25.

Department of Internal Medicine and the Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, United States.

Existing guidelines recommend continuation of aspirin therapy prior to outpatient endoscopic procedures, as it reduces peri-procedural cardiovascular events and is not associated with an increased risk of bleeding. Despite this, many patients at our institution inappropriately alter their aspirin prior to endoscopy. We sought to identify why this occurs and implement an intervention that could reduce improper aspirin alteration. All adult patients undergoing outpatient endoscopy at the Medical University of South Carolina were administered a survey querying demographics, aspirin use, endoscopic procedure, thromboembolic risk factors, and pre-procedural aspirin alteration, if any. An intervention involving revised written and verbal instructions as well as an automated voicemail aimed at ensuring patients adhere to guidelines was then undertaken. The same survey was administered after the intervention to assess for improved adherence. A total of 240 patients from the initial survey reported daily aspirin use, of which 114 (47.5 %) inappropriately altered aspirin therapy. A total of 182 patients from the post-intervention survey reported daily aspirin use, of which 66 (36.3 %) inappropriately altered aspirin therapy. This was a statistically significant reduction (  = 0.04), which included adjustments for age, sex, procedure type, and thromboembolic risk. A high proportion of patients at our institution inappropriately alter aspirin therapy prior to outpatient endoscopy. The reasons for this behavior include patient self-direction, misguidance from staff, and instruction from other physicians. This alteration can be reduced significantly through an intervention that educates both patients and staff on continuation of aspirin therapy prior to outpatient endoscopy.
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http://dx.doi.org/10.1055/a-1134-4813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247888PMC
June 2020

An Unsuccessful Randomized Trial of Percutaneous vs Endoscopic Drainage of Suspected Malignant Hilar Obstruction.

Clin Gastroenterol Hepatol 2021 Jun 23;19(6):1282-1284. Epub 2020 May 23.

Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.

Percutaneous transhepatic biliary drainage (PTBD) and endoscopic retrograde cholangiopancreatography (ERCP) are widely accepted but competing approaches for the management of malignant obstruction at the hilum of the liver. ERCP is favored in the United States on the basis of high success rates for non-hilar indications, the perceived safety and superior tissue sampling capability of ERCP relative to PTBD, and the avoidance of external drains that are undesirable to patients. A recent randomized controlled trial (RCT) comparing the 2 modalities in patients with resectable hilar cholangiocarcinoma was terminated prematurely because of higher mortality in the PTBD group. In contrast, most observational data suggest that PTBD is superior for achieving complete drainage. Because the preferred procedure remains uncertain, we aimed to compare PTBD and ERCP as the primary intervention in patients with cholestasis due to malignant hilar obstruction (MHO).
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http://dx.doi.org/10.1016/j.cgh.2020.05.035DOI Listing
June 2021