Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

BACKGROUND: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention. METHODS: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete. FINDINGS: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups. INTERPRETATION: For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines. FUNDING: US National Institutes of Health.

A Randomized Controlled Phase 2 Dose-Finding Trial to Evaluate the Efficacy and Safety of Camostat in the Treatment of Painful Chronic Pancreatitis: The TACTIC Study.

BACKGROUND & AIMS: Chronic pancreatitis (CP) causes an abdominal pain syndrome associated with poor quality of life. We conducted a clinical trial to further investigate the efficacy and safety of camostat, an oral serine protease inhibitor that has been used to alleviate pain in CP. METHODS: This was a double-blind randomized controlled trial that enrolled adults with CP with a baseline average daily worst pain score ≥4 on a numeric rating system. Participants were randomized (1:1:1:1) to receive camostat at 100, 200, or 300 mg 3 times daily or placebo. The primary end point was a 4-week change from baseline in the mean daily worst pain intensity score (0-10 on a numeric rating system) using a mixed model repeated measure analysis. Secondary end points included changes in alternate pain end points, quality of life, and safety. RESULTS: A total of 264 participants with CP were randomized. Changes in pain from baseline were similar between the camostat groups and placebo, with differences of least squares means of -0.11 (95% CI, -0.90 to 0.68), -0.04 (95% CI, -0.85 to 0.78), and -0.11 (95% CI, -0.94 to 0.73) for the 100 mg, 200 mg, and 300 mg groups, respectively. Multiple subgroup analyses were similar for the primary end point, and no differences were observed in any of the secondary end points. Treatment-emergent adverse events attributed to the study drug were identified in 42 participants (16.0%). CONCLUSION: We were not able to reject the null hypothesis of no difference in improvements in pain or quality of life outcomes in participants with painful CP who received camostat compared with placebo. Studies are needed to further define mechanisms of pain in CP to guide future clinical trials, including minimizing placebo responses and selecting targeted therapies. CLINICALTRIALS: gov, Number: NCT02693093.

Sphincterotomy for biliary sphincter of Oddi disorder and idiopathic acute recurrent pancreatitis: the RESPOnD longitudinal cohort.

OBJECTIVE: Sphincter of Oddi disorders (SOD) are contentious conditions in patients whose abdominal pain, idiopathic acute pancreatitis (iAP) might arise from pressurisation at the sphincter of Oddi. The present study aimed to measure the benefit of sphincterotomy for suspected SOD. DESIGN: Prospective cohort conducted at 14 US centres with 12 months follow-up. Patients undergoing first-time endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy for suspected SOD were eligible: pancreatobiliary-type pain with or without iAP. The primary outcome was defined as the composite of improvement by Patient Global Impression of Change (PGIC), no new or increased opioids and no repeat intervention. Missing data were addressed by hierarchal, multiple imputation scheme. RESULTS: Of 316 screened, 213 were enrolled with 190 (89.2%) of these having a dilated bile duct, abnormal labs, iAP or some combination. By imputation, an average of 122/213 (57.4% (95% CI 50.4% to 64.4%)) improved; response rate was similar for those with complete follow-up (99/161, 61.5% (54.0% to 69.0%)); of these, 118 (73.3%) improved by PGIC alone. Duct size, elevated labs and patient characteristics were not associated with response. AP occurred in 37/213 (17.4%) at a median of 6 months post ERCP and was more likely in those with a history of AP (30.9% vs 2.9%, p<0.0001). CONCLUSION: Nearly 60% of patients undergoing ERCP for suspected SOD improve, although the contribution of a placebo response is unknown. Contrary to prevailing belief, duct size and labs are poor response predictors. AP recurrence was common and like observations from prior non-intervention cohorts, suggesting no benefit of sphincterotomy in mitigating future AP episodes.

A phase 2 study of a brachyury-targeting vaccine in combination with radiation therapy for the treatment of advanced chordoma.

BACKGROUND: This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma. METHODS: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients. RESULTS: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study. CONCLUSIONS: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours.

BACKGROUND: Gartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours. METHODS: This phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients). RESULTS: Overall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation. CONCLUSION: Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued. CLINICALTRIALS: GOV: NCT02278250.

Phosphatidylethanol Detects Occult Heavy Alcohol Use in Patients With Acute and Chronic Pancreatitis.

Given the paucity of interventions to treat pancreatitis, it is imperative to identify and intervene upon modifiable risk factors such as heavy alcohol use. Current trends indicate a concerning increase in alcohol misuse and alcohol-related disease since the onset of the coronavirus disease-2019 pandemic.1 The incidence of pancreatitis associated with alcohol misuse has increased by approximately 3% annually from 1961 to 2016.2 Alcohol recidivism may be the most important risk factor for pancreatitis recurrence and development of chronic pancreatitis in the United States.3 Early identification of alcohol misuse as a modifiable risk factor is paramount to mitigating pancreatitis-related morbidity. However, blood ethanol and urine ethyl glucuronide levels may be low in symptomatic individuals because they clear rapidly and patients may abstain from drinking in the days before their clinical presentation. Patient self-report may underestimate the quantity of alcohol intake and falsely reassure the provider that this is not a contributing factor to the presentation.4.

An Evaluation of Critical Factors for the Cost-Effectiveness of Real-Time Computer-Aided Detection: Sensitivity and Threshold Analyses Using a Microsimulation Model.

BACKGROUND & AIMS: The use of computer-aided detection (CAD) increases the adenoma detection rates (ADRs) during colorectal cancer (CRC) screening/surveillance. This study aimed to evaluate the requirements for CAD to be cost-effective and the impact of CAD on adenoma detection by endoscopists with different ADRs. METHODS: We developed a semi-Markov microsimulation model to compare the effectiveness of traditional colonoscopy (mean ADR, 26%) to colonoscopy with CAD (mean ADR, 37%). CAD was modeled as having a $75 per-procedure cost. Extensive 1-way sensitivity and threshold analysis were performed to vary cost and ADR of CAD. Multiple scenarios evaluated the potential effect of CAD on endoscopists' ADRs. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay threshold of $100,000/quality-adjusted life year. RESULTS: When modeling CAD improved ADR for all endoscopists, the CAD cohort had 79 and 34 fewer lifetime CRC cases and deaths, respectively, per 10,000 persons. This scenario was dominant with a cost savings of $143 and incremental effectiveness of 0.01 quality-adjusted life years. Threshold analysis demonstrated that CAD would be cost-effective up to an additional cost of $579 per colonoscopy, or if it increases ADR from 26% to at least 30%. CAD reduced CRC incidence and mortality when limited to improving ADRs for low-ADR endoscopists (ADR <25%), with 67 fewer CRC cases and 28 CRC deaths per 10,000 persons compared with traditional colonoscopy. CONCLUSIONS: As CAD is implemented clinically, it needs to improve mean ADR from 26% to at least 30% or cost less than $579 per colonoscopy to be cost-effective when compared with traditional colonoscopy. Further studies are needed to understand the impact of CAD when used in community practice.

Rise in First-Time ERCP for Benign Indications >1 Year After Cholecystectomy Is Associated With Worse Outcomes.

BACKGROUND & AIMS: Greater availability of less invasive biliary imaging to rule out choledocholithiasis should reduce the need for diagnostic endoscopic retrograde cholangiopancreatography (ERCP) in patients who have a remote history of cholecystectomy. The primary aims were to determine the incidence, characteristics, and outcomes of individuals who undergo first-time ERCP >1 year after cholecystectomy (late-ERCP). METHODS: Data from a commercial insurance claim database (Optum Clinformatics) identified 583,712 adults who underwent cholecystectomy, 4274 of whom underwent late-ERCP, defined as first-time ERCP for nonmalignant indications >1 year after cholecystectomy. Outcomes were exposure and temporal trends in late-ERCP, biliary imaging utilization, and post-ERCP outcomes. Multivariable logistic regression was used to examine patient characteristics associated with undergoing late-ERCP. RESULTS: Despite a temporal increase in the use of noninvasive biliary imaging (35.9% in 2004 to 65.6% in 2021; P < .001), the rate of late-ERCP increased 8-fold (0.5-4.2/1000 person-years from 2005 to 2021; P < .001). Although only 44% of patients who underwent late-ERCP had gallstone removal, there were high rates of post-ERCP pancreatitis (7.1%), hospitalization (13.1%), and new chronic opioid use (9.7%). Factors associated with late-ERCP included concomitant disorder of gut-brain interaction (odds ratio [OR], 6.48; 95% confidence interval [CI], 5.88-6.91) and metabolic dysfunction steatotic liver disease (OR, 3.27; 95% CI, 2.79-3.55) along with use of anxiolytic (OR, 3.45; 95% CI, 3.19-3.58), antispasmodic (OR, 1.60; 95% CI, 1.53-1.72), and chronic opioids (OR, 6.24; 95% CI, 5.79-6.52). CONCLUSIONS: The rate of late-ERCP postcholecystectomy is increasing significantly, particularly in patients with comorbidities associated with disorder of gut-brain interaction and mimickers of choledocholithiasis. Late-ERCPs are associated with disproportionately higher rates of adverse events, including initiation of chronic opioid use.

The Clinical Impact and Cost-Effectiveness of Surveillance of Incidentally Detected Gastric Intestinal Metaplasia: A Microsimulation Analysis.

BACKGROUND & AIMS: Gastric intestinal metaplasia (GIM) is associated with a higher risk of noncardia intestinal gastric adenocarcinoma (GA). The aim of this study was to estimate lifetime benefits, complications, and cost-effectiveness of GIM surveillance using esophagogastroduodenoscopy (EGD). METHODS: We developed a semi-Markov microsimulation model of patients with incidentally detected GIM, to compare the effectiveness of EGD surveillance with no surveillance at 10-year, 5-year, 3-year, 2-year, and 1-year intervals. We modeled a simulated cohort of 1,000,000 US individuals aged 50 with incidental GIM. Outcome measures were lifetime GA incidence, mortality, number of EGDs, complications, undiscounted life-years gained, and incremental cost-effectiveness ratio with a willingness-to-pay threshold of $100,000/quality-adjusted life-year (QALY). RESULTS: In the absence of surveillance, the model simulated 32.0 lifetime GA cases and 23.0 lifetime GA deaths per 1000 individuals with GIM, respectively. Among surveilled individuals, simulated lifetime GA incidence (per 1000) decreased with shorter surveillance intervals (10-year to 1-year, 11.2-6.1) as did GA mortality (7.4-3.6). Compared with no surveillance, all modeled surveillance intervals yielded greater life expectancy (87-190 undiscounted life-years gained per 1000); 5-year surveillance provided the greatest number of life-years gained per EGD performed and was the cost-effective strategy ($40,706/QALY). In individuals with risk factors of family history of GA or anatomically extensive, incomplete-type GIM intensified 3-year surveillance was cost-effective (incremental cost-effectiveness ratio $28,156/QALY and $87,020/QALY, respectively). CONCLUSIONS: Using microsimulation modeling, surveillance of incidentally detected GIM every 5 years is associated with reduced GA incidence/mortality and is cost-effective from a health care sector perspective. Real-world studies evaluating the impact of GIM surveillance on GA incidence and mortality in the United States are needed.

Technical Factors Associated With the Benefit of Prophylactic Pancreatic Stent Placement During High-Risk Endoscopic Retrograde Cholangiopancreatography: A Secondary Analysis of the SVI Trial Data Set.

INTRODUCTION: Prophylactic pancreatic stent placement (PSP) is effective for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk cases, but the optimal technical approach to this intervention remains uncertain. METHODS: In this secondary analysis of 787 clinical trial patients who underwent successful stent placement, we studied the impact of (i) whether pancreatic wire access was achieved for the sole purpose of PSP or naturally during the conduct of the case, (ii) the amount of effort expended on PSP, (iii) stent length, (iv) stent diameter, and (v) guidewire caliber. We used logistic regression models to examine the adjusted association between each technical factor and post-ERCP pancreatitis (PEP). RESULTS: Ninety-one of the 787 patients experienced PEP. There was no clear association between PEP and whether pancreatic wire access was achieved for the sole purpose of PSP (vs occurring naturally; odds ratio [OR] 0.82, 95% confidence interval [CI] 0.37-1.84), whether substantial effort expended on stent placement (vs nonsubstantial effort; OR 1.58, 95% CI 0.73-3.45), stent length (>5 vs ≤5 cm; OR 1.01, 95% CI 0.63-1.61), stent diameter (≥5 vs <5 Fr; OR 1.13, 95% CI 0.65-1.96), or guidewire caliber (0.035 vs 0.025 in; 0.83, 95% CI 0.49-1.41). DISCUSSION: The 5 modifiable technical factors studied in this secondary analysis of large-scale randomized trial data did not appear to have a strong impact on the benefit of prophylactic PSP in preventing PEP after high-risk ERCP. Within the limitations of post hoc subgroup analysis, these findings may have important implications in procedural decision making and suggest that the benefit of PSP is robust to variations in technical approach.

Development and Usability of an Endoscopist Report Card Assessing ERCP Quality.

BACKGROUND AND AIMS: Audit and feedback (A&F) for endoscopic retrograde cholangiopancreatography (ERCP) is relatively understudied despite the demonstrated effectiveness of A&F for endoscopic procedures such as colonoscopy. Endoscopist 'report cards' are one A&F tool. We aimed to develop an ERCP report card and assess its appropriateness, acceptability and feasibility through usability testing. METHODS: A prototype report card was designed using a combination of published quality indicators and established predictors of adverse events (AE). Exploratory analyses from a prospective multi-center registry were performed to further identify novel and/or understudied parameters for possible inclusion. Semi-structured interviews with ERCP endoscopists were conducted and framework analysis performed. Validated post-interview usability instruments were administered. Feedback was incorporated to create a final report card. RESULTS: The report card included domains of technical parameters, AE rates/prevention, and patient-reported experience measures (PREMs). Qualitative feedback was positive, with respondents agreeing with inclusion of relevant content in most domains. Post-interview instruments revealed adequate appropriateness and acceptability. PREMs were felt by respondents to be poorly actionable and were replaced with appropriateness of indication and fluoroscopy usage parameters in the final report card. Concerns were raised regarding the feasibility of implementation due to reliance on difficult-to-obtain granular intraprocedural data. CONCLUSIONS: We designed and tested an ERCP report card that has potential to be an effective A&F intervention for endoscopists in clinical practice. Though feasibility of data capture and implementation are currently limitations, advances in video recording and artificial intelligence technologies could accelerate widespread adoption of such a tool.

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

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

The Impact of Difficult Biliary Cannulation on Post-ERCP Pancreatitis: A Secondary Analysis of the Stent versus Indomethacin Trial Dataset.

BACKGROUND AND AIMS: Difficult biliary cannulation (DBC) is a known risk factor for developing post-ERCP pancreatitis (PEP). To better understand how DBC increases PEP risk, we examined the interplay between technical aspects of DBC and known PEP risk factors. METHODS: This was a secondary analysis of a multicenter, randomized controlled trial comparing rectal indomethacin alone with the combination of rectal indomethacin and prophylactic pancreatic duct (PD) stent placement for PEP prophylaxis in high-risk patients. Participants were categorized into 3 groups: 1) DBC with high pre-procedure risk for PEP, 2) DBC without high pre-procedure risk, and 3) non-DBC at high pre-procedure risk. RESULTS: In all, 1601 (84.1%) participants experienced DBC, which required a mean of 12 (SD 10) cannulation attempts and mean duration of 14.7 minutes (SD 14.9). PEP rate was highest (20.7%) in DBC with high pre-procedure risk, followed by non-DBC with high pre-procedure risk (13.5%) and then DBC without high pre-procedure risk (8.8%). Increasing number of PD-wire passages (aOR:1.97, 95% CI:1.25-3.1) was associated with PEP in DBC, but PD injection, pancreatic sphincterotomy and number of cannulation attempts were not associated with PEP. Combining indomethacin with PD stenting lowered PEP risk (aOR:0.61, 95% CI:0.44-0.84) in DBCs. This protective effect was evident in up to at least 4 PD wire passages. CONCLUSIONS: DBC confers higher PEP risk in additive fashion to pre-procedural risk factors. PD wire passages appear to add the greatest PEP risk in DBCs, but combining indomethacin with PD stenting reduces this risk, even with increasing PD wire passages.

Cost-effectiveness of endoscopic, surgical and pharmacological obesity therapies: a microsimulation and threshold analyses.

OBJECTIVE: Weight loss interventions to treat obesity include sleeve gastrectomy (SG), lifestyle intervention (LI), endoscopic sleeve gastroplasty (ESG) and semaglutide. We aimed to identify which treatments are cost-effective and identify requirements for semaglutide to be cost-effective. DESIGN: We developed a semi-Markov microsimulation model to compare the effectiveness of SG, ESG, semaglutide and LI for weight loss in 40 years old with class I/II/III obesity. Extensive one-way sensitivity and threshold analysis were performed to vary cost of treatment strategies and semaglutide adherence rate. Outcome measures were incremental cost-effectiveness ratios (ICERs), with a willingness-to-pay threshold of US$100 000/quality-adjusted life-year (QALY). RESULTS: When strategies were compared with each other, ESG was cost-effective in class I obesity (US$4105/QALY). SG was cost-effective in class II obesity (US$5883/QALY) and class III obesity (US$7821/QALY). In class I/II/III, obesity, SG and ESG were cost-effective compared with LI. However, semaglutide was not cost-effective compared with LI for class I/II/III obesity (ICER US$508 414/QALY, US$420 483/QALY and US$350 637/QALY). For semaglutide to be cost-effective compared with LI, it would have to cost less than US$7462 (class III), US$5847 (class II) or US$5149 (class I) annually. For semaglutide to be cost-effective when compared with ESG, it would have to cost less than US$1879 (class III), US$1204 (class II) or US$297 (class I) annually. CONCLUSIONS: Cost-effective strategies were: ESG for class I obesity and SG for class II/III obesity. Semaglutide may be cost-effective with substantial cost reduction. Given potentially higher utilisation rates with pharmacotherapy, semaglutide may provide the largest reduction in obesity-related mortality.

Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor.

Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.

A Rare Presentation of Aggressive Renal Cell Carcinoma and the Utility of Early Molecular Testing in Rapidly Progressing Malignancies: A Case Report.

In rapidly progressing cancers, appropriate selection of first-line therapy is essential in prolonging survival. Alongside immunohistochemistry (IHC), comprehensive genomics, including whole exome and transcriptome sequencing (WES/WTS), can improve diagnostic accuracy and guide therapeutic management. Here, we report a young patient with rapidly progressing malignancy and unexpected post-mortem results, a scenario that may have been altered by early, comprehensive genomic sequencing. A 43-year-old man with no relevant medical history presented to the emergency department with progressive cough and dyspnea despite treatment for pneumonia. Radiology revealed enlarged subcarinal, hilar, retroperitoneal, and mesenteric lymph nodes, suspicious for metastasis, and a right kidney mass. Pathologic analysis of a retroperitoneal lymph node was felt to be most consistent with metastatic epithelioid angiomyolipoma (mEAML). Three weeks later, he was urgently treated with an mTOR inhibitor for presumed mEAML due to rapid clinical decline, and a subsequent 4R lymph node biopsy was performed to confirm the diagnosis and identify genomic targets via IHC and WES/WTS. Unfortunately, he developed hypoxic respiratory failure, and only posthumously did WES/WTS reveal pathogenic variants in BAP1 and VHL, consistent with clear cell renal cell carcinoma (ccRCC). With an earlier ccRCC diagnosis, he would have received combination immunotherapy/tyrosine kinase inhibition, which has significantly greater activity than mTOR inhibition in ccRCC. He could have received systemic treatment earlier, with optimal therapy, while potentially carrying lower tumor burden and greater clinical stability. In cases of rapidly progressing malignancies with complex histopathological presentations, early comprehensive molecular-based testing can aid in diagnosis and critical therapeutic decision-making.

A Prospective Cohort Study Evaluating PAN-PROMISE, a Patient-reported Outcome Measure to Detect Post-ERCP Morbidity.

BACKGROUND & AIMS: The Cotton Consensus (CC) criteria for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) may not capture post-ERCP morbidity. PAN-PROMISE, a patient-reported outcome measure (PROM), was developed to quantify acute pancreatitis-related morbidity. This study aims to determine the value of PAN-PROMISE in independently defining ERCP-related morbidity. METHODS: We conducted a prospective cohort study of patients undergoing ERCP at 2 academic centers from September 2021 to August 2022. We administered PAN-PROMISE and assessed quality of life and work productivity at baseline, 48 to 72 hours, 7 days, and 30 days following ERCP. PEP was defined by a 3-physician committee using the CC criteria. We defined high morbidity following ERCP (elevated PROM) by an increase of PAN-PROMISE score of >7 at 7 days post-procedure. The McNemar test assessed discordance between PEP and elevated-PROM. RESULTS: A total of 679 patients were enrolled. Choledocholithiasis (30%) and malignant biliary obstruction (29%) were the main indications for ERCP. Thirty-two patients (4.7%) developed PEP. One hundred forty-seven patients (21.6%) had an elevated PROM, whereas only 20 of them (13.4%) had PEP by the CC criteria (P < .001 for discordance). An elevated PROM strongly correlated with lower physical quality of life and increased direct and indirect health care costs ($80 and $25 per point increase in PAN-PROMISE, respectively). Patients with pancreatic cancer (odds ratio, 4.52; 95% confidence interval, 1.68-10.74) and primary sclerosing cholangitis (odds ratio, 1.79; 95% confidence interval, 1.29-2.45) had the highest odds of elevated PROM. CONCLUSIONS: A substantial number of patients experience significant morbidity after ERCP despite not developing PEP or other adverse events. Future studies are needed to characterize better the reasons behind this increase in symptoms and potential interventions to reduce the symptom burden post-ERCP. CLINICALTRIALS: gov number, NCT05310409.

Prognostic Significance of Percentage and Size of Dedifferentiation in Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma is rare, aggressive, and microscopically bimorphic. How pathologic features such as the amounts of dedifferentiation affect prognosis remains unclear. We evaluated the percentages and sizes of dedifferentiation in a consecutive institutional series of dedifferentiated chondrosarcomas from 1999 to 2021. The statistical analysis included cox proportional hazard models and log-rank tests. Of the 67 patients (26 women, 41 men; age, 39 to >89 [median 61] years; 2 with Ollier disease), 58 presented de novo; 9 were identified with conventional chondrosarcomas 0.6-13.2 years (median, 5.5 years) prior. Pathologic fracture and distant metastases were noted in 27 and 7 patients at presentation. The tumors involved the femur (n = 27), pelvis (n = 22), humerus (n = 7), tibia (n = 4), scapula/ribs (n = 4), spine (n = 2), and clivus (n = 1). In the 56 resections, the tumors ranged in size from 3.5 to 46.0 cm (median, 11.5 cm) and contained 1%-99.5% (median, 70%) dedifferentiated components that ranged in size from 0.6 to 24.0 cm (median, 7.3 cm). No correlation was noted between total size and percentage of dedifferentiation. The dedifferentiated components were typically fibrosarcomatous or osteosarcomatous, whereas the associated cartilaginous components were predominantly grade 1-2, rarely enchondromas or grade 3. The entire cohort's median overall survival and progression-free survival were 11.8 and 5.4 months, respectively. In the resected cohort, although the total size was not prognostic, the percentage of dedifferentiation ≥20% and size of dedifferentiation >3.0 cm each predicted worse overall survival (9.9 vs 72.5 months; HR, 3.76; 95% CI, 1.27-11.14; P = .02; 8.7 vs 58.9 months; HR, 3.03; 95% CI, 1.21-7.57; P = .02, respectively) and progression-free survival (5.3 vs 62.1 months; HR, 3.05; 95% CI, 1.13-8.28; P = .03; 5.3 vs 56.6 months; HR, 2.50; 95% CI, 1.06-5.88; P = .04, respectively). In conclusion, both the percentages and sizes of dedifferentiation were better prognostic predictors than total tumor sizes in dedifferentiated chondrosarcomas, highlighting the utility of their pathologic evaluations.