Development of a novel CT-based index for predicting the number of extracorporeal shockwave lithotripsy (ESWL) sessions required for successful fragmentation of obstructing pancreatic duct stones.

BACKGROUND & AIM: Extracorporeal shock wave lithotripsy (ESWL) is used for the treatment of pancreatic duct stones (PDS) in patients with chronic pancreatitis (CP). We aimed to develop a CT based index to predict the required number of ESWL sessions for technical success. METHODS: We retrospectively evaluated patients with PDS secondary to CP who underwent ESWL. Technical success was defined as the complete fragmentation of stones to <3 mm. CT features including PDS size, number, location, and density in Hounsfield units (HU) were noted. We analyzed the relationship between PDS characteristics and the number of ESWL sessions required for technical success. A multiple linear regression model was used to combine size and density into the pancreatic duct stone (PDS) index that was translated into a web-based calculator. RESULTS: There were 206 subjects (mean age 38.6 ± 13.7 years, 59.2% male) who underwent ESWL. PDS size showed a moderate correlation with the number of ESWL sessions (r = 0.42, p < 0.01). PDS in the head required a fewer number of sessions in comparison to those in the body (1.4 ± 0.6 vs. 1.6 ± 0.7, p = 0.01). There was a strong correlation between PDS density and the number of ESWL sessions (r = 0.617, p-value <0.01). The PDS index {0.3793 + [0.0009755 x PDS density (HU)] + [0.02549 x PDS size (mm)]} could accurately predict the required number of ESWL sessions with an AUC of 0.872 (p < 0.01). CONCLUSION: The PDS index is a useful predictor of the number of ESWL sessions needed for technical success that can help in planning and patient counseling.

A machine learning-based choledocholithiasis prediction tool to improve ERCP decision making: a proof-of-concept study.

BACKGROUND: Previous studies demonstrated limited accuracy of existing guidelines for predicting choledocholithiasis, leading to overutilization of endoscopic retrograde cholangiopancreatography (ERCP). More accurate stratification may improve patient selection for ERCP and allow use of lower-risk modalities. METHODS: A machine learning model was developed using patient information from two published cohort studies that evaluated performance of guidelines in predicting choledocholithiasis. Prediction models were developed using the gradient boosting model (GBM) machine learning method. GBM performance was evaluated using 10-fold cross-validation and area under the receiver operating characteristic curve (AUC). Important predictors of choledocholithiasis were identified based on relative importance in the GBM. RESULTS: 1378 patients (mean age 43.3 years; 61.2% female) were included in the GBM and 59.4% had choledocholithiasis. Eight variables were identified as predictors of choledocholithiasis. The GBM had accuracy of 71.5% (SD 2.5%) (AUC 0.79 [SD 0.06]) and performed better than the 2019 American Society for Gastrointestinal Endoscopy (ASGE) guidelines (accuracy 62.4% [SD 2.6%]; AUC 0.63 [SD 0.03]) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines (accuracy 62.8% [SD 2.6%]; AUC 0.67 [SD 0.02]). The GBM correctly categorized 22% of patients directed to unnecessary ERCP by ASGE guidelines, and appropriately recommended as the next management step 48% of ERCPs incorrectly rejected by ESGE guidelines. CONCLUSIONS: A machine learning-based tool was created, providing real-time, personalized, objective probability of choledocholithiasis and ERCP recommendations. This more accurately directed ERCP use than existing ASGE and ESGE guidelines, and has the potential to reduce morbidity associated with ERCP or missed choledocholithiasis.

Lactated Ringers Use in the First 24 Hours of Hospitalization Is Associated With Improved Outcomes in 999 Patients With Acute Pancreatitis.

INTRODUCTION: Recent pilot trials in acute pancreatitis (AP) found that lactated ringers (LR) usage may result in decreased risk of moderately severe/severe AP compared with normal saline, but their small sample sizes limit statistical power. We investigated whether LR usage is associated with improved outcomes in AP in an international multicenter prospective study. METHODS: Patients directly admitted with the diagnosis of AP were prospectively enrolled at 22 international sites between 2015 and 2018. Demographics, fluid administration, and AP severity data were collected in a standardized prospective manner to examine the association between LR and AP severity outcomes. Mixed-effects logistic regression analysis was performed to determine the direction and magnitude of the relationship between the type of fluid administered during the first 24 hours and the development of moderately severe/severe AP. RESULTS: Data from 999 patients were analyzed (mean age 51 years, female 52%, moderately severe/severe AP 24%). Usage of LR during the first 24 hours was associated with reduced odds of moderately severe/severe AP (adjusted odds ratio 0.52; P = 0.014) compared with normal saline after adjusting for region of enrollment, etiology, body mass index, and fluid volume and accounting for the variation across centers. Similar results were observed in sensitivity analyses eliminating the effects of admission organ failure, etiology, and excessive total fluid volume. DISCUSSION: LR administration in the first 24 hours of hospitalization was associated with improved AP severity. A large-scale randomized clinical trial is needed to confirm these findings.

Interpretation of serum pancreatic enzymes in pancreatic and nonpancreatic conditions.

PURPOSE OF REVIEW: Serum levels of amylase and lipase can be elevated in nonpancreatic conditions that may or may not be associated with abdominal pain. This leads to a large proportion of patients being falsely labeled as having acute pancreatitis. In this review, we aim to summarize the existing evidence on pancreatic enzyme elevation in various pancreatic and nonpancreatic conditions and its practical implications in clinical practice and healthcare. RECENT FINDINGS: Serum amylase and lipase levels are not specific for pancreatitis. Attempts have been made to validate newer biomarkers including pancreatic elastase, serum trypsin, urinary trypsinogen-activated peptide, phospholipase A2, carboxypeptidase B, activated peptide of carboxypeptidase B, the trypsin 2 alpha 1 activation complex, and circulating cell-free DNA for the diagnosis of acute pancreatitis. SUMMARY: Serum lipase levels can be elevated in many intra-abdominal inflammatory conditions. Although more sensitive and specific than amylase, serum lipase levels are not sufficient to diagnose acute pancreatitis in patients with abdominal pain. There is a need to increase stress on radiological evidence as well increase cut-off levels of enzyme elevation for a more accurate diagnosis of acute pancreatitis.

Pancreatic duct pressure: A review of technical aspects and clinical significance.

Pancreatic duct pressure (PDP) dynamics comprise an intricately modulated system that helps maintain homeostasis of pancreatic function. It is affected by various factors, including the rate of pancreatic fluid secretion, patency of the ductal system, sphincter of Oddi function, and pancreatic fluid characteristics. Disease states such as acute and chronic pancreatitis can alter the normal PDP dynamics. Ductal hypertension or increased PDP is suspected to be involved in the pathogenesis of pancreatic pain, endocrine and exocrine pancreatic insufficiency, and recurrent pancreatitis. This review provides a comprehensive appraisal of the available literature on PDP, including the methods used in the measurement and clinical implications of elevated PDP.

Incidence, severity, and mortality of post-ERCP pancreatitis: an updated systematic review and meta-analysis of 145 randomized controlled trials.

BACKGROUND AND AIMS: The incidence, severity, and mortality of post-ERCP pancreatitis (PEP) largely remain unknown with changing trends in ERCP use, indication, and techniques. We sought to determine the incidence, severity, and mortality of PEP in consecutive and high-risk patients based on a systemic review and meta-analysis of patients in placebo and no-stent arms of randomized control trials (RCTs). METHODS: The MEDLINE, Embase, and Cochrane databases were searched from the inception of each database to June 2022 to identify full-text RCTs evaluating PEP prophylaxes. The incidence, severity, and mortality of PEP from the placebo or no-stent arms of RCTs were recorded for consecutive and high-risk patients. A random-effects meta-analysis for a proportions model was used to calculate PEP incidence, severity, and mortality. RESULTS: One hundred forty-five RCTs were found with 19,038 patients in the placebo or no-stent arms. The overall cumulative incidence of PEP was 10.2% (95% confidence interval [CI], 9.3-11.3), predominantly among the academic centers conducting such RCTs. The cumulative incidences of severe PEP and mortality were .5% (95% CI, .3-.7) and .2% (95% CI, .08-.3), respectively, across 91 RCTs with 14,441 patients. The cumulative incidences of PEP and severe PEP were 14.1% (95% CI, 11.5-17.2) and .8% (95% CI, .4-1.6), respectively, with a mortality rate of .2% (95% CI, 0-.3) across 35 RCTs with 3733 patients at high risk of PEP. The overall trend for the incidence of PEP among patients randomized to placebo or no-stent arms of RCTs has remained unchanged from 1977 to 2022 (P = .48). CONCLUSIONS: The overall incidence of PEP is 10.2% but is 14.1% among high-risk patients based on this systematic review of placebo or no-stent arms of 145 RCTs; this rate has not changed between 1977 and 2022. Severe PEP and mortality from PEP are relatively uncommon.

Bulking agents in gastrointestinal endoscopy: present applications and future advances.

PURPOSE OF REVIEW: Bulking agents are inert materials injected into an organ to affect the physical properties of the organ for a therapeutic purpose. Various agents have been developed to aid in the treatment of diseases like gastroesophageal reflux disease (GERD), fecal incontinence, obesity, malignancy, hemostasis, and tissue dissection. Here, we review the state of the art in bulking agents in gastrointestinal endoscopy, past failures, current limitations, and where we see the field heading in the future. RECENT FINDINGS: Though bulking agents have been trialed for various different gastrointestinal diseases, there are currently limited uses in gastrointestinal endoscopy. Though various agents have been trialed for GERD, numerous complications and adverse events have limited its current use. However, for the treatment of fecal incontinence endoscopic bulking agent therapy is a reasonable option. Though in early stages of exploration, bulking agent therapy for enteric protection from radiotherapy may be a promising tool to improve treatment of pancreatic cancer. Bulking agents for tissue dissection have substantially improved lifting agents and complex polyp removal. Bulking agent therapy has not really been explored for endoscopic bariatric therapy or hemostasis but may be a fruitful area for exploration in the future. SUMMARY: Bulking agent therapy has been trialed for various gastrointestinal diseases with mixed success. There is currently a therapeutic roll in the endoscopic management of fecal incontinence and tissue dissection. A future role in the treatment of GERD, obesity, malignancy, and hemostasis seem feasible.

Prevalence of primary painless chronic pancreatitis: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: While pain is the predominant symptom of chronic pancreatitis (CP), a subset of patients may experience a painless course. This systematic review aimed to determine the prevalence of primary painless CP. METHODS: MEDLINE (PubMed), EMBASE and Web of Science Core Collection databases were searched for published studies through September 15, 2020 that included at least 10 consecutive patients with CP and which reported the number with painless CP. The presence of a history of recurrent acute pancreatitis (RAP), exocrine pancreatic insufficiency (EPI), diabetes mellitus (DM) and pancreatic adenocarcinoma (PA) in the painless CP patients was also recorded. A random effects model was used to determine pooled prevalence estimates with 95% confidence intervals (95% CI). RESULTS: Among the 5057 studies identified and screened, 42 full-text articles were included in the final analysis. There were a total of 14,277 patients with CP among whom 1569 had painless CP. The pooled prevalence of painless CP was 12% (95% CI 10-15%). Among a subset of studies that reported on calcifications (n = 11), DM (n = 12), EPI (n = 8) and history of RAP (n = 14), the pooled prevalence estimates were 96% (95% CI 73-100%), 51% (95% CI 32-70%), and 47% (95% CI 15-81%), respectively. Alcohol, idiopathic/genetic and other etiologies were attributed to be the cause of painless CP in 32.4%, 56.9% and 8.9% patients, respectively. CONCLUSION: Approximately one in ten patients with CP have primary painless disease with the majority being attributable to an idiopathic/genetic etiology. Further research is needed to determine the optimal management of these patients.

Rectal INdomethacin, oral TacROlimus, or their combination for the prevention of post-ERCP pancreatitis (INTRO Trial): Protocol for a randomized, controlled, double-blinded trial.

BACKGROUND: Acute pancreatitis remains the most common and morbid complication of endoscopic retrograde cholangiopancreatography (ERCP). The use of rectal indomethacin and pancreatic duct stenting has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP), but these interventions have limitations. Recent clinical and translational evidence suggests a role for calcineurin inhibitors in the prevention of pancreatitis, with multiple retrospective case series showing a reduction in PEP rates in tacrolimus users. METHODS: The INTRO trial is a multicenter, international, randomized, double-blinded, controlled trial. A total of 4,874 patients undergoing ERCP will be randomized to receive either oral tacrolimus (5 mg) or oral placebo 1-2 h before ERCP, and followed for 30 days post-procedure. Blood and pancreatic aspirate samples will also be collected in a subset of patients to quantify tacrolimus levels. The primary outcome of the study is the incidence of PEP. Secondary endpoints include the severity of PEP, ERCP-related complications, adverse drug events, length of hospital stay, cost-effectiveness, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of tacrolimus immune modulation in the pancreas. CONCLUSIONS: The INTRO trial will assess the role of calcineurin inhibitors in PEP prophylaxis and develop a foundation for the clinical optimization of this therapeutic strategy from a pharmacologic and economic standpoint. With this clinical trial, we hope to demonstrate a novel approach to PEP prophylaxis using a widely available and well-characterized class of drugs. TRIAL REGISTRATION: NCT05252754, registered on February 14, 2022.

Traction-assisted endoscopic submucosal dissection reduces procedure time and risk of serious adverse events: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Conventional endoscopic submucosal dissection (C-ESD) is a technically demanding procedure with prolonged procedure times and higher risk of adverse events. To overcome the procedural difficulty of ESD, several traction-assisted techniques (T-ESD) have been developed to improve visualization of the submucosa in hopes to facilitate safe and effective dissection. The aim of this study was to conduct a meta-analysis that compares short-term outcomes (30-day) of T-ESD to C-ESD. METHODS: Clinical studies published up to April 2020 comparing the efficacy and safety of T-ESD and C-ESD were identified using electronic bibliographic searches. Both randomized controlled trials and observational studies were included. Outcomes of interests were procedure time, rates of en bloc and R0 resection, and rates of adverse events. Fixed effect and random effect model were used to calculate pooled mean difference for continuous variables and risk differences (RDs) for categorical variables. RESULTS: Twenty-three studies with 2574 patients were included in this meta-analysis, with a total of 2582 lesions (1292 T-ESD and 1290 C-ESD). Pooled estimates of T-ESD showed shorter procedure times (weighted mean difference = -20.35 min, 95% CI -27.51 to -13.19, p < 0.001), higher R0 resection rates (RD 0.04, 95% CI 0.01-0.06, p = 0.004) and lower perforation rates (RD -0.03, 95% CI -0.04 to -0.01, p = < 0.0001). No significant differences were seen in en bloc rates and bleeding risk between the two groups. CONCLUSIONS: Traction-assisted ESD results in shorter procedure time, improved R0 resection rates and lower risk of perforation as compared to conventional ESD.

Morphologic Severity of Acute Pancreatitis on Imaging Is Independently Associated with Opioid Dose Requirements in Hospitalized Patients.

BACKGROUND: Prior studies have evaluated clinical characteristics associated with opioid dose requirements in hospitalized patients with acute pancreatitis (AP) but did not incorporate morphologic findings on CT imaging. AIMS: We sought to determine whether morphologic severity on imaging is independently associated with opioid dose requirements in AP. METHODS: Adult inpatients with a diagnosis of AP from 2006 to 2017 were reviewed. The highest modified CT severity index (MCTSI) score and the daily oral morphine equivalent (OME) for each patient over the first 7 days of hospitalization were used to grade the morphologic severity of AP and calculate mean OME per day(s) of treatment (MOME), respectively. Multiple regression analysis was used to evaluate the association of MOME with MCSTI. RESULTS: There were 249 patients with AP, of whom 196 underwent contrast-enhanced CT. The mean age was 46 ± 13.6 years, 57.9% were male, and 60% were black. The mean MOME for the patient cohort was 60 ± 52.8 mg/day. MCTSI (ß = 3.5 [95% CI 0.3, 6.7], p = 0.03), early hemoconcentration (ß = 21 [95% CI 4.6, 39], p = 0.01) and first episode of AP (ß = - 17 [95% CI - 32, - 2.7], p = 0.027) were independently associated with MOME. Among the 19 patients undergoing ≥ 2 CT scans, no significant differences in MOME were seen between those whose MCTSI score increased (n = 12) versus decreased/remained the same (n = 7). CONCLUSION: The morphologic severity of AP positively correlated with opioid dose requirements. No difference in opioid dose requirements were seen between those who did versus those who did not experience changes in their morphologic severity.

Risk factors for lymph node metastasis and survival of patients with nonampullary duodenal carcinoid tumors treated with endoscopic therapy versus surgical resection: analysis of the Surveillance, Epidemiology, and End Results program.

BACKGROUND AND AIMS: Endoscopic therapy (ET) has been used to treat nonampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in size, but data on long-term outcomes are limited. In addition, management of 11- to 19-mm NAD-NETs is not well defined because of variable estimates of risk of metastasis. We aimed to determine the prevalence and risk factors of metastasis of NAD-NETs ≤19 mm and evaluate the long-term survival of patients after ET as compared with radical surgery. METHODS: The Surveillance Epidemiology and End Result database was used to identify 1243 patients with T1-2 histologically confirmed NAD-NETs ≤19 mm in size. Cancer-specific survival (CSS) and overall survival (OS) were calculated. RESULTS: Overall, 4.8% of cases had metastasis at the time of diagnosis, with lower prevalence in ≤10-mm lesions (3.1%) versus 11- to 19-mm lesions (11.7%, P < .001). The risk factors for metastases included invasion to the muscularis propria (odds ratio, 25.95; 95% confidence interval, 9.01-76.70), age <65 years (odds ratio, 1.93), submucosal involvement (odds ratio, 3.1), and 11 to 19 mm in size (vs ≤10 mm). In patients with well- to moderately differentiated T1-2N0M0 NAD-NETs ≤19 mm confined to the mucosa/submucosa who underwent ET or surgery, the 5-year CSS was 100%. The 5-year OS was similar between the ≤10-mm and 11- to 19-mm groups (86.6% vs 91.0%, P = .31) and the ET and surgery groups (87.4% vs 87.5%, P = .823). CONCLUSIONS: In NAD-NETs, invasion to the muscularis propria is the strongest risk factor for metastasis. In the absence of metastasis, in lesions with well/moderate differentiation and without muscle invasion, ET is adequate for NAD-NETs ≤10 mm and is a viable option for 11- to 19-mm lesions.

Artificial intelligence in pancreaticobiliary endoscopy.

Artificial intelligence (AI) applications in health care have exponentially increased in recent years, and a few of these are related to pancreatobiliary disorders. AI-based methods were applied to extract information, in prognostication, to guide clinical treatment decisions and in pancreatobiliary endoscopy to characterize lesions. AI applications in endoscopy are expected to reduce inter-operator variability, improve the accuracy of diagnosis, and assist in therapeutic decision-making in real time. AI-based literature must however be interpreted with caution given the limited external validation. A multidisciplinary approach combining clinical and imaging or endoscopy data will better utilize AI-based technologies to further improve patient care.

Comparable Cancer-Specific Mortality of Patients With Early Gastric Cancer Treated With Endoscopic Therapy vs Surgical Resection.

BACKGROUND & AIMS: Endoscopic therapy is used commonly for superficial gastric cancer with very low risk of metastasis to the lymph nodes. However, limited population-based studies from the West have evaluated long-term outcomes of patients who received endoscopic therapy vs surgery. METHODS: We used the Surveillance Epidemiology and End Results database to identify and compare features and outcomes of patients who underwent endoscopic therapy (n = 786) or surgery (n = 2577) for Tis or T1aN0M0 superficial gastric cancer, diagnosed from 1998 to 2014. Multivariate logistic regression was performed to identify factors associated with endoscopic therapy. Overall survival and gastric cancer-specific survival times were compared after we controlled for covariates. RESULTS: Use of endoscopic therapy increased from 15.1% of cases in 1998 to 2000 to 39.0% of cases in 2013 to 2014. Endoscopic therapy was used more frequently in patients who were older, female, or Caucasian, or with lesions that were located in the proximal stomach or were limited in depth (Tis vs T1a) and size, compared with surgery. The median follow-up time was 59 months (interquartile range, 31-102 mo). Percentages of 5-year overall and cancer-specific survival were 57% and 99% in the endoscopic therapy group and 76% and 95% in the surgery group. After we adjusted for clinical factors using a multivariate Cox proportional hazards model, we found no significant difference in gastric cancer-specific mortality between patients who received endoscopic therapy vs surgery (hazard ratio, 1.42; 95% CI, 0.91-2.23; P = .12). CONCLUSIONS: In an analysis of a large population database, we found an increased trend in endoscopic therapy for superficial gastric cancer compared with surgery from 1998 through 2014. Patients who received endoscopic therapy vs surgery had comparable long-term cancer-specific mortality.

The Gut Microbiome in Pancreatic Disease.

The gut microbiome increasingly is recognized for its role in human health and disease. Initial evidence has indicated that gut microbial dysbiosis is associated with several pancreatic diseases. Although it is not known if these associations are causative, gut dysbiosis is hypothesized to mediate chronic proinflammatory changes in the pancreas. Further mechanistic and epidemiologic studies of the microbiome are needed. Ultimately, targeted modulation of the microbiota could have therapeutic value.

A Randomized Trial of Topical Epinephrine and Rectal Indomethacin for Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis in High-Risk Patients.

INTRODUCTION: Rectal indomethacin and topical spray of epinephrine have separately shown efficacy in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) in randomized controlled trials. We hypothesized that the combination of indomethacin and topical spray of epinephrine on the duodenal papillae would further reduce PEP than when indomethacin was used alone. METHODS: We conducted a comparative effectiveness, multicenter, double-blinded, randomized trial of rectal indomethacin alone vs a combination of rectal indomethacin and topical spray of epinephrine for the prevention of PEP in high-risk patients. The primary outcome was the incidence of PEP and the secondary outcome was the severity of PEP. A 2-tailed Fisher's exact test was used to analyze the difference in the proportion of patients with PEP in the indomethacin alone vs the combination group. RESULTS: A total of 960 patients (mean age 52.33 ± 14.96 years; 551 [57.4%] females) were randomized and 959 completed follow-up. The baseline demographic and clinical characteristics were similar between the 2 groups. Women <50 years of age (25.4%) and difficult cannulation (84.9%) were the most common PEP risk factors. The incidence of PEP was 6.4% in the indomethacin alone group (n = 482) compared to 6.7% in the combination group (n = 477; P = 0.87). Severe PEP was found in 5 (12%) and 7 (16%) patients in the indomethacin alone and combination groups, respectively (P = 0.88). The overall mortality was 0.6%, which was unrelated to the primary outcome. CONCLUSIONS: The combination of rectal indomethacin and topical spray of epinephrine does not reduce the incidence of PEP compared to rectal indomethacin alone in high-risk patients; https://clinicaltrials.gov/ct2/show/NCT02116309.

Cystic fibrosis transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis among adult patients with pancreas sufficient cystic fibrosis.

BACKGROUND: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history. METHODS: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period. RESULTS: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ±â€¯13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ±â€¯21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up. CONCLUSIONS: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.