Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study.

OBJECTIVE: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study.

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

Circulating immune signatures across clinical stages of chronic pancreatitis: a pilot study.

OBJECTIVE: This pilot study seeks to identify serum immune signatures across clinical stages of patients with chronic pancreatitis (CP). METHODS: We performed a cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies-study. CP subjects were categorised into three clinical stages based on the presence/absence of metabolic complications: (1) CP with no diabetes and exocrine pancreatic dysfunction (EPD), (2) CP with either diabetes or EPD, and (3) CP with diabetes and EPD. Blinded samples were analysed using an 80-plex Luminex assay of cytokines/chemokines/adhesion molecules. Group and pairwise comparisons were performed to characterise immune signatures across CP subgroups. RESULTS: A total of 135 CP subjects (evenly distributed between clinical stages) and 50 controls were studied. Interleukin-6 (IL-6), interleukin-8 (IL-8), and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in CP subjects compared to controls. The levels of IL-6 and IL-8 increased with advancing disease stages, with the highest levels observed in CP with diabetes and EPD (clinical stage 3). Furthermore, hepatocyte growth factor and macrophage-derived chemokine were significantly increased in clinical stage 3 compared to controls. CONCLUSION: Our study reveals a progressive elevation in pro-inflammatory cytokines and chemokines with advancing clinical stages of CP. These findings indicate potential targets for the development of disease-modifying interventions.

Prevalence of Osteopathy in Chronic Pancreatitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Individuals with chronic pancreatitis (CP) are at increased risk for nutritional complications during their clinical course. We appraised the literature to provide updated estimates of the prevalence and predictors of osteoporosis, osteopenia, and osteopathy in CP using a systematic review and meta-analysis. METHODS: Search strategies were developed for major databases from inception through October 2021. Outcomes of interest included rates of osteopenia and osteoporosis based on dual-energy X-ray absorptiometry scans and risk factors. A random-effects model was used for analysis, and results were expressed as pooled cumulative rates along with 95% confidence interval (CI). RESULTS: From an initial total of 1,704 identified articles, we ultimately selected 17 studies that involved 1,659 subjects (n = 1,067 men) with CP. The pooled rate of osteopathy was 58% (95% CI: 49%-67%; P < 0.001; I 2 = 91.8%). The pooled rate of osteoporosis was 18% (95% CI: 12%-23%; P < 0.001; I 2 = 86.3%), and the pooled rate of osteopenia was 39% (95% CI: 31%-48%; P < 0.001; I 2 = 91.53%). In the systematic review, factors associated with decreased bone mineral density included smoking, alcohol consumption, older age, female sex, low body mass index, decreased vitamins D and K, and fecal elastase levels. DISCUSSION: Patients with CP have high rates of osteopathy when assessed with dual-energy X-ray absorptiometry imaging. Additional studies with longitudinal follow-up are needed to understand the observed heterogeneity, the cumulative burden of disease, and rate of bone loss in CP.

Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study.

BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS: A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS: Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.

Development of a Clinical Prediction Model for Diabetes in Chronic Pancreatitis: The PREDICT3c Study.

OBJECTIVE: Diabetes that arises from chronic pancreatitis (CP) is associated with increased morbidity and mortality. Methods to predict which patients with CP are at greatest risk for diabetes are urgently needed. We aimed to examine independent risk factors for diabetes in a large cohort of patients with CP. RESEARCH DESIGN AND METHODS: This cross-sectional study comprised 645 individuals with CP enrolled in the PROCEED study, of whom 276 had diabetes. We conducted univariable and multivariable regression analyses of potential risk factors for diabetes. Model performance was assessed by area under the receiver operating characteristic curve (AUROC) analysis, and accuracy was evaluated by cross validation. Exploratory analyses were stratified according to the timing of development of diabetes relative to the diagnosis of pancreatitis. RESULTS: Independent correlates of diabetes in CP included risk factors for type 2 diabetes (older age, overweight/obese status, male sex, non-White race, tobacco use) as well as pancreatic disease-related factors (history of acute pancreatitis complications, nonalcoholic etiology of CP, exocrine pancreatic dysfunction, pancreatic calcification, pancreatic atrophy) (AUROC 0.745). Type 2 diabetes risk factors were predominant for diabetes occurring before pancreatitis, and pancreatic disease-related factors were predominant for diabetes occurring after pancreatitis. CONCLUSIONS: Multiple factors are associated with diabetes in CP, including canonical risk factors for type 2 diabetes and features associated with pancreatitis severity. This study lays the groundwork for the future development of models integrating clinical and nonclinical data to identify patients with CP at risk for diabetes and identifies modifiable risk factors (obesity, smoking) on which to focus for diabetes prevention.

Cystic fibrosis transmembrane conductance regulator modulators and the exocrine pancreas: A scoping review.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve pulmonary outcomes in subjects with cystic fibrosis (CF); however, the effects on pancreatic manifestations are not well characterized. We hypothesized that CFTR modulators would improve measures of exocrine pancreatic function and outcomes. METHODS: We performed a systematic search to identify studies reporting measures of the exocrine pancreas in humans treated with CFTR modulators. Only studies reporting baseline and on-treatment assessments were included. RESULTS: Of 630 identified studies, 41 met inclusion criteria. CFTR modulators reduced acute pancreatitis events by 85% overall (rate ratio 0.15, 95% confidence interval (CI) 0.04, 0.52), with a greater effect seen in the subgroup with pancreas sufficient CF (PS-CF) (rate ratio 0.13 (95% CI 0.03, 0.53). Among 293 subjects with baseline and on-treatment evaluation of pancreas sufficiency, 253 were pancreas insufficient at baseline and 54 (21.3%) converted to pancreas sufficiency. Of 32 subjects with baseline FE-1 values <200 mcg/g, 16 (50%) increased to ≥200 mcg/g. Serum trypsin decreased by a mean of 565.9 ng/mL (standard deviation (SD) 311.8), amylase decreased by 38.2 U/L (SD 57.6), and lipase decreased by 232.3 U/L (SD 247.7). CONCLUSIONS: CFTR modulator use reduces acute pancreatitis frequency and improves indirect measures of exocrine pancreas function. Future interventional studies that evaluate the mechanism and impact of CFTR modulators on acute pancreatitis and pancreas sufficiency in patients with CFTR dysfunction are warranted.

Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies.

ABSTRACT: Pain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N = 681) with CP, 80% experienced abdominal pain within the year before enrollment. Subjects who experienced pain in the week before enrollment (N = 391) completed PROMIS Neuropathic and Nociceptive Pain Quality instruments which were then used to classify them by pain type: 40% had nociceptive, 5% had neuropathic-like, and 32% had both types of pain. The prevalence of having both types of pain was higher among women and subjects with diabetes mellitus, whereas nociceptive-only pain was more prevalent among men and those with pancreatic duct stricture. Other factors, including pain medication use and healthcare utilization, did not differ between groups based on pain type. Subjects in the Both group had significantly worse health and QoL scores relative to those with nociceptive-only pain, suggesting that using psychosocial pain surveys may be useful for understanding pain subtypes in patients with CP. Additional research is needed to identify biochemical and biophysical signatures that may associate with and predict responses to mechanism-specific interventions.

Incidence and Risk Factors for New-Onset Diabetes Mellitus After Surgical Resection of Pancreatic Cystic Lesions: A MarketScan Study.

OBJECTIVES: There is a paucity of literature evaluating new-onset diabetes mellitus (NODM) after resection of pancreatic cystic lesions (PCLs). We sought to characterize the incidence and risk factors associated with NODM after partial pancreatectomy for PCLs. METHODS: We utilized the IBM MarketScan Database (2012-2018) to identify all nondiabetic adults who underwent partial pancreatectomy for PCLs. Patients with any other pancreatic disease were excluded. We performed Kaplan-Meier analysis and multivariable Cox proportional hazards regression to define the incidence and risk factors of postoperative NODM. RESULTS: Among 311 patients, the overall risk (95% confidence interval) of NODM was 9.1% (6.3-12.9%), 15.1% (11.3-20.2%), and 20.2% (15.3-26.4%) at 6, 12 and 24 months, respectively. Multivariable analysis (adjusted hazard ratio; 95% confidence interval) revealed that older age (1.97; 1.04-3.72; 55-64 vs 18-54 years), obesity (2.63; 1.35-5.12), hypertension (1.79; 1.01-3.17), and cardiovascular disease (2.54; 1.02-6.28) were independent predictors of NODM. Rates of NODM were similar after distal pancreatectomy versus pancreaticoduodenectomy. CONCLUSIONS: Within 2 years, 1 in 5 patients without any other pancreatic disease will develop NODM after partial pancreatectomy for PCLs. Those with advanced age, metabolic syndrome features, and/or cardiovascular disease may benefit from preoperative counseling and intensive postoperative monitoring, education, and treatment for diabetes mellitus.

Urine Proteomics Reveals Sex-Specific Response to Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical option for refractory chronic pancreatitis-related pain. Despite the known clinical implications of TPIAT, the molecular effects remain poorly investigated. We performed the first hypothesis-generating study of the urinary proteome before and after TPIAT. METHODS: Twenty-two patients eligible for TPIAT were prospectively enrolled. Urine samples were collected the week before and 12 to 18 months after TPIAT. The urine samples were prepared for bottom-up label-free quantitative proteomics using the "MStern" protocol. RESULTS: Using 17 paired samples, we identified 2477 urinary proteins, of which 301 were significantly changed post-TPIAT versus pre-TPIAT. Our quantitative analysis revealed that the molecular response to TPIAT was highly sex-specific, with pronounced sex differences pre-TPIAT but minimal differences afterward. Comparing post-TPIAT versus pre-TPIAT, we found changes in cell-cell adhesion, intracellular vacuoles, and immune response proteins. After surgery, immunoglobulins, complement proteins, and cathepsins were increased, findings that may reflect glomerular damage. Finally, we identified both known and novel markers for immunoglobulin A nephropathy after 1 patient developed the disease 2 years after TPIAT. CONCLUSIONS: We found distinct changes in the urinary proteomic profile after TPIAT and the response to TPIAT is highly sex-specific.

Altered Plasma Fatty Acid Abundance Is Associated with Cachexia in Treatment-Naïve Pancreatic Cancer.

Cachexia occurs in up to 80% of pancreatic ductal adenocarcinoma (PDAC) patients and is characterized by unintentional weight loss and tissue wasting. To understand the metabolic changes that occur in PDAC-associated cachexia, we compared the abundance of plasma fatty acids (FAs), measured by gas chromatography, of subjects with treatment-naïve metastatic PDAC with or without cachexia, defined as a loss of > 2% weight and evidence of sarcopenia (n = 43). The abundance of saturated, monounsaturated, and polyunsaturated FAs was not different between subjects with cachexia and those without. Oleic acid was significantly higher in subjects with cachexia (p = 0.0007) and diabetes (p = 0.015). Lauric (r = 0.592, p = 0.0096) and eicosapentaenoic (r = 0.564, p = 0.015) acids were positively correlated with age in cachexia patients. Subjects with diabetes (p = 0.021) or both diabetes and cachexia (p = 0.092) had low palmitic:oleic acid ratios. Linoleic acid was lower in subjects with diabetes (p = 0.018) and correlated with hemoglobin (r = 0.519, p = 0.033) and albumin (r = 0.577, p = 0.015) in subjects with cachexia. Oleic or linoleic acid may be useful treatment targets or biomarkers of cachexia in patients with metastatic PDAC, particularly those with diabetes.

Surgical approach and short-term outcomes in adults and children undergoing total pancreatectomy with islet autotransplantation: A report from the Prospective Observational Study of TPIAT.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation. METHODS: We evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n = 84) with adults (n = 195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP. RESULTS: Children more commonly underwent splenectomy (100% versus 91%, p = 0.002), pylorus preservation (93% versus 67%; p < 0.0001), Roux-en-Y duodenojejunostomy reconstruction (92% versus 35%; p < 0.0001), and enteral feeding tube placement (93% versus 63%; p < 0.0001). Median islet equivalents/kg transplanted was higher in children (4577; IQR 2816-6517) than adults (2909; IQR 1555-4479; p < 0.0001), with COBE purification less common in children (4% versus 15%; p = 0.0068). Median length of hospital stay was higher in children (15 days; IQR 14-22 versus 11 days; IQR 8-14; p < 0.0001), but 30-day readmissions were lower in children (13% versus 26%, p = 0.018). Rate of portal vein thrombosis was significantly lower in children than in adults (2% versus 10%, p = 0.028). There were no mortalities in the first 90 days post-TPIAT. CONCLUSIONS: Pancreatectomy techniques differ between children and adults, with islet yields higher in children. The rates of portal vein thrombosis and early readmission are lower in children.

Incidence and Risk of Pancreatic Cancer in Patients with a New Diagnosis of Chronic Pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC); nevertheless, the true incidence of PDAC in CP patients in the United States remains unclear. AIMS: We evaluated the risk of developing PDAC two or more years after a new diagnosis of CP. METHODS: Retrospective study of veterans from September 1999 to October 2015. A three-year washout period was applied to exclude patients with preexisting CP and PDAC. PDAC risk was evaluated in patients with new-diagnosis CP and compared with controls without CP using Cox-proportional hazards model. CP, PDAC, and other covariates were extracted using ICD-9 codes. RESULTS: After exclusions, we identified 7,883,893 patients [new-diagnosis CP - 21,765 (0.28%)]. PDAC was diagnosed in 226 (1.04%) patients in the CP group and 15,858 (0.20%) patients in the control group (p < 0.001). CP patients had a significantly higher PDAC risk compared to controls > 2 years [adjusted hazard ratio (HR) 4.28, 95% confidence interval (CI) 3.74-4.89, p < 0.001], 5 years (adjusted HR 3.32, 95% CI 2.75-4.00, p < 0.001) and 10 years of follow-up (adjusted HR 3.14, 95% CI 1.99-4.93, p < 0.001), respectively. By multivariable analysis, age (odds ratio 1.02, 95% CI 1.00-1.03, p = 0.03), current smoker (odds ratio 1.67, 95% CI 1.02-2.74, p = 0.042), current smoker + alcoholic (odds ratio 2.29, 95% CI 1.41-3.52, p < 0.001), and diabetes (odds ratio 1.51, 95% CI 1.14-1.99, p = 0.004) were the independent risk factors for PDAC. CONCLUSION: Our data show that after controlling for etiology of CP and other cofactors, the risk of PDAC increased in CP patients after two years of follow-up, and risk was consistent and sustained beyond 5 years and 10 years of follow-up.

The Impact of Bariatric Surgery on Diverticulitis Outcomes and Risk of Recurrent Hospitalizations in Adults with Clinically Severe Obesity.

PURPOSE: Clinically severe obesity (SO) is a known risk factor for worsened outcomes and recurrence of acute diverticulitis. Paucity of data exist on outcomes of diverticulitis after bariatric surgery. METHODS: The Nationwide Readmissions Database was queried for diverticulitis hospitalizations between the years 2010 and 2014. We restricted analysis to patients with SO and those who had bariatric surgery (BRS). Outcomes of mortality, surgical events, and recurrent diverticulitis admissions were compared using multivariable analysis and one-to-one propensity score matching. RESULTS: Among 52,274 diverticulitis admissions, 91.2% (47,694) patients had SO and 8.8% (4580) had prior BRS. Patients with SO had higher odds of suffering mortality on index diverticulitis admission when compared to those with prior BRS [adjusted odds ratio (aOR): 10.55; 95%CI 1.45,76.75]. Patients with SO were also more likely to undergo emergency surgery (aOR: 1.71; 95%CI 1.25,2.34) and colectomy (aOR: 1.45; 95%CI 1.26,1.68). Rates of recurrent diverticulitis readmissions within 30 days and 6 months were also higher in patients with SO compared to BRS patients (aOR: 7.94; 95%CI 1.09,57.83 and aOR: 1.98; 95%CI 1.14,3.43, respectively). Propensity score matching confirmed our findings of increased rates of mortality (OR: 17.28; 95%CI 2.02,147.6), recurrent diverticulitis, and worsened surgical outcomes within 30 days in patients with SO compared to BRS. CONCLUSION: This study is first to show improved outcomes and less recurrent hospitalizations for diverticulitis after bariatric surgery compared to patients with clinically severe obesity. Further studies are needed to understand mechanisms leading to this improvement and the role of weight loss in prevention of severe diverticulitis.

Lower Interobserver Reliability for Nondimensional Intracystic Features Among Abdominal Radiologists for Characterizing Intraductal Papillary Mucinous Neoplasms Using Magnetic Resonance Imaging.

OBJECTIVES: Current guidelines recommend magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) for risk stratification of intraductal papillary mucinous neoplasms (IPMNs). We assessed the interobserver agreement among radiologists in evaluating and risk stratifying IPMNs. METHODS: This single-center study evaluated 30 patients with IPMNs who had undergone MRI/MRCP, endoscopic ultrasound, and/or surgical resection. Six abdominal radiologists evaluated the MRI/MRCPs to document multiple parameters. The analysis applied Landis and Koch κ interpretation for categorical variables and intraclass correlation coefficient (r) for continuous variables. RESULTS: Radiologists demonstrated almost perfect agreement for location (κ = 0.81, 95% confidence interval [CI], 0.74-0.87), size (r = 0.95; 95% CI, 0.89-0.98), and main pancreatic duct diameter (r = 0.98; 95% CI, 0.96-0.99). Substantial agreement was observed for communication with the main pancreatic duct (κ = 0.66; 95% CI, 0.57-0.75) and classification of IPMN subtype (κ = 0.77; 95% CI, 0.67-0.86). Presence of intracystic nodules (κ = 0.31; 95% CI, 0.21-0.42) and wall thickening (κ = 0.09; 95% CI, -0.01 to 0.18) reached only fair and slight agreement, respectively. CONCLUSIONS: Although MRI/MRCP is excellent in the evaluation of spatial aspects, there is lower reliability for nondimensional characteristics of IPMNs. These data support guideline-recommended complementary evaluation of IPMNs with MRI/MRCP and endoscopic ultrasound.

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use Is Associated With Reduced Pancreatitis Hospitalizations in Patients With Cystic Fibrosis.

INTRODUCTION: Acute pancreatitis (AP) occurs among patients with pancreas-sufficient cystic fibrosis (PS-CF) but is reportedly less common among patients with pancreas-insufficient cystic fibrosis (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF. METHODS: MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by the use of pancreas enzyme replacement therapy. RESULTS: A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, P = 0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval [CI] 0.10, 1.11, P = 0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, P = 0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations, respectively. In a subset analysis of 1,795 patients who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, P = 0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, P = 0.26) for PI-CF. DISCUSSION: CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. These observational data support the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.

Outcomes of inpatient cholecystectomy among adults with cystic fibrosis in the United States.

BACKGROUND: Symptomatic biliary and gallbladder disorders are common in adults with cystic fibrosis (CF) and the prevalence may rise with increasing CF transmembrane conductance regulator modulator use. Cholecystectomy may be considered, but the outcomes of cholecystectomy are not well described among modern patients with CF. AIM: To determine the risk profile of inpatient cholecystectomy in patients with CF. METHODS: The Nationwide Inpatient Sample was queried from 2002 until 2014 to investigate outcomes of cholecystectomy among hospitalized adults with CF compared to controls without CF. A propensity weighted sample was selected that closely matched patient demographics, patient's individual comorbidities, and hospital characteristics. The propensity weighted sample was used to compare outcomes among patients who underwent laparoscopic cholecystectomy. Hospital outcomes of open and laparoscopic cholecystectomy were compared among adults with CF. RESULTS: A total of 1239 inpatient cholecystectomies were performed in patients with CF, of which 78.6% were performed laparoscopically. Mortality was < 0.81%, similar to those without CF (P = 0.719). In the propensity weighted analysis of laparoscopic cholecystectomy, there was no difference in mortality, or pulmonary or surgical complications between patients with CF and controls. After adjusting for significant covariates among patients with CF, open cholecystectomy was independently associated with a 4.8 d longer length of stay (P = 0.018) and an $18449 increase in hospital costs (P = 0.005) compared to laparoscopic cholecystectomy. CONCLUSION: Patients with CF have a very low mortality after cholecystectomy that is similar to the general population. Among patients with CF, laparoscopic approach reduces resource utilization and minimizes post-operative complications.

Serum biomarkers for chronic pancreatitis pain patterns.

OBJECTIVES: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns. METHODS: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes. RESULTS: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P. DISCUSSION: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.

The Association of Smoking and Alcohol Abuse on Anxiety and Depression in Patients With Recurrent Acute or Chronic Pancreatitis Undergoing Total Pancreatectomy and Islet Autotransplantation: A Report From the Prospective Observational Study of TPIAT Cohort.

OBJECTIVES: Smoking and alcohol use are risk factors for acute and chronic pancreatitis, and their role on anxiety, depression, and opioid use in patients who undergo total pancreatectomy and islet autotransplantation (TPIAT) is unknown. METHODS: We included adults enrolled in the Prospective Observational Study of TPIAT (POST). Measured variables included smoking (never, former, current) and alcohol abuse or dependency history (yes vs no). Using univariable and multivariable analyses, we investigated the association of smoking and alcohol dependency history with anxiety and depression, opioid use, and postsurgical outcomes. RESULTS: Of 195 adults studied, 25 were current smokers and 77 former smokers, whereas 18 had a history of alcohol dependency (of whom 10 were current smokers). A diagnosis of anxiety was associated with current smoking (P = 0.005), and depression was associated with history of alcohol abuse/dependency (P = 0.0001). However, active symptoms of anxiety and depression at the time of TPIAT were not associated with smoking or alcohol status. Opioid use in the past 14 days was associated with being a former smoker (P = 0.005). CONCLUSIONS: Active smoking and alcohol abuse history were associated with a diagnosis of anxiety and depression, respectively; however, at the time of TPIAT, symptom scores suggested that they were being addressed.