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Background Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA. Methods The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0–10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded. Discussion NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain. Trial registration ClinicalTrials.gov, NCT02693093 . Registered through the National Institutes of Health on 26 February 2016.

Germline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages. Individuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included. Test results and information collected from test requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel (pathogenic, likely pathogenic, and/or increased risk variants) in pancreatitis-related genes. Overall, 2,468 subjects with primary indication of acute pancreatitis (AP) (n = 401), chronic pancreatitis (CP) (n = 631), pancreatic cancer (n = 128), or other indications (n = 1,308) completed germline testing. Among patients with AP or CP, the prevalence of any positive result for those <35 versus ≥35 years of age was 32.1% and 24.5% (p = 0.007), and the prevalence of a clinically meaningful result was 10.8% and 5.4%, respectively (p = 0.001). Positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92-25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83-0.95). The highest prevalence of pathogenic variants is seen in younger individuals with a positive family history of pancreatitis. However, clinically meaningful results are identified in older subjects, suggesting that genetic counseling and testing should be considered for all age groups.

Background Sarcopenia is common in chronic pancreatitis (CP) and has been associated with unfavorable outcomes; however, it is not well studied in acute pancreatitis (AP). Aims To evaluate risk factors for sarcopenia among individuals with AP or CP. Methods A cross sectional analysis was performed among subjects with AP or CP seen in a tertiary care Pancreas Clinic. TeraRecon software was used to calculate the cross-sectional area of skeletal muscle, visceral fat, and subcutaneous fat at the level of the L3 vertebrae. Sarcopenia was classified using sex-specific skeletal muscle index. Univariate and multivariate logistic regressions were performed to assess differences between groups and associations with sarcopenia. Results A total of 49 subjects with AP and 54 subjects with CP were included. Sarcopenia was more frequently observed in CP compared to AP (83.3% vs. 46.9%, p  < 0.001). The multivariate logistic regression demonstrated CP, male sex, increased age, and decreased subcutaneous fat were independently associated with sarcopenia. Conclusion Sarcopenia is observed in both CP and AP. In addition to traditional risk factors (including male sex, older age, and decreased subcutaneous fat), CP is independently associated with sarcopenia. Further investigations are necessary to gain deeper insights into sarcopenia pathogenesis, which could inform potential intervention strategies.

Background Cancer‐associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer‐induced cachexia in patients with earlier stages of disease. Methods A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high‐sensitivity multiplex was used for increased sensitivity for nine cytokines. Results Resectable pancreatic cancer patients with cachexia had low levels of canonical pro‐inflammatory cytokines including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), interferon‐γ (IFN‐γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein‐1 (MCP‐1) was increased in treatment‐naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were found to be decreased in the same cohort of treatment‐naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. Conclusions Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment‐naïve patients have higher levels of MCP‐1, suggesting that MCP‐1 may be useful as a biomarker of cancer cachexia.

Chronic pancreatitis is a disease that leads to irreversible changes in the pancreatic morphology and function. The loss of function can lead to diabetes mellitus and exocrine pancreatic insufficiency. The inflammation and fibrosis can also lead to other complications including a chronic abdominal pain syndrome, metabolic bone disease, and pancretic cancer. This article reviews our current understanding of the mechanisms and management of these complications of chronic pancreatitis.

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.

INTRODUCTION:Lipomas can occur anywhere throughout the gastrointestinal tract and can range widely in size. When symptomatic, these lipomas require removal, and several techniques have been described depending on the size of the lesion. Recently, a method utilizing an endoloop ligation has been proposed and validated for use in colonic lipomas. However, there remains a lack of literature on the safety and efficacy of endoloop ligation for the removal of symptomatic lipomas in the small intestine.CASE DESCRIPTION/METHODS:A 55-year-old male with a history of neurofibromatosis, prior prostate cancer, and tobacco use presented for evaluation of melena. He underwent an upper endoscopy which was reportedly normal and was transferred to our center for consideration of small bowel endoscopy. He continued to have melena and labile hemoglobin. A push enteroscopy revealed a long, submucosal lesion in the proximal jejunum with several areas of ulceration which were presumed to be the source of his bleeding. The mass was biopsied, and pathology was consistent with a lipoma. Subsequently, the patient underwent EUS and endoloop ligation. A video from this case is submitted to demonstrate the proper use of endoloop ligation of a large lipoma in the small intestine. Following placement of the endoloop ligature, the patient had no further bleeding and a follow-up enteroscopy one month later revealed complete loss of the lipoma with unremarkable appearing mucosa.DISCUSSION:In this case, we demonstrate that endoloop ligation is a safe technique for the removal of symptomatic large lipomas in the small bowel. In the video, we demonstrate how to apply the endoloop ligature to such a lesion effectively.Watch the video: http://bit.ly/2JSdmLE.

ObjectiveSeveral factors have been suggested to mediate pain in patients with chronic pancreatitis. However, it is unknown whether these factors are overlapping and if they have cumulative effects on patient-reported outcomes (PROs).DesignWe performed a multicentre cross-sectional study of 201 prospectively enrolled subjects with definitive chronic pancreatitis. All subjects underwent evaluation for pancreatic duct obstruction, abnormalities in pain processing using quantitative sensory testing, and screening for psychological distress (anxiety, depression and pain catastrophising) based on validated questionnaires. Abnormality was defined by normal reference values. PROs included pain symptom severity (Brief Pain Inventory short form) and quality of life (EORTC-QLQ-C30 questionnaire). Associations between pain-related factors and PROs were investigated by linear trend analyses, multiple regression models and mediation analyses.ResultsClinical evaluation suggestive of pancreatic duct obstruction was observed in 29%, abnormal pain processing in 23%, anxiety in 47%, depression in 39% and pain catastrophising in 28%; each of these factors was associated with severity of at least one PRO. Two or more factors were present in 51% of subjects. With an increasing number of factors, there was an increase in pain severity scores (p<0.001) and pain interference scores (p<0.001), and a reduction in quality of life (p<0.001). All factors had independent and direct effects on PROs, with the strongest effect size observed for psychological distress.ConclusionPain-related factors in chronic pancreatitis are often present in an overlapping manner and have a cumulative detrimental effect on PROs. These findings support a multidisciplinary strategy for pain management.Trial registration numberThe study was registered with ClinicalTrials.gov (NCT03434392).

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. 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. 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. 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.