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Current treatments for chronic pancreatitis focus on symptom management and therapeutics targeting disease reversal are lacking. Given the role of the cyclooxygenase-2 (COX-2) enzyme in producing prostaglandin E 2 (PGE 2), a key component in the inflammatory pathway of chronic pancreatitis, this study evaluates the physiologic effect of oral indomethacin, a COX-2 inhibitor, on PGE 2 levels in pancreatic fluid. This pilot two-center randomized controlled trial seeks to examine 32 subjects with chronic pancreatitis who have no contraindications to indomethacin. Subjects will be randomized to either oral indomethacin 50 mg twice a day or placebo twice a day for a total of 28 days. Baseline (pre-treatment) assessment of pain and quality of life will be performed using the Brief Pain Inventory and the PROMIS-10 questionnaires, respectively. Biological specimens including blood, urine, and saliva will be collected at pre-treatment and post-treatment(day 28). Endoscopic pancreatic function testing with concomitant pancreatic fluid collection will also be performed pre- and post-treatment to assess the change in pancreatic fluid PGE 2 levels. The relationship between pancreatic fluid PGE 2 levels with blood and saliva PGE 2 levels will be examined. This study will elucidate the effect of oral indomethacin on PGE 2 levels in the pancreas to assess its role in the inflammatory pathway of chronic pancreatitis. Should indomethacin significantly reduce PGE 2 levels, this may represent a potential disease-altering treatment for chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, and the increasing incidence of PDAC may be related to the prevalence of obesity. Physical activity (PA), a method known to mitigate obesity by increasing total energy expenditure, also modifies multiple cellular pathways associated with cancer hallmarks. Epidemiologic evidence has shown that PA can lower the risk of developing a variety of cancers, reduce some of the detrimental side effects of treatments, and improve patient's quality of life during cancer treatment. However, little is known about the pathways underlying the correlations observed between PA interventions and PDAC. Moreover, there is no standard dose of PA intervention that is ideal for PDAC prevention or as an adjuvant of cancer treatments. In this review, we summarize relevant literature showing how PDAC patients can benefit from PA, the potential of PA as an adjuvant treatment for PDAC, the studies using preclinical models of PDAC to study PA, and the clinical trials to date assessing the effects of PA in PDAC. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis (CP) does not have diagnostic or prognostic biomarkers. CP is the end stage of a progressive inflammatory syndrome that is diagnosed at late stages by morphologic features. To diagnose earlier stages of the disease, a new mechanistic definition was established based on identifying underlying pathogenic processes and biomarker evidence of disease activity and stage. Although multiple risk factors are known, the corresponding biomarkers needed to make a highly accurate diagnosis of earlier disease stages have not been established. The goal of this study is to systematically analyze the literature to identify the most likely candidates for development into biomarkers of CP. We conducted a systematic review of candidate analytes from easily accessible biological fluids and identified 67 studies that compared CP to nonpancreatic-disease controls. We then ranked candidate biomarkers for sensitivity and specificity by area under the receiver operator curves (AUROCs). Five biomarkers had a large effect size (an AUROC > 0.96), whereas 30 biomarkers had a moderate effect size (an AUROC between 0.96 and 0.83) for distinguishing CP cases from controls or other diseases. However, the studies reviewed had marked variability in design, enrollment criteria, and biospecimen sample handling and collection. Several biomarkers have the potential for evaluation in prospective cohort studies and should be correlated with risk factors, clinical features, imaging studies and outcomes. The Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreas Cancer provides recommendations for avoiding design biases and heterogeneity in sample collection and handling in future studies. [ABSTRACT FROM AUTHOR]

The incidence rates of acute pancreatitis (AP) and the prevalence of class III obesity, and metabolic syndrome (MetS) are increasing in the US. Since class III obesity was associated with adverse clinical outcomes of AP, we sought to understand if the presence of metabolic comorbidities collectively recognized, as MetS were associated with worse clinical outcomes and increased health-care utilization. The Nationwide Readmissions Database (NRD) (2010–2014) was reviewed to identify all adult subjects with a principal discharge diagnosis of AP. Inpatient mortality, severe AP (SAP), and 30-day readmissions were the primary outcomes analyzed. Propensity score weighted analyses were used to compare AP subjects with and without MetS and were further stratified by class III obesity status. MetS was associated with 12.91% (139,165/1,078,183) of all admissions with AP. Propensity score weighted analyses showed that MetS was associated with an increased proportion of SAP (OR 1.21, 95% CI 1.17, 1.25), but decreased mortality (OR 0.62, 95% CI 0.54, 0.70) and 30-day readmissions (OR 0.86, 95% CI 0.83, 0.89). Propensity score weighted analyses also revealed that class III obesity was independently associated with increased mortality in AP subjects with (OR 1.92, 95% CI 1.41, 2.61) and without MetS (OR 1.55, 95% CI 1.26, 1.92), and increased SAP in subjects with and without MetS. Class III obesity appears to be the primary factor associated with adverse clinical outcomes in subjects with MetS admitted with AP. This has significant implications for patient management and future research targeting AP. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis is a chronic inflammatory disease, which progresses to fibrosis. Currently there are no interventions to delay or stop the progression to irreversible organ damage. In this study, we assessed the tolerability and feasibility of administering soy bread to reduce circulating inflammatory mediators. Subjects with chronic pancreatitis diagnosed using the American Pancreatic Association diagnostic guidelines were enrolled. During the dose escalation (DE) phase, subjects received one week of soy bread based using a 3 + 3 dose-escalation design, which was then followed by a maximally tolerated dose (MTD) phase with four weeks of intervention. Dose-limiting toxicities (DLTs) were monitored. Plasma cytokine levels were measured using a Meso Scale Discovery multiplex assay kit. Isoflavonoid excretion in 24-h urine collection was used to measure soy bread compliance. Nine subjects completed the DE phase, and one subject completed the MTD phase without any DLTs at a maximum dosage of three slices (99 mg of isoflavones) per day. Reported compliance to soy bread intervention was 98%, and this was confirmed with urinary isoflavones and their metabolites detected in all subjects. There was a significant decline in the TNF-α level during the DE phase (2.667 vs 2.382 pg/mL, p = 0.039); other levels were similar. In this feasibility study, there was excellent compliance with a short-term intervention using soy bread in chronic pancreatitis. Reduction was seen in at least one pro-inflammatory cytokine with short-term intervention. Larger cohorts and longer interventions with soy are warranted to assess the efficacy of reducing pro-inflammatory mediators of disease. [ABSTRACT FROM AUTHOR]

Lipocalin-2 (LCN2) is a secreted molecule, expressed in various cell types, that is involved in the progression of numerous diseases and disorders. The biological functions and expression levels of LCN2 in diseases including pancreatic cancer, pancreatitis (acute and chronic), and diabetes mellitus, suggest the potential role of LCN2 as a biomarker and/or therapeutic target. However, findings on the role of LCN2 in pancreatic diseases have been contradictory. In pancreatic cancer and pancreatitis, LCN2 has been identified as a potential biomarker; increased expression levels in various biological specimens correlate with the presence of the disease and may be able to differentiate cancer and chronic pancreatitis from healthy subjects. LCN2 is also known to be an adipokine; it is upregulated in obesity and is a common co-factor in the development of pancreatic diseases. Emerging research suggests LCN2 is elevated in type 2 diabetes mellitus, but the exact role of LCN2 in this disease is not clear. In this review, we summarize research on LCN2 as it relates to pancreatic diseases, highlighting the discrepancies in the literature. By explaining and clarifying the role of LCN2 in these disorders, we aim to promote research in developing novel diagnostic and treatment strategies to reduce the burden of pancreatic diseases. [ABSTRACT FROM AUTHOR]

Cathepsin E (CTSE) is an intracellular, hydrolytic aspartic protease found to be expressed in cells of the immune and gastrointestinal systems, lymphoid tissues, erythrocytes, and cancer cells. The precise functions are not fully understood; however, various studies have investigated its numerous cell-type specific roles. CTSE expression has been shown to be a potential early biomarker for pancreatic ductal adenocarcinoma (PDAC). PDAC patients have low survival rates mostly due to the lack of early detection methods. CTSE-specific activity probes have been developed and tested to assist in tumor imaging and functional studies investigating the role of CTSE expression in PDAC tumors. Furthermore, a CTSE protease-specific, photodynamic therapy pro-drug was developed to explore its potential use to treat tumors that express CTSE. Since CTSE is expressed in pancreatic diseases that are risk factors for PDAC, such as pancreatic cysts and chronic pancreatitis, learning about its function in these disease types could assist in early PDAC detection and in understanding the biology of PDAC progression. Overall, CTSE expression and activity shows potential to detect PDAC and other pancreatic diseases. Further research is needed to fully understand its functions and potential translational applicability. [ABSTRACT FROM AUTHOR]

Abstract Background Cachexia is a wasting syndrome characterized by involuntary loss of >5% body weight due to depletion of adipose and skeletal muscle mass. In cancer, the pro-inflammatory cytokine interleukin-6 (IL-6) is considered a mediator of cachexia and a potential biomarker, but the relationship between IL-6, weight loss, and cancer stage is unknown. In this study we sought to evaluate IL-6 as a biomarker of cancer cachexia while accounting for disease progression. Methods We retrospectively studied 136 subjects with biopsy-proven pancreatic ductal adenocarcinoma (PDAC), considering the high prevalence of cachexia is this population. Clinical data were abstracted from subjects in all cancer stages, and plasma IL-6 levels were measured using a multiplex array and a more sensitive ELISA. Data were evaluated with univariate comparisons, including Kaplan-Meier survival curves, and multivariate Cox survival models. Results On multiplex, a total of 43 (31.4%) subjects had detectable levels of plasma IL-6, while by ELISA all subjects had detectable IL-6 levels. We found that increased plasma IL-6 levels, defined as detectable for multiplex and greater than median for ELISA, were not associated with weight loss at diagnosis, but rather with the presence of metastasis (p < 0.001 for multiplex and p = 0.007 for ELISA). Further, while >5% weight loss was not associated with worse survival, increased plasma IL-6 by either methodology was. Conclusion Circulating IL-6 levels do not correlate with cachexia (when defined by weight loss), but rather with advanced cancer stage. This suggests that IL-6 may mediate wasting, but should not be considered a diagnostic biomarker for PDAC-induced cachexia. [ABSTRACT FROM AUTHOR]