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Background & Aims Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP. Methods We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy. Results The majority of subjects had osteopathy on DXA scan (56.0%; 17.0% osteoporosis; 39.0% osteopenia). Subjects with osteopathy had a higher prevalence of traumatic (40.0% vs 26.4%; P = .02) and spontaneous fractures (3.9% vs 0; P = .04). On multivariate analysis, older age (odds ratio [OR], 1.29 per 5 years; 95% confidence interval [CI], 1.15–1.45), female sex (OR, 3.08; 95% CI, 1.75–5.43), white race (OR, 2.68; 95% CI, 1.20–6.01), and underweight body mass index category (OR, 7.40; 95% CI, 1.56–34.99) were associated with higher probability of osteopathy. There were no significant associations between osteopathy and other patient and disease-related features of CP. Conclusion In the largest study of patients with CP who underwent DXA screening, the majority had osteopathy. There are overlapping risk factors with osteopathy in the general population, but the high prevalence in men and younger women supports the need for future investigations into the mechanisms of bone loss in CP. ClinicalTrials.gov number, NCT03099850.

Nutritional dermatoses are traditionally taught in the context of developing countries, famine, population displacement, and limited access to healthcare. In the United States, nutritional dermatoses may be underdiagnosed and lead to increased morbidity and utilization of hospital resources. These findings underscore the need for providers in developed nations to be able to identify these deficiencies. Dermatologists play a critical role in the diagnosis and management of nutritional deficiencies as they often present with cutaneous findings. Part two of this review series will focus on the epidemiology, impact, manifestations, and diagnosis of B-complex vitamins that can present with cutaneous findings, including thiamine, riboflavin, niacin, pyridoxine, and biotin.

Background and Aims : EUS-guided needle-based confocal laser endomicroscopy (nCLE) improves the diagnostic accuracy of pancreatic cystic lesions (PCLs) but concerns regarding its expense have limited widespread adoption of this technology. We conducted a cost-benefit analysis to assess the healthcare resource implications of adding EUS-nCLE to the standard of care (SOC) management of PCLs. Methods : A post-hoc analysis of a prospective study (2015-2018) evaluating EUS-nCLE for the diagnosis of PCLs was performed. The SOC diagnosis was based on clinical history, PCL morphology, and cyst fluid analysis. A minimum of 5-years of surveillance was included, the cost of EUS and MRI/MRCP was derived from institutional billing data (US$), and the total hospital costs (adjusted for inflation) for pancreatic operations were derived from the National (US) Readmission Database. Results : A reference diagnosis was available in 93 subjects (mean cyst size=36.4±15.7 mm; surgical histopathology, n=67 and diagnostic molecular markers in cyst fluid, n=26). SOC and nCLE were discordant in 13 (14%) subjects. The addition of nCLE led to 11 subjects being clinically downstaged from mucinous to non-mucinous not warranting surgery (total cost savings= $1,080,418), 1 subject upstaged from non-mucinous to mucinous, warranting surgical resection (cost savings of 5-years surveillance: $46,200), and 1 subject incorrectly classified as non-mucinous (cost excess of 5-years surveillance: $46,200). Overall, the addition of nCLE led to a net savings of $ 442,438 (mean: $ 4,757.40 /patient) for this cohort. Conclusions : EUS-nCLE is potentially cost-beneficial in the management of PCLs (≥ 3 cm) by preventing at least one unnecessary pancreatic surgery for every ten subjects undergoing evaluation by current practices. ClinicalTrials.gov number: NCT02516488.

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 (pConclusionPain-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).

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.

PURPOSE OF REVIEW: Diabetes secondary to pancreatic diseases (i.e., acute pancreatitis, chronic pancreatitis, and pancreatic cancer) is increasingly studied, but remains challenging to distinguish from type 2 diabetes (T2DM). We review the clinical significance and potential biomarkers that may help differentiate these types of diabetes. RECENT FINDINGS: Recent studies have identified several complications (including non-vascular) that occur more frequently in patients with diabetes secondary to acute and chronic pancreatitis than T2DM, and biomarkers to differentiate the two types of diabetes. There have been advances that may enable the enrichment of a population of adults with new onset diabetes to potentially screen for occult pancreatic cancer, but efforts are needed to identify and validate promising diagnostic biomarkers. SUMMARY: High-quality studies are needed to more precisely understand the risk factors and natural course of diabetes secondary to pancreatic diseases. Mechanistic and interventional studies are awaited to provide insights that will distinguish diabetes secondary to pancreatic diseases and refine the management of hyperglycemia in this patient population.

Same-admission cholecystectomy (CCY) is recommended for mild acute biliary pancreatitis (biliary-AP). However, there is a paucity of research investigating reasons for early (30-day) unplanned readmissions in patients who undergo CCY for biliary-AP. Hence, we sought to investigate this gap using a large population database. Using the Nationwide Readmission Database (2010–2014), we identified all adults (age ≥ 18 years) with a principal diagnosis of biliary-AP who had undergone CCY during the index hospitalization. Multivariable logistic regression models were obtained to assess independent predictors for 30-day readmission. Principal diagnosis for all readmissions was collected to ascertain the indications for early readmission. During the study period, 118,224 patients underwent same-admission CCY for biliary-AP. Three-fourths of all patients underwent invasive cholangiography during the hospitalization (intraoperative cholangiogram (IOC) = 57,038, ERCP = 31,500). The rate of early (30-day) readmission was 7.25% (n = 8574). Exacerbation of prior medical conditions (42.2%), sequelae of biliary-AP (resolving and recurrent pancreatitis, pseudocysts) (27.6%), surgical site and other postoperative complications (16%), choledocholithiasis and/or bile leak (9.6%), and preventable hospital-acquired conditions (4.6%) accounted for early readmissions. On multivariable analysis, predictors for readmission included male sex (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.08–1.28), insurance type (Medicare insurance [OR 1.26, 95% CI 1.13–1.40]; Medicaid [OR 1.22, 95% CI 1.09–1.38]), outside-facility discharge (OR 1.35, 95% CI 1.16–1.57), severe AP (OR 1.35, 95% CI 1.21–1.50), and ≥ 3 Elixhauser comorbidities (OR 1.55, 95% CI 1.41–1.69). Performance of IOC (OR 0.90, 95% CI 0.82–0.97) and ERCP (OR 0.81, 95% CI 0.73–0.89) were associated with decreased risk of early readmission. In this study, using a national population database evaluating patients who underwent same-admission CCY after biliary-AP, we identified potentially modifiable risk factors and causes for early readmission as well as opportunities to improve clinical care.

PURPOSE OF REVIEW: The purpose of this review is to delineate risk factors for the development of diabetes in patients with chronic pancreatitis. The natural history including progression to diabetes and complications that develop once diabetes occurs in chronic pancreatitis is also reviewed. RECENT FINDINGS: Studies have found that predictors of diabetes in chronic pancreatitis include both risk factors for type 2 diabetes (e.g., obesity, genetic variants) as well as pancreas-specific factors (e.g., pancreatic calcification, exocrine insufficiency). Rates of diabetes in chronic pancreatitis are strongly related to the duration of chronic pancreatitis, reflecting progressive dysfunction and damage to the insulin-secreting beta-cells. Patients with diabetes and chronic pancreatitis experience an excess burden of complications, including higher all-cause and cancer-related mortality. SUMMARY: The high incidence and significant impact of diabetes on the morbidity and mortality of patients with chronic pancreatitis highlights the urgent need for clinically applicable models to predict diabetes in those with chronic pancreatitis, allowing efforts for targeted interventions to prevent diabetes. Research being carried out in the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) holds promise to fulfill these goals.

Biliary strictures caused by inflammation or fibrosis lead to jaundice and cholangitis which often make it difficult to distinguish malignant strictures. In cases when malignancy cannot be excluded, surgery is often performed. The concept of immunoglobulin G4 (IgG4)-related sclerosing cholangitis (SC) as a benign biliary stricture was recently proposed. The high prevalence of the disease in Asian countries has resulted in multiple diagnostic and treatment guidelines; however, there is need to formulate a standardized diagnostic strategy among various countries considering the utility, invasiveness, and cost-effectiveness. We evaluated accuracies of various diagnostic modalities for biliary strictures comparing pathology in the Delphi meetings which were held in Rochester, MN. The diagnostic utility for each modality was graded according to the experts, including gastroenterologists, endoscopists, radiologists, and pathologists from the United States and Japan. Diagnostic utility of 10 modalities, including serum IgG4 level, noninvasive imaging, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography-related diagnostic procedures were advocated and the reasons were specified. Serum IgG4 level, noninvasive imaging, diagnostic endoscopic ultrasound and intraductal ultrasonography under endoscopic retrograde cholangiopancreatography were recognized as useful modalities for the diagnosis. The information in this article will aid in the diagnosis of biliary strictures particularly for distinguishing IgG4-SC from cholangiocarcinoma and/or primary SC.

OBJECTIVE The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk. RESEARCH DESIGN AND METHODS We calculated dietary scores from baseline (1993–1998) food frequency questionnaires among 73,495 postmenopausal women in the Women’s Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes. RESULTS During a median 13.3 years of follow-up, 11,009 incident cases of type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were EDIH 1.49 (1.32–1.68; Ptrend < 0.0001) and EDIP 1.45 (1.29–1.63; Ptrend < 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) cases per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88–1.12; Ptrend = 0.46) and GL 1.01 (0.89–1.16; Ptrend = 0.30). CONCLUSIONS Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.

There is limited research in prognosticators of hospital transfer in acute pancreatitis (AP). Hence, we sought to determine the predictors of hospital transfer from small/medium-sized hospitals and outcomes following transfer to large acute-care hospitals.Using the 2010-2013 Nationwide Inpatient Sample (NIS), patients ≥18 years of age with a primary diagnosis of AP were identified. Hospital size was classified using standard NIS Definitions. Multivariable analyses were performed for predictors of "transfer-out" from small/medium-sized hospitals and mortality in large acute-care hospitals.Among 381,818 patients admitted with AP to small/medium-sized hospitals, 13,947 (4%) were transferred out to another acute-care hospital. Multivariable analysis revealed that older patients (OR = 1.04; 95%CI 1.03-1.06), men (OR = 1.15; 95%CI 1.06-1.24), lower income quartiles (OR = 1.54; 95%CI 1.35-1.76), admission to a non-teaching hospital (OR = 3.38; 95%CI 3.00-3.80), gallstone pancreatitis (OR = 3.32; 95%CI 2.90-3.79), pancreatic surgery (OR = 3.14; 95%CI 1.76-5.58), and severe AP (OR = 3.07; 95%CI 2.78-3.38) were predictors of "transfer-out". ERCP (OR = 0.53; 95%CI 0.43-0.66) and cholecystectomy (OR = 0.14; 95%CI 0.12-0.18) were associated with decreased odds of "transfer-out". Among 507,619 patients admitted with AP to large hospitals, 31,058 (6.1%) were "transferred-in" from other hospitals. The mortality rate for patients "transferred-in" was higher than those directly admitted (2.54% vs. 0.91%, p 0.001). Multivariable analysis revealed that being "transferred-in" from other hospitals was an independent predictor of mortality (OR = 1.47; 95% CI 1.22-1.77).Patients with AP transferred into large acute-care hospitals had a higher mortality than those directly admitted likely secondary to more severe disease. Early implementation of published clinical guidelines, triage, and prompt transfer of high-risk patients may potentially offset these negative outcomes.

Background and study aims There is limited evidence on the diagnostic performance of endoscopic ultrasound (EUS)-guided tissue acquisition in autoimmune pancreatitis (AIP). The aim of this meta-analysis was to provide a pooled estimate of the diagnostic performance of EUS-guided fine-needle aspiration (FNA) and fine-needle biopsy (FNB) in patients with AIP. Patients and methods Computerized bibliographic search was performed through January 2020. Pooled effects were calculated using a random-effects model by means of DerSimonian and Laird test. Primary endpoint was diagnostic accuracy compared to clinical diagnostic criteria. Additional outcomes were definitive histopathology, pooled rates of adequate material for histological diagnosis, sample adequacy, mean number of needle passes. Diagnostic sensitivity and safety data were also analyzed. Results Fifteen studies with 631 patients were included, of which four were prospective series and one randomized trial. Overall diagnostic accuracy of EUS tissue acquisition was 54.7 % (95 % confidence interval, 40.9 %–68.4 %), with a clear superiority of FNB over FNA (63 %, 52.7 % to 73.4 % versus 45.7 %, 26.5 %–65 %; p Conclusion The results of this meta-analysis demonstrate that the diagnostic performance of EUS-guided tissue acquisition is modest in patients with AIP, with an improved performance of FNB compared to FNA.

Objectives 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. Methods 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. Results 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. Conclusions 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.

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.

BACKGROUND/OBJECTIVES: The relationship between pre-existing diabetes mellitus (DM) and acute pancreatitis (AP) severity has not been established. We assessed the impact of pre-existing DM on AP severity in an international, prospectively ascertained registry. METHODS: APPRENTICE registry prospectively enrolled 1543 AP patients from 22 centers across 4 continents (8 US, 6 Europe, 5 Latin America, 3 India) between 2015 and 2018, and collected detailed clinical information. Pre-existing DM was defined a diagnosis of DM prior to AP admission. The primary outcome was AP severity defined by the Revised Atlanta Classification (RAC). Secondary outcomes were development of systemic inflammatory response syndrome (SIRS) or intensive care unit (ICU) admission. RESULTS: Pre-existing DM was present in 270 (17.5%) AP patients, of whom 252 (93.3%) had type 2 DM. Patients with pre-existing DM were significantly (p

INTRODUCTION: Experimental data suggest that nonsteroidal antiinflammatory drugs may prevent disease severity and mortality in acute pancreatitis (AP). The aim of this study was to compare the efficacy of rectal indomethacin vs placebo in reducing the systemic inflammatory response syndrome (SIRS) score in a high-risk AP population for clinical progression. METHODS: We conducted a single-center, quadruple-blinded, randomized, placebo-controlled trial. Eligible criteria were subjects with AP and SIRS within 72 hours of presentation and those without organ failure. Subjects were allocated in a 1:1 ratio to indomethacin or placebo using simple randomization. Both interventions were administered rectally every 8 hours for 6 doses and compared using both intention-to-treat and per-protocol analyses. RESULTS: A total of 42 subjects (mean age 52 years, 55% men) were randomized to indomethacin (n = 18) or placebo (n = 24). There was no significant difference between the indomethacin and placebo groups in the change of SIRS score, proportion of subjects with SIRS, and distribution of SIRS scores at 24, 48, and 72 hours from randomization. There were no significant differences in the change of C-reactive protein levels at 48 hours or clinical outcomes between both treatment groups. Indomethacin was as safe as placebo, with 2 adverse events occurring in the placebo and none in the indomethacin arm. DISCUSSION: Rectal indomethacin can be safely administered over 48 hours; however, it is not superior to placebo in reducing the SIRS or clinical progression in a high-risk population with AP (ClinicalTrials.gov: NCT02692391).

Chronic pancreatitis (CP) is characterized by progressive, irreversible morphologic and functional changes that are most commonly attributed to environmental insults, particularly when there is a genetic or anatomic predisposition. Heavy alcohol use and cigarette smoking are the most common environmental risk factors, but both may be absent. Antecedent episodes of acute pancreatitis occur in about half of patients, so active interventions are needed to reduce the risk of disease progression. Abdominal pain is the most common symptom, and requires a tailored approach depending on the anatomic changes in the pancreas. Other clinical manifestations include diabetes mellitus, exocrine pancreatic insufficiency, metabolic bone disease, pancreatic cancer, and anatomic complications. Current disease management is centered on risk factor reduction, and screening for and treating disease complications. There are no current therapies to delay or retard disease progression, but there are ongoing efforts to more fully understand the natural history of CP and underlying mechanisms of disease. These studies are expected to provide insights that will transform our approach to disease management and provide further hope to patients.

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.

Chronic pancreatitis (CP) is a progressive, irreversible disease characterized by maldigestion and frequently accompanied by epigastric pain, exocrine insufficiency, and/or endocrine insufficiency. There is limited information about the dietary patterns in CP from which to guide medical nutrition therapy recommendations. Study design was a cross-sectional, case–control study comparing subjects with CP (n = 52) to healthy controls (n = 48). Vioscreen™ food frequency questionnaire was used to assess the dietary pattern and nutrient intake in both groups. Dietary quality scores (the Healthy Eating Index, Mediterranean Diet score), and daily energy, macronutrient, and micronutrient intake levels were compared between groups. Two sample t tests and Wilcoxon rank sum tests were used to evaluate differences in continuous variables, and Chi-squared tests were used for categorical variables. CP was associated with a lower body mass index (BMI) (24 vs. 31 mg/kg2; p

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 (p5% 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 weight loss (i.e., cachexia), 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.

OBJECTIVES We hypothesized that hospitalizations in cystic fibrosis (CF) would reflect the development of age-related comorbidities. METHODS A retrospective analysis was performed using the Nationwide Inpatient Sample (2002-2017). Hospitalizations for which the principal diagnosis was CF were analyzed regarding age at discharge and presence of comorbidities. Trends were assessed for significance using the Cochran-Armitage test. RESULTS The mean age of patients hospitalized for CF increased from 19.7 years in 2002 to 23.0 years in 2017 (P = 0.017). Several comorbidities are more than 10 times more prevalent among adults as compared with children, including congestive heart failure, substance abuse, and chronic kidney disease (P < 0.001). In addition, diabetes with chronic complications was more prevalent in adults than children (10.0% vs 3.9%; P < 0.001), as was hypertension (7.2% vs 1.3%; P < 0.001) and osteoporosis (10.2% vs 1.9%; P < 0.001). More than 65% of CF hospitalizations in 2017 were in individuals older than 18 years. CONCLUSIONS Hospitalizations for adults with CF are increasing, and individuals with CF are developing age-related comorbidities. Providers equipped to manage the health care needs of adults need to be ready and able to care for this unique and growing patient population.

Introduction Existing laboratory markers and clinical scoring systems have shown suboptimal accuracies for early prediction of persistent organ failure (POF) in acute pancreatitis (AP). We used information theory and machine learning to select the best-performing panel of circulating cytokines for predicting POF early in the disease course and performed verification of the cytokine panel's prognostic accuracy in an independent AP cohort. Methods The derivation cohort included 60 subjects with AP with early serum samples collected between 2007 and 2010. Twenty-five cytokines associated with an acute inflammatory response were ranked by computing the mutual information between their levels and the outcome of POF; 5 high-ranking cytokines were selected. These cytokines were subsequently measured in early serum samples of an independent prospective verification cohort of 133 patients (2012-2016), and the results were trained in a Random Forest classifier. Cross-validated performance metrics were compared with the predictive accuracies of conventional laboratory tests and clinical scores. Results Angiopoietin 2, hepatocyte growth factor, interleukin 8, resistin, and soluble tumor necrosis factor receptor 1A were the highest-ranking cytokines in the derivation cohort; each reflects a pathologic process relevant to POF. A Random Forest classifier trained the cytokine panel in the verification cohort and achieved a 10-fold cross-validated accuracy of 0.89 (area under the curve 0.91, positive predictive value 0.89, and negative predictive value 0.90), which outperformed individual cytokines, laboratory tests, and clinical scores (all P ≤ 0.006). Discussion We developed a 5-cytokine panel, which accurately predicts POF early in the disease process and significantly outperforms the prognostic accuracy of existing laboratory tests and clinical scores.

Dermatologists play a critical role in diagnosing and managing nutritional deficiencies as they often present with cutaneous findings. Traditionally, nutritional dermatoses are taught in the context of developing countries, famine, population displacement, and poor healthcare access; however, in the United States, common risk factors include chronic liver disease, alcoholism, psychiatric disease, bariatric surgery, inflammatory bowel disease, and hemodialysis. Additionally, nutritional dermatoses may be underdiagnosed in the United States and result in increased morbidity and utilization of hospital resources. There is a need for providers in developed nations to identify these deficiencies, and this review aims to meet that practice gap and provide relevant context to these diseases for dermatologists. This two-part review series will focus on the epidemiology, impact, appearance, and diagnostic modalities for micronutrient deficiencies, including zinc, selenium, copper, and vitamins A and C in part one. The companion review will focus on the B-complex vitamins.

OBJECTIVES: There is a paucity of studies evaluating predictors of new-onset diabetes mellitus (DM) following acute pancreatitis (AP-related DM). We utilized a population-based database to evaluate predictors of AP-related DM. METHODS: The Nationwide Readmissions Database (2010–2014) was utilized to identify all non-diabetic adults with an index primary diagnosis of acute pancreatitis (AP). Multiple exclusions were applied to identify cohorts with and without AP-related DM. A case-control study was conducted to identify risk factors for developing AP-related DM within the calendar year. RESULTS: We identified 2510 subjects with AP-related DM and 40,308 controls with AP who did not develop DM. Multivariable analysis revealed that increasing age (50–64 years, adjusted Odds Ratio [aOR], 1.35, 95% confidence interval [CI], 1.14–1.60), male sex (aOR, 1.2, 95% CI, 1.03–1.40), lowest income quartile (aOR, 1.48, 95% CI, 1.18–1.84), Elixhauser comorbidity index ≥3 (aOR, 1.47, 95% CI, 1.23–1.75), components of metabolic syndrome (aOR, 2.12, 95% CI, 1.21–3.70), severe AP (aOR, 1.60, 95% CI, 1.34–1.90), and recurrent AP (aOR, 1.46, 95% CI, 1.24–1.72) were independently associated with increased risk of AP-related DM. CONCLUSION: These population-level variables predictive of developing AP-related DM can potentially identify patients who may benefit from closer follow-up, intensive education, and implementation of preventative strategies.

Background: Compared with patients who undergo pancreatic surgery for chronic pancreatitis and malignancy, patients with pancreatic cystic lesions (PCLs) generally have normal adjacent pancreatic parenchyma. There is a paucity of literature evaluating new-onset diabetes mellitus (NODM) following PCL resection. We sought to characterize the incidence and risk factors associated with NODM following partial pancreatectomy for PCLs. Methods: We utilized the IBM MarketScan Database (2012-2018) to identify all non-diabetic adult patients who underwent elective partial pancreatectomy for PCLs. Rigorous stepwise exclusion criteria were applied to identify patients without other pancreatic disease. We performed time-to-event analyses using Kaplan-Meier curves and multivariable Cox proportional hazards regression to define the incidence and risk factors associated with postoperative NODM. Findings: Among 311 patients with PCLs who underwent partial pancreatectomy, the overall risk of NODM was 9.1% (95% CI 6.3-12.9%), 15.1% (95% CI 11.3-20.2%), and 20.2% (95% CI 15.3-26.4%) at six, 12 and 24 months, respectively. Multivariable analysis revealed that older age (55-64 years, adjusted Hazard Ratio (aHR) 1.97, 95% CI 1.04-3.72 vs. 18-54 years), obesity (aHR 2.63, 95% CI 1.35-5.12), hypertension (aHR 1.79, 95% CI 1.01-3.17), and cardiovascular disease (aHR 2.54, 95% CI 1.02-6.28) were independent predictors of postoperative NODM. Rates of NODM were similar following distal pancreatectomy versus pancreaticoduodenectomy. Interpretation: Within two years, approximately one in five patients will develop NODM following partial pancreatectomy for PCLs. Those with advanced age, metabolic syndrome features, and/or cardiovascular disease may benefit from preoperative counselling for risk-reduction and intensive postoperative monitoring, education, and treatment strategies for DM. Funding: National Center for Advancing Translational Sciences, award number UL1TR002733. Declaration of Interests: None of the authors have any conflicts of interest or financial ties to disclose related to the current study. Ethics Approval Statement: This database is a publicly available population-based dataset. As such, the study was exempt from approval by the Ohio State University Institutional Review Board.

Background Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF. Objective We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF. Methods We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders. Results 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF (p, Key Summary What is known? Persistent organ failure (POF; >48 h) is the strongest determinant of mortality in acute pancreatitis (AP).There is lack of evidence on the impact of different attributes of failing organs on AP mortality.The association of systemic inflammatory response syndrome (SIRS) characteristics with POF, has not been well studied. What is new here? Mortality risk in AP patients with POF is determined by the number, type, and sequence of organ systems affected.Multiple POF affecting the cardiovascular and respiratory systems first or concurrently carries the highest mortality in AP compared to the renal system.Involvement of the renal system as the first failing organ or concurrently with other organs during multiple POF is associated with lower mortality than respiratoy or cardiovascular systems as first failing organs.Onset and duration of POF are not associated with mortality in AP patients.SIRS on admission, persistent SIRS, and three to four SIRS criteria, are independently associated with higher risk of POF.

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 μg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP (p = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels (p p p = 0.055) and CP mice on a control diet were determined to spend more time at rest (p = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.

BACKGROUND AND AIM: The primary aim was to validate the Pancreatitis Activity Scoring System (PASS) in a multicenter prospectively ascertained acute pancreatitis (AP) cohort. Second, we investigated the association of early PASS trajectories with disease severity and length of hospital stay (LOS). METHODS: Data were prospectively collected through the APPRENTICE consortium (2015-2018). AP severity was categorized based on revised Atlanta classification. Delta PASS (ΔPASS) was calculated by subtracting activity score from baseline value. PASS trajectories were compared between severity subsets. Subsequently, the cohort was subdivided into three LOS subgroups as short (S-LOS): 2-3 days; intermediate (I-LOS): 3-7 days; and long (L-LOS): ≥7 days. The generalized estimating equations model was implemented to compare PASS trajectories. RESULTS: There were 434 subjects analyzed including 322 (74%) mild, 86 (20%) moderately severe, and 26 (6%) severe AP. Severe AP subjects had the highest activity levels and the slowest rate of decline in activity (P = 0.039). Focusing on mild AP, L-LOS subjects (34%) had 28 points per day slower decline; whereas, S-LOS group (13%) showed 34 points per day sharper decrease compared with I-LOS (53%; P

Diabetes represents a group of diseases involving persistent hyperglycaemia. Exocrine disorders of the pancreas are increasingly recognised to cause or precede the onset of diabetes, which in this context is referred to as pancreatogenic or type 3c diabetes. Diabetes, as a sequela of acute pancreatitis, is observed across the spectrum of severity in acute pancreatitis and can be associated with other clinical complications. The pathophysiology of acute pancreatitis-related diabetes is poorly understood, and observations suggest that it is probably multifactorial. In this Review, we discuss the epidemiology, pathophysiology, and management considerations of diabetes following acute pancreatitis, and highlight knowledge gaps in this topic.

Background: Pancreatic cancer risk is increasing in countries with high consumption of Western dietary patterns and rising obesity rates. We examined the hypothesis that specific dietary patterns reflecting hyperinsulinemia (empirical dietary index for hyperinsulinemia; EDIH), systemic inflammation (empirical dietary inflammatory pattern; EDIP), and postprandial glycemia [glycemic index (GI); glycemic load (GL)] are associated with pancreatic cancer risk, including the potential modifying role of type 2 diabetes (T2D) and body mass index (BMI). Methods: We calculated dietary scores from baseline (1993–1998) food frequency questionnaires among 129,241 women, 50–79 years-old in the Women's Health Initiative. We used multivariable-adjusted Cox regression to estimate HRs and 95% confidence intervals (95% CI) for pancreatic cancer risk. Results: During a median 19.9 years of follow-up, 850 pancreatic cancer cases were diagnosed. We observed no association between dietary scores and pancreatic cancer risk overall. However, risk was elevated among participants with longstanding T2D (present >3 years before pancreatic cancer diagnosis) for EDIH. For each 1 SD increment in dietary score, the HRs (95% CIs) were: EDIH, 1.33 (1.06–1.66); EDIP, 1.26 (0.98–1.63); GI, 1.26 (0.96–1.67); and GL, 1.23 (0.96–1.57); although interactions were not significant (all Pinteraction >0.05). Separately, we observed inverse associations between GI [0.86 (0.76–0.96), Pinteraction = 0.0068] and GL [0.83 (0.73–0.93), Pinteraction = 0.0075], with pancreatic cancer risk among normal-weight women. Conclusions: We observed no overall association between the dietary patterns evaluated and pancreatic cancer risk, although women with T2D appeared to have greater cancer risk. Impact: The elevated risk for hyperinsulinemic diets among women with longstanding T2D and the inverse association among normal-weight women warrant further examination.

Background and Aims EUS-guided needle-based confocal laser endomicroscopy (EUS-nCLE) can differentiate high-grade dysplasia/adenocarcinoma (HGD-Ca) in intraductal papillary mucinous neoplasms (IPMNs) but requires manual interpretation. We sought to derive predictive computer-aided diagnosis (CAD) and artificial intelligence (AI) algorithms to facilitate accurate diagnosis and risk stratification of IPMNs. Methods A post hoc analysis of a single-center prospective study evaluating EUS-nCLE (2015-2019; INDEX study) was conducted using 15,027 video frames from 35 consecutive patients with histopathologically proven IPMNs (18 with HGD-Ca). We designed 2 CAD-convolutional neural network (CNN) algorithms: (1) a guided segmentation-based model (SBM), where the CNN-AI system was trained to detect and measure papillary epithelial thickness and darkness (indicative of cellular and nuclear stratification), and (2) a reasonably agnostic holistic-based model (HBM) where the CNN-AI system automatically extracted nCLE features for risk stratification. For the detection of HGD-Ca in IPMNs, the diagnostic performance of the CNN-CAD algorithms was compared with that of the American Gastroenterological Association (AGA) and revised Fukuoka guidelines. Results Compared with the guidelines, both n-CLE-guided CNN-CAD algorithms yielded higher sensitivity (HBM, 83.3%; SBM, 83.3%; AGA, 55.6%; Fukuoka, 55.6%) and accuracy (SBM, 82.9%; HBM, 85.7%; AGA, 68.6%; Fukuoka, 74.3%) for diagnosing HGD-Ca, with comparable specificity (SBM, 82.4%; HBM, 88.2%; AGA, 82.4%; Fukuoka, 94.1%). Both CNN-CAD algorithms, the guided (SBM) and agnostic (HBM) models, were comparable in risk stratifying IPMNs. Conclusion EUS-nCLE-based CNN-CAD algorithms can accurately risk stratify IPMNs. Future multicenter validation studies and AI model improvements could enhance the accuracy and fully automatize the process for real-time interpretation.

Introduction 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. Methods 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. Results 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. Conclusions 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.

Pancreatic ductal adenocarcinoma is most frequently detected at an advanced stage. Such late detection restricts treatment options and contributes to a dismal 5-year survival rate of 3-15%. Pancreatic ductal adenocarcinoma is relatively uncommon and screening of the asymptomatic adult population is not feasible or recommended with current modalities. However, screening of individuals in high-risk groups is recommended. Here, we review groups at high risk for pancreatic ductal adenocarcinoma, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss studies aimed at finding ways of identifying pancreatic ductal adenocarcinoma in high-risk groups, such as among individuals with new-onset diabetes mellitus and people attending primary and secondary care practices with symptoms that suggest this cancer. We review early detection biomarkers, explore the potential of using social media for detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to medical imaging for the purposes of early detection.

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and translational stuDies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis in the US. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in chronic pancreatitis. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of chronic pancreatitis - controls, Suspected chronic pancreatitis and Definite chronic pancreatitis. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium to study Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of chronic pancreatitis. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of chronic pancreatitis.

Hepatic parenchymal disease, including chronic viral hepatitis, has traditionally been considered a relative contraindication to islet transplantation as the islets are infused into the recipient’s liver. We present a case study of a patient with treated chronic hepatitis C infection (HCV) who safely received an autologous islet transplant following total pancreatectomy with excellent clinical outcomes. The patient was a 60-year-old woman diagnosed with debilitating abdominal pain secondary to chronic pancreatitis and with preserved islet function. She had previously been treated >10 years prior to surgical evaluation with interferon monotherapy for 1 year that led to sustained virologic response, including at the time of surgical evaluation for total pancreatectomy and islet autotransplantation (TPIAT). She underwent comprehensive preoperative evaluation of the liver, including liver biopsy, which showed no significant portal inflammation or fibrosis. Following a multidisciplinary meeting and discussion of the potential risks for the patient, the decision was made to proceed with TPIAT. The patient underwent a standard total pancreatectomy, and an autologous islet dose of 6638 islet equivalents/kg body weight was infused into the liver via the portal vein. Portal vein pressure was monitored throughout the infusion with a transient peak pressure of 27 cm H2O (basal pressure of 14 cm H2O) and final pressure of 23 cm H20 at 10 min post-infusion. Aside from a transient transaminitis, liver enzymes were normal at the time of hospital discharge. At greater than 1 year of follow-up, the patient has improved quality of life, with reduction in narcotic analgesia, remains insulin independent (with normal islet function), and has normal liver function. This case illustrates that islet autotransplant into the liver can be safely performed and suggests that carefully selected patients with liver disease may be eligible for TPIAT.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.

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-naive 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-naive 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-naive patients have higher levels of MCP-1, suggesting that MCP-1 may be useful as a biomarker of cancer cachexia.

Purpose To determine magnetic resonance elastography (MRE)-derived stiffness of pancreas in healthy volunteers with emphasis on: 1) short term and midterm repeatability; and 2) variance as a function of age. Methods Pancreatic MRE was performed on 22 healthy volunteers (age range:20–64 years) in a 3 T–scanner. For evaluation of reproducibility of stiffness estimates, the scans were repeated per volunteer on the same day (short term) and one month apart (midterm). MRE wave images were analyzed using 3D inversion to estimate the stiffness of overall pancreas and different anatomic regions (i.e., head, neck, body, and tail). Concordance and Spearman correlation tests were performed to determine reproducibility of stiffness measurements and relationship to age. Results A strong concordance correlation (ρ c = 0.99; p -value 0.81; p 45 yrs) had significantly higher stiffness compared to the younger group (≤ 45 yrs) ( p p > 0.05) in stiffness measurements was observed between different anatomical regions of pancreas, except neck stiffness was slightly lower ( p Conclusion MRE-derived pancreatic stiffness measurements are highly reproducible in the short and midterm and increase linearly with age in healthy volunteers. Further studies are needed to examine these effects in patients with various pancreatic diseases to understand potential clinical applications.

Although autoimmune pancreatitis is a relatively uncommon pancreatic disorder, it is an important consideration in the differential diagnosis of jaundice and pancreatic masses to avoid unnecessary surgical resection. The clinical diagnosis of autoimmune pancreatitis involves considering multiple pieces of information including the pancreatic imaging, serum IgG4 level, presence of characteristic other involvement, and histologic findings. Unlike other pancreatic disorders, this condition rapidly responds to treatment with steroids. In the more common disease subtype (type 1 autoimmune pancreatitis) disease relapses can occur necessitating the use of maintenance treatment with low-dose steroids, steroid-sparing immunomodulators, or rituximab. This chapter reviews the diagnosis and treatment of the autoimmune pancreatitis subtypes.

Chronic pancreatitis (CP) is a progressive inflammatory disease, which leads to loss of pancreatic function and other disease-related morbidities. A group of academic physicians and scientists developed comprehensive guidance statements regarding the management of CP that include its epidemiology, diagnosis, medical treatment, surgical treatment, and screening. The statements were developed through literature review, deliberation, and consensus opinion. These statements were ultimately used to develop a conceptual framework for the multidisciplinary management of chronic pancreatitis referred to as an academic pancreas center of excellence (APCOE).

The epidemiological trends contributing to increasing acute pancreatitis (AP) hospitalizations remain unknown. We sought to analyze etiological factors and outcomes of increasing AP hospitalizations.Utilizing the Nationwide Inpatient Sample, retrospective analyses of adult (≥18 years) inpatient admissions with a primary diagnosis of AP (N = 2,016,045) were performed. Patient hospitalizations from 2009 to 2012 were compared with those from 2002 to 2005.Compared with 2002-2005, there was a 13.2% (P0.001) increase in AP admissions in 2009-2012. Multivariate analysis adjusted for "period," patient and hospital demographics, AP etiologies, and disease associations demonstrated an increase in the odds of associated chronic pancreatitis (CP) [2002-2005: odds ratio, (OR), 32.04; 95% confidence interval (CI), 30.51-33.64; 2009-2012: OR, 35.02; 95% CI, 33.94-36.14], whereas associated odds of gallstones (2002-2005: OR, 36.37; 95% CI, 35.32-37.46; 2009-2012: OR, 29.85; 95% CI, 29.09-30.64) decreased. Compared with 2002-2005, the AP-related mortality decreased in 2009-2012 (1.62%-0.79%, P0.001) and was lower in AP with associated CP (0.65%-0.26%; P0.001) compared with AP without CP.In the preceding decade, AP hospitalizations increased, but associated mortality declined. Associated CP has emerged as a leading contributor for AP-related hospitalizations. Further research is needed to identify novel interventions to prevent disease progression of AP.

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. Electronic supplementary material The online version of this article (10.1186/s13063-019-3606-y) contains supplementary material, which is available to authorized users.

Background and Aims Previous studies have validated EUS-guided needle-based confocal laser endomicroscopy (nCLE) diagnosis of intraductal papillary mucinous neoplasms (IPMNs). We sought to derive EUS-guided nCLE criteria for differentiating IPMNs with high-grade dysplasia/adenocarcinoma (HGD-Ca) from those with low/intermediate-grade dysplasia (LGD). Methods We performed a post hoc analysis of consecutive IPMNs with a definitive diagnosis from a prospective study evaluating EUS-guided nCLE in the diagnosis of pancreatic cysts. Three internal endosonographers reviewed all nCLE videos for the patients and identified potential discriminatory EUS-guided nCLE variables to differentiate HGD-Ca from LGD IPMNs (phase 1). Next, an interobserver agreement (IOA) analysis of variables from phase 1 was performed among 6 blinded external nCLE experts (phase 2). Last, 7 blinded nCLE-naive observers underwent training and quantified variables with the highest IOA from phase 2 using dedicated software (phase 3). Results Among 26 IPMNs (HGD-Ca in 16), the reference standard was surgical histopathology in 24 and cytology confirmation of metastatic liver lesions in 2 patients. EUS-guided nCLE characteristics of increased papillary epithelial “width” and “darkness” were the most sensitive variables (90%; 95% confidence interval [CI], 84%-94% and 91%; 95% CI, 85%-95%, respectively) and accurate (85%; 95% CI, 78%-90% and 84%; 95% CI, 77%-89%, respectively) with substantial (κ = 0.61; 95% CI, 0.51-0.71) and moderate (κ = 0.55; 95% CI, 0.45-0.65) IOAs for detecting HGD-Ca, respectively (phase 2). Logistic regression models were fit for the outcome of HGD-Ca as predictor variables (phase 3). For papillary width (cut-off ≥50 μm), the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.95, respectively. For papillary darkness (cut-off ≤90 pixel intensity), the sensitivity, specificity, and AUC for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.90, respectively. Conclusions In this derivation study, quantification of papillary epithelial width and darkness identified HGD-Ca in IPMNs with high accuracy. These quantifiable variables can be used in multicenter studies for risk stratification of IPMNs. (Clinical trial registration number: NCT02516488.)