Contrast-enhanced ultrasonography of the pancreas shows impaired perfusion in pancreas insufficient cystic fibrosis patients.

BACKGROUND: Perfusion assessment of the pancreas is challenging and poorly evaluated. Pancreatic affection is a prevalent feature of cystic fibrosis (CF). Little is known about pancreatic perfusion in CF. We aimed to assess pancreatic perfusion by contrast-enhanced ultrasound (CEUS) analysed in the bolus-and-burst model and software. METHODS: We performed contrast enhanced ultrasound of the pancreas in 25 CF patients and 20 healthy controls. Perfusion data was analysed using a dedicated perfusion model providing the mean capillary transit-time (MTT), blood flow (BF) and blood-volume (BV). CF patients were divided according to exocrine function. RESULTS: The pancreas insufficient CF patients had longer MTT (p ≤ 0.002), lower BF (p < 0.001) and lower BV (p < 0.05) compared to the healthy controls and sufficient CF patients. Interrater analysis showed substantial agreement for the analysis of mean transit time. CONCLUSION: The bolus-and-burst method used on pancreatic CEUS-examinations demonstrates reduced perfusion in CF patients with pancreas affection. The perfusion model and software requires further optimization and standardization to be clinical applicable for the assessment of pancreatic perfusion.

Fecal elastase-1 in healthy children up to 2 years of age: a cross-sectional study.

BACKGROUND: Fecal elastase-1 (E-1) levels in infants and young children may be expected to differ from those in adults and older children because of the immaturity of the gastrointestinal tract and the specificity of their diet. Despite the availability of data describing E-1 levels in the stools of preterm infants, older children, adults and subjects with malabsorption, there is still a lack of data regarding E-1 in healthy infants and toddlers. The aim of this cross-sectional study was to evaluate fecal E-1 concentrations in infants and children from 1 up to 24 months of age. MATERIAL AND METHODS: E-1 was measured in 160 healthy subjects aged 1-24 months (8 groups of 20: aged 1-3, 4-6 months, etc.) using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Fecal E-1 concentrations ranged from 200 to 1695 µg/g of feces. No child had a fecal E-1 level below 200 µg/g of feces. Fecal E-1 concentrations did not significantly differ between age groups. However, fecal E-1 levels in the first 3 months were lower than in the second year of life (1-3 months vs 13-24 months, p=0.0230). A statistically significant correlation between the E-1 concentration and age was found (p=0.0007, r=0.2639; however, it does not affect the cut-off level of the reference values). The trend was rather exponential. Fecal E-1 values reached a plateau around the age of 6-10 months. CONCLUSIONS: Our study has shown that the fecal E-1 test can be reliably applied in infants and toddlers to confirm normal exocrine pancreatic function. However, within the first months of life fecal E-1 concentrations may be lower than later in life.

Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis.

OBJECTIVE: The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. DESIGN: Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. RESULTS: A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, p<0.00001; I2=89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I2=86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. CONCLUSIONS: PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition.

The impact of pancreaticoduodenectomy on endocrine and exocrine pancreatic function: A prospective cohort study based on pre- and postoperative function tests.

BACKGROUND/OBJECTIVES: Studies reporting on function after pancreatic surgery are frequently based on diabetes history, fasting glycemia or random glycemia. The aim of this study was to investigate prospectively the evolution of pancreatic function in patients undergoing pancreaticoduodenectomy based on proper pre- and postoperative function tests. It was hypothesised that pancreatic function deteriorates after pancreaticoduodenectomy. METHODS: Between 2013 and 2016, 78 patients undergoing pancreaticoduodenectomy for oncologic indications had a prospective evaluation of their endocrine and exocrine pancreatic function. Endocrine function was evaluated with the 75 g oral glucose tolerance test (OGTT) and the 1 mg intravenous glucagon test. Exocrine function was evaluated with a 13C-labelled mixed-triglyceride breath test. Tests were performed pre- and postoperatively. RESULTS: In 90.5% (19/21) of patients with preoperatively known diabetes, no change in endocrine function was observed. In contrast, endocrine function improved in 68.1% (15/22) of patients with newly diagnosed diabetes. 40% (14/35) of patients with a preoperative normal OGTT or prediabetes experienced deterioration in function. In multivariate analysis, improvement of newly diagnosed diabetes was correlated with preoperative bilirubin levels (p = 0.045), while progression towards diabetes was correlated with preoperative C-peptidogenic index T30 (p = 0.037). A total of 20.5% (16/78) of patients had pancreatic exocrine insufficiency preoperatively. Another 51.3% (40/78) of patients deteriorated on exocrine level. In total, 64.1% (50/78) of patients required pancreatic enzyme-replacement therapy postoperatively. CONCLUSIONS: Although deterioration of endocrine function was expected after pancreatic resection, improvement is frequently observed in patients with newly diagnosed diabetes. Exocrine function deteriorates after pancreaticoduodenectomy.

Glucagon-like peptide-1 receptor agonist exenatide has no acute effect on MRI-measured exocrine pancreatic function in patients with type 2 diabetes: a randomized trial.

AIMS: To investigate the effect of infusion of the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide on exocrine pancreatic function. METHODS: This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct (PD) diameter were measured. RESULTS: Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean ± standard error of the mean 142.2 ± 15.6 ml vs 142.6 ± 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 ± 1.4 vs 36.9 ± 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups. CONCLUSIONS: Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion.

Diagnostic accuracy of secretin-stimulated ultrasonography of the pancreas assessing exocrine pancreatic failure in cystic fibrosis and chronic pancreatitis.

OBJECTIVE: Volume output failure is a feature of decreasing exocrine pancreatic function. This parameter is assessed by secretin-stimulated MRI in several studies. Our purpose was to evaluate ultrasonography of the fluid in the descending duodenum and Wirsung duct (WD) after secretin stimulation as a measure of pancreatic fluid flow in patients expected to have severe output failure. MATERIAL AND METHODS: We included subjects with chronic pancreatitis (CP), cystic fibrosis (CF) and a group of healthy controls in a prospective observation study. Transabdominal ultrasonography was performed before and during 15 min after secretin i.v. duodenal juice was collected by endoscopic short test (EST), and bicarbonate concentration measured. Patient groups were classified according to exocrine pancreatic function. RESULTS: Pancreatic insufficient CF (CFI) patients and CP insufficient (CPI) patients showed less duodenal fluid filling compared to other groups (p < 0.001). Measures of the WD diameter could only identify the most severe failure in the CFI group (p < 0.001). CONCLUSION: Secretin-stimulated ultrasonography can be used to assess pancreatic fluid flow and may be combined with EST in the evaluation of exocrine pancreatic function. Fluid filling in the descending part of duodenum was the most accurate predictor of pancreatic insufficiency in both patient groups. The test demonstrated better diagnostic accuracy diagnosing exocrine pancreatic failure in the CF patients than in CP patients.

Assessment of exocrine pancreatic function by secretin-stimulated magnetic resonance cholangiopancreaticography and diffusion-weighted imaging in healthy controls.

PURPOSE: To characterize and quantify exocrine pancreatic function by secretin-stimulated magnetic resonance cholangiopancreaticography (s-MRCP) and diffusion-weighted imaging (DWI) in healthy subjects and compare these findings to morphological features, ie, pancreatic volume and secretin-stimulated peak bicarbonate concentration measured in pancreatic juice. MATERIALS AND METHODS: Pancreatic magnetic resonance imaging (MRI) (1.5 T) was performed in 20 healthy volunteers among which 10 underwent gastroscopy with duodenal intubation. MRI included T2-weighted imaging and DWI acquired before and 1, 5, 9, and 13 minutes after secretin administration. Secreted pancreatic juice volumes were calculated based on the sequential T2-weighted images and pancreatic volumes and apparent diffusion coefficient (ADC) values were estimated. RESULTS: The mean pancreatic secretion rate declined from 9.5 mL/min at 1-5 minutes (postsecretin) to 2.9 mL/min at 9-13 minutes. Pancreatic head ADC values significantly increased from baseline (1.29 × 10(-3) mm(2) /s) to 1 minute postsecretin (1.48 × 10(-3) mm(2) /s) (P = 0.003). Secreted pancreatic juice volume at 1 minute after secretin correlated positively with peak bicarbonate concentration (n = 10, P = 0.05). CONCLUSION: Secretin-stimulated MRCP and DWI can characterize and quantify exocrine pancreatic function in healthy subjects. These imaging methods may prove relevant for patients with exocrine pancreatic dysfunction.

Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice.

OBJECTIVES: Previous studies have suggested an important role of the transcription factor Gata6 in endocrine pancreas, while GATA6 haploinsufficient inactivating mutations cause pancreatic agenesis in humans. We aimed to analyse the effects of Gata6 inactivation on pancreas development and function. DESIGN: We deleted Gata6 in all epithelial cells in the murine pancreas at the onset of its development. Acinar proliferation, apoptosis, differentiation and exocrine functions were assessed using reverse transcriptase quantitative PCR (RT-qPCR), chromatin immunoprecipitation, immunohistochemistry and enzyme assays. Adipocyte transdifferentiation was assessed using electron microscopy and genetic lineage tracing. RESULTS: Gata6 is expressed in all epithelial cells in the adult mouse pancreas but it is only essential for exocrine pancreas homeostasis: while dispensable for pancreatic development after e10.5, it is required for complete acinar differentiation, for establishment of polarity and for the maintenance of acinar cells in the adult. Gata6 regulates directly the promoter of genes coding for digestive enzymes and the transcription factors Rbpjl and Mist1. Upon pancreas-selective Gata6 inactivation, massive loss of acinar cells and fat replacement take place. This is accompanied by increased acinar apoptosis and proliferation, acinar-to-ductal metaplasia and adipocyte transdifferentiation. By contrast, the endocrine pancreas is spared. CONCLUSIONS: Our data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms. In addition, it is required for the maintenance of the adult acinar cell compartment. Our studies suggest that GATA6 alterations may contribute to diseases of the human adult exocrine pancreas.

What is the clinical significance of low serum amylase? Systematic review of the conditions associated with low serum amylase.

Objective: Most studies have assessed the impact of elevated serum amylase levels in clinical practice, but only a few have investigated the significance of low serum amylase. We therefore, aimed to review the literature to understand the conditions associated with low serum amylase and its clinical relevance. Method: This systematic review was performed in accordance with the criteria established in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search was conducted on Medline and Embase databases until November 2022. After identifying relevant titles, abstracts were read and data of eligible articles retrieved. The conditions associated with low serum amylase were evaluated. The quality of the studies was assessed using the Newcastle-Ottawa Score. Results: Our search strategy identified 19 studies including a total of 15 097 patients for systematic review. All the studies were observational including two studies which used secretin-induced test. The main conditions associated with low serum amylase were diabetes mellitus (n=9), metabolic syndrome (n=3), chronic pancreatitis (CP) (n=3), non-alcoholic fatty liver disease (n=2) and obesity (n=1). Low serum amylase showed a high specificity (94%) with low sensitivity (38.7%-59%) in diagnosing chronic pancreatitis. Conclusion: This systematic review revealed a unique insight into the relevance of low serum amylase in clinical practice. Low serum amylase can be a useful adjunct test in the assessment of patients with CP, pancreatic exocrine insufficiency, diabetes mellitus and metabolic syndrome.

The influence of exocrine pancreatic function on the exposure and pharmacokinetics of ivacaftor in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and show robust treatment effects at group level. The individual effect however, is variable which might be (partially) related to differences in drug exposure. The profound influence of fat containing food compared to fasting on drug exposure gives need to investigate if the exocrine pancreatic function changes the degree and rate of absorption of ivacaftor and thereby may contribute to differences in drug exposure. METHODS: Pharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient (PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic parameters were investigated with and without the use pancreatic enzymes and compared in each individual. RESULTS: We demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor. CONCLUSION: The exocrine pancreatic function of pwCF does not significantly influence the absorption and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function.

Changes in fecal elastase-1 following initiation of CFTR modulator therapy in pediatric patients with cystic fibrosis.

BACKGROUND: Improvement in exocrine pancreatic function in persons with CF (pwCF) on cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been documented in clinical trials using fecal pancreatic elastase-1 (FE-1). Our group endeavored to evaluate real-world data on FE-1 in children on CFTR modulator therapy at three pediatric cystic fibrosis (CF) centers. METHODS: Pediatric pwCF were offered FE-1 testing if they were on pancreatic enzyme replacement therapy (PERT) and on CFTR modulator therapy according to their center's guideline. FE-1 data were collected retrospectively. The primary outcome was absolute change in FE-1. RESULTS: 70 pwCF were included for analysis. 53 had baseline and post-modulator FE-1 values. There was a significant increase in FE-1 from median 25 mcg/g (IQR 25-60) at baseline to 57 mcg/g (IQR 20-228) post-modulator (p<0.001 by Wilcoxon matched pairs), with an absolute change in FE-1 of median 28 mcg/g (IQR -5-161) and mean 93.5 ± 146.8 mcg/g. Age was negatively correlated with change in FE-1 (Spearman r=-0.48, p<0.001). 15 pwCF (21%) had post-modulator FE-1 values ≥200 mcg/g, consistent with pancreatic sufficiency (PS). The PS group was significant for younger age at initiation of first CFTR modulator and a higher baseline FE-1. CONCLUSIONS: Most pwCF experienced an increase in FE-1 while receiving CFTR modulator treatment and a small percentage demonstrated values reflective of PS. These data suggest that PS may be attained in those that initiated modulator therapy at a younger age or had a higher baseline FE-1. FE-1 testing is suggested for children on any CFTR modulator therapy.

Managing inoperable pancreatic cancer: the role of the pancreaticobiliary physician.

Despite our understanding of pancreatic cancer (PC), the majority of patients with this disease are incurable. Both the incidence and mortality rates for PC have increased over the last decade. At diagnosis, the majority of patients have locally advanced PC, less than 20% of patients are eligible for potentially curative resection and approximately one-third have metastatic disease. The combination of frequent advanced presentation, low resection rates and poor responses to chemotherapy make PC one of the most lethal tumours. The treatment goals are to maintain local control, manage tumour-related morbidities and improve quality of life. Patients with inoperable PC are likely to experience significant symptoms associated with their tumour, including pancreatic insufficiency, nutritional deficiencies, pain, biliary obstruction, gastric outlet obstruction and diabetes. As a result, guidance on the management of patients with inoperable PC is critical. PC is commonly referred centrally to specialist centres particularly for surgery; however, the majority do not undergo surgical intervention and thus the importance of pancreaticobiliary physicians and endoscopists. This review will focus on the non-operative management of patients with unresectable pancreatic adenocarcinoma and review some of the issues that centralisation has contributed to.

Consensus for the management of pancreatic exocrine insufficiency: UK practical guidelines.

INTRODUCTION: Pancreatic exocrine insufficiency is a finding in many conditions, predominantly affecting those with chronic pancreatitis, pancreatic cancer and acute necrotising pancreatitis. Patients with pancreatic exocrine insufficiency can experience gastrointestinal symptoms, maldigestion, malnutrition and adverse effects on quality of life and even survival.There is a need for readily accessible, pragmatic advice for healthcare professionals on the management of pancreatic exocrine insufficiency. METHODS AND ANALYSIS: A review of the literature was conducted by a multidisciplinary panel of experts in pancreatology, and recommendations for clinical practice were produced and the strength of the evidence graded. Consensus voting by 48 pancreatic specialists from across the UK took place at the 2019 Annual Meeting of the Pancreatic Society of Great Britain and Ireland annual scientific meeting. RESULTS: Recommendations for clinical practice in the diagnosis, initial management, patient education and long term follow up were developed. All recommendations achieved over 85% consensus and are included within these comprehensive guidelines.

Exocrine Pancreatic Function in Girls with Anorexia Nervosa.

OBJECTIVES: To assess pancreatic exocrine function in patients with anorexia nervosa using a breath test with 13C-labeled mixed triglycerides (MTG-BT) and to determine the relationship between the test results and selected biochemical and hormonal parameters. MATERIAL AND METHODS: Anthropometric measurements, biochemical and hormonal parameters (serum leptin, soluble leptin receptor (sLR), acylated and desacylated ghrelin, free leptin index (FLI)), and MTG-BT were performed in a group of 31 girls with the restrictive type of AN, as well as 38 healthy girls (C). RESULTS: The average cumulative dose of 13C-triglycerides recovered with exhaled air (%CD) was similar in both study groups, while the average time from 13C-triglycerides administration to peak 13CO2 excretion in expired air (time to peak (TTP)) was significantly longer in patients with AN compared to C. In both groups, %CD correlated negatively with FLI. TTP correlated negatively with sLR and FLI in the AN and with serum insulin and HOMA-IR values in the C. CONCLUSIONS: In girls with AN, the pancreatic efficiency of lipase secretion was found to be normal, while the kinetics of this enzyme secretion were disturbed. These changes may result from disorders in the functioning of the adipose-insular and islet-acinar axes.

The Effect of Bariatric Surgery on Exocrine Pancreatic Function.

INTRODUCTION: After bariatric surgery (BS), patients might suffer from nutrient maldigestion, malabsorption, and vitamin deficiencies. In this study, our aim was to assess pancreatic functions after BS using fecal elastase-1 assay (FE-1). MATERIAL AND METHODS: Sixty patients (21M) undergoing BS and 20 (6M) healthy controls were included into the study. Stool samples were collected 1 year after surgery. Ten patients from one anastomosis gastric bypass (OAGB) and single anastomosis duodenal switch (SADS) groups with the lowest value of FE-1 and GIQLI scores were given pancreatic enzyme replacement therapy (PERT). After PERT, FE-1, excess weight loss (EWL), BMI, GIQLI scores, and vitamin D levels were measured. RESULTS: Vitamin D levels were detected as 19.04 (9-46.5) pg/ml, 15.1 (8.4-23.6) pg/ml, 17.8 (5-30) pg/ml, and 21.79 (11-40.3) pg/ml after sleeve gastrectomy (SG), OAGB, SADS, and control groups, respectively (p = 0.04). GIQLI scores in the first year were found to have increased in all patients (p = 0.02). FE-1 levels were found as 642.35 (566.3-711.4) µg/g, 378.52 (183.5-561.1) µg/g, 458.88 (252.5-593, 5) µg/g, and 518.2 (351.6-691) µg/g for the SG, OAGB, SADS, and control groups, respectively. There was a strong inverse correlation between EWL and FE-1 levels at the end of the first year (Spearman's rho = - 0.688, p = 0.003). After having performed PERT for patients with the lowest FE-1 levels, the levels increased to 683.39 (615.5-720) µg/g in the OAGB and 691.5 (643.1-720) µg/g in the SADS groups (p = 0.011). CONCLUSION: FE-1 measurements demonstrated that many patients suffer from malabsorption after OAGB or SADS, whereas functions remain normal after SG. PERT corrects pancreatic functions without affecting weight loss and also contributes to the normal serum level of vitamin D.

Practical guide to the management of chronic pancreatitis.

Chronic pancreatitis (CP) is an irreversible fibroinflammatory disorder of the pancreas. It presents with relapsing, remitting upper abdominal pain accompanied by features of malabsorption due to pancreatic exocrine insufficiency and endocrine deficiency with the development of diabetes mellitus. The associated increased hospitalisation and high economic burden are related to CP often presenting at advanced stage with irreversible consequences. Diagnosing CP at an early stage is still challenging and therefore CP is believed to be under-reported. Our understanding of this disease has evolved over the last few years with attempts to redesign the definition of CP. Better recognition of the risk factors and conditions associated with CP can lead to an earlier diagnosis and coupled with a multidisciplinary approach to treatment, ultimately reduce complications. This article reviews the epidemiology, risk factors, diagnosis and management of CP.

The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype.

AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up. CONCLUSIONS: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Risk factors of exocrine and endocrine pancreatic insufficiency after pancreatic resection: A multi-center prospective study.

Management of functional consequences after pancreatic resection has become a new therapeutic challenge. The goal of our study is to evaluate the risk factors for exocrine (ExoPI) and endocrine (EndoPI) pancreatic insufficiency after pancreatic surgery and to establish a predictive model for their onset. PATIENTS AND METHODS: Between January 1, 2014 and June 19, 2015, 91 consecutive patients undergoing pancreatoduodenectomy (PD) or left pancreatectomy (LP) (72% and 28%, respectively) were followed prospectively. ExoPI was defined as fecal elastase content<200µg per gram of feces while EndoPI was defined as fasting glucose>126mg/dL or aggravation of preexisting diabetes. The volume of residual pancreas was measured according to the same principles as liver volumetry. RESULTS: The ExoPI and EndoPI rates at 6 months were 75.9% and 30.8%, respectively. The rate of ExoPI after PD was statistically significantly higher than after LP (98% vs. 21%; P<0.001), while the rate of EndoPI was lower after PD vs. LP, but this difference did not reach statistical significance (28% vs. 38.5%; P=0.412). There was no statistically significant difference in ExoPI found between pancreatico-gastrostomy (PG) and pancreatico-jejunostomy (PJ) (100% vs. 98%; P=1.000). Remnant pancreatic volume less than 39.5% was predictive of ExoPI. CONCLUSION: ExoPI occurs quasi-systematically after PD irrespective of the reconstruction scheme. The rate of EndoPI did not differ between PD and LP.