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BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

The article analysed the data about the role of adipocytokines in pancreatic remodeling in chronic pancreatitis. Data, obtained by generalizing the current literature, enable to identify the role of some adipocytokines (apelin, tumor necrosis factor α) in the development and progression of the pathophysiological processes in the pancreas, especially in regard to the mechanism of chronic pancreatitis. Adipocytokines being studied play a role in carbohydrate and lipid metabolism disorders, promote the induction of inflammation, tissue maladaptive hypertrophy, the onset of steatosis, fibrosis of the pancreas and have an impact on the various stages of the pathogenesis of chronic pancreatitis. We should pay close attention to the diagnostic role of cytokines that can help to develop new algorithms for non-invasive diagnosis of chronic pancreatitis.

У 49 хворих, у 20 з яких діагностовано поєднане ураження підшлункової залози (хронічний панкреатит у стадії загострення) та печінки (цироз печінки класу А, В за Чайльд — П’ю) алкогольної етіології, у 12 — хронічний панкреатит у стадії загострення без супутньої патології та в 17 — алкогольний цироз печінки аналогічної стадії без втягнення в процес підшлункової залози, проведено визначення концентрації фосфоліпази А2 типу ІІА та рівня колагену ІV у сироватці крові. Найбільш високу концентрацію фосфоліпази А2 типу ІІА виявлено у хворих із поєднаним алкогольним ураженням підшлункової залози та печінки (568,57 ± 30,34 пг/мл), що в 1,58 раза перевищувала її рівень в обстежених з ізольованим алкогольним ураженням підшлункової залози (Р < 0,05). У хворих на алкогольний цироз печінки класу А, В за Чайльд — П’ю концентрація фосфоліпази А2 типу ІІА становила (171,35 ± 22,46) пг/мл (у здорових — (123,00 ± 10,12) пг/мл). Відповідно до давності поєднаного ураження підшлункової залози та печінки (понад 5 років) рівень фосфоліпази А2 типу ІІА знижувався, тоді як концентрація колагену ІV зросла у 2,5 раза порівняно з таким показником у хворих при давності захворювання до одного року, а між ними був встановлений обернений кореляційний зв’язок середньої сили.

The article presents an analysis of the literature data on the connection of chronic pancreatitis of biliary genesis and obesity. The obesity is associated with hormonal disorders with excessive production of hormones with anti-inflammatory action, and reduction of pro-inflammatory hormones. It is accompanied by maintenance and enhancement of the chronic inflammatory process in pancreas as well as increases the risk of further complications. Obesity reduces the pancreatic exocrine function due to fatty degeneration of the acinar cells; it also leads to atherosclerosis of vessels with further deterioration of pantreatic trophism. The obesity is associated with enhanced synthesis and excretion of cholesterol with bile following concurrent increase of its lithogenicity as well as appearance of biliary sludge and concretion.

Background. Chronic pancreatitis (CP) is characterized by a number of specific changes in the structure and function of the pancreas, including atrophy of functional tissue, fibrosis and ductal degeneration, a decrease in the number of islets. Despite a large number of possible etiological factors, the main pathophysiological mechanisms of CP development have much in common. Thus, with the preservation of secretory activity under obstruction of the ducts and their compensatory expansion, pancreatic secret infiltrates the surrounding tissue with the formation of edema, followed by intrapancreatic activation of digestive enzymes, in particular trypsinogen, which initiates proteolytic necrobiosis of the pancreocytes. The duct cells make up to 30 % of the human pancreas, compared to 1–2 % of endocrine cells. One of the first signs of CP is the abnormal increase in the number of ductal branches. It has also been shown that in the ducts of CP patients, the number of cells containing insulin increases, as well as cells that contain other endocrine and exocrine markers. Modeling chronic, acute and complicated pancreatitis in rats also confirmed that epithelial cells are involved in the regulation of extracellular matrix of the pancreas. Materials and methods. Comprehensive histopathological and immunohistochemical (IHC) study was performed in the laboratory of histological and immunohistochemical diagnosis of the university hospital of Zaporizhia State Medical University on postoperative material of 40 patients with CP aged 28 to 74 years, who were opera­ted at the clinic of surgery and minimally invasive technologies of Zaporizhia State Medical University. Immunohistochemical exa­mination was carried out according to standard procedures using a mouse monoclonal antibody Alpha Smooth Muscle Actin (Clone 1A4) against the a-isoform of smooth muscle actin (a-SMA) and Desmin (Clone D33) against desmin (DAKO, USA), monoclonal rabbit antibody against collagen I (Clone RAH C11) anti-collagen type 1 (Imtek, RF) and rabbit polyclonal antibodies against fibronectin (DAKO, USA). Quantitative determination of the intensity and the relative area of the markers’ stromal expression was reproduced using the program for medical digital image processing ImageJ v.1.48, embedded plugin Colour Deconvolution analysis circuit and coloring H DAB (hematoxylin + DAB) for determi­ning the area occupied by immunopositive structure in immunohistochemical preparations and optical (densitometric) intensity of immunostaining by patented procedure. Results. Pathohistological study of biopsies with a specific staining of collagen (by Van Gieson and Masson’s trichrome) showed that fibrotic changes in all the patients with CP were characterized by a combination of pronounced perilobular fibrosis, which covered all lobules, widespread intralobular fibrosis, and significant periductal fibrosis near large, sharply defined narrowed and cystically dilated ducts. There was also a pronounced expansion of interlobular fibrosis, a noticeable thickening of intralobular connective tissue strands directed deep into the lobules and connective tissue strands that surrounded some acini, as well as a significant tortuosity and widening of the ducts with retention cysts. In most cases, the deformation of the ductal system was one of the most significant structural changes. Thus, 87.5 % of cases were characterized by the unevenly narrowed and cystic-altered interlobular ducts, pronounced concentric fibrosis, protein plugs and concrements observed in the ducts. In 7.5 % of the cases, in the main pancreatic duct, foci of the epithelium atrophy were present, which alternated with foci of papillary intraepithelial hyperplasia, identified as pancreatic intraepithelial neoplasia. The parenchyma of the pancreas was thus constituted small, atrophic acini, surrounded by dense fibrous strands, with an increased number of gaping ducts of different diameters. Also, in 17.5 % of cases, phenomena of acinar-ductal metaplasia were observed. In the centers of the acinar-ductal metaplasia zones, the transformation of some acinar cells into ductal cells was determined with the formation of small duct-like structures, the so-called tubular complexes, which, according to the literature, are the primary focus of acinar tissue regeneration. In particular, a large number of activated a-SMA + pancreatic stellate cells (PSC) is detected in the zones of fibrosis. The pattern of expression of this marker is characterized by pronounced a-SMA-immunopositive staining of both PSC and their processes, and, in part, of the fibrillar component. Primary statistical processing of morphometry data revealed a direct relationship between the expression of a-SMA and the area of collagen I type, but this relationship was not significant (r = +0.321, p > 0.05). In order to further objectify the statistical studies, we isolated a group of cases characterized by low a-SMA expression (n = 9). A further study using medical statistics methods showed that the average area of type I collagen and the intensity of its expression in this group was significantly lower than in the other biopsy specimens (p < 0.05). In contrast, desmin expression was identified both in connective tissue, which was characterized by a lower intensity of immunostaining, in acinar tissue and in the epithelium of the pancreatic ducts. The pattern of its expression in fibrosis zones in CP was similar to that of a-SMA, but in 27.5 % of cases, the intensity of staining was below the threshold for determination by morphometric methods. We isolated a group of cases characterized by high expression of fibronectin (n = 9). A further study using medical statistics showed that the average area of type I collagen and the intensity of its expression in this group was significantly higher than in the other biopsy specimens (p < 0.05). Thus, IHC study of the material obtained from patients with CP showed that a large number of activated PSC expressing a-SMA and desmin are concentrated in the pancreatic ductal zones. Also, in these zones, a significant accumulation of fibronectin was found, which is synthesized in excess by activated PSC. The pattern of IHC staining of type I collagen in the zones of severe pancreatic fibrosis is characterized by a weak and moderate intensity with a average level of its expression. Conclusions. A characteristic morphological picture of the CP development is a combination of fibrosis with deformation of the ductal system due to periductal fibrosis with the expansion of interlobular fibrosis, thickening of intralobular connective tissue strands, as well as considerable tortuosity and widening of the ducts with retention cysts. Significant structural reorganization of the pancreatic duct system in patients with CP was observed in 87.5 % of cases, in 17.5 % of cases, the picture was supplemented by phenomena of acinar-ductal metaplasia with the transformation of acinar cells into ductal cells and the formation of small duct-like structures, the so-called tubular complexes. In 7.5 % of cases, in the main pancreatic duct, foci of atrophy of the epithelium were identified, which alternated with foci of papillary intraepithelial epithelial hyperplasia (PanIN). The development of pancreatic fibrosis in CP is facilitated by the accumulation of a-SMA+ activated pancreatic stellate cells synthesizing an excess of components of the extra-cellular matrix, in particular type I collagen. The mean area of type I collagen and the intensity of its expression were significantly lower with reduced a-SMA expression (p < 0.05), and significantly higher in cases of pronounced fibronectin expression (p < 0.05).

Background. Early diagnosis of pancreatic steatosis is essential for the early metabolic risk detection and chronic gastroenterological morbidity reduction. The purpose was to examine the clinical and sonographic features of pancreatic steatosis in children with overweight and obesity. Materials and methods. The presence of pancreatic steatosis was determined by ultrasonography in 53 children with functional disorders of the gastrointestinal tract. Division in groups was performed on the basis of pancreatic steatosis and obesity/overweight presence: group 1 consisted of 24 patients with pancreatic steatosis and obesity/overweight, group 2 included 18 children with obesity/overweight with no signs of pancreatic steatosis, the control group consisted of 11 patients without pancreatic steatosis and with normal weight. Results. The clinical picture in children with pancreatic steatosis may be explained by concomitant gastroenterological diseases, but 29.1 % of group 1 patients complained of pain in the left upper quadrant. Patients with steatosis often complained of nausea (58.3 %), flatulence (45.8 %) in comparison to patients who had normal weight, but the significance of the differences was not sufficient. Group 1 patients often reported pain on palpation of the intestine compared with other 2 groups. Pain on palpation in pancreatic points was significantly higher in group 1 patients (54.1 %) compared to group 3. Increased liver echogenicity was found 2.4 times more often in group 1 patients compared with group 2. In particular, changes in liver grains were three times more common in patients with steatosis (p < 0.05), as compared to the obese patients without steatosis and to the children with normal weight. Pancreatic changes in steatosis manifested not only by the changes in echogenicity, but also by fuzzy contours of the pancreas, increased grain (65.5 %) in almost half of patients (45.8 %). Gallbladder volume and wall thickness were significantly higher in the group of children with steatosis compared to the control group. Symptoms of biliary sludge were twice more common in children with steatosis compared to children without steatosis and 4 times more likely than in children with normal weight (43.87 % in group 1; 21 % in group 2, and 9 % in group 3). Conclusions. Thus, clinical and sonographic features in patients with steatosis indicate the possibility of inflammatory changes in the parenchyma associated with systemic inflammation due to steatosis and concomitant diseases of the gastrointestinal tract.

Background. The prevalence of pancreatitis in children with digestive disorders is 5–25 %. Aim of research: to determine the prevalence of pancreatic pathology in children. Material and methods. The research was conducted on the basis of department of gastroenterology of Chernivtsi Regional Clinical Children’s Hospital during 2013–2015. Results. The overall prevalence of chronic pancreatitis in children of Chernivtsi region is 1.8 %. It should also be noted that 66 % of children with chronic gastroduodenitis and 100 % of children with duodenal bulb ulcer had ultrasound changes of pancreas. Signs of chronic pancreatitis were detected in 1 child with celiac disease and 4 children with lactose intolerance; 17 children had identified ultrasound signs of pancreatic fibrosis, and reduced elastase‑1 in stool, which can be considered as signs of chronic pancreatitis; 9 children had identified ultrasound signs of structural changes of pancreas, but the level of elastase‑1 was normal (patients with recurrent pancreatitis); 18 children had no ultrasound changes of pancreas and no deviation in the structure and the level of elastase‑1. Conclusion. The chronic pancreatitis in children is often associated with pain (epigastric paroxysmal pain with frequent changes of pain location), dyspeptic (often manifested by nausea and vo­miting) and astheno-vegetative syndromes which are associated with disharmonious physical development. All patients with chronic pancreatitis were revealed to have focal or linear fibrotic changes in the parenchyma of the pancreas, nonspecific changes in coprogram and a significant reduction of elastase‑1 level in blood.

В огляді літератури обговорюються питання лікування абдомінального больового синдрому, синдрому зовнішньосекреторної недостатності підшлункової залози, супутніх хронічному панкреатиту дисфункції сфінктера Одді, жовчного міхура, жовчовивідних шляхів, дисбіозу, дискінезії кишечника згідно з положеннями останніх європейських рекомендацій та міжнародних консенсусів.

Aim of study: to identify functional status of pancreas in patients with chronic pancreatitis depending on the stage of fibrotic transformation and activity of parenchymal inflammation. Materials and methods. The preoperative laboratory results and the data of morphological study performed on biopsies obtained during surgery in 88 patients with complications of chronic pancreatitis (CP) were compared. According to morphological study of pancreatic biopsies, the early pancreatic parenchymal fibrosis (I–II degree) has been diagnosed in 31 cases (35.2 %), late fibrosis (III–IV degree) — in 57 (64.8 %) cases. Results. Active parenchymal inflammation at early and late stages of pancreatic fibrosis are associated with changes in pancreatic secretion and intracellular activation of pancreatic enzymes, leading to autodigestion and release of these enzymes from acinar cells into the blood, which has been confirmed by an increase of trypsin and amylase activity in blood compared with inactive inflammation. At late stages of fibrosis reduction of fecal elastase‑1 (161.7 ± 4.8) mg/g was observed in 73.9 % of patients. Reverse correlation has been found between fibrotic transformation of pancreatic parenchyma and the level of fecal elastase‑1 (r = –0.46; p = 0.05), i.e. progressing fibrotic transformation of pancreas leads to reduced exocrine function. Correlation analysis showed that the progression of fibrotic transformation violates carbohydrate metabolism — a direct correlation with glycosylated hemoglobin (r = 0.496; p = 0.05), namely, the endocrine secretion deficiency. Novelty in science. The pancreas functioning was studied depending on the inflammation activity and stage of fibrosis transformation of its parenchyma at chronic pancreatitis. The active inflammation of the pancreas was found to be accompanied by significant activation of pancreatic enzymes (significant increase in blood amylase and trypsin activity), which causes the progression of fibrotic transformation of pancreas in CP. Conclusions. Progression of fibrotic transformation of the pancreatic parenchyma in CP leads to deterioration of the exocrine pancreatic function, as defined by a decrease in the level of fecal elastase‑1 in case of late fibrosis of the pancreas and to the deterioration of endocrine pancreatic function, as manifested by impaired fasting glucose metabolism both at early and late stages of fibrosis, the development of pancreatogenic type II diabetes at the early stages of pancreatic fibrotic transformation, insulin resistance and type I diabetes at later stages of pancreatic fibrotic transformation.

Актуальність. Неалкогольна жирова хвороба підшлункової залози — патологічний стан, тісно асоційований з ожирінням та іншими компонентами метаболічного синдрому. Клінічні прояви обумовлюються порушенням екзокринної функції залози, що супроводжується розвитком дисбіотичних змін та інтестинальних розладів. Мета. Вивчити клініко-лабораторні особливості стеатозу підшлункової залози у дітей з надлишковою вагою та ожирінням. Матеріали та методи. У 24 дітей з функціональними розладами шлунково-кишкового тракту визначали наявність стеатозу підшлункової залози за допомогою ультра­звукового дослідження. Для характеристики стану тонкокишкової мікробіоти проводили водневий дихальний тест з навантаженням глюкозою або лактозою. Виявлення стеатозу печінки проводили за допомогою транзієнтної еластрографії печінки з визначенням контрольованого параметра ультразвукового затухання. Розподіл за групами відбувся на підставі наявності стеатозу підшлункової залози: контрольну групу (S0) становили 12 пацієнтів без стеатозу підшлункової залози, основну групу (S+) — 12 пацієнтів зі стеатозом підшлункової залози. Результати. Стеатоз підшлункової залози у дітей з надлишковою вагою та ожирінням характеризувався неспецифічною клінічною картиною з переважанням диспептичних явищ. Встановлено, що у дітей основної групи спостерігалось зниження рівня амілази сироватки крові порівняно з конт­рольною групою (середнє значення (30,40 ± 12,45) ммоль/л в основній групі та (51,88 ± 19,81) ммоль/л у контрольній, p < 0,05). Було виявлено, що у пацієнтів основної групи вірогідно частіше зустрічалась стеаторея (75 % хворих основної групи проти 33,3 % дітей контрольної групи, p < 0,05). Стеатоз підшлункової залози у дітей був асоційований з розвитком синдрому надмірного бактеріального росту (50 % хворих основної групи проти 8,3 % дітей контрольної групи, р < 0,05). Серед пацієнтів зі стеатозом підшлункової залози 41,6 % мали ознаки стеатозу печінки, в той час як панкреатичний стеатоз зустрічався у 62,5 % пацієнтів із неалкогольною жировою хворобою печінки. Діти зі стеатозом підшлункової залози мали помірне прискорення швидкості осідання еритроцитів (середній показник становив (16,6 ± 6,76) мм/год у пацієнтів основної групи проти (7,17 ± 3,18) мм/год у пацієнтів контрольної групи). Висновки. Панкреатичний стеатоз може виступати більш раннім маркером ектопічного накопичення жиру порівняно зі стеатозом печінки. Стеатоз підшлункової залози у дітей з надлишковою вагою та ожирінням характеризується наявністю низькорівневого системного запалення, диспептичних явищ, непрямих ознак зовнішньосекреторної недостатності залози та синдромом надмірного бактеріального росту.

Стаття присвячена стеатозу підшлункової залози (ПЗ) у дітей — патологічному стану, що характеризується акумуляцією жиру в ПЗ. В огляді проаналізовані дані, що стосуються факторів ризику, можливостей діагностики і терапії стеатозу ПЗ. Продемонстровано, що провідними чинниками, асоційованими з розвитком стеатозу ПЗ, вважаються ожиріння і метаболічний синдром. Охарактеризовані переваги неінвазивних візуалізаційних методів, таких як трансабдомінальне ультразвукове дослідження, комп’ютерна томографія, магнітно-резонансна томографія та ендоскопічне ультразвукове дослідження в діагностиці стеатозу ПЗ у дітей. Представлені й обґрунтовані основні напрямки терапії стеатозу ПЗ: модифікація способу життя, корекція дисліпідемії та порушень вуглеводного обміну, екзокринної недостатності. Для написання огляду здійснювався пошук інформації з використанням баз даних Scopus, Web of Science, MedLine, PubMed, Google Scholar, CyberLeninka, РІНЦ за ключовими словами: «стеатоз підшлункової залози», «неалкогольна жирова хвороба підшлункової залози», «діти».

For 2011–2015 at the department of the surgery of the digestive system of the State Institution «Institute of Gastroenterology of National Academy of Medical Sciences of Ukraine», there were observed 472 patients with pathological changes in the pancreas. Surgical treatment was conducted in 87 patients with pancreatic cysts. Depending on the origin and maturity of cysts, state of the ductal system and activity of inflammation in the pancreatic parenchyma, surgeries were divided into four types: I — draining (performed in 52 (59.8 %) patients); II — cystectomy (4; 4.6 %); III — resection-draining (11; 12.6 %) and IV — resection (14; 16.1 %) operations. Indirect types of surgeries were performed in 6 (6.9 %) patients. Postoperative complications were detected in 16 (18.3 %) cases. Mortality was diagnosed in one case (1.2 %).

Актуальність. Ожиріння асоційовано з ектопічним накопиченням жиру з відкладенням жиру у паренхіматозних органах, у тому числі у підшлунковій залозі (ПЗ) з формуванням її стеатозу. Тривалий перебіг стеатозу підшлункової залози здатний призводити до хронічного запалення та фіброзу органу. Обмеженість проведення інвазивних досліджень у дітей обумовлює потребу у розробці та впровадженні в практику охорони здоров’я новітніх неінвазивних методів обстеження підшлункової залози. Мета: вивчити можливість ультразвукової діагностики стеатозу та фіброзу підшлункової залози у дітей з використанням методу стеатометрії (оцінка швидкості згасання ультразвуку) та еластометрії. Матеріали та методи. Було обстежено 60 дітей, які знаходились на стаціонарному лікуванні у відділенні дитячої гастроентерології ДУ «Інститут гастроентерології НАМН України». Розподіл за групами відбувся на основі наявності ожиріння й надмірної маси тіла: 1-шу групу становили 44 пацієнти з ожирінням і надмірною масою тіла, 2-гу групу — 16 дітей з нормальною масою тіла. Сонологічне дослідження, еластометрія та стеатометрія проводились на апараті Ultima PA Expert («Радмір», Україна). Наявність та ступінь стеатозу підшлункової залози визначались при попарному порівнянні ехогенності ПЗ з ехогенністю нирок та заочеревинного жиру. Результати. Було виявлено, що серед пацієнтів 1-ї групи 25 дітей (56,8 %) мали сонологічні ознаки стеатозу підшлункової залози, третина хворих мала ехографічні ознаки неспецифічних запальних зміни паренхіми залози. Аналіз даних стеатометрії ПЗ виявив, що середня величина коефіцієнту затухання ультразвуку у представників 1-ї групи була вірогідно вище за відповідний показник 2-ї групи (р < 0,05) і становила (2,45 ± 0,39) дБ/см у представників 1-ї групи та (1,80 ± 0,23) дБ/см у представників 2-ї групи. Середній показник жорсткості паренхіми ПЗ у дітей із нормальною масою тіла був вище за аналогічний показник пацієнтів з ожирінням і надмірною масою тіла, але вірогідність відмінностей не була достатньою. У представників 1-ї групи середнє значення жорсткості паренхіми ПЗ становило (3,69 ± 0,78) кПа та (3,78 ± 0,27) кПа — у 2-й групі. Висновки. Встановлено, що середній показник коефіцієнту затухання ультразвуку під час сонографії підшлункової залози у дітей з ожирінням і надмірною масою тіла є вірогідно вищим порівняно з пацієнтами, які мають нормальну масу тіла, що свідчить на користь наявності стеатозу підшлункової залози у дітей з ожирінням/надмірною масою тіла. Проведене дослідження свідчить про можливість використання стеатометрії та еластометрії як методів діагностики стеатозу й фіброзу підшлункової залози у дітей.

Description The purpose of this American Gastroenterological Association Institute Clinical Practice Update is to describe the indications for screening for pancreas cancer in high-risk individuals. Methods The evidence reviewed in this work is based on reports of pancreas cancer screening studies in high-risk individuals and expert opinion. Best Practice Advice 1 Pancreas cancer screening should be considered in patients determined to be at high risk, including first-degree relatives of patients with pancreas cancer with at least 2 affected genetically related relatives. Best Practice Advice 2 Pancreas cancer screening should be considered in patients with genetic syndromes associated with an increased risk of pancreas cancer, including all patients with Peutz–Jeghers syndrome, hereditary pancreatitis, patients with CDKN2A gene mutation, and patients with 1 or more first-degree relatives with pancreas cancer with Lynch syndrome, and mutations in BRCA1, BRCA2, PALB2, and ATM genes. Best Practice Advice 3 Genetic testing and counseling should be considered for familial pancreas cancer relatives who are eligible for surveillance. A positive germline mutation is associated with an increased risk of neoplastic progression and may also lead to screening for other relevant associated cancers. Best Practice Advice 4 Participation in a registry or referral to a pancreas Center of Excellence should be pursued when possible for high-risk patients undergoing pancreas cancer screening. Best Practice Advice 5 Clinicians should not screen average-risk individuals for pancreas cancer. Best Practice Advice 6 Pancreas cancer screening in high-risk individuals should begin at age 50 years, or 10 years younger than the initial age of familial onset. Screening should be initiated at age 40 years in CKDN2A and PRSS1 mutation carriers with hereditary pancreatitis and at age 35 years in the setting of Peutz–Jeghers syndrome. Best Practice Advice 7 Magnetic resonance imaging and endoscopic ultrasonography (EUS) should be used in combination as the preferred screening modalities in individuals undergoing pancreas cancer screening. Best Practice Advice 8 The target detectable pancreatic neoplasms are resectable stage I pancreatic ductal adenocarcinoma and high-risk precursor neoplasms, such as intraductal papillary mucinous neoplasms with high-grade dysplasia and some enlarged pancreatic intraepithelial neoplasias. Best Practice Advice 9 Screening intervals of 12 months should be considered when there are no concerning pancreas lesions, with shortened intervals and/or the performance of EUS in 6–12 months directed towards lesions determined to be low risk (by a multidisciplinary team). EUS evaluation should be performed within 3–6 months for indeterminate lesions and within 3 months for high-risk lesions, if surgical resection is not planned. New-onset diabetes in a high-risk individual should lead to additional diagnostic studies or change in surveillance interval. Best Practice Advice 10 Decisions regarding therapy directed towards abnormal findings detected during screening should be made by a dedicated multidisciplinary team together with the high-risk individual and their family. Best Practice Advice 11 Surgical resection should be performed at high-volume centers. Best Practice Advice 12 Clinicians should consider discontinuing pancreas cancer screening in high-risk individuals when they are more likely to die of non-pancreas cancer–related causes due to comorbidity and/or are not candidates for pancreas resection. Best Practice Advice 13 The limitations and potential risks of pancreas cancer screening should be discussed with patients before initiating a screening program.

[Background & Aims] The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial. [Methods] We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions. [Results] The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition. [Conclusions] Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.

BACKGROUND & AIMS: Acute pancreatitis is a major adverse event of endoscopic retrograde cholangiopancreatography (ERCP). Rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of post-ERCP pancreatitis (PEP). Little is known about the combined effects of sublingual nitrate and NSAIDs. We performed a randomized trial to assess whether the combination of NSAIDs and sublingual nitrate is more effective than NSAIDs alone in preventing PEP. METHODS: In a prospective superiority trial, eligible patients underwent ERCP at 12 endoscopic units in Japan, from March 2015 through May 2018. Patients were randomly assigned to groups given diclofenac suppositories (50 mg) within 15 minutes after the endoscopic procedure alone (diclofenac-alone group, n = 442) or in combination with sublingual isosorbide dinitrate (5 mg) 5 minutes before the endoscopic procedure (combination group, n = 444). The primary endpoint was the occurrence of PEP. RESULTS: PEP developed in 25 patients in the combination group (5.6%), and in 42 patients in the diclofenac-alone group (9.5%) (relative risk 0.59; 95% confidence interval 0.37-0.95; P = .03). Moderate to severe pancreatitis developed in 4 patients (0.9%) in the combination group, and 10 patients (2.3%) in the diclofenac-alone group (relative risk 0.12; 95% confidence interval 0.13-1.26; P = .12). There was no serious adverse event related to the additional administration of sublingual nitrate. CONCLUSIONS: In a randomized controlled trial, we found that prophylaxis with rectal diclofenac and sublingual nitrate significantly reduces the overall incidence of PEP compared with diclofenac suppository alone. ClinicalTrials.gov, no: UMIN 000016274.

Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas, and resolve spontaneously within days or severe, with systemic inflammatory response syndrome- associated extrapancreatic organ failure and even death. Importantly, there are no therapeutic agents currently in use that can alter the course of the disease. This article emphasizes emerging findings that stressors (environmental and genetic) that cause acute pancreatitis initially cause injury to organelles of the acinar cell (endoplasmic reticulum, mitochondria, and endolysosomal–autophagy system), and that disorders in the functions of the organelles lead to inappropriate intracellular activation of trypsinogen and inflammatory pathways. We also review emerging work on the role of damage-associated molecular patterns in mediating the local and systemic inflammatory response in addition to known cytokines and chemokine pathways. In the review, we provide considerations for correction of organelle functions in acute pancreatitis to create a discussion for clinical trial treatment and design options.

Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-to-ductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood. Methods The Ptf1aCre/+ LSL-KrasG12D/+ and Ptf1aCre/+ LSL-KrasG12D/+ LSL-p53R172H/+ and cerulein-induced acute pancreatitis mice models were used. mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM. Results We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic KrasG12D-induced transformation. Genetic ablation of mir-802 cooperates with KrasG12D by promoting ADM formation. miR-802 deficiency results in de-repression of the miR-802 targets Arhgef12, RhoA, and Sdc4, activation of RhoA, and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1, and EZRIN, thereby increasing F-actin rearrangement. mir-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistently with these findings, we show that this miR-802–RhoA–F-actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival. Conclusions We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming, and PDAC initiation. Modulation of the miR-802–RhoA–F-actin network may be a new strategy to interfere with pancreatic carcinogenesis.

Background And Aims Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. Methods We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. Results Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor–β, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. Conclusions We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

Alteration of the gut microbiota is implicated in the development of autoimmune type 1 diabetes (T1D), as shown in humans and the nonobese diabetic (NOD) mouse model. However, how gut dysbiosis arises and promotes the autoimmune response remains an open question. We investigated whether early events affecting the intestinal homeostasis in newborn NOD mice may explain the development of the autoimmune response in the adult pancreas.We profiled the transcriptome and the microbiota in the colon between newborn NOD mice and nonautoimmune strains. We identified a seminal defect in the intestinal homeostasis of newborn NOD mice and deciphered the mechanism linking this defect to the diabetogenic response in the adult.We determined that the cathelicidin-related antimicrobial peptide (CRAMP) expression was defective in the colon of newborn NOD mice, allowing inducing dysbiosis. Dysbiosis stimulated the colonic epithelial cells to produce type I interferons that pathologically imprinted the local neonatal immune system. This pathological immune imprinting later promoted the pancreatic autoimmune response in the adult and the development of diabetes. Increasing colonic CRAMP expression in newborn NOD mice by means of local CRAMP treatment or CRAMP-expressing probiotic restored colonic homeostasis and halted the diabetogenic response, preventing autoimmune diabetes.We identified whether a defective colonic expression in the CRAMP antimicrobial peptide induces dysbiosis, contributing to autoimmunity in the pancreas. Hence, the manipulation of intestinal antimicrobial peptides may be considered a relevant therapeutic approach to prevent autoimmune diabetes in at-risk children.

BACKGROUND & AIMS: Advances in cross-sectional imaging have resulted in increased detection of intraductal papillary mucinous neoplasms (IPMNs) and their management remains controversial. At present, there is no reliable non-invasive method to distinguish between indolent and high risk IPMNs. We performed extracellular vesicle (EV) analysis to identify markers of malignancy in an attempt to better stratify these lesions. METHODS: Using a novel ultrasensitive digital extracellular vesicle screening technique (DEST) we measured putative biomarkers of malignancy (MUC1, MUC2, MUC4, MUC5AC, MUC6, Das-1, STMN1, TSP1, TSP2, EGFR, EpCAM, GPC1, WNT-2, EphA2, S100A4, PSCA, MUC13, ZEB1, PLEC1, HOOK1, PTPN6, and FBN1) in EV from patient-derived cell lines and then on circulating EV obtained from peripheral blood drawn from patients with IPMNs. We enrolled a total of 133 patients in two separate cohorts: a clinical discovery cohort (n=86) and a validation cohort (n=47). RESULTS: From 16 validated EV proteins in plasma samples collected from the discovery cohort, only MUC5AC showed significantly higher levels in high grade lesions. Of the 11 patients with invasive IPMN (inv/HG), 9 had high MUC5AC expression in plasma EV and of the 11 patients with high grade dysplasia alone, only 1 had high MUC5AC expression (specificity of 82%, sensitivity of 100%). These findings were corroborated in a separate validation cohort. The addition of MUC5AC as a biomarker to imaging and high risk stigmata allowed detection of all cases requiring surgery, whereas imaging and high risk stigmata alone would have missed 5/14 cases (36%). CONCLUSIONS: MUC5AC in circulating EV can predict the presence of invasive carcinoma within IPMN. This approach has the potential to improve the management and follow-up of patients with IPMN including avoiding unnecessary surgery.