Exocrine Dysfunction Research Articles

Chronic pancreatitis: Risk Factors and Clinico-Radiological Profile

Chronic pancreatitis is a disease condition characterized by progressive inflammation and fibrosis of pancreas. It manifests with pain abdomen, endocrine and exocrine dysfunction. Diagnosis is often difficult and is relied mostly on radiological examination. The aim of this study was to identify associated risk factors and correlate the clinical presentation with various radiological changes of the pancreas.We conducted a prospective hospital based observational study in patients presenting with abdominal pain and evaluated the etiology, clinical presentation and radiological changes of pancreas among 68 chronic pancreatitis patients visiting Gastroenterology Unit, Department of Medicine, National Academy of Medical Sciences, Bir Hospital during 1 year period (November 2019 to October 2020 AD). The results showed mean age of 35.75 ± 11.43 years with predominant male patients (76.4%). Pain abdomen was present in all patients with mean duration of 16.5 months, followed by diabetes in 27.9%. Alcohol was the major risk (n=42, 61.8%) and no cause was identified in 22 (32.3%) patients. Pancreatic parenchymal calcification in 65 (95.6%), duct dilation in 61 (89.7%) and gland atrophy in 39 (57.3%) were major structural changes detected in computed tomography scan, more reliably than ultrasonography. One third of patients had diabetes mellitus, which was significantly higher in female (63.2%) and had major radiological changes of chronic pancreatitis at diagnosis. Alcohol was the common risk of chronic pancreatitis. Structural changes suggestive of disease was demonstrated better by computed tomography.

Immune-Intrinsic Myd88 Directs the Production of Antibodies With Specificity for Extracellular Matrix Components in Primary Sjögren's Syndrome.

Primary Sjögren’s syndrome is an autoimmune disease that is predominantly seen in women. The disease is characterized by exocrine gland dysfunction in combination with serious systemic manifestations. At present, the causes of pSS are poorly understood. Pulmonary and renal inflammation are observed in pSS mice, reminiscent of a subset of pSS patients. A growing body of evidence indicates that inflammation mediated by Damage-Associated Molecular Patterns (DAMPs) contributes to autoimmunity, although this is not well-studied in pSS. Degraded extracellular matrix (ECM) constituents can serve as DAMPs by binding pattern-recognition receptors and activating Myd88-dependent signaling cascades, thereby exacerbating and perpetuating inflammatory cascades. The ECM components biglycan (Bgn) and decorin (Dcn) mediate sterile inflammation and both are implicated in autoimmunity. The objective of this study was to determine whether these ECM components and anti-ECM antibodies are altered in a pSS mouse model, and whether this is dependent on Myd88 activation in immune cells. Circulating levels of Bgn and Dcn were similar among pSS mice and controls and tissue expression studies revealed pSS mice had robust expression of both Bgn and Dcn in the salivary tissue, saliva, lung and kidney. Sera from pSS mice displayed increased levels of autoantibodies directed against ECM components when compared to healthy controls. Further studies using sera derived from conditional knockout pSS mice demonstrated that generation of these autoantibodies relies, at least in part, on Myd88 expression in the hematopoietic compartment. Thus, this study demonstrates that ECM degradation may represent a novel source of chronic B cell activation in the context of pSS.

Pancreatic Fibrosis (Early Chronic Pancreatitis) as Emerging Diagnosis in Structural Causes of Dyspepsia: Evidence from Endoscopic Ultrasonography and Shear Wave Elastography.

A new concept for the diagnosis and management of non-functional dyspepsia in guidelines was lacking in the past decade. Medical advancement has proven pancreatic fibrosis (essential image evidence of early chronic pancreatitis) to be a cause of dyspepsia and related to pancreatic exocrine dysfunction. This study aimed to analyze the clinical picture, biomarker, and percentage of pancreatic fibrosis in the dyspeptic population. A total of 141 consecutive patients were retrospectively enrolled. They were diagnosed with peptic ulcer disease, 9.2% (n = 13); pancreatic fibrosis, 17% (n = 24); pure Helicobacter pylori infection, 19.9% (n = 28); functional dyspepsia, 53.2% (n = 75); and chronic pancreatitis, 0.7% (n = 1). Among those with pancreatic fibrosis, (n = 24), 11 were diagnosed on the basis of a pancreatic acoustic radiation force impulse exceeding 1.4 m/s, and the remaining 13 were diagnosed with early chronic pancreatitis with at least three of the Japanese endoscopic ultrasonography criteria. The anatomic distribution of parenchymal criteria of early chronic pancreatitis was head, 53%; body, 38%; and tail, 9%. There were 17 cases (71%, 17/24) without Helicobacter pylori and whose dyspepsia improved after pancreatic enzyme replacement with a ratio of 82.3% (14/17). Of the 141 cases, 19 received gastric emptying scintigraphy and Western blot analysis of chromogranin-A in duodenal mucosa. Delayed gastric emptying was more common in functional dyspepsia and chromogranin-A was expressed more in pancreatic fibrosis. In conclusion, pancreatic fibrosis (including early chronic pancreatitis) outnumbered peptic ulcer disease in the dyspeptic population and pancreatic enzyme therapy was effective for 82% of cases. In early chronic pancreatitis, pancreatic fibrosis is dominant in the head location, and duodenum mucosa chromogranin-A is a potential biomarker with increased expression in an age-matched manner.

Pancreatic fluid lipocalin-2 levels are altered in early chronic pancreatitis patients and are related to the exocrine pancreatic dysfunction degree and smoking

Pancreatic fluid lipocalin-2 levels are altered in early chronic pancreatitis patients and are related to the exocrine pancreatic dysfunction degree and smoking

Serum trypsin-like immunoreactivity in dogs with diabetes mellitus.

BackgroundConcurrent exocrine pancreatic dysfunction and decreased pancreatic organ size are common findings in various stages of human type 1 diabetes mellitus (DM). Exocrine pancreatic insufficiency (EPI) is incompletely described in diabetic dogs.ObjectiveTo compare canine trypsin‐like immunoreactivity (cTLI) of diabetic dogs with that of healthy controls. A secondary aim was to evaluate the correlation between duration of DM and cTLI.AnimalsThirty client‐owned diabetic dogs and thirty client‐owned control dogs.MethodsCross‐sectional study. Diabetic and healthy control dogs were included if they had no clinical evidence of pancreatitis and if serum samples obtained after food was withheld were available. Serum cTLI was measured at a reference laboratory and compared between groups. Canine pancreatic lipase immunoreactivity (cPLI) was analyzed concurrently as an indicator of pancreatitis.ResultsThe median cTLI concentration in all diabetic dogs (36.4 μg/L [range, 7.0‐288 μg/L]) did not differ from control dogs (28.7 μg/L [range, 12.8‐58.6 μg/L]) (P = .07; difference −7.8 μg/L [95% Confidence Interval (CI), −23.5 to 0.6 μg/L]). There was still no difference in cTLI between groups after exclusion of dogs with cPLI consistent with pancreatitis (n = 8 diabetic dogs). There was no correlation between cTLI and DM duration in all diabetic dogs (r = −0.07, [95% CI, −0.43 to 0.3], P = .7).Conclusions and Clinical ImportanceThere was no evidence of EPI as evaluated using cTLI in this cohort of diabetic dogs, but concurrent increases in cPLI suggest cTLI might not be the optimal indicator of exocrine pancreatic dysfunction in dogs with DM.

MDS and AML in Shwachman-Diamond Syndrome: Clinical Features and Outcomes

Genetic predisposition to MDS and AML is recognized in a growing subset of patients, but data to inform medical management and outcomes are sparse. Shwachman-Diamond syndrome (SDS) is an inherited marrow failure syndrome associated with increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML). The aim of this multi-institutional retrospective study was to investigate clinical features, treatment, and outcomes of 37 patients with SDS who developed MDS or AML. Diagnosis of SDS was established by SBDS genetic testing (n=30), exocrine pancreatic dysfunction (n=5), or data were unavailable (n=2). Nine individuals presented with AML (4 male, 5 female), 26 with MDS (13 male and 13 female), one male with refractory cytopenia (RC), and one male with isolated persistent somatic TP53 mutation. Eight of 26 MDS patients, had MDS-EB1 or EB2 at diagnosis, of whom two progressed to AML. Three patients initially presenting with early MDS progressed to MDS-EB1, MDS-EB2, or AML. Median age (years) at diagnosis of early MDS was 13.8 (range 0.5-28.8), for MDS-EB1/2 was 16 (range 9-30) and for AML was 33 (range 5.5-47). Nine patients with MDS and 1 patient with AML were receiving G-CSF chronically prior to diagnosis of MDS/AML.Complex cytogenetics, (>3 cytogenetic abnormalities per clone), were noted in 8/9 AML cases. One AML patient presented with normal cytogenetics. Complex clonal cytogenetic abnormalities were noted in 5 of 6 patients with MDS-EB1/EB2 for whom reports were available. Cytogenetic data were available for 16 MDS cases and clonal abnormalities were noted in 10. Aberrations involving chromosome 7 were most common. The patient with the somatic TP53 mutation had normal cytogenetics. Centralized bone marrow pathology review is currently ongoing.Follow up data were available for 8 patients with AML; 6 are deceased. Six received chemotherapy with intent to proceed to hematopoietic stem cell transplant (HSCT), of whom 5 failed to achieve remission and died with disease without proceeding to transplant. One AML patient proceeded to HSCT with progressive disease post-chemotherapy, but died with relapsed disease. One patient proceeded to HSCT without prior chemotherapy and was in remission at day 30 post-HSCT. The sole long-term surviving AML patient achieved remission with chemotherapy and underwent HSCTs with 3 separate stem cell infusions due to primary graft failure after the initial two infusions. He remains alive in remission more than 4 years after diagnosis. Notably this surviving AML patient was the only AML patient with normal cytogenetics at diagnosis.Follow up data are available for 6 of 8 patients presenting with MDS-EB1/EB2, 4 of whom are deceased. One patient who presented with MDS-EB1 is alive with relapsed disease after HSCT and one patient is in remission 100 days after HSCT.Follow up data are available for 17 of 18 early MDS patients, 7 of whom are deceased including three who had progressed to MDS-EB1, MDS-EB2, or AML. Four of the 7 deceased patients had received a HSCT. One individual with MDS died of hepatic failure unrelated to MDS. Seven MDS patients are alive in remission after HSCT without prior chemotherapy. Treatment was not reported for an additional 2 surviving patients. One patient receiving a hypomethylating agent is alive with stable disease 4.8 years from diagnosis. The patients with RC and with a TP53 clonal abnormality are alive at 6.5 years and 1.7 years from diagnosis respectively.In summary,prognosis is poor for patients with SDS who develop AML or MDS-EB1/2, with few long-term survivors due to resistant disease and treatment-related complications. Outcomes are better if transplanted for MDS prior to acquisition of increased blasts, with 10 of 17 (59%) subjects surviving (median follow up 6 years, range 1.5-11.2). AML often presents in adulthood highlighting the need for continued surveillance of SDS patients with bone marrow examinations including cytogenetics and FISH. These data demonstrate the importance of early detection of clonal evolution in this leukemia predisposition syndrome. Better markers for risk stratification are needed to identify patients who would benefit from early transplant prior to advanced clonal disease. Novel therapeutic strategies, such as targeted therapies, are urgently needed to improve outcomes of SDS patients with advanced MDS or AML. DisclosuresDiNardo:Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Norkin:Celgene: Honoraria, Research Funding. Shimamura:TransCellular Therapeutics: Other: Spouse is majority shareholder .

A Rare Case of Pearson's Syndrome with Predominant Hematological Manifestations and Novel Mitochondrial Deletion

Summary- Pearson's syndrome is a very rare cause of transfusion dependent anemia in infants with presence of pancreatic exocrine deficiency and other systemic abnormalities. We present a case of Pearson syndrome in an infant with primary hematological manifestations and a novel mitochondrial deletion.Introduction- Pearson syndrome is a very rare cause of refractory transfusion dependent childhood anemia caused by mitochondrial DNA defects resulting in refractory sideroblastic anaemia, vacuolization of bone marrow precursors, exocrine pancreatic dysfunction and other metabolic defectsMaterial and Methods- A 6 month old infant presented with complaints of progressive pallor since one month, failure to thrive and fast breathing for 2 days. On examination he had severe anaemia with signs of congestive cardiac failure and hepatomegaly.Results- Peripheral smear findings revealed macrocytic anaemia with mild thrombocytopenia. Bone marrow aspirate revealed a cellular marrow with mild erythroid hyperplasia and characteristic cytoplasmic vacuolations in myeloid and occasional erythroid precursors. There were about 30% ring sideroblasts observed on perl's stain. In view of suspicion of Pearson's syndrome, baby was further investigated which revealed high serum lactate levels (35mg/dl). However, fecal fat excretion was normal. Mitochondrial DNA analysis revealed a point mutation in NADH dehydrogenase 3 (ND3 region) of mt DNA as opposed to large mtDNA deletions observed in previously reported cases of Pearson's syndrome.Discussion- Sideroblastic anemia presenting in infancy is an uncommon cause of anemia often requiring multiple transfusions. Pearson's syndrome is a rare cause of sideroblastic anaemia, it presents in infancy, carrying a grave prognosis and requires high index of suspicion. Clinical picture is highly variable due to Mitochondrial DNA heteroplasmia. Mitochondrial DNA deletion/duplication studies carry a confirmative value. Pyridoxine was not very effective and child required repeated transfusions. This case is presented for its rarity, hematological features and associated novel mitochondrial mutation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Granny Smith Apple Extract Lowers Inflammation and Improves Antioxidant Status in L-arginine-induced Exocrine Pancreatic Dysfunction in Rats

Granny Smith is a cultivated hybrid variety of apple with a high antioxidant content relative to all other species of apple. Acute pancreatitis (AP) is an instantly emerging inflammatory condition with a high mortality rate. The preferred treatment is restricted to symptomatic relief and supportive care. The present study was undertaken to evaluate the favorable effects of Granny Smith apple extract (GSAE) as a prophylactic treatment for L-arginine-induced AP in rats. Male Sprague Dawley rats were divided in to five groups (n=6): Normal control (saline), disease control (a single dose of L-arginine 2.5 g/kg I.P.), positive control (pelatonin 10 mg/kg I.P.), and GSAE I and II (200 mg/kg and 400 mg/kg, orally, respectively). All groups were treated for 7 days. At the end of the study, blood samples were collected from the retro-orbital plexus, serum separated, and subjected to estimation of biomarker enzymes such as amylase, lipase, antioxidant enzymes, etc. The animals were then sacrificed, and the pancreas was isolated and subjected to estimation of tissue biomarkers, DNA fragmentation assay, and histopathological studies. Serum levels of amylase and lipase were significantly (p<0.001) reduced in L-arginine-treated rats. Similar results were also observed with tissue inflammatory markers such as malondialdehyde, nitrate, etc. There was a dramatic increase (p<0.001) in the overall antioxidant enzyme levels when compared with disease control rats. Histopathological examination of pancreatic tissue showed an intact structural feature of acinar cells in the extract-treated group of rats, which was further in pact with the intact DNA found in the DNA fragmentation assay. Thus, GSAE treatment was found to be beneficial in lowering the inflammatory conditions of AP by improving the overall antioxidant levels, and a further investigation into its exact molecular mechanism is needed.

Pancreatic volumes in immune checkpoint inhibitor-induced diabetes.

2644 Background: Immune checkpoint inhibitor-mediated insulin dependent diabetes (ICI-DM) is a rare and irreversible adverse event often presenting with life-threatening diabetic ketoacidosis (DKA). Pancreatic volume changes have been studied in classic Type 1 and Type 2 diabetes as a surrogate for functional β-cell mass. In this study, we investigate longitudinal changes in pancreatic volumes in patients who develop ICI-DM. Methods: Among patients with ICI-DM seen at our institution between 2014 and 2020, 20 patients who had serial CT scans of the abdomen and pelvis before and after ICI DM diagnosis were identified for inclusion in this study. Demographic data and clinical variables were obtained from the electronic medical record. Weight-adjusted pancreatic volumes were calculated from CT scans at three time points. The most recent CT scan prior to ICI initiation was used as baseline, the CT scan immediately prior to ICI DM diagnosis was used as a midpoint, and the most recent CT scan prior to the end of the study period was used as the final time point for comparison. Results: Median age was 63 years old (range 35 to 83). Renal cell carcinoma and melanoma were the most common cancer types. Male gender predominated (80%). 18/20 patients were on a PD-1 inhibitor with the remaining two on a PD-L1 inhibitor. After initiation of ICI therapy there was a variable response in pancreatic volumes prior to the diagnosis of ICI-DM with 20% patients experiencing a volume loss of &gt; 10% and 25% experiencing a volume gain of &gt; 10%. Volume loss nor volume gain prior to diabetes diagnosis was associated with presentation with DKA. 9/13 (69%) of patients who had pancreatic enzymes checked at diagnosis of ICI-DM had elevated levels. Pancreatic atrophy with a median volume loss of 41% was seen in all patients at a median of 14.9 months (range 3-77 months) after ICI-DM diagnosis. Most had more than 20% volume loss from baseline to most recent scan with no correlation in degree of volume loss with the time interval. There was no evidence of pancreatic ductal dilation, increased pancreatic fat nor any changes consistent with chronic pancreatitis. Conclusions: This study shows a variable response in pancreatic volumes after initiation of ICI in patients who progress to developing ICI-DM, though most had a significant decline in volume after the diagnosis of ICI-DM with long-term pancreatic atrophy. As β-cell mass is thought to comprise 1-2% of the pancreas, these findings may suggest both endocrine and exocrine compartment changes because of ICI-DM, though exocrine dysfunction has not been clinically described in this patient population. As these patients receive frequent imaging during treatment, fluctuations in pancreatic volumes with new or worsening hyperglycemia may portend the onset of ICI-DM and clinicians should have a low threshold to screen for this diagnosis as many will present with life-threatening DKA.

Surgical Management of Large Gastrinomas in a Young Patient With MEN1

Multiple Endocrine Neoplasia 1 (MEN1) is a well-described hereditary disorder that requires a multidisciplinary approach. Gastrinomas are the most common enteropancreatic tumors found in MEN1. They often appear as small (< 0.5 cm) multifocal lesions and are rarely found as large masses in the pancreas. The crossroads of deciding between medical versus surgical management when treating these tumors requires an evidenced-based- and patient-centered approach. We describe a rare case of a young patient with MEN1 and large pancreatic gastrinomas. A 23-year-old female patient with MEN1 (prolactinoma, primary hyperparathyroidism) was evaluated for the development of hypocalcemia after surgical excision of 3 parathyroid glands. A prior history of a perforated peptic ulcer prompted further evaluation that revealed gastrin levels of 481 pg/ml (13 - 115 pg/ml) off any acid suppression therapy, and an abdominopelvic MRI that revealed two T1 hypointense lesions measuring 2.4 cm and 1.4 cm at pancreatic head and tail, respectively. Both lesions resulted to be grade 2/3 neuroendocrine tumors consistent with gastrinoma. Abdominopelvic CT scan for staging showed 6 isodense lesions distributed within the pancreas measuring up to 3.2 cm without lymphadenopathy nor metastatic liver lesions. After extensive discussion regarding management, the patient opted for a surgical approach. A total pancreaticoduodenectomy was performed. The pathology revealed 7 grade 2 well-differentiated neuroendocrine tumors (6 in pancreas and 1 in duodenum) and 18 of 22 positive lymph nodes. Post-surgically she experienced multiple admissions due to surgical complications and the expected endocrine and exocrine dysfunction. Eight weeks after surgery gastrin remained elevated [652 pg/ml (13 - 115 pg/ml)]. The surgical management of gastrinomas in MEN1 remains without consensus. Due to the multifocality of gastrinomas associated with MEN1 and the high probability of persistent hypergastrinemia, surgery is not usually recommended. However, most guidelines are in favor of surgical excision for tumors > 2 cm to decrease their associated risk for liver metastasis and improve long-term survival. In this young patient with a 3.2 cm tumor, a surgical approach was favored to improve prognosis. Persistent hypersecretion may occur, as in our patient, due to residual hypertrophy of gastric parietal cells, although the possibility of remaining tumors still exists, especially in view of high lymph node positivity. The best available evidence-based treatment alternatives were offered to our patient; unfortunately, both the disease itself and surgical treatment options impose high morbidity and decreased quality of life. More studies reporting on the long-term outcomes after surgical resection of gastrinomas in MEN1 are needed to identify predictors to help recognize patients which benefit from a surgical approach.

Myd88 activation in immune cells governs distinct disease manifestations in primary Sjögren’s syndrome

Abstract Studies in mice and humans identify Myd88 activation as an important driver of autoimmune disease, although the role of this adapter molecule in primary Sjögren’s syndrome (pSS) is poorly understood. In pSS, patients exhibit exocrine gland dysfunction along with serious systemic disease manifestations. Although Myd88-dependent signaling networks are essential for pSS disease pathogenesis, these pathways remain incompletely understood in the context of pSS. The objective of this study was to establish the contribution of Myd88 activation in immune cells to local and systemic pSS manifestations. To this end, we generated a novel conditional knockout pSS mouse model lacking Myd88 in the hematopoietic compartment. We found that ablation of Myd88 in immune cells altered inflammatory mediators in salivary tissue, but did not affect the degree of lymphocytic infiltration in exocrine glands or salivary production. Nephritis was diminished and pulmonary inflammation was increased in mice lacking Myd88 in hematopoietic cells. Finally, we found total IgM titers and autoreactive IgM and IgG were attenuated in pSS mice lacking Myd88 in immune cells. Thus, we demonstrated that Myd88 activation in the hematopoietic compartment is essential for distinct aspects of disease. This study establishes a rationale for design of targeted therapeutics that modulate Myd88 activation in a tissue-specific manner to ameliorate salivary inflammation and systemic disease manifestations characteristic of pSS.

ДУОДЕНУМ-СОХРАНЯЮЩАЯ РЕЗЕКЦИЯ ГОЛОВКИ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ ПРИ ХРОНИЧЕСКОМ ПАНКРЕАТИТЕ, ДОБРОКАЧЕСТВЕННЫХ И ПРЕДРАКОВЫХ ОПУХОЛЯХ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ

Objective. To report the institutional experience of the evolution of duodenum-preserving pancreatic head resection (DPPHR) as a surgical treatment for chronic pancreatitis with an inflammatory tumor as well as cystic and benign, premalignant neoplasms and neuroendocrine tumors of the pancreatic head. Methods. DPPHR is associated with preservation of gastric antrum, common bile duct and duodenum/upper jejunal loop, contrary to Kausch-Whipple resection, which is a multivisceral procedure, including duodenectomy. Duodenum-preserving pancreatic head resection was first established in clinical setting in Berlin in 1969. Results. For chronic pancreatitis with an inflammatory infiltrat in the pancreatic head, duodenum-preserving pancreatic head resection has become a standard surgical treatment with worldwide acceptance. In a series of 603 patients with chronic pancreatitis following DPPHR, the frequency of pancreatic fistula was 3.3 %, intra-abdominal abscess 2.8 %, hemorrhage 2.8 %, frequency of reoperation 5.6%, in-hospital mortality 0.82 % and 90-day rehospitalisation 8 %. DPPHR for benign and premalignant cystic neoplasms of the pancreatic head is used predominantly for IPMN, MCN and SPN tumors. In a review of international publications comprising 503 patients, the general morbidity was 38.2 %, severe surgery-related complications 12.7% of them pancreatic fistula B+C 13.6 %, resurgery 2.7 % and 90-day mortality 0.4 %. When pancreatic neuroendocrine tumors of pancreatic head are treated with DPPHR, a local lymph node dissection is additionally recommended. The long-term morbidity following DPPHR revealed new onset of diabetes mellitus and exocrine dysfunctions in only 5-7 % of patients. Conclusion. Kausch-Whipple resection is associated with considerable high metabolic complications. Duodenum-sparing pancreatic head resection for inflammatory tumor, benign and premalignant neoplasms, and neuroendocrine tumors of the pancreatic head has the advantage of the duodenum preservation and maintenance of the pancreatic endocrine and exocrine functions.

Low-grade Appendiceal Mucinous Neoplasm (Appendiceal Villous Adenoma) with Cystic Fibrosis: A Case Report

Cystic fibrosis (CF) is an autosomal dominant disease characterized by the dysfunction of exocrine secretory glands resulting from a mutation in the transmembrane regulator protein (CFTR) gene. As life expectancy increases in patients with cystic fibrosis secondary to advances in treatment, advanced age malignancies secondary to cystic fibrosis emerge. Especially, the frequency of gastrointestinal system malignancies and colon cancers increases with aging. Appendiceal tumors are a rare entity and constitute less than 1% of gastrointestinal tumors. We presented a villous adenoma encountered in an 18-year-old male patient with CF accompanied by clinical and radiological findings. Our case is the first reported appendiceal tumor that emerged in patients with cystic fibrosis.

Parenchymal Sparing Resection: Options in Duodenal and Pancreatic Surgery.

Parenchymal sparing duodenal and pancreatic resection are safe procedures in selected patients with the aim to reduce endocrine and exocrine long-term dysfunction. When the tumor is benign or borderline malignant, this appears to be a good option for the surgeon, associated with low rates of severe surgery-related early postoperative complications and low in-hospital mortality. This mini review offers comments, tips and tricks, and a review of literature concerning those different options with specific illustrations in order to clarify their indication.

P0154 / #2091: EXOCRINE PANCREATIC FUNCTION IN CRITICALLY ILL PEDIATRIC PATIENTS

Aims & Objectives: To determine the exocrine pancreatic function of critically ill children. Methods: Prospective observational study conducted in the PICU of a tertiary hospital in Madrid, Spain. Children admitted to PICU whose expected PICU length of stay was more than one week were enrolled. Fecal elastase-1, amylase levels were analyzed on admission, day 7 and discharge. Stool samples were taken in the first week of hospitalization to analyze fecal elastase-1 by immunochromatographic tests. Elastase-1 concentration of 1-2 μg/g was considered normal, whereas levels <1 μg/g revealed exocrine pancreas dysfunction. Results: 15 critically ill children were enrolled in the study with a median age of 5 months (IQR 4-20 months). The median PRISM III was 9 (IQR 6-16) and the median length of PICU stay was 15 days (IQR 9-63). Two of them died and only one of them developed diarrhea during the study period. Fecal elastase-1 was collected in 10 children and was normal in all of them. Mean amylase levels on admission, on day 7 and at PICU discharge were 13 U/L (IQR 6.5-41.5), 16 U/L (IQR 4.8-61.5) and 15.5 U/L (IQR 7-44) respectively. Mean lipase levels on admission, on day 7 and at PICU discharge were 11 U/L (IQR 6.8-19.5) 14 U/L (IQR 11-28) and 16.5 U/L (IQR 12.3-36.8). Conclusions: Exocrine pancreatic function seems to be normal during the first week of critical illness in children. More studies including a higher number of patients and using more specific test are required to confirm these results.

Surgical management of chronic calcified pancreatitis

Abstract Background Chronic pancreatitis is a progressive inflammation of the pancreas associated to fibrosis, pancreatic atrophy, calcifications, and chronic pain. Intractable pain is the main indication for surgical treatment. Surgical procedures are based in ductal decompression, ductal drainage, and resection. Aim Analyze the surgical management of patients with symptomatic calcified chronic pancreatitis. Methods From March 2009 and September 2019, 12 patients underwent surgical treatment due to chronic calcified pancreatitis. There were eleven male (91.7%) and one female (8.3%) and the mean age was 58.2 years (range 48–70 years). Regular alcohol ingestion was observed in all patients (100%). The main indication for surgery was pain control in ten patients (83.3%). Results The procedures included Partington-Rochelle (6 patients, 50.0%), Frey procedure (3 patients, 25.0 %), pancreatoduodenectomy (2 patients, 16.6%) and total pancreatectomy (1 patient, 8.3%). Four patients (33.3%) had postoperative complications. No Clavien-Dindo ≥ 3b complications and no 90-days mortality were recorded in this series. Postoperative exocrine dysfunction was observed in 4 patients (33.3%), and all of them received pancreatic enzyme supplement. Conclusions Surgical treatment is a safe and feasible choice with acceptable morbidity and no mortality for symptomatic patients with calcified chronic pancreatitis.

Pancreatic Disorders in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) can involve multiple organ systems, and pancreatic manifestations of IBD are not uncommon. The incidence of several pancreatic diseases is more frequent in patients with Crohn's disease and ulcerative colitis than in the general population. Pancreatic manifestations in IBD include a heterogeneous group of disorders and abnormalities ranging from mild, self-limited disorders to severe diseases. Asymptomatic elevation of amylase and/or lipase is common. The risk of acute pancreatitis in patients with IBD is increased due to the higher incidence of cholelithiasis and drug-induced pancreatitis in this population. Patients with IBD commonly have altered pancreatic histology and chronic pancreatic exocrine dysfunction. Diagnosing acute pancreatitis in patients with IBD is challenging. In this review, we discuss the manifestations and possible causes of pancreatic abnormalities in patients with IBD.

Tissue-specific activation of Myd88-dependent pathways governs disease severity in primary Sjögren's syndrome.

Myd88 activation is an important driver of autoimmunity. Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by exocrine gland dysfunction in combination with serious systemic disease manifestations. Myd88-dependent signaling networks remain incompletely understood in the context of pSS. The objective of this study was to establish the contribution of tissue-specific Myd88 activation to local (exocrine) and systemic pSS manifestations. To this end, we generated two novel conditional knockout pSS mouse models; one lacking Myd88 in hematopoietic cells and a second strain in which Myd88 was deleted in the stromal compartment. Spontaneous production of inflammatory mediators was altered in salivary tissue, and nephritis was diminished in both conditional knockout strains. In contrast, pulmonary inflammation was increased in mice lacking Myd88 in hematopoietic cells and was reduced when Myd88 was ablated in stromal cells. Finally, anti-nuclear autoantibodies (ANAs) were attenuated in pSS mice lacking Myd88 in immune cells. Additionally, the ANA-specific B cell repertoire was skewed in the Myd88-deficient strains. Collectively, these data demonstrate that Myd88 activation in specific cell types is essential for distinct aspects of pSS pathology.

Acute recurrent and chronic pancreatitis in children.

Acute recurrent pancreatitis (ARP) is defined as two distinct episodes of acute pancreatitis (AP), whereas chronic pancreatitis (CP) is caused by persistent inflammation of the pancreas. In children they are caused by genetic mutations, autoimmune pancreatitis, congenital pancreatic abnormalities, and other conditions. Acute recurrent pancreatitis is frequently a precursor to CP, and both are thought to be on the same disease continuum. In particular, genetic factors are associated with early progression of ARP to CP. The diagnosis of CP, as in AP, is based on clinical findings, biochemical tests, and imaging studies. Findings of exocrine pancreatic dysfunction are also important in the diagnosis of CP. A step-up strategy has become increasingly standard for the treatment of patients with CP. This strategy starts with endoscopic treatment, such as pancreatic sphincterotomy and stenting, and progresses to surgery should endoscopic therapy fail or prove technically impossible. Non-opioid (e.g. ibuprofen / naproxen) and opioid (e.g. oxycodone) forms of analgesia are widely used in pediatric patients with AP or CP, whereas pancreatic enzyme replacement therapy may be beneficial for patients with abdominal pain, steatorrhea, and malnutrition. Despite the disparity in the age of onset, pediatric CP patients display some similarities to adults in terms of disease progress. To reduce the risk of developing pancreatic exocrine inefficiency, diabetes and pancreatic cancer in the future, clinicians need to be aware of the current diagnostic approach and treatment methods for ARP and CP and refer them to a pediatric gastroenterologist in a timely manner.

Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease.

Maturity-onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron-2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (<IVS2nt+1G>T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β-cell volume. These defects were associated with a 30% decrease in expression of the pro-endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.