Stellate cells are in utero markers of pancreatic disease in cystic fibrosis.

BACKGROUND: Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. METHODS: Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. RESULTS: Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR-/- pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR-/- animals at 80- and 120-days gestation, as are stellate cells at term. CONCLUSION: The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

Pancreatic Crosstalk in the Disease Setting: Understanding the Impact of Exocrine Disease on Endocrine Function.

The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.

Pancreas Fine Needle Aspiration: Current and Future Impact on Patient Care.

Pancreatic lesions can be solid or cystic and comprise a wide range of benign, premalignant, and malignant entities. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the current primary sampling method for the preoperative diagnosis of pancreatic lesions. Optimal handling of cytology/small tissue specimens is critical to ensure that the often-scant diagnostic material is appropriately utilized for ancillary and/or molecular studies when appropriate. Ultimately, evaluation of EUS-FNA cytology and small biopsy material can provide accurate and timely diagnoses to guide patient management and triage them to surveillance or surgical intervention.

EUS-FNA diagnosis of pancreatic tophaceous gout: Two rare cases.

We report two patients with pancreatic tophaceous gout diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of presumed cystic mass lesions. The first case involved a patient who had a recent episode of acute pancreatitis 6 months prior, with subsequent imaging concerning for a pseudocyst or mass lesion. The second case involved a patient with epigastric pain associated with a pancreatic head cystic mass and an erroneous original diagnosis of a mucinous pancreatic neoplasm on EUS-FNA. Diff-Quik stained direct smears on fresh material obtained from EUS-FNA of the lesions showed chalky debris with needle shaped negatively birefringent crystals consistent with gout. For the first case, the chalky material was not present on the H&E stained paraffin embedded formalin fixed cellblock slides. The importance of inclusion of cytologic specimen preparations to examine monosodium urate crystals is emphasized.

The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases.

The pancreas is an organ with both exocrine and endocrine functions, comprising a highly organized and complex tissue microenvironment composed of diverse cellular and non-cellular components. The impairment of microenvironmental homeostasis, mediated by the dysregulation of cell-to-cell crosstalk, can lead to pancreatic diseases such as pancreatitis, diabetes, and pancreatic cancer. Macrophages, key immune effector cells, can dynamically modulate their polarization status between pro-inflammatory (M1) and anti-inflammatory (M2) modes, critically influencing the homeostasis of the pancreatic microenvironment and thus playing a pivotal role in the pathogenesis of the pancreatic disease. This review aims to summarize current findings and provide detailed mechanistic insights into how alterations mediated by macrophage polarization contribute to the pathogenesis of pancreatic disorders. By analyzing current research comprehensively, this article endeavors to deepen our mechanistic understanding of regulatory molecules that affect macrophage polarity and the intricate crosstalk that regulates pancreatic function within the microenvironment, thereby facilitating the development of innovative therapeutic strategies that target perturbations in the pancreatic microenvironment.

Pancreatic stellate cells: Key players in pancreatic health and diseases (Review).

As a pluripotent cell, activated pancreatic stellate cells (PSCs) can differentiate into various pancreatic parenchymal cells and participate in the secretion of extracellular matrix and the repair of pancreatic damage. Additionally, PSCs characteristics allow them to contribute to pancreatic inflammation and carcinogenesis. Moreover, a detailed study of the pathogenesis of activated PSCs in pancreatic disease can offer promise for the development of innovative therapeutic strategies and improved patient prognoses. Therefore, the present study review aimed to examine the involvement of activated PSCs in pancreatic diseases and elucidate the underlying mechanisms to provide a viable therapeutic strategy for the management of pancreas­related diseases.

Contrast-enhanced guided endoscopic ultrasound procedures.

Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside inhomogeneous tumours and improving the characterization of these tumours. Despite the initial enthusiasm that oriented needle sampling under CH-EUS guidance could provide better diagnostic yield in pancreatic solid lesions, further studies did not confirm the supplementary values in cases of tissue acquisition guided by CH-EUS. This review details the knowledge based on the available data on contrast-guided procedures. The indications for CH-EUS tissue acquisition include isoechoic EUS lesions with poor visible delineation where CH-EUS can differentiate the lesion vascularisation from the surrounding parenchyma and also the mural nodules within biliopancreatic cystic lesions, which occur in select cases. Additionally, the roles of CH-EUS-guided therapy in patients whose pancreatic fluid collections or bile ducts that have an echogenic content have indications for drainage, and patients who have nonvisualized vessels that need to be highlighted via Doppler EUS are presented. Another indication is represented if there is a need for an immediate assessment of the post-radiofrequency ablation of pancreatic neuroendocrine tumours, in which case CH-EUS can be used to reveal the incomplete tumour destruction.

Mechanisms of spinophilin-dependent pancreas dysregulation in obesity.

Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino-/-) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. Although spinophilin is enriched in neurons, its roles in nonneuronal tissues, such as ß cells of the pancreatic islets, are unclear. We have corroborated and expanded upon previous studies to determine that Spino-/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. We have identified multiple putative spinophilin-interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that normally act to mediate peptide hormone production, processing, and/or release in Leprdb/db and/or high-fat diet-fed (HFF) models of obesity. In addition, we have found that spinophilin interacts with proteins from similar classes in isolated islets, suggesting a role for spinophilin in the pancreatic islet. Consistent with a pancreatic ß cell type-specific role for spinophilin, using our recently described conditional spinophilin knockout mice, we found that loss of spinophilin specifically in pancreatic ß cells improved glucose tolerance without impacting body weight in chow-fed mice. Our data further support the role of spinophilin in mediating pathophysiological changes in body weight and whole body metabolism associated with obesity. Our data provide the first evidence that pancreatic spinophilin protein interactions are modulated by obesity and that loss of spinophilin specifically in pancreatic ß cells impacts whole body glucose tolerance.NEW & NOTEWORTHY To our knowledge, these data are the first to demonstrate that obesity impacts spinophilin protein interactions in the pancreas and identify spinophilin specifically in pancreatic ß cells as a modulator of whole body glucose tolerance.

Effect of pancreas disease vaccines on infection levels and virus transmission in Atlantic salmon (Salmo salar) challenged with salmonid alphavirus, genotype 2.

Salmonid alphavirus (SAV) causes pancreas disease (PD), which negatively impacts farmed Atlantic salmon. In this study, fish were vaccinated with a DNA-PD vaccine (DNA-PD) and an oil-adjuvanted, inactivated whole virus PD vaccine (Oil-PD). Controls were two non-PD vaccinated groups. Fish were kept in one tank and challenged by cohabitation with SAV genotype 2 in seawater. Protection against infection and mortality was assessed for 84 days (Efficacy study). Nineteen days post challenge (dpc), subgroups of fish from all treatment groups were transferred to separate tanks and cohabited with naïve fish (Transmission study 1) or fish vaccinated with a homologous vaccine (Transmission study 2), to evaluate virus transmission for 26 days (47 dpc). Viremia, heart RT-qPCR and histopathological scoring of key organs affected by PD were used to measure infection levels. RT-droplet digital PCR quantified shedding of SAV into water for transmission studies. The Efficacy study showed that PD associated growth-loss was significantly lower and clearance of SAV2 RNA significantly higher in the PD-DNA group compared to the other groups. The PD-DNA group had milder lesions in the heart and muscle. Cumulative mortality post challenge was low and not different between groups, but the DNA-PD group had delayed time-to-death. In Transmission study 1, the lowest water levels of SAV RNA were measured in the tanks containing the DNA-PD group at 21 and 34 dpc. Despite this, and irrespective of the treatment group, SAV2 was effectively transmitted to the naïve fish during 26-day cohabitation. At 47 dpc, the SAV RNA concentrations in the water were lower in all tanks compared to 34 dpc. In Transmission study 2, none of the DNA-PD immunized cohabitants residing with DNA-PD-vaccinated, pre-challenged fish got infected. In contrast, Oil-PD immunized cohabitants residing with Oil-PD-vaccinated, pre-challenged fish, showed infection levels similar to the naïve cohabitants in Transmission study 1. The results demonstrate that the DNA-PD vaccine may curb the spread of SAV infection as the DNA-PD vaccinated, SAV2 exposed fish, did not spread the infection to cohabiting DNA-PD vaccinated fish. This signifies that herd immunity may be achieved by the DNA-PD vaccine, a valuable tool to control the PD epizootic in farmed Atlantic salmon.

Difficulty in the diagnosis of pancreatic cancer based on the initial CT report: A retrospective study.

The role of computed tomography (CT) in the initial diagnosis of pancreatic cancer (PC) is well-known. CT reports made by radiologists are important as not all patients with PC are examined by specialists; however, some cases are not identified based on CT reports. Diagnosis via imaging of PC is sometimes difficult, and the diagnostic rate of PC and other pancreatic diseases can vary across radiologists. This study aimed to examine the diagnostic rate of PC in initial CT reports and the details of cases with diagnostic difficulties. This single-centered, retrospective study collected clinical data of 198 patients with histologically diagnosed PC between January 2018 and April 2022. Out of these contrast-enhanced CT was performed in 192 cases. PC was not reported as the main diagnosis in 18 patients (9.4%; 11 men and 7 women). Among these 18 cases, intrapancreatic mass lesions were detected in 3 (1.6%), indirect findings such as bile/pancreatic duct stenosis or dilation were detected in 5 (2.6%), and no PC-related findings were found in 10 (5.2%). The specialists suspected PC in 15 of these 18 cases based on initial CT reports. 17 cases were confirmed by endoscopic ultrasound-fine needle aspiration and one by biopsy after upper gastrointestinal endoscopy. To improve accuracy of its diagnosis, it is important that specialists provide feedback to diagnostic radiologists regarding the findings they did not report. Endoscopic ultrasound-fine needle aspiration should be performed by specialists when there is clinical information which indicates pancreatic disease of any kind.

Mast Cell Concentrations in Pancreatic Disease Processes.

Mast cells enumeration has been performed using various histologic staining techniques with the goal of elucidating the influence mast cells exert on pathologic processes. In this study, 77 human pancreatic tissues evidencing morphologically normal pancreas, benign fibrotic changes, endocrine tumors, and adenocarcinoma were evaluated using Wright stain and immunohistochemistry markers for tryptase and CD117. Mast cell counts were similar with tryptase and CD117 but were both significantly higher than counts obtained with the Wright stain. Furthermore, all analyses demonstrated that endocrine tumors and morphologically normal pancreatic tissues had significantly lower mast cell counts as compared with benign fibrosis and adenocarcinoma suggesting that the highly fibrotic nature of both pancreatitis and adenocarcinoma are related to increased mast cell concentrations.

Prediction of pancreatic fibrosis by dual-energy CT-derived extracellular volume fraction: Comparison with MRI.

OBJECTIVES: To investigate the correlation between dual-energy CT (DECT) and MRI measurements of the extracellular volume fraction (ECV) and to assess the accuracy of both methods in predicting pancreatic fibrosis (PF). METHODS: We retrospectively analyzed 43 patients who underwent pancreatectomy and preoperative pancreatic DECT and MRI between November 2018 and May 2022. The ECV was calculated using the T1 relaxation time (for MR-ECV) or absolute enhancement (for DECT-ECV) at equilibrium phase (180 s after contrast injection in our study). Pearson coefficient and Bland-Altman analysis were used to compare the correlation between the two ECVs, Spearman correlations were used to investigate the association between imaging parameters and PF, Receiver operating characteristic (ROC) curves were used to assess the diagnostic performance of the ECVs for advanced fibrosis (F2-F3), and multivariate logistic regression analysis was used to examine the relationship between PF and imaging parameters. RESULTS: There was a strong correlation between DECT- and MR-derived ECVs (r = 0.948; p < 0.001). The two ECVs were positively correlated with PF (DECT: r = 0.647, p < 0.001; MR: r = 0.614, p < 0.001), and the mean values were 0.34 ± 0.08 (range: 0.22-0.62) and 0.35 ± 0.09 (range: 0.24-0.66), respectively. The area under the operating characteristic curve (AUC) for subjects with advanced fibrosis diagnosed by ECV was 0.86 for DECT-ECV and 0.87 for MR-ECV. Multivariate logistic regression analysis showed that the DECT-ECV was an independent predictor of PF. CONCLUSIONS: The ECV could be an effective predictor of histological fibrosis, and DECT is equivalent to MRI for characterizing pancreatic ECV changes.

Quantitative Magnetic Resonance Imaging for the Pancreas: Current Status.

ABSTRACT: Magnetic resonance imaging (MRI) is important for evaluating pancreatic disorders, and anatomical landmarks play a major role in the interpretation of results. Quantitative MRI is an effective diagnostic modality for various pathologic conditions, as it allows the investigation of various physical parameters. Recent advancements in quantitative MRI techniques have significantly improved the accuracy of pancreatic MRI. Consequently, this method has become an essential tool for the diagnosis, treatment, and monitoring of pancreatic diseases. This comprehensive review article presents the currently available evidence on the clinical utility of quantitative MRI of the pancreas.

Imaging Diagnosis and Management of Fistulas in Pancreatitis.

Pancreatic fistula is a highly morbid complication of pancreatitis. External pancreatic fistulas result when pancreatic secretions leak externally into the percutaneous drains or external wound (following surgery) due to the communication of the peripancreatic collection with the main pancreatic duct (MPD). Internal pancreatic fistulas include communication of the pancreatic duct (directly or via intervening collection) with the pleura, pericardium, mediastinum, peritoneal cavity, or gastrointestinal tract. Cross-sectional imaging plays an essential role in the management of pancreatic fistulas. With the help of multiplanar imaging, fistulous tracts can be delineated clearly. Thin computed tomography sections and magnetic resonance cholangiopancreatography images may demonstrate the communication between MPD and pancreatic fluid collections or body cavities. Endoscopic retrograde cholangiography (ERCP) is diagnostic as well as therapeutic. In this review, we discuss the imaging diagnosis and management of various types of pancreatic fistulas with the aim to sensitize radiologists to timely diagnosis of this critical complication of pancreatitis.

Peripancreatic tuberculosis.

Peripancreatic tuberculosis (PTB) is a very rare variant of tuberculosis and its clinical and radiological findings are similar to those of pancreatic malignancy. Diagnosis of PTB is usually incidental and is made after surgical resection. We are presenting a male patient who had complaints of prolonged fever, significant weight loss and yellowish discolouration of eyes and dark-coloured urine. Investigations revealed that there was a pancreatic mass causing obstructive jaundice. However, the aetiology of the mass, whether tubercular or malignant, was not clear. Hence, the patient was planned for endoscopic ultrasound-guided fine needle aspiration cytology. Cytology and aspirate were sent for a cartridge-based nucleic acid amplification test which revealed the presence of Mycobacterium tuberculosis, sensitive to rifampicin. The patient improved completely after treatment with antitubercular therapy.

A journey to and with the stars: The pancreatic stellate cell story.

The George E Palade Prize is the highest honour awarded by the International Association of Pancreatology, that recognises an individual who has made outstanding contributions to the understanding of the pancreas and pancreatic diseases. The 2023 Palade Prize was awarded to Professor Minoti Apte, University of New South Wales Sydney on September 16, 2023 during the Joint Meeting of the International Association of Pancreatology and the Indian Pancreas Club, held in Delhi, India. This paper summarises her Palade lecture wherein she reflects on her journey as a medical graduate, an academic and a researcher, with a particular focus on her team's pioneering work on pancreatic stellate cell biology and the role of these cells in health and disease. While there has been much progress in this field with the efforts of researchers worldwide, there is much still to be learned; thus it is a topic with ample scope for innovative research with the potential to translate into better outcomes for patients with pancreatic disease.

Liver Transplantation in a Woman with Mahvash Disease.

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

A Comparison of Robotic Versus Laparoscopic Distal Pancreatectomy for Benign or Malignant Lesions: A Meta-Analysis.

Background: The momentum of robotic surgery is increasing, and it has great prospects in pancreatic surgery. It has been widely accepted and expanding to more and more centers. Robotic distal pancreatectomy (RDP) is the most recent advanced minimally invasive approach for pancreatic lesions and malignancies. However, laparoscopic distal pancreatectomy (LDP) also showed good efficacy. We compared the effect of RDP with LDP using a meta-analysis. Methods: From January 2010 to June 2023, clinical trials of RDP versus LDP were determined by searching PubMed, Medline, and EMBASE. A meta-analysis was conducted to compare the effect of RDP with LDP. This meta-analysis evaluated the R0 resection rate, lymph node metastasis rate, conversion to open surgery rate, spleen preservation rate, intraoperative blood loss, postoperative pancreatic fistula, postoperative hospital stay, 90-day mortality rate, surgical cost, and total cost. Results: This meta-analysis included 38 studies. Conversion to open surgery, blood loss, and 90-day mortality in the RDP group were all significantly less than that in the LDP group (P < .05). There was no difference in lymph node resection rate, R0 resection rate, or postoperative pancreatic fistula between the two groups (P > .05). Spleen preservation rate in the LDP group was higher than that in the RDP group (P < .05). Operation cost and total cost in the RDP group were both more than that in the LDP group (P < .05). It is uncertain which group has an advantage in postoperative hospital stay. Conclusions: To some degree, RDP and LDP were indeed worth comparing in clinical practice. However, it may be difficult to determine which is absolute advantage according to current data. Large sample randomized controlled trials are needed to confirm which is better treatment. PROSPERO ID: CRD4202345576.