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Pancreatic adenosquamous carcinoma, an uncommon subtype of pancreatic adenocarcinoma, is characterized by an aggressive course and poor prognosis, with the only method of cure being surgical resection at the time of diagnosis. It is a complex condition, as it presents nonspecifically and remains indistinguishable from pancreatic adenocarcinoma without imaging techniques despite its aggressive nature. We report an atypical case of pancreatic adenosquamous carcinoma, presenting with marked anemia, found on endoscopy to have a gastric mass. This is of interest to readers as a reminder that pancreatic cancers may present with gastric invasion and should remain on the differential diagnosis for gastric lesions.

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OBJECTIVE: Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. DESIGN: Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. RESULTS: After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. CONCLUSIONS: The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. TRIAL REGISTRATION NUMBER: NCT04777812.

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The relationship between chronic intestinal disease, including inflammatory bowel disease (IBD) and celiac disease (CelD), and pancreatic disorders has been little investigated. Although an increased risk of acute pancreatitis (AP), exocrine pancreatic insufficiency with or without chronic pancreatitis, and chronic asymptomatic pancreatic hyperenzymemia have been described in these patients, the pathogenetic link remains unclear. It may potentially involve drugs, altered microcirculation, gut permeability/motility with disruption of enteric-mediated hormone secretion, bacterial translocation, and activation of the gut-associated lymphoid tissue related to chronic inflammation. In addition, the risk of pancreatic cancer seems to be increased in both IBD and CelD patients with unknown pathogenesis. Finally, other systemic conditions (e.g., IgG4-related disease, sarcoidosis, vasculitides) might affect pancreatic gland and the intestinal tract with various clinical manifestations. This review includes the current understandings of this enigmatic association, reporting a clinical and pathophysiological overview about this topic.

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BACKGROUND AND STUDY AIM: Immunoglobulin G4-related disease (IgG4-RD) is a rare immune mediated fibroinflammatory condition. Pancreaticobiliary (PB) and head and neck (HN) are two of the most commonly involved anatomical sites. It has been postulated that PB IgG4-RD and HN IgG4-RD have distinct clinical phenotypes. Whether the optimum treatment regimen or response to therapy differs between them is unknown. We aimed to assess differences between PB and HN IgG4-RD in a cohort of IgG4 disease managed by an IgG4-RD multispecialty team. METHODS: We performed a retrospective study of a prospectively maintained multidisciplinary IgG4-RD database to identify patients diagnosed with PB and HN IgG4-RD (based on initial presentation) between 2005 and 2019. The electronic patient records were reviewed. Use of immunosuppressive agents and clinical course was analysed. RESULTS: 60 patients with PB IgG4-RD and 14 with HN IgG4-RD were included in the study. PB IgG4-RD was associated with older age at diagnosis 64 versus 51 years (p<0.001), higher serum IgG4 level as a multiple of upper limit of normal median (IQR) 2 (1-3.75) vs 1 (1-2), (p=0.04) and greater proportion with more than one organ involved 68% vs 33% (p=0.03). HN IgG4-RD was more likely to receive second-line therapy 71% versus 36% (p=0.03). Persistent elevation of serum IgG4 after therapy was more common in PB IgG4-RD 84% versus 43% (p=0.03). CONCLUSION: These findings support the contention that PB IgG4-RD and HN IgG4-RD have different clinical profiles and represent distinct subtypes of IgG4-RD.

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BACKGROUND: Prompt and accurate staging of pancreatic cancer is essential to distinguish patients to benefit from resection with curative intent and those with unresectable disease. A staging laparoscopy is used preoperatively to identify macroscopic or occult metastases not identified on imaging. This single-institution study aims to evaluate the role of staging laparoscopy in patients with pancreatic adenocarcinoma and its effect on overall survival. METHOD: Clinicopathologic data were evaluated for all patients undergoing staging laparoscopy for pancreatic adenocarcinoma from July 2014 to December 2019. The study identified 155 patients eligible for analysis. All patients were followed for at least 2 years. Clinical backgrounds, survival curves and prognostic factors were investigated. RESULTS: Resectability status among the cohort was 62 (40%) upfront resectable, 53 (34%) borderline resectable and 40 (26%) locally advanced disease. The median age was 69, with 44% male patients. Median CA19-9 value was 125 kU/L, and median CA125 value was 22 kU/L. Staging laparoscopy resulted in upstaging nine (15%) upfront resectable patients, five (9%) borderline resectable patients and ten (25%) locally advanced patients. There was positive cytology in 19 (12%), peritoneal deposits in six (4%) and peritoneal liver deposits in seven (5%) patients. Overall, the number needed to treat (NNT) to avoid an unnecessary laparotomy was eight patients. CONCLUSION: Staging laparoscopy continues to be a valuable investigation of pancreatic adenocarcinoma. In this institution, one in every eight patients undergoing a staging laparoscopy was upstaged to metastatic disease, thus avoiding an unnecessary laparotomy or a non-curative resection.

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Background: Diabetes mellitus among patients with exocrine pancreatic disorders is commonly known to be associated with chronic inflammation, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). The neutrophil-to-lymphocyte ratio (NLR) is a novel marker that indicates the presence of various chronic inflammatory diseases, including type 2 diabetes (T2DM). However, no studies have examined the relationship between the NLR value and diabetes secondary to exocrine pancreatic disorders. Aim: To determine whether the NLR value is associated with diabetes secondary to exocrine pancreatic disorders. Methods: The medical data of subjects with confirmed pancreatic disease who were admitted to the Department of Pancreatic Surgery of our institution from August 2017 to October 2021 were obtained from the database and retrospectively analyzed. Anthropometric measures, laboratory data, including HbA1c, fasting insulin, and fasting C-peptide levels and the inflammatory index (white blood cell count, NLR, platelet-to-lymphocyte ration, monocyte-to-lymphocyte ratio) were recorded. The NLR is the ratio of neutrophils to lymphocytes. A homeostasis model (HOMA-B and HOMA-IR) was used to measure beta-cell dysfunction and insulin resistance. Results: The NLR values of the diabetes secondary to exocrine pancreatic disorders group were significantly higher than those of the nondiabetic group (P=0.001). In multivariate logistic regression, after adjusting for covariates, high NLR values were found to be an independent risk factor for diabetes secondary to exocrine pancreatic disorders (OR: 1.37, 95% CI: 1.138-1.649, P=0.001). According to Spearman correlation analysis, the NLR was significantly correlated with fasting plasma glucose levels (P<0.0001) and HOMA2-IR values (P=0.02). Conclusion: The NLR inflammation marker was significantly higher in subjects with diabetes secondary to exocrine pancreatic disorders and was associated with insulin resistance. NLR values may be reliable predictive markers for diabetes among patients with exocrine pancreatic disorders.

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This review aimed to analyze the scientific literature on pancreatic diseases (especially exocrine pancreatic insufficiency). This review also describes the correlation between the physiological fitness of the pancreas and obesity. The influence of the pancreatic exocrine function on the development of the organism of adults and adolescents was also described. The results of piglet studies available in the literature were cited as an established model used to optimize treatments for pancreatic diseases in humans. The pancreas has an exocrine and hormonal function. Consequently, it is one of the key internal organs in animals and humans. Pancreatic diseases are usually severe and particularly troublesome. A properly composed diet and taken dietary supplements significantly improve the patient's well-being, as well as the course of the disease. Therefore, a diet and a healthy lifestyle positively affect maintaining the optimal physiological efficiency of the pancreas.

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Immunoglobulin subclass 4 related disease (IgG4-RD) is an increasingly recognised autoimmune disease with the potential of affecting various organs. It has a predilection for certain anatomical hotspots and the pancreatobiliary tract is the the most common area involved. Due to the relative novelty of IgG4-RD, the understanding of the disease process continues to involve. Recent European guidelines on IgG4-RD have been published by a working group collaboration between the United European Gastroenterology and Swedish Society of Gastroenterology. In our commentary, we aim to extract the key practical points with an emphasis on diagnosis and management of IgG4-RD with specific focus on the pancreatobiliary tract.

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Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis that is often overlooked and is usually characterised clinically by frequent presentations with obstructive jaundice. Serum IgG4 testing as a means to 'rule out' IgG4-related disease may not be as helpful as initially thought and may lead to a missed diagnosis if suspicion is low. We present a patient with a years long history of recurrent pancreatitis ultimately found to have AIP after undergoing evaluation with a relatively new technology, SpyGlass, which allows for direct cholangioscopy and enabled us to make the correct diagnosis.

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

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OBJECTIVE: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to organ dysfunction, chronic pain, an increased risk for pancreatic cancer and considerable morbidity. Due to a lack of specific biomarkers, diagnosis is based on symptoms and specific but insensitive imaging features, preventing an early diagnosis and appropriate management. DESIGN: We conducted a type 3 study for multivariable prediction for individual prognosis according to the TRIPOD guidelines. A signature to distinguish CP from controls (n=160) was identified using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry on ethylenediaminetetraacetic acid (EDTA)-plasma and validated in independent cohorts. RESULTS: A Naive Bayes algorithm identified eight metabolites of six ontology classes. After algorithm training and computation of optimal cut-offs, classification according to the metabolic signature detected CP with an area under the curve (AUC) of 0.85 ((95% CI 0.79 to 0.91). External validation in two independent cohorts (total n=502) resulted in similar accuracy for detection of CP compared with non-pancreatic controls in EDTA-plasma (AUC 0.85 (95% CI 0.81 to 0.89)) and serum (AUC 0.87 (95% CI 0.81 to 0.95)). CONCLUSIONS: This is the first study that identifies and independently validates a metabolomic signature in plasma and serum for the diagnosis of CP in large, prospective cohorts. The results could provide the basis for the development of the first routine laboratory test for CP.

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Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.

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BACKGROUND/OBJECTIVES: Black Americans are at increased risk of chronic pancreatitis (CP) compared to their White counterparts. We aimed to describe the race-specific smoking history and lifetime drinking in patients diagnosed with CP. METHODS: We analyzed data on 334 Black and White CP participants of the North American Pancreatitis Study 2 Continuation and Validation Study and Ancillary Study. Lifetime drinking history and lifetime smoking history were collected through in-person interviews. Intensity, frequency, duration and current status of drinking and smoking were compared between Black and White CP participants, stratified by physician-defined alcohol etiology. In addition, drinking levels at each successive decades in life (20s, 30s, 40s) were compared by race and graphically portrayed as heat diagrams. RESULTS: Among patients with alcoholic CP, current smoking levels were not different by race (67-70%), but a smaller proportion of Black patients reported having smoked 1 or more packs per day in the past (32%) as compared to White patients (58%, p < 0.0001). Black patients were more likely to report current consumption of alcohol (31%), as opposed to White patients (17%, p = 0.016). Black patients also reported more intense drinking at age 35 and 45 years as compared to White patients, while age at CP onset were similar between the two groups. CONCLUSION: We found more intense drinking but less intense smoking history in Black CP patients as compared to White CP patients. Effective alcohol abstinence and smoking cessation program with sustained impact are needed in CP patients.

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The increasing prevalence of pancreatic disorders worldwide has provided challenges in its clinical care and management. This review was aimed to evaluate recent literature on diagnosis, treatment, and management of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), as well as chronic pancreatitis (CP) documented during the past 5-6 years. An extensive literature review was carried out based on studies within the last 6 years (2013-2019). Articles were selected based on updates and therapeutic management. Critical appraisal of literature was performed using the Mixed Methods Appraisal Tool (MMAT), and a PRISMA flowchart was used to avoid bias. The study identified recent updates on the prophylactic treatment in preventing RAP. The risk factors and the therapeutic management options were evaluated and discussed. The findings show that although many lifesaving new protocols are available for implementation in clinical practice, current literature lacks detailed and comprehensive guidelines that cover special populations and comorbidities. The literature evaluated showed that eight genes were involved in pancreatitis, CASR, CFTR, CLDN2, CPA1, CTRC, PRSS1, SBDS, and SPINK1, but the most common gene implicated was found to be CFTR, at 11%. Therefore, it is recommended that a comprehensive guideline should be formulated to facilitate the diagnosis, management, treatment, and prophylactic measures of pancreatic disease. This could in turn reduce disease complications and hospitalization time, and improve clinical practice for management of pancreatitis.

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Pancreatic cancer is one of the leading causes of cancer-related mortality in western countries. Early diagnosis of pancreatic cancers plays a key role in the management by identification of patients who are surgical candidates. The advancement in the radiological imaging and interventional endoscopy (including endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography and endoscopic enteral stenting techniques) has a significant impact in the diagnostic evaluation, staging and treatment of pancreatic cancer. The multidisciplinary involvement of radiology, gastroenterology, medical oncology and surgical oncology is central to the management of patients with pancreatic cancers. This review aims to highlight the diagnostic and therapeutic role of EUS in the management of patients with pancreatic malignancy, especially pancreatic ductal adenocarcinoma.

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Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development; nevertheless, the precise space-temporal signaling activation still needs to be clarified. This study reports a dissection of the pancreatic embryogenesis, highlighting the molecular network surrounding the epithelium-mesenchyme interaction. To investigate this crosstalk, pancreatic epithelium and surrounding mesenchyme, at embryonic day 10.5, were collected through laser capture microdissection (LCM) and characterized based on their global gene expression. We performed a bioinformatic analysis to hypothesize crosstalk interactions, validating the most promising genes and verifying the precise localization of their expression in the compartments, by RNA in situ hybridization (ISH). Our analyses pointed out also the c-Met gene, a very well-known factor involved in stimulating motility, morphogenesis, and organ regeneration. We also highlighted the potential crosstalk between Versican (Vcan) and Syndecan4 (Sdc4) since these genes are involved in pancreatic tissue repair, strengthening the concept that the same signaling pathways required during pancreatic embryogenesis are also involved in tissue repair. This finding leads to novel strategies for obtaining functional pancreatic stem cells for cell replacement therapies.

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