Discharge protocol in acute pancreatitis: an international survey and cohort analysis.

There are several overlapping clinical practice guidelines in acute pancreatitis (AP), however, none of them contains suggestions on patient discharge. The Hungarian Pancreatic Study Group (HPSG) has recently developed a laboratory data and symptom-based discharge protocol which needs to be validated. (1) A survey was conducted involving all members of the International Association of Pancreatology (IAP) to understand the characteristics of international discharge protocols. (2) We investigated the safety and effectiveness of the HPSG-discharge protocol. According to our international survey, 87.5% (49/56) of the centres had no discharge protocol. Patients discharged based on protocols have a significantly shorter median length of hospitalization (LOH) (7 (5;10) days vs. 8 (5;12) days) p < 0.001), and a lower rate of readmission due to recurrent AP episodes (p = 0.005). There was no difference in median discharge CRP level among the international cohorts (p = 0.586). HPSG-protocol resulted in the shortest LOH (6 (5;9) days) and highest median CRP (35.40 (13.78; 68.40) mg/l). Safety was confirmed by the low rate of readmittance (n = 35; 5%). Discharge protocol is necessary in AP. The discharge protocol used in this study is the first clinically proven protocol. Developing and testifying further protocols are needed to better standardize patients' care.

Exocrine pancreatic insufficiency following bariatric surgery: unveiling alternative aetiology-case report and short review.

Bariatric surgery (BS) is currently the most effective treatment for severe obesity, requiring ongoing multidisciplinary follow-up to ensure proper progress and nutrition post-procedure. Despite its favourable safety profile, it is not exempt from complications, one of which being exocrine pancreatic insufficiency (EPI). The underlying pathophysiological mechanisms of EPI after BS are multifactorial, including poorly synchronized pancreatic enzyme secretion with the passage of nutrients (pancreaticocibal or postcibal asynchrony), insufficient pancreatic stimulation and bacterial overgrowth. We conducted a short literature review of the topic through a case of a patient who underwent BS in our centre and subsequently developed EPI and severe malnutrition. EPI initially was attributed to the surgery, but after a comprehensive evaluation, an unexpected cause was revealed.

Elevated Serum Triglyceride Levels in Acute Pancreatitis: A Parameter to be Measured and Considered Early.

BACKGROUND: The value of serum triglycerides (TGs) related to complications and the severity of acute pancreatitis (AP) has not been clearly defined. Our study aimed to analyze the association of elevated levels of TG with complications and the severity of AP. METHODS: The demographic and clinical data of patients with AP were prospectively analyzed. TG levels were measured in the first 24 h of admission. Patients were divided into two groups: one with TG values of<200 mg/dL and another with TG≥200 mg/dL. Data on the outcomes of AP were collected. RESULTS: From January 2016 to December 2019, 247 cases were included: 200 with TG<200 mg/dL and 47 with TG≥200 mg/dL. Triglyceride levels≥200 mg/dL were associated with respiratory failure (21.3 vs. 10%, p=0.033), renal failure (23.4 vs. 12%, p=0.044), cardiovascular failure (19.1 vs. 7.5%, p=0.025), organ failure (34 vs. 18.5%, p=0.02), persistent organ failure (27.7 vs. 9.5%, p=0.001), multiple organ failure (19.1 vs. 8%, p=0.031), moderately severe and severe AP (68.1 vs. 40.5%, p=0.001), pancreatic necrosis (63.8 vs. 34%, p<0.001), and admission to the intensive care unit (27.7 vs. 9.5%, p=0.003). In the multivariable analysis, a TG level of≥200 mg/dL was independently associated with respiratory, renal, and cardiovascular failure, organ failure, persistent organ failure, multiple organ failure, pancreatic necrosis, severe pancreatitis, and admission to the intensive care unit (p<0.05). CONCLUSIONS: In our cohort, TG≥200 mg/dL was related to local and systemic complications. Early determinations of TG levels in AP could help identify patients at risk of complications.

A faecal microbiota signature with high specificity for pancreatic cancer.

BACKGROUND: Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. OBJECTIVE: To explore the faecal and salivary microbiota as potential diagnostic biomarkers. METHODS: We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. RESULTS: Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. CONCLUSION: Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.

Chronic pancreatitis for the clinician. Complications and special forms of the disease. Interdisciplinary position paper of the Catalan Society of Digestology (SCD) and the Catalan Pancreatic Society (SCPanc).

Chronic pancreatitis tends to develop a number of complications that may constitute the form of presentation of the disease. Some societies have issued guidelines for diagnosis and treatment of chronic pancreatitis complications, but the level of evidence for any topic is usually low and recommendations tend to be weak. We aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The goal was to propose defined terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 14 sections related to complications and special forms of chronic pancreatitis (early chronic, groove and autoimmune pancreatitis) were reviewed by 21 specialists from 6 different fields to generate 32 statements. Featured statements assert common bile duct stenosis does not require invasive treatment (endoscopic or surgical) unless cholestasis, cholangitis, lithiasis or other symptoms develop. Pancreatic duct strictures and calculi should be approached (after ruling out malignancy) if causing pain, pancreatitis, pseudocysts or other complications. Treatment of symptomatic pseudocysts must be individualized, considering associated main duct stenosis, vascular and pericystic complications. Higher risk conditions for pancreatic cancer are advance age, smoking, genetic background, recent diagnosis of chronic pancreatitis or diabetes, and appearance of new symptoms. Groove pancreatitis can initially be treated with conservative measures. Both prednisolone or rituximab can induce remission and maintenance of autoimmune pancreatitis. Internal fistula, vascular complications, bacterial overgrowth, osteoporosis and renal lithiasis require specific therapeutic approaches.

Pancreatitis crónica para el clínico. Parte 1: etiología y diagnóstico. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees / Chronic pancreatitis for the clinician. Part 1: Etiology and diagnosis. Interdisciplinary position paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees

La pancreatitis crónica es una enfermedad fibroinflamatoria del páncreas originada por acción combinada de factores etiológicos. Muestra formas de presentación, tipos de complicaciones y grados evolutivos variables. Las opciones terapéuticas son tan diversas como los múltiples escenarios clínicos. Algunas sociedades médicas han desarrollado guías sobre diagnóstico y tratamiento basadas en evidencia científica. Pero la elevada variabilidad que conforman la conjunción de elementos etiológicos, presentaciones clínicas, complicaciones y progresión de la enfermedad hace que los niveles de evidencia obtenidos sean generalmente bajos y, por tanto, las recomendaciones tienden a ser vagas o débiles, salvo excepciones.En los presentes documentos de posicionamiento de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees hemos buscado redactar declaraciones bien definidas orientadas al clínico, basadas en revisiones actualizadas de literatura y acuerdos de expertos. El objetivo es proponer el uso de terminología común y circuitos diagnóstico/terapéuticos racionales basados en el conocimiento actual. Para este fin se revisaron 51 secciones relacionadas con pancreatitis crónica por 21 expertos de 6 especialidades diferentes para generar finalmente 88 declaraciones que buscan armonizar conceptos y formular recomendaciones precisas.La parte 1 de esta serie de documentos discute tópicos sobre etiología, diagnóstico y diagnóstico diferencial. Factores etiológicos de mayor relevancia son tóxicos (alcohol y tabaco), genéticos y obstructivos. Dolor abdominal, insuficiencia exocrina y endocrina y síntomas derivados de complicaciones son las presentaciones más frecuentes. Algunos pacientes permanecen asintomáticos. El diagnóstico (seguro, probable o incierto) debe sustentarse en datos objetivos obtenidos en pruebas de imagen, histología y pruebas de función pancreática.(AU)

Chronic pancreatitis is a chronic fibroinflammatory disease of the pancreas with prevalence around 50 cases per 100,000 inhabitants. It appears to originate from diverse and yet mixed etiological factors. It shows highly variable presenting features, complication types and disease progression rates. Treatment options are as wide as the multiple personalized scenarios the disease might exhibit at a given time point. Some medical societies have developed guidelines for diagnosis and treatment based on scientific evidence. Although these efforts are to be acknowledged, the gathered level of evidence for any topic is usually low and, therefore, recommendations tend to be vague or weak.In the present series of position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on interdisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 1 of this paper series discusses topics on aetiology and diagnosis of chronic pancreatitis. Main clinical features are abdominal pain, exocrine and endocrine insufficiency and symptoms derived from complications. Some patients remain symptom-free. Diagnosis (definitive, probable or uncertain) should be based on objective data obtained from imaging, histology, or functional tests.(AU)

Chronic pancreatitis for the clinician. Part 2: Treatment and follow-up. Interdisciplinary Position Paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. / Pancreatitis crónica para el clínico. Parte 2: Tratamiento y seguimiento. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees.

Chronic pancreatitis is associated with impaired quality of life, high incidence of comorbidities, serious complications and mortality. Healthcare costs are exorbitant. Some medical societies have developed guidelines for treatment based on scientific evidence, but the gathered level of evidence for any individual topic is usually low and, therefore, recommendations tend to be vague or weak. In the present position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 2 of these paper series discuss topics on treatment and follow-up. The therapeutic approach should include assessment of etiological factors, clinical manifestations and complications. The complexity of these patients advocates for detailed evaluation in multidisciplinary committees where conservative, endoscopic, interventional radiology or surgical options are weighed. Specialized multidisciplinary units of Pancreatology should be constituted. Indications for surgery are refractory pain, local complications, and suspicion of malignancy. Enzyme replacement therapy is indicated if evidence of exocrine insufficiency or after pancreatic surgery. Response should be evaluated by nutritional parameters and assessment of symptoms. A follow-up program should be planned for every patient with chronic pancreatitis.

Chronic pancreatitis for the clinician. Part 1: Etiology and diagnosis. Interdisciplinary position paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. / Pancreatitis crónica para el clínico. Parte 1: etiología y diagnóstico. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees.

Chronic pancreatitis is a chronic fibroinflammatory disease of the pancreas with prevalence around 50 cases per 100,000 inhabitants. It appears to originate from diverse and yet mixed etiological factors. It shows highly variable presenting features, complication types and disease progression rates. Treatment options are as wide as the multiple personalized scenarios the disease might exhibit at a given time point. Some medical societies have developed guidelines for diagnosis and treatment based on scientific evidence. Although these efforts are to be acknowledged, the gathered level of evidence for any topic is usually low and, therefore, recommendations tend to be vague or weak. In the present series of position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on interdisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 1 of this paper series discusses topics on aetiology and diagnosis of chronic pancreatitis. Main clinical features are abdominal pain, exocrine and endocrine insufficiency and symptoms derived from complications. Some patients remain symptom-free. Diagnosis (definitive, probable or uncertain) should be based on objective data obtained from imaging, histology, or functional tests.

Acquired hepatocerebral degeneration in a metastatic neuroendocrine tumor long-term survivor - an update on neuroendocrine neoplasm's treatment: A case report.

BACKGROUND: Metastatic small bowel low-grade neuroendocrine tumors (NETs) have a good prognosis. Surgery is the only curative treatment; however, this may induce advanced liver disease, particularly in long-term survivor patients. Acquired hepatocerebral degeneration or Parkinsonism in cirrhosis is characterized by rapidly progressive extrapyramidal symptoms in patients with advanced liver disease. CASE SUMMARY: A 70-year-old man presented to the emergency department with diminished consciousness and disorientation, and was diagnosed with hepatic encephalopathy. The patient was diagnosed in 1993 with a metastatic small bowel NET, for which he twice underwent hepatic surgery, with metastatic resection in 1993 and a right hepatectomy in 2002 to remove two hepatic metastases. In 2003, the patient started first-line chemotherapy and in 2004 started the first of three consecutive biological treatments, followed by radio-molecular therapy, achieving stable disease for 14 years. Disease progression was identified and he underwent an endoscopic retrograde cholangiopancreatography. However, in 2019 advanced liver disease was identified. We diagnosed the development of acquired hepatocerebral degeneration, an unusual long-term side effect after multiple hepatic procedures. CONCLUSION: The importance of regular and ongoing surveillance in long-term NET survivors who undergo hepatic procedures should be integrated into the therapeutic management plan, as some of these negative outcomes could be prevented.

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, mainly due to late diagnosis at advanced tumor stages. In this study, we aimed to identify plasma protein biomarkers for early detection of PDAC. Totally, 135 PDAC patients (early PDAC, Stage I/II, n = 71; advanced PDAC, Stage III/IV, n = 64), 13 benign lesions/chronic pancreatitis patients and 72 healthy individuals, with corresponding plasma samples from a case-control study in Sweden were included. A proximity extension assay was used to detect 92 cancer-related proteins, and an enzyme-linked immunosorbent assay/electrochemiluminescence immunoassay was used to detect CA19-9. Predictive features were selected from these 93 candidate proteins and three covariates in the Swedish participants, and then validated in Spanish participants, including 37 early PDAC patients, 38 advanced PDAC patients, 19 chronic pancreatitis patients and 36 healthy controls. A panel of eight proteins discriminating early PDAC from healthy individuals was identified, and the cross-validated area under the curves (AUCs) were 0.85 (95% confidence interval, 95% CI, 0.78-0.91) and 0.81 (95% CI, 0.70-0.92) in the Swedish and Spanish participants, respectively. Another eight-protein panel was predictive for classifying advanced PDAC from healthy controls in two populations, with cross-validated AUCs of 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.83-0.98), respectively. In conclusion, eight protein biomarkers were identified and externally validated, potentially allowing early detection of PDAC patients if validated in additional prospective studies.

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.

OBJECTIVES: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.

Motor dysfunction of the gut in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Cystic fibrosis transmembrane conductance regulator is extensively expressed in the intestine and has an important role in the regulation of the viscosity and pH of gut secretions. Several studies have reported a delay in small bowel and colonic transit times in patients with CF which have been attributed to the secretory dysfunction. Our aim was to determine whether intestinal contractility is affected in these patients. METHODS: Consecutive patients with CF referred to our institution between 2014 and 2017 (n = 16) were prospectively investigated using automated non-invasive techniques for morpho-functional evaluation of the gut developed in our laboratory. On separate days, intraluminal images of the gut were obtained by capsule endoscopy and external images by abdominal MRI. Analysis of images (endoluminal and external) was performed with original, previously validated programs based on computer vision and machine learning techniques and compared with age- and sex-matched controls. KEY RESULTS: Patients with CF exhibited important reduction in contractile activity and increased retention of static turbid luminal content in the small bowel by endoluminal image analysis. Morpho-volumetric analysis of MRI images found increased ileo-colonic volumes in CF. Significant correlations between abnormalities detected by intraluminal and external imaging techniques were found. The presence and severity of digestive symptoms were not related to abnormal gut function. CONCLUSION AND INFERENCES: Impaired transit and pooling of gut contents in patients with CF is associated with impaired intestinal motility.

International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP. METHODS: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers. CONCLUSIONS: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.

Pancreatic Cancer Risk in Relation to Lifetime Smoking Patterns, Tobacco Type, and Dose-Response Relationships.

BACKGROUND: Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case-control study. METHODS: Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose-response relationships and to analyze their shape. RESULTS: Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39-2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11-1.99) or chest (OR = 1.33; 95% CI, 1.12-1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10-2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31-3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely. CONCLUSIONS: This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations. IMPACT: This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches.

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations.

Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1ß, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.

Zeb1 in Stromal Myofibroblasts Promotes Kras-Driven Development of Pancreatic Cancer.

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/- littermates, with PDAC developing eventually in KPC;Z+/- aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/- mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624-37. ©2018 AACR.

Oleic acid chlorohydrin, a new early biomarker for the prediction of acute pancreatitis severity in humans.

BACKGROUND: The early prediction of the severity of acute pancreatitis still represents a challenge for clinicians. Experimental studies have revealed the generation of specific halogenated lipids, in particular oleic acid chlorohydrin, in the early stages of acute pancreatitis. We hypothesized that the levels of circulating oleic acid chlorohydrin might be a useful early prognostic biomarker in acute pancreatitis in humans. METHODS: In a prospective, multicenter cohort study, plasma samples collected within 24 h after presentation in the emergency room from 59 patients with acute pancreatitis and from 9 healthy subjects were assessed for oleic acid chlorohydrin levels. RESULTS: Pancreatitis was mild in 30 patients, moderately severe in 16 and severe in 13. Oleic acid chlorohydrin levels within 24 h after presentation were significantly higher in patients that later progressed to moderate and severe acute pancreatitis. Using 7.49 nM as the cutoff point, oleic acid chlorohydrin distinguished mild from moderately severe-to-severe pancreatitis with high sensitivity/specificity (96.6/90.0%) and positive/negative predictive values (90.3/96.4%). Using 32.40 nM as the cutoff value sensitivity, specificity, positive and negative predictive values were all 100% for severe acute pancreatitis. It was found to be a better prognostic marker than BISAP score, hematocrit at 48 h, SIRS at admission, persistent SIRS or C-reactive protein at 48 h. CONCLUSIONS: Oleic acid chlorohydrin concentration in plasma is elevated in patients with acute pancreatitis on admission and correlates with a high degree with the final severity of the disease, indicating that it has potential to serve as an early prognostic marker for acute pancreatitis severity.