Quantitative Metabolomics and Lipoprotein Analysis of PDAC Patients Suggests Serum Marker Categories for Pancreatic Function, Pancreatectomy, Cancer Metabolism, and Systemic Disturbances.

Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose in the early stages and lacks reliable biomarkers. The scope of this project was to establish quantitative nuclear magnetic resonance (NMR) spectroscopy to comprehensively study blood serum alterations in PDAC patients. Serum samples from 34 PDAC patients obtained before and after pancreatectomy as well as 83 age- and sex-matched control samples from healthy donors were analyzed with in vitro diagnostics research (IVDr) proton NMR spectroscopy at 600 MHz. Uni- and multivariate statistics were applied to identify significant biofluid alterations. We identified 29 significantly changed metabolites and 98 lipoproteins when comparing serum from healthy controls with those of PDAC patients. The most prominent features were assigned to (i) markers of pancreatic function (e.g., glucose and blood triglycerides), (ii) markers related to surgery (e.g., ketone bodies and blood cholesterols), (iii) PDAC-associated markers (e.g., amino acids and creatine), and (iv) markers for systemic disturbances in PDAC (e.g., gut metabolites DMG, TMAO, DMSO2, and liver lipoproteins). Quantitative serum NMR spectroscopy is suited as a diagnostic tool to investigate PDAC. Remarkably, 2-hydroxybutyrate (2-HB) as a previously suggested marker for insulin resistance was found in extraordinarily high levels only after pancreatectomy, suggesting this metabolite is the strongest marker for pancreatic loss of function.

Endoscopic papillectomy for ampullary lesions of minor papilla.

BACKGROUND AND AIMS: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied. METHODS: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test. RESULTS: Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months). CONCLUSIONS: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.

Serum Amyloid A as a Potential Biomarker in Inflammatory Bowel Diseases, Especially in Patients with Low C-Reactive Protein.

The acute phase protein Serum Amyloid A (SAA) is synthesised by the liver in response to inflammatory stimuli. Previous studies have revealed that SAA may be a better biomarker of disease activity in inflammatory bowel disease (IBD) compared to C-reactive protein (CRP). This retrospective monocentric study evaluated whether SAA correlates with biomarkers like faecal calprotectin (FC), CRP, the Neutrophil to Lymphocyte ratio (NLR), the platelet count and clinical disease activity of IBD patients. Serum samples from the IBD outpatient clinic of the University Hospital Heidelberg were analysed for SAA concentrations if an FC concentration measurement was available from ±14 days to collection of the serum sample. Three hundred and six serum samples from 265 patients (166 with Crohn's disease, 91 with ulcerative colitis and 8 with IBD unclassified) met the inclusion criteria. There was a significant positive correlation between SAA and FC, CRP, NLR, platelet count and the Simple Clinical Colitis Activity Index (SCCAI). The cut-off for SAA serum concentration at 4.55 mg/L achieved a sensitivity of 57.5% and a specificity of 69.7% for the detection of active inflammation in IBD. SAA may be used as an additional biomarker in the disease monitoring strategy of IBD patients, especially in patients with low CRP concentrations.

Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) represent a distinct hypervascularized tumor entity, often diagnosed at metastatic stage. Therapeutic efficacy of anti-angiogenic multi-kinase inhibitors is frequently limited by primary or acquired resistance in vivo. This study aimed to characterize the molecular mode of action as well as resistance mechanisms to the anti-angiogenic multi-tyrosine kinase inhibitor (TKI) Regorafenib in vitro and in vivo. METHODS: In vitro, human and murine pancreatic neuroendocrine cell lines were comparatively treated with Regorafenib and other TKIs clinically used in PNETs. Effects on cell viability and proliferation were analyzed. In vivo, transgenic RIP1Tag2 mice were treated with Regorafenib at two different time periods during carcinogenesis and its impact on angiogenesis and tumor progression was evaluated. RESULTS: Compared to the established TKI therapies with Sunitinib and Everolimus, Regorafenib showed the strongest effects on cell viability and proliferation in vitro, but was unable to induce apoptosis. Unexpectedly and in contrast to these in vitro findings, Regorafenib enhanced proliferation during early tumor development in RIP1Tag2 mice and had no significant effect in late tumor progression. In addition, invasiveness was increased at both time points. Mechanistically, we could identify an upregulation of the pro-survival protein Bcl-2, the induction of the COX2-PGE2-pathway as well as the infiltration of CSF1R positive immune cells into the tumors as potential resistance mechanisms following Regorafenib treatment. DISCUSSION: Our data identify important tumor cell-autonomous and stroma-dependent mechanisms of resistance to antiangiogenic therapies.

[Climate Crisis: What Gastrointestinal Complications of this Medical Emergency Should We Be Aware Of?] / Klimakrise: Welche gastroenterologischen Folgeerkrankungen dieses medizinischen Notfalls sollten wir kennen?

INTRODUCTION: The climate crisis has serious consequences for many areas of life. This applies in particular to human health - also in Europe. While cardiovascular, pneumological and dermatological diseases related to the climate crisis are often discussed, the crisis' significant gastroenterological consequences for health must also be considered. METHODS: A literature search (Pubmed, Cochrane Library) was used to identify papers with relevance particularly to the field of gastroenterology in (Central) Europe. Findings were supplemented and discussed by an interdisciplinary team. RESULTS: The climate crisis impacts the frequency and severity of gastrointestinal diseases in Europe due to more frequent and severe heat waves, flooding and air pollution. While patients with intestinal diseases are particularly vulnerable to acute weather events, the main long-term consequences of climate change are gastrointestinal cancer and liver disease. In addition to gastroenteritis, other infectious diseases such as vector-borne diseases and parasites are important in the context of global warming, heat waves and floods. DISCUSSION: Adaptation strategies must be consistently developed and implemented for vulnerable groups. Patients at risk should be informed about measures that can be implemented individually, such as avoiding heat, ensuring appropriate hydration and following hygiene instructions. Recommendations for physical activity and a healthy and sustainable diet are essential for the prevention of liver diseases and carcinomas. Measures for prevention and the promotion of resilience can be supported by the physicians at various levels. In addition to efforts fostering sustainability in the immediate working environment, a system-oriented commitment to climate protection is important.

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

BACKGROUND: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. METHODS: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. RESULTS: Variants at the CTRC (p = 1.22 × 10-21) and SPINK1 (p = 6.59 × 10-47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. CONCLUSIONS: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.

Inflammatory Bowel Disease and COVID-19: How Have Patients Coped So Far?

OBJECTIVE: Knowledge about SARS-CoV2 and coronavirus disease 2019 (COVID-19) is growing fast. Massive changes in the health care system imposed by the COVID-19 pandemic clearly impact the overall quality of medical care. In this survey, we aim to explore experiences and concerns of patients with inflammatory bowel disease (IBD) regarding the current pandemic. METHODS: A 40-item web-based questionnaire on disease-related experiences and concerns during the COVID-19 pandemic was made available to patients with IBD from 28 April 2020 to 31 July 2020. RESULTS: An increased risk of SARS-CoV2 infection was a concern for 56.7% of the 1199 patients (aged 41.3±12.8, women 77%, Crohn's disease 58.8%, ulcerative colitis 38.5%); 61.7% feared an increased risk of severe disease course of COVID-19. Effective preventive measures in either outpatient practices or hospitals were observed by 84.7% of the patients. Appointments with an IBD specialist were canceled in 38.7%, frequently on the patients' initiative. Telecommunication visits were considered an acceptable alternative to personal visits by 71.0%. Medication was reduced or paused in 6.9% because of the pandemic. A swab (SARS-CoV2-PCR) was done in 13.2% of the patients; only 3 patients (0.25%) were tested positive. CONCLUSION: The COVID-19 pandemic is a major concern of patients with IBD. However, the cumulative prevalence in our cohort is low. Patients at risk should be identified and counseled individually. When required because of the local COVID-19 situation, telecommunication visits and liberal prescription policies are advisable to reduce in-person contacts, while ensuring continuous therapy and maintaining communication with patients.

The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer.

The IGF2 mRNA-binding protein 1 (IGF2BP1) is a non-catalytic post-transcriptional enhancer of tumor growth upregulated and associated with adverse prognosis in solid cancers. However, conserved effector pathway(s) and the feasibility of targeting IGF2BP1 in cancer remained elusive. We reveal that IGF2BP1 is a post-transcriptional enhancer of the E2F-driven hallmark in solid cancers. IGF2BP1 promotes G1/S cell cycle transition by stabilizing mRNAs encoding positive regulators of this checkpoint like E2F1. This IGF2BP1-driven shortening of the G1 cell cycle phase relies on 3'UTR-, miRNA- and m6A-dependent regulation and suggests enhancement of cell cycle progression by m6A-modifications across cancers. In addition to E2F transcription factors, IGF2BP1 also stabilizes E2F-driven transcripts directly indicating post-transcriptional 'super'-enhancer role of the protein in E2F-driven gene expression in cancer. The small molecule BTYNB disrupts this enhancer function by impairing IGF2BP1-RNA association. Consistently, BTYNB interferes with E2F-driven gene expression and tumor growth in experimental mouse tumor models.

Presence of Color Transition in Biopsy Specimens Predicts Outcome of Liver Lesion Biopsies.

Background: The aim of this study was to evaluate the usefulness of the presence of tissue transition in liver lesion biopsies to predict a successful outcome, as observed by modified macroscopic on-site evaluation (MOSE). Methods: This is a retrospective analysis of 264 ultrasound-guided liver lesion biopsies, examining the influence the presence of tissue transition (visible color changes in biopsy specimens as evaluated visually) has on two endpoints (1) material retrieval, (2) attaining a definitive diagnosis) representing successful liver lesion biopsies, compared to previously evaluated variables in this context. Uni- and multivariate analyses were performed using SPSS 21.0. Results: Material retrieval and a definitive diagnosis occurred in 224/264 (84.8%) and 217/264 (82.2%) cases, the latter occurring more often when visual inspection revealed macroscopic tissue transition (92/96 [95.8%]) than when not (124/165 [75.2%]), P < 0.001. Tissue transition in biopsies was more common in secondary (74/162 [45.7%]) than (18/54 [33.3%]) primary liver lesions, though this was not significant (P = 0.112). On multivariate analysis, tissue transition in biopsies was an independent predictor of a definitive diagnosis and material retrieval. Conclusion: In liver lesion biopsies, MOSE of color transition in biopsies can indicate success. This is easily incorporated into clinical practice and can help overcome the lack of an on-site pathologist.

Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): study protocol for a multicenter single-arm trial.

BACKGROUND: Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. METHODS: The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1. DISCUSSION: This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. TRIAL REGISTRATION: EudraCT: 2017-001207-68 . Date of registration: 2018.01.03.

The three common polymorphisms p.A986S, p.R990G and p.Q1011E in the calcium sensing receptor (CASR) are not associated with chronic pancreatitis.

BACKGROUND: The calcium sensing receptor (CASR) is a G protein-coupled receptor that is responsible for assessing extracellular Ca2+ levels and thus plays a crucial role in calcium homeostasis. Hypercalcemia is a metabolic risk factor for pancreatitis and rare CASR variants have been described in patients with chronic pancreatitis. At the carboxy-terminal tail of CASR, there is a cluster of three common polymorphisms, p.A986S (rs1801725), p.R990G (rs1042636) and p.Q1011E (rs1801726), which have been associated with chronic pancreatitis in various studies, but with conflicting results. METHODS: We examined 542 German and 339 French patients with chronic pancreatitis as well as 1025 German controls for the 3 common CASR polymorphism by melting curve analysis. For comparison, we used genotype data from 583 French controls from a previous study. In addition, we functionally analyzed the three variants by NFAT and SRE luciferase reporter systems as well as Western blotting and verified cell surface expression by ELISA. RESULTS: In both cohorts, neither the genotype nor the allele frequencies differed significantly between patients and controls. In both luciferase assays, p.R990G showed a significant leftward shift, indicating an increased responsiveness of the receptor. p.A986S showed a leftward shift in the SRE but not in the NFAT reporter assay, while the responsiveness of p.Q1011E did not differ from the wild-type. These functional studies therefore do not support the contributions of variant CASR to increasing the risk of pancreatitis. CONCLUSIONS: The three frequent CASR polymorphisms are unlikely to increase the risk for chronic pancreatitis.

Fluoroscopy-guided endoscopic sclerotherapy: a novel hybrid approach for symptomatic rectosigmoidal venous malformation (with video).

BACKGROUND AND AIMS: Recommendations for the treatment of lower GI bleeding do not include bleeding from venous malformations (VMs). The aim of this study was to delineate the usefulness of a novel hybrid intervention (fluoroscopy-guided endoscopic sclerotherapy) for the treatment of symptomatic VMs in the rectosigmoidal colon with bleeding. METHODS: The magnetic resonance images of 421 patients with VM, referred to multicenter vascular anomaly centers from 2009 to 2017, were analyzed retrospectively. Treatment was performed for all patients who experienced bleeding from rectosigmoidal VMs using fluoroscopy-guided endoscopic sclerotherapy with polidocanol foam as a novel approach. RESULTS: A total of 27 patients displayed VM in the rectosigmoidal area. Eleven of these presented with acute or previous bleeding and received treatment. Active bleeding was observed in 8 patients (72.7%), whereas 3 patients (27.3%) had signs of previous bleeding. Six of the 11 patients had anemia (54.5%). There were no adverse events within 24 hours of the intervention. In a 2-year follow-up period, only 1 patient (9.1%) presented with recurrent bleeding after 13 months and was successfully treated again with fluoroscopy-guided endoscopic sclerotherapy. CONCLUSIONS: Fluoroscopy-guided endoscopic sclerotherapy was shown to be a safe and effective treatment of symptomatic VMs of the rectosigmoidal area. Thus, fluoroscopy-guided endoscopic sclerotherapy should be considered for patients with bleeding from VMs of the rectosigmoid after a comprehensive workup and interdisciplinary case discussion.

Family planning with inflammatory bowel disease: the challenge of childlessness and parent concerns.

BACKGROUND: In patients with inflammatory bowel disease (IBD), diagnosis is often established at the beginning of childbearing age. Accordingly, concerns about family planning and pregnancy (FPP) are common. Poor knowledge regarding FPP might contribute to increased childlessness in patients with IBD. METHODS: The Crohn's and Colitis Pregnancy Knowledge Score (CCPKnow, 17 multiple-choice questions) was translated into German and then used for a web-based survey. Childlessness was analyzed with respect to socio-demographic and disease-related information, and the knowledge (CCPKnow) and concerns of IBD patients with children were compared to those of voluntarily childless (VC) and non-voluntarily childless (NVC) IBD patients. RESULTS: Childlessness was observed in 57.4 % of the 533 participants (90.6 % women, 63.0 % Crohn's disease, 31.5 % ulcerative colitis, mean age 33.2 ±â€Š8.6 years), voluntary childlessness in 9 %. The mean overall CCPKnow was adequate (9.38 ±â€Š3.96). Poor knowledge was not associated with increased childlessness (CCPKnow of < 8 was found in 29.8 % of patients with children and 28.9 % of childless patients, p > 0.5). Instead, the patients' education, medical advice, FPP-related concerns, impaired body image, and sexual dysfunction had a significant impact on childlessness. Frequent concerns included adverse effects of the patient's medication on their child (36 % of the respondents), malformation (33 %), miscarriage (34.5 %), and the inheritability of IBD (57 %). CONCLUSIONS: Factual knowledge does not reduce disease-related concerns or childlessness. Correct but possibly bothersome information on FPP might contribute to childlessness in patients with IBD. Our findings underline the need for qualified counseling of IBD patients regarding FPP by an experienced IBD physician.

The quality of pain management in pancreatic cancer: A prospective multi-center study.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with severe pain. Given the almost inevitably fatal nature of the disease, pain control is crucial. However, data on quality of pain management in PDAC is scarce. METHODS: This is a multi-center, prospective study to evaluate the quality of pain management in PDAC. Insufficient pain treatment (undertreatment) was prevalent if there was an incongruence between the patients level of pain and the potency of analgesic drug therapy. Determinants of pain and undertreatment were identified using multivariable logistic regression. RESULTS: 139 patients with histologically confirmed PDAC were analyzed. The prevalence of pain was 63%, with approximately one third of the patients grading their pain as moderate to severe. Palliative stage (OR: 3.37, 95%CI: 1.23-9.21, p = 0.018) and localization of the primary tumor in the body or tail (OR: 2.57, 95%CI: 1.05-6.31, p = 0.039) were independent determinants of pain. Of those reporting pain, 60% were undertreated and in 89% pain interfered with activities and emotions. Age ≥ 70 years (OR: 3.20, 95%CI: 1.09-9.41, p = 0.035) was an independent predictor of undertreatment. Patients with longer-known PDAC ( ≥ 30 days) showed improved pain management compared to new cases (OR: 0.19, 95%CI: 0.05-0.81, p = 0.025). Treatment by gastroenterologists (OR: 0.22, 95%CI: 0.05-0.89, p = 0.034) was associated with less undertreatment. CONCLUSIONS: The results show a high proportion of PDAC patients with pain, pain interference and undertreatment, whose characteristics could help to identify patients at risk in the future. Several changes in the management of cancer-related pain are necessary to overcome barriers to optimal treatment.

Sequencing of the complex CTRB1-CTRB2 locus in chronic pancreatitis.

BACKGROUND: /Objectives: A recent Genome-wide Association Study (GWAS) in alcoholic chronic pancreatitis (ACP) identified a novel association with the CTRB1-CTRB2 (chymotrypsinogen B1, B2) locus, linked to a 16.6 kb inversion that was confirmed in non-alcoholic chronic pancreatitis (NACP). Moreover, recent findings on the function of CTRB1 and CTRB2 suggest a protective role in pancreatitis development. The aim of the present study was to investigate the CTRB1-CTRB2 locus for rare genetic variants associated with chronic pancreatitis (CP). METHODS: We analyzed 134 patients with ACP and 203 patients with NACP and compared them to up to 258 healthy controls. Genotyping was performed with polymerase chain reaction, followed by Sanger sequencing of all exons and the exon-intron-boundaries of CTRB1 and CTRB2. Finally, in silico analyses of the identified variants were conducted. RESULTS: None of the seven rare missense variants or the single 5'-UTR variant in CTRB1 and CTRB2 was associated with ACP or NACP. In silico analysis predicted that variant p. Trp5Leu in CTRB1 and variant c.-4C > T in CTRB2 might alter protein expression and variants p. Asp222His in CTRB1 and p. Ala247Thr in CTRB2 might affect protein function. However, all of these variants were also described in public databases. CONCLUSIONS: The present study did not reveal an association of rare variants in CTRB1 and CTRB2 with ACP or NACP. Although rare missense variants were almost exclusively found in patients, only four variants were predicted to affect protein expression or function. Thus, a major influence of rare variants in the CTRB1-CTRB2 locus on CP development is unlikely.

Serum levels of advanced glycation end products and their receptors sRAGE and Galectin-3 in chronic pancreatitis.

BACKGROUND: /Objectives: AGE and their receptors like RAGE and Galectin-3 can activate inflammatory pathways and have been associated with chronic inflammatory diseases. Several studies investigated the role of AGE, Galectin-3 and sRAGE in pancreatic diseases, whereas no comprehensive data for chronic pancreatitis (CP) are available. METHODS: Serum samples from CP patients without an active inflammatory process (85 ACP; 26 NACP patients) and 40 healthy controls were collected. Levels of AGE, sRAGE and Galectin-3 were measured by ELISA. To exclude potential influences of previously described RAGE SNPs on detected serum levels, we analyzed variants rs207128, rs207060, rs1800625, and rs1800624 by melting curve technique in 378 CP patients and 338 controls. RESULTS: AGE and Galectin-3 serum levels were significantly elevated in both ACP and NACP patients compared to controls (AGE: 56.61 ± 3.043 vs. 31.71 ± 2.308 ng/mL; p < 0.001; Galectin-3: 16.63 ± 0.6297 vs. 10.81 ± 0.4835 ng/mL; p < 0.001). In contrast, mean serum sRAGE levels were significantly reduced in CP patients compared to controls (sRAGE: 829.7 ± 37.10 vs. 1135 ± 55.74 ng/mL; p < 0.001). All results were consistent after correction for gender, age and diabetes mellitus. No genetic association with CP was found. CONCLUSIONS: Our extensive analysis demonstrated the importance of aging related pathways in the pathogenesis of CP. As the results were consistent in ACP and NACP, both entities most likely share common pathomechanisms. Most probably the involved pathways are a general hallmark of an inflammatory state in CP that is even present in symptom-free intervals.

Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis.

BACKGROUND/OBJECTIVES: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer. METHODS: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry. RESULTS: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls. CONCLUSIONS: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.

Analysis of GPRC6A variants in different pancreatitis etiologies.

BACKGROUND: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10-5) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.

[Challenges of the COVID-19 pandemic in gastrointestinal endoscopy: expectations and implementation of recommendations]. / Gastrointestinale Endoskopie in Zeiten der COVID-19-Pandemie: Umsetzung von Empfehlungen und Erwartungen für die Zukunft.

INTRODUCTION: The COVID-19 pandemic represents a major challenge for health care systems worldwide. Recent data suggests an increased risk for personnel of gastrointestinal (GI) endoscopy units for SARS-CoV-2 infections. Several societies have provided recommendations for the current situation, but their feasibility is unclear and real-world data on preparedness of endoscopy units are lacking. AIMS & METHODS: A web-based survey among German GI-endoscopy heads was conducted from April 1 to April 7, 2020. It comprised 33 questions based on the ESGE (European Society of Gastrointestinal Endoscopy) recommendations and was distributed electronically by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). RESULTS: Of 551 completed surveys, 202 (37 %) endoscopy units cancelled less than 40 % of their procedures. Small-volume units (< 4000 procedures/year) cancelled significantly less procedures than high-volume units (> 4000). Complete spatial separation of high-risk patients was possible in only 17 %. Most units systematically identified patients at risk (91 %) and used risk adapted personal protective equipment (PPE, 85 %). For the future, shortages in PPE (83 %), staff (69 %) and relevant financial losses (80 %) were expected. CONCLUSIONS: Recommendations on structural measures were only partially fulfilled and cancellations of procedures were heterogeneous. Clear definitions of indications to perform endoscopies during such a pandemic are needed. Further, structural recommendations should be adapted and strategies to compensate financial losses need to be developed.

RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL.