Szilárd Gódi

Upregulation of the transient receptor potential ankyrin 1 ion channel in the inflamed human and mouse colon and its protective roles.

Transient Receptor Potential Ankyrin 1 (TRPA1) channels are localized on sensory nerves and several non-neural cells, but data on their functional significance are contradictory. We analysed the presence and alterations of TRPA1 in comparison with TRP Vanilloid 1 (TRPV1) at mRNA and protein levels in human and mouse intact and inflamed colons. The role of TRPA1 in a colitis model was investigated using gene-deficient mice. TRPA1 and TRPV1 expressions were investigated in human colon biopsies of healthy subjects and patients with inflammatory bowel diseases (IBD: ulcerative colitis, Crohns disease) with quantitative PCR and immunohistochemistry. Mouse colitis was induced by oral 2% dextran-sulphate (DSS) for 10 days. For investigating the functions of TRPA1, Disease Activity Index (weight loss, stool consistency, blood content) was determined in C57BL/6-based Trpa1-deficient (knockout: KO) and wildtype (WT) mice. Sensory neuropeptides, their receptors, and inflammatory cytokines/chemokines were determined with qPCR or Luminex. In human and mouse colons TRPA1 and TRPV1 are located on epithelial cells, macrophages, enteric ganglia. Significant upregulation of TRPA1 mRNA was detected in inflamed samples. In Trpa1 KO mice, Disease Activity Index was significantly higher compared to WTs. It could be explained by the greater levels of substance P, neurokinins A and B, neurokinin 1 receptor, pituitary adenylate-cyclase activating polypeptide, vasoactive intestinal polypeptide, and also interleukin-1beta, macrophage chemoattractant protein-1, monokine induced by gamma interferon-1, tumor necrosis factor-alpha and B-lymphocyte chemoattractant in the distal colon. TRPA1 is upregulated in colitis and its activation exerts protective roles by decreasing the expressions of several proinflammatory neuropeptides, cytokines and chemokines.

Prospective, Multicentre, Nationwide Clinical Data from 600 Cases of Acute Pancreatitis

Objective The aim of this study was to analyse the clinical characteristics of acute pancreatitis (AP) in a prospectively collected, large, multicentre cohort and to validate the major recommendations in the IAP/APA evidence-based guidelines for the management of AP. Design Eighty-six different clinical parameters were collected using an electronic clinical research form designed by the Hungarian Pancreatic Study Group. Patients 600 adult patients diagnosed with AP were prospectively enrolled from 17 Hungarian centres over a two-year period from 1 January 2013. Main Results With respect to aetiology, biliary and alcoholic pancreatitis represented the two most common forms of AP. The prevalence of biliary AP was higher in women, whereas alcoholic AP was more common in men. Hyperlipidaemia was a risk factor for severity, lack of serum enzyme elevation posed a risk for severe AP, and lack of abdominal pain at admission demonstrated a risk for mortality. Abdominal tenderness developed in all the patients with severe AP, while lack of abdominal tenderness was a favourable sign for mortality. Importantly, lung injury at admission was associated with mortality. With regard to laboratory parameters, white blood cell count and CRP were the two most sensitive indicators for severe AP. The most common local complication was peripancreatic fluid, whereas the most common distant organ failure in severe AP was lung injury. Deviation from the recommendations in the IAP/APA evidence-based guidelines on fluid replacement, enteral nutrition and timing of interventions increased severity and mortality. Conclusions Analysis of a large, nationwide, prospective cohort of AP cases allowed for the identification of important determinants of severity and mortality. Evidence-based guidelines should be observed rigorously to improve outcomes in AP.

Pancreatic Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian Pancreatic Study Group.

BACKGROUND AND AIMS Pancreatic cancer is a devastating disease with poor prognosis. There is very limited information available regarding the epidemiology and treatment strategies of pancreatic cancer in Central Europe. The purpose of the study was to prospectively collect and analyze data of pancreatic cancer in the Hungarian population. METHODS The Hungarian Pancreatic Study Group (HPSG) organized prospective, uniform data collection. Altogether 354 patients were enrolled from 14 Hungarian centers. RESULTS Chronic pancreatitis was present in 3.7% of the cases, while 33.7% of the patients had diabetes. Family history for pancreatic cancer was positive in 4.8%. The most frequent presenting symptoms included pain (63.8%), weight loss (63%) and jaundice (52.5%). The reported frequency of smoking and alcohol consumption was lower than expected (28.5% and 27.4%, respectively). The majority of patients (75.6%) were diagnosed with advanced disease. Most patients (83.6%) had a primary tumor located in the pancreatic head. The histological diagnosis was ductal adenocarcinoma in 90.7% of the cases, while neuroendocrine tumor was present in 5.3%. Biliary stent implantation was performed in 166 patients, 59.2% of them received metal stents. Primary tumor resection was performed in 60 (16.9%) patients. Enteral or biliary bypass was done in 35 and 49 patients, respectively. In a multivariate Cox-regression model, smoking status and presence of gemcitabine-based chemotherapy were identified as independent predictors for overall survival. CONCLUSION We report the first data from a large cohort of Hungarian pancreatic cancer patients. We identified smoking status and chemotherapy as independent predictors in this cohort.

Analysis of research activity in gastroenterology: Pancreatitis is in real danger

Objective Biomedical investment trends in 2015 show a huge decrease of investment in gastroenterology. Since academic research usually provides the basis for industrial research and development (R&D), our aim was to understand research trends in the field of gastroenterology over the last 50 years and identify the most endangered areas. Methods We searched for PubMed hits for gastrointestinal (GI) diseases for the 1965–2015 period. Overall, 1,554,325 articles were analyzed. Since pancreatology was identified as the most endangered field of research within gastroenterology, we carried out a detailed evaluation of research activity in pancreatology. Results In 1965, among the major benign GI disorders, 51.9% of the research was performed on hepatitis, 25.7% on pancreatitis, 21.7% on upper GI diseases and only 0.7% on the lower GI disorders. Half a century later, in 2015, research on hepatitis and upper GI diseases had not changed significantly; however, studies on pancreatitis had dropped to 10.7%, while work on the lower GI disorders had risen to 23.4%. With regard to the malignant disorders (including liver, gastric, colon, pancreatic and oesophageal cancer), no such large-scale changes were observed in the last 50 years. Detailed analyses revealed that besides the drop in research activity in pancreatitis, there are serious problems with the quality of the studies as well. Only 6.8% of clinical trials on pancreatitis were registered and only 5.5% of these registered trials were multicentre and multinational (more than five centres and nations), i.e., the kind that provides the highest level of impact and evidence level. Conclusions There has been a clear drop in research activity in pancreatitis. New international networks and far more academic R&D activities should be established in order to find the first therapy specifically for acute pancreatitis.

High versus low energy administration in the early phase of acute pancreatitis (GOULASH trial): protocol of a multicentre randomised double-blind clinical trial

Introduction Acute pancreatitis (AP) is an inflammatory disease with no specific treatment. Mitochondrial injury followed by ATP depletion in both acinar and ductal cells is a recently discovered early event in its pathogenesis. Importantly, preclinical research has shown that intracellular ATP delivery restores the physiological function of the cells and protects from cell injury, suggesting that restoration of energy levels in the pancreas is therapeutically beneficial. Despite several high quality experimental observations in this area, no randomised trials have been conducted to date to address the requirements for energy intake in the early phase of AP. Methods/design This is a randomised controlled two-arm double-blind multicentre trial. Patients with AP will be randomly assigned to groups A (30 kcal/kg/day energy administration starting within 24 hours of hospital admission) or B (low energy administration during the first 72 hours of hospital admission). Energy will be delivered by nasoenteric tube feeding with additional intravenous glucose supplementation or total parenteral nutrition if necessary. A combination of multiorgan failure for more than 48 hours and mortality is defined as the primary endpoint, whereas several secondary endpoints such as length of hospitalisation or pain will be determined to elucidate more detailed differences between the groups. The general feasibility, safety and quality checks required for high quality evidence will be adhered to. Ethics and dissemination The study has been approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (55961-2/2016/EKU). This study will provide evidence as to whether early high energy nutritional support is beneficial in the clinical management of AP. The results of this trial will be published in an open access way and disseminated among medical doctors. Trial registration The trial has been registered at the ISRCTN (ISRTCN 63827758).

Transient elastography as a predictor of oesophageal varices in patients with liver cirrhosis

INTRODUCTION One of the most serious complications of liver cirrhosis is variceal bleeding. Early recognition of the oesophageal varices is of primary importance in the prevention of variceal bleeding. Endoscopy is the only means to directly visualize varices and measure their size, as one of the most important predictor of the risk of bleeding. During the course of cirrhosis repeated oesophago-gastro-bulboscopic examinations are recommended. As these interventions are expensive and often poorly accepted by patients who may refuse further follow-up, there is a need for non-invasive methods to predict the progression of portal hypertension as well as the presence and the size of oesophageal varices. After several combinations of biological and ultrasonographical parameters proposed for the detection of advanced fibrosis, it was suggested that liver stiffness measured by transient elastography, a novel non-invasive technology may reflect not only fibrosis and portal pressure but it may even predict the presence or absence of large oesophageal varices in patients with cirrhosis. AIM The aim of the authors was to study the diagnostic accuracy of transient elastography using FibroScan for selecting patients who are at risk of bearing large (Paquet-grade ≥ II) oesophageal varices and high risk of bleeding. METHOD The authors performed upper tract endoscopy and transient elastography in 74 patients with chronic liver disease (27 patients with chronic hepatitis and 47 patients with liver cirrhosis). The relationships between the presence of oesophageal varices (Paquet-grade 0-IV) and liver stiffness (kPa), as well as the hematological and biochemical laboratory parameters (prothrombine international normalized ratio, platelet count, aspartate aminotransferase, alanine aminotransferase, albumin, and aspartate aminotransferase/platelet ratio index) were investigated. The predictive role of liver stiffness for screening patients with varices and those who are at high risk of variceal bleeding was also analysed. RESULTS Liver stiffness values significantly correlated with the grade of oesophageal varices (Paquet-grade) (r = 0.67, p<0.0001). The liver stiffness value of 19.2 kPa was highly predictive for the presence of oesophageal varices (AUROC: 0.885, 95% CI: 0.81-0.96) and for the presence of high grade varices (P≥II) (AUROC: 0.850, 95% CI: 0.754-0.94). Using the cut-off value of 19.2 kPa, the sensitivity of transient elastography was 85%, specificity was 87%, positive predictive value was 85%, negative predictive value was 87% and validity was 86% for the detection of varices. Liver stiffness values less than 19.2 kPa were highly predicitive for the absence of large (P≥II) varices (sensitivity, 95%; specificity, 70%; positive predictive value, 54%; negative predictive value, 97%). CONCLUSIONS Transient elastography may help to screen patients who are at high risk of bearing large (P≥II) oesophageal varices which predict variceal bleeding and, therefore, need endoscopic screening. Lives stiffness values higher than 19.2 kPa indicate the need for oesophageal-gastro-bulboscopy, while liver stiffness values lower than 19.2 kPa make the presence of large oesophageal varices unlikely.

Az endoszkópos regiszterek szerepe a minőségi betegellátásban. Az új magyar Endoszkópos Retrográd Cholangiopancreatographia (ERCP) Regiszter első eredményei

INTRODUCTION The continuous monitoring of quality indicators in gastrointestinal endoscopy has become an essential requirement nowadays. Most of these data cannot be extracted from the currently used free text reports, therefore a structured web-based data-collecting system was developed to record the indicators of pancreatobiliary endoscopy. AIM A structured data-collecting system, the ERCP Registry, was initiated to monitor endoscopic retrograde cholangiopancreatography (ERCP) examinations prospectively, and to verify its usability. METHOD From January 2017, all ERCPs performed at the First Department of Medicine, University of Pecs, have been registered in the database. In the first year, the detailed data of 595 examinations were entered into the registry. After processing these data, the testing period of the registry is now finished. RESULTS On 447 patients, 595 ERCPs were performed. The success rate of cannulation is 93.8% if all cases are considered. Difficult biliary access was noted in 32.1% of patients with native papilla, and successful cannulation was achieved in 81.0% of these cases during the first procedure. Post-ERCP pancreatitis was observed in 13 cases (2.2%), clinically significant post-papillotomy bleeding was registered in 2 cases (0.3%), while 27 patients (4.5%) developed temporary hypoxia during the procedure. 30-day follow-up was successful in 75.5% of the cases to detect late complications. All of the quality indicators determined by the American Society of Gastrointestinal Endoscopy (ASGE) were possible to monitor with the help of the registry. Our center already complies with most of these criteria. CONCLUSIONS Continuous monitoring of the quality indicators of endoscopic interventions are not supported by the current hospital information system but it became possible with our registry. The ERCP Registry is a suitable tool to detect the quality of patient care and also useful for clinical research. Several endoscopy units have joined already this initiative and it is open for further centres through our web page ( https://tm-centre.org/hu/regiszterek/ercp-regiszter/ ). Orv Hetil. 2018; 159(37): 1506-1515.

Centralized care for acute pancreatitis significantly improves outcomes

AIMS In this observational study, we investigated whether specialized care improves outcomes for acute pancreatitis (AP). METHODS Consecutive patients admitted to two university hospitals with AP were enrolled in this study between 1 January 2016 and 31 December 2016 (Center A: specialized center; Center B: general hospital). Data on demographic characteristics and AP etiology, severity, mortality and quality of care (enteral nutrition and antibiotic use) were extracted from the Hungarian Acute Pancreatitis Registry. An independent sample t-test, Mann-Whitney test, chi-squared test or Fishers test were used for statistical analyses. Costs of care were calculated and compared in the two models of care. RESULTS There were 355 patients enrolled, 195 patients in the specialized center (Center A) and 160 patients in the general hospital (Center B). There was no difference in mean age (57.02 +/-17.16 vs. 57.31 +/-16.50 P=0.872) and sex ratio (56% males vs. 57% males, P=0.837) between centres, allowing a comparison without selection bias. Center A had lower mortality (n=2, 1.03% vs. n=16, 6.25%, p=0.007), more patients received enteral feeding (n=179, 91.8%, vs. n=36, 22.5%, p<0.001) and fewer patients were treated with antibiotics (n=85, 43.6% vs. n=123, 76.9%, p=0.001). In Center A the median length of hospitalization was shorter (Me 6, IQR 5-9 vs. Me 8, IQR 6-11, p=0.02) and the costs of care were by 25% lower. CONCLUSION Our data suggests that treatment of AP in specialized centers reduces mortality, length of hospitalization and thus might reduce the costs.

A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort:

Objectives Variant c.811+32C>A in intron 4 of the cholecystokinin-B receptor gene (CCKBR) was reported to correlate with higher pancreatic cancer risk and poorer survival. The variant was suggested to induce retention of intron 4, resulting in a new splice form with enhanced receptor activity. Our objective was to validate the c.811+32C>A variant as an emerging biomarker for pancreatic cancer risk and prognosis. Methods We genotyped variant c.811+32C>A in 122 pancreatic adenocarcinoma case patients and 106 control subjects by sequencing and examined its association with cancer risk and patient survival. We tested the functional effect of variant c.811+32C>A on pre–messenger RNA splicing in human embryonic kidney 293T and Capan-1 cells transfected with CCKBR minigenes. Results The allele frequency of the variant was similar between patients and control subjects (18.4% and 17.9%, respectively). Survival analysis showed no significant difference between median survival of patients with the C/C genotype (266 days) and patients with the A/C or A/A genotypes (257 days). CCKBR minigenes with or without variant c.811+32C>A exhibited no difference in expression of the intron-retaining splice variant. Conclusion These data indicate that variant c.811+32C>A in CCKBR does not have a significant impact on pancreatic cancer risk or survival in a Hungarian cohort.