Ákos Szücs

Vectorial bicarbonate transport by Capan-1 cells: a model for human pancreatic ductal secretion

Human pancreatic ducts secrete a bicarbonate-rich fluid but our knowledge of the secretory process is based mainly on studies of animal models. Our aim was to determine whether the HCO₃^- transport mechanisms in a human ductal cell line are similar to those previously identified in guinea-pig pancreatic ducts. Intracellular pH was measured by microfluorometry in Capan-1 cell monolayers grown on permeable filters and loaded with BCECF. Epithelial polarization was assessed by immunolocalization of occludin. Expression of mRNA for key electrolyte transporters and receptors was evaluated by RT-PCR. Capan-1 cells grown on permeable supports formed confluent, polarized monolayers with well developed tight junctions. The recovery of pH_i from an acid load, induced by a short NH₄⁺ pulse, was mediated by Na⁺-dependent transporters located exclusively at the basolateral membrane. One was independent of HCO₃^- and blocked by EIPA (probably NHE1) while the other was HCO₃^--dependent and blocked by H₂DIDS (probably pNBC1). Changes in pH_i following blockade of basolateral HCO₃^- accumulation confirmed that the cells achieve vectorial HCO₃^- secretion. Dose-dependent increases in HCO₃^- secretion were observed in response to stimulation of both secretin and VPAC receptors. ATP and UTP applied to the apical membrane stimulated HCO₃^- secretion but were inhibitory when applied to the basolateral membrane. HCO₃^- secretion in guinea-pig ducts and Capan-1 cell monolayers share many common features, suggesting that the latter is an excellent model for studies of human pancreatic HCO₃^- secretion.

Chronic pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group

Chronic pancreatitis is an inflammatory disease associated with structural and functional damage of the pancreas. In most cases pain, maldigestion and weight loss are the leading symptoms, which significantly worsen the quality of life. Correct diagnosis and differential diagnosis of chronic pancreatitis and treatment of these patients requires up-to-date and evidence based treatment guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available international guidelines and evidence. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and complemented and/or modified the international guidelines if it was necessary. 123 relevant clinical questions in 11 topics were defined. Evidence was classified according to the UpToDate® grading system. The draft of the guidelines were presented and discussed at the consensus meeting in September 12, 2014. All clinical questions were accepted with total or strong agreement. The present guideline is the first evidence based guideline for chronic pancreatitis in Hungary. This guideline provides very important and helpful data for tuition, everyday practice and proper financing of chronic pancreatitis. Therefore, the authors believe that these guidelines will widely become a basic reference in Hungary.

Pediatric pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group

Pediatric pancreatitis is a rare disease with variable etiology. In the past 10-15 years the incidence of pediatric pancreatitis has been increased. The management of pediatric pancreatitis requires up-to-date and evidence based management guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available international guidelines and evidences. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and complemented and/or modified the international guidelines if it was necessary. In 8 clinical topics (diagnosis; etiology; prognosis; imaging; therapy; biliary tract management; complications; chronic pancreatitis) 50 relevant questions were defined. Evidence was classified according to the UpToDate(®) grading system. The draft of the guidelines was presented and discussed at the consensus meeting on September 12, 2014. All clinical statements were accepted with total (more than 95%) agreement. The present Hungarian Pancreatic Study Group guideline is the first evidence based pediatric pancreatitis guideline in Hungary. The present guideline is the first evidence-based pancreatic cancer guideline in Hungary that provides a solid ground for teaching purposes, offers quick reference for daily patient care in pediatric pancreatitis and guides financing options. The authors strongly believe that these guidelines will become a standard reference for pancreatic cancer treatment in Hungary.

Pancreatic cancer. Evidence based management guidelines of the Hungarian Pancreatic Study Group

A pancreasrak gyakran kesőn diagnosztizalt korkep, amely a legrosszabb korlefolyasu betegsegek csoportjaba sorolhato, ezert a szűrese, diagnosztikaja, kezelese es palliacioja korszerű es bizonyitekokon alapulo utmutatot igenyel. A Magyar Hasnyalmirigy Munkacsoport celul tűzte ki, hogy a jelenleg elerhető nemzetkozi iranyvonalakat, illetve evidenciakat alapul veve a pancreasrak kezelesenek kulcskerdesei vonatkozasaban bizonyitek alapu iranyelveket fogalmazzon meg. A Magyar Hasnyalmirigy Munkacsoport altal kijelolt előkeszitő es konzulens munkacsoport leforditotta, es ahol szuksegesnek talalta, kiegeszitette es/vagy modositotta a nemzetkozi iranyelveket. Osszesen 10 temakorben (Rizikofaktorok es genetika, Szűres, Diagnozis, Staging, Sebeszi kezeles, Patologiai feldolgozas, Szisztemas kezeles, Sugarterapia, Palliacio es szupportiv kezeles, Utankovetes es rekurrencia) 37 relevans iranyelv kerult osszeallitasra. Az evidencia osztalyozasa a National Comprehensive Cancer Network (NCCN) rendszere alapjan kerult meghatarozasra. Az osszeallitott iranyelvek a 2014. szeptember 12-ei konszenzustalalkozon kerultek bemutatasra es megvitatasra. A resztvevők 15 iranyelvet teljes (95% feletti) egyetertessel, mig 22 iranyelvet erős (70% feletti) egyetertessel fogadtak el. A Magyar Hasnyalmirigy Munkacsoport kezelesi iranyelvei az első, bizonyitek alapjan keszult pancreasrak-kezelesi utmutato hazankban. Az iranyelv komoly segitseget nyujthat a pancreasrak oktatasahoz, a mindennapi betegellatashoz es a megfelelő finanszirozas kialakitasahoz. Ezert a szerzők biznak abban, hogy ezen iranyelvek minel szelesebb korben alapreferenciakent fognak szolgalni Magyarorszagon. Orv. Hetil., 2015, 156(8), 326–339.Pancreatic cancer is a disease with a poor prognosis usually diagnosed at a late stage. Therefore, screening, diagnosis, treatment and palliation of pancreatic cancer patients require up-to-date and evidence based management guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available scientific evidence and international guidelines. The preparatory and consultation board appointed by the Hungarian Pancreatic Study Group translated and complemented/modified the recent international guidelines. 37 clinical statements in 10 major topics were defined (Risk factors and genetics, Screening, Diagnosis, Staging, Surgical care, Pathology, Systemic treatment, Radiation therapy, Palliation and supportive care, Follow-up and recurrence). Evidence was graded according to the National Comprehensive Cancer Network (NCCN) grading system. The draft of the guideline was presented and discussed at the consensus meeting in September 12, 2014. Statements were accepted with either total (more than 95% of votes, n = 15) or strong agreement (more than 70% of votes, n = 22). The present guideline is the first evidence-based pancreatic cancer guideline in Hungary that provides a solid ground for teaching purposes, offers quick reference for daily patient care and guides financing options. The authors strongly believe that these guidelines will become a standard reference for pancreatic cancer treatment in Hungary.

Meta-analysis of the long term success rate of different interventions in benign biliary strictures

Background Benign biliary stricture is a rare condition and the majority of the cases are caused by operative trauma or chronic inflammation based on various etiology. Although the initial results of endoscopic, percutaneous and surgical treatment are impressive, no comparison about long term stricture resolution is available. Aims The goal of this study was to compare the long term disease free survival in benign biliary strictures with various etiology after surgery, percutaneous transhepatic—and endoscopic treatment. Methods PubMed, Embase, and Cochrane Library were searched by computer and manually for published studies. The investigators selected the publications according to the inclusion and exclusion criteria, processed the data and assessed the quality of the selected studies. Meta-analysis of data of 24 publications was performed to compare long term disease free survival of different treatment groups. Results Compared the subgroups surgery resulted in the highest long term stricture resolution rate, followed by the percutaneous transhepatic treatment, the multiple plastic stent insertion and covered self-expanding metal stents (SEMS), however the difference was not significant. All compared methods are significantly superior to the single plastic stent placement. Long term stricture resolution rate irrespectively of any therapy is still not more than 84%. Conclusions In summary, the use of single plastic stent is not recommended. Further randomized studies and innovative technical development are required for improving the treatment of benign biliary strictures.

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.

Autoimmun pancreatitis. A Magyar Hasnyálmirigy Munkacsoport bizonyítékon alapuló kezelési irányelvei

Az autoimmun pancreatitis ritka megbetegedes, amely megjeleneseben akar hasnyalmirigy-daganatot utanozhat, azonban ez utobbival ellentetben nem műteti, hanem gyogyszeres kezelest igenyel. A betegseg korrekt diagnozisa, differencialdiagnosztikaja es a betegek megfelelő kezelese korszerű es bizonyitekokon alapulo kezelesi utmutatot igenyel. A Magyar Hasnyalmirigy Munkacsoport celul tűzte ki, hogy a jelenleg elerhető nemzetkozi iranyvonalakat, illetve evidenciakat alapul veve az autoimmun pancreatitis kezelesenek kulcskerdesei vonatkozasaban bizonyitekalapu iranyelveket fogalmazzon meg. A Magyar Hasnyalmirigy Munkacsoport altal kijelolt előkeszitő es konzulens munkacsoport leforditotta, es ahol szuksegesnek talalta, kiegeszitette es/vagy modositotta a nemzetkozi iranyelveket. Osszesen 4 temakorben (Alapok, Diagnozis, Differencialdiagnosztika, Terapia) 29 relevans kerdest allitott ossze. Az evidencia osztalyozasat az UpToDate ® rendszere alapjan hatarozta meg. Az osszeallitott iranyelvek a 2014. szeptember 12-ei konszenzustalalkozon kerultek bemutatasra es megvitatasra. A resztvevők minden kerdest csaknem teljes (95% feletti) egyetertessel fogadtak el. A Magyar Hasnyalmirigy Munkacsoport kezelesi iranyelvei az első, bizonyitek alapjan keszult autoimmun pancreatitis kezelesi utmutato hazankban. Az iranyelv komoly segitseget nyujthat az autoimmun pancreatitis oktatasahoz, a mindennapi betegellatashoz es a megfelelő finanszirozas kialakitasahoz. Ezert a szerzők biznak abban, hogy ezen iranyelvek minel szelesebb korben alapreferenciakent fognak szolgalni Magyarorszagon. Orv. Hetil., 2015, 156(8), 292–307.

Restoration of energy level in the early phase of acute pediatric pancreatitis

Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatment of acute pediatric pancreatitis. The preferred reporting items for systematic review (PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (PubMed: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly (SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better presentation of research are crucially needed to achieve a higher level of evidence.

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39–0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.