[Pancreatic cancer with liver metastases: is it possible to improve survival by resection of oligopersistent primary tumor following neoadjuvant chemotherapy?] / Májáttétes pancreasrák: meghosszabbítható-e a túlélés az oligoperzisztens primer daganat neoadjuváns kemoterápiát követo reszekciójával?

The prognosis of pancreatic cancer is one of the worst of all cancers. Though the routine use of modern targeted and immunotherapy is still pending, the recently applied new chemotherapy combinations resulted in obvious improvement in the clinical management of pancreatic cancer. Adjuvant treatment followed by radical operation can increase the survival of the patients, moreover, neoadjuvant therapy for locally advanced tumors is associated with higher resectability rate. However, in metastatic disease only palliative chemotherapy could be indicated due to the dismal prognosis. The introduction of new chemotherapy combinations produced a major evolution by extending the median survival time of these patients. According to recent publications, even complete remission of the metastases can be achieved by the palliative chemotherapy, justifying a radical operation. This approach can be more advantageous, compared to patients treated with chemotherapy only. Reporting our two primary metastatic cases, we also endorse this new approach. The clinical significance of complex management is justified in the case of oligopersistence which is traditionally treated only with palliative systemic therapy. Orv Hetil. 2023; 164(43): 1712-1718.

Krónikus pancreatitis miatt végzett pancreasfej-resectiós mutéteink elemzése.

Introduction: In case of chronic pancreatitis with inflammatory enlargement of the pancreatic head, several operations exist for the treatment, such as the Beger-, Frey-, Whipple-procedures and the Berne modification. A comparison of the results of these procedures is presented in this study. In addition to this, innovations in pancreatojejunal and biliodigestive anastomosis are also described. Material and Methods: 231 pancreatic head resections were carried out between 1991 and 2021. The data were retrospectively evaluated. Late results were also examined using questionnaires. Results: The Berne modification and the Frey-procedure were more advantageous, than the Whipple- and the Beger-operation in terms of operating time, need for transfusion (P < 0,001), while regarding, the postoperative intensive care unit and total hospital stay both procedures were more favourable, than the Whipple one (P < 0,001). The early morbidity rate was the highest after the Whipple-procedure (P = 0,004). These differences were statistically significant. The reoperation and mortality rates were comparable between the groups. The quality of life of the patients was acceptable, nevertheless in the majority of the cases the alcohol and nicotine abuse was not stopped. Conclusion: The Frey-operation and the Berne modification were the most advantageous, regarding the early postoperative outcomes. However the latter one is preferable, due to its simplicity. During these procedures a single layer continuous suture technique was used for the pancreatojejunal anastomosis, and an extrapancreatic biliodigestive anastomosis is recommended for the solution of cholestasis. due to the superior results.

A Simple Classification of Pancreatic Duct Size and Texture Predicts Postoperative Pancreatic Fistula: A classification of the International Study Group of Pancreatic Surgery.

OBJECTIVE: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking. METHODS: A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort. RESULTS: Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001). CONCLUSION: For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Evidence Map of Pancreatic Surgery-A living systematic review with meta-analyses by the International Study Group of Pancreatic Surgery (ISGPS).

BACKGROUND: Pancreatic surgery is associated with considerable morbidity and, consequently, offers a large and complex field for research. To prioritize relevant future scientific projects, it is of utmost importance to identify existing evidence and uncover research gaps. Thus, the aim of this project was to create a systematic and living Evidence Map of Pancreatic Surgery. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched for all randomized controlled trials and systematic reviews on pancreatic surgery. Outcomes from every existing randomized controlled trial were extracted, and trial quality was assessed. Systematic reviews were used to identify an absence of randomized controlled trials. Randomized controlled trials and systematic reviews on identical subjects were grouped according to research topics. A web-based evidence map modeled after a mind map was created to visualize existing evidence. Meta-analyses of specific outcomes of pancreatic surgery were performed for all research topics with more than 3 randomized controlled trials. For partial pancreatoduodenectomy and distal pancreatectomy, pooled benchmarks for outcomes were calculated with a 99% confidence interval. The evidence map undergoes regular updates. RESULTS: Out of 30,860 articles reviewed, 328 randomized controlled trials on 35,600 patients and 332 systematic reviews were included and grouped into 76 research topics. Most randomized controlled trials were from Europe (46%) and most systematic reviews were from Asia (51%). A living meta-analysis of 21 out of 76 research topics (28%) was performed and included in the web-based evidence map. Evidence gaps were identified in 11 out of 76 research topics (14%). The benchmark for mortality was 2% (99% confidence interval: 1%-2%) for partial pancreatoduodenectomy and <1% (99% confidence interval: 0%-1%) for distal pancreatectomy. The benchmark for overall complications was 53% (99%confidence interval: 46%-61%) for partial pancreatoduodenectomy and 59% (99% confidence interval: 44%-80%) for distal pancreatectomy. CONCLUSION: The International Study Group of Pancreatic Surgery Evidence Map of Pancreatic Surgery, which is freely accessible via www.evidencemap.surgery and as a mobile phone app, provides a regularly updated overview of the available literature displayed in an intuitive fashion. Clinical decision making and evidence-based patient information are supported by the primary data provided, as well as by living meta-analyses. Researchers can use the systematic literature search and processed data for their own projects, and funding bodies can base their research priorities on evidence gaps that the map uncovers.

PACAP and PAC1 receptor expression in pancreatic ductal carcinoma.

Pancreatic carcinoma is one of the most malignant diseases and is associated with a poor survival rate. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide that acts on three different G protein-coupled receptors: the specific PAC1 and the VPAC1/2 that also bind vasoactive intestinal peptide. PACAP is widely distributed in the body and has diverse physiological effects. Among other things, it acts as a trophic factor and influences proliferation and differentiation of several different cells both under normal circumstances and tumourous transformation. Changes of PACAP and its receptors have been shown in various tumour types. However, it is not known whether PACAP and its specific receptor are altered in pancreatic cancer. Perioperative data of patients with pancreas carcinoma was investigated over a five-year period. Histological results showed Grade 2 or Grade 3 adenocarcinoma in most cases. PACAP and PAC1 receptor expression were investigated by immunohistochemistry. Staining intensity of PAC1 receptor was strong in normal tissues both in the exocrine and endocrine parts of the pancreas, the receptor staining was markedly weaker in the adenocarcinoma. PACAP immunostaining was weak in the exocrine part and very strong in the islets and nerve elements in non-tumourous tissues. The PACAP immunostaining almost disappeared in the adenocarcinoma samples. Based on these findings a decrease or lack of the PAC1 receptor/PACAP signalling might have an influence on tumour growth and/or differentiation.

Observational longitudinal multicentre investigation of acute pancreatitis (GOULASH PLUS): follow-up of the GOULASH study, protocol.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory condition that can lead to late consequences. Recurrent AP (RAP) develops in 20% of patients and chronic pancreatitis (CP) occurs in 7%-12.8%. However, we do not have sufficient information to establish an evidence-based statement to define early CP, or how to prevent its development. AIM: The aim of this study was to understand the influencing factors and to determine which parameters should be measured or used as a biomarker to detect the early phase of CP. METHODS/DESIGN: This is an observational prospective follow-up study of the GOULASH-trial (ISRTCN 63827758) in which (1) all severity of pancreatitis are included; (2) patients receive only therapeutic modalities which are accepted by the evidence based medicine (EBM) guideline; (3) whole blood, serum and plasma samples are stored in our biobank; and (4) large amount of variables are collected and kept in our electronic database including anamnestic data, physical examination, laboratory parameters, imaging, therapy and complications. Therefore, this fully characterised patient cohort are well suitable for this longitudinal follow-up study. Patients' selection: patients enrolled in the GOULASH study will be offered to join to the longitudinal study. The follow-up will be at 1, 2, 3, 4, 5 and 6 years after the episode of AP. Anamnestic data will be collected by questionnaires: (1) diet history questionnaire, (2) 36-Item Short-Form Health Survey, (3) physical activity questionnaire and (4) stress questionnaire. Genetic tests will be performed for the genes associated with CP. The exocrine and endocrine pancreatic, liver and kidney functions will be determined by laboratory tests, stool sample analyses and imaging. Cost-effectiveness will be analysed to examine the relationship between events of interest and health-related quality of life or to explore subgroup differences. CONCLUSION: This study will provide information about the risk and influencing factors leading to CP and identify the most useful measurable parameters. TRIAL REGISTRATION NUMBER: ISRCTN63396106.

Endoscopic sphincterotoMy for delayIng choLecystectomy in mild acute biliarY pancreatitis (EMILY study): protocol of a multicentre randomised clinical trial.

INTRODUCTION: According to the literature, early cholecystectomy is necessary to avoid complications related to gallstones after an initial episode of acute biliary pancreatitis (ABP). A randomised, controlled multicentre trial (the PONCHO trial) revealed that in the case of gallstone-induced pancreatitis, early cholecystectomy was safe in patients with mild gallstone pancreatitis and reduced the risk of recurrent gallstone-related complications, as compared with interval cholecystectomy. We hypothesise that carrying out a sphincterotomy (ES) allows us to delay cholecystectomy, thus making it logistically easier to perform and potentially increasing the efficacy and safety of the procedure. METHODS/DESIGN: EMILY is a prospective, randomised, controlled multicentre trial. All patients with mild ABP, who underwent ES during the index admission or in the medical history will be informed to take part in EMILY study. The patients will be randomised into two groups: (1) early cholecystectomy (within 6 days after discharge) and (2) patients with delayed (interval) cholecystectomy (between 45 and 60 days after discharge). During a 12-month period, 93 patients will be enrolled from participating clinics. The primary endpoint is a composite endpoint of mortality and recurrent acute biliary events (that is, recurrent ABP, acute cholecystitis, uncomplicated biliary colic and cholangitis). The secondary endpoints are organ failure, biliary leakage, technical difficulty of the cholecystectomy, surgical and other complications. ETHICS AND DISSEMINATION: The trial has been registered internationally ISRCTN 10667869, and approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (EKU/2018/12176-5). TRIAL REGISTRATION NUMBER: ISCRTN 10667869; Pre-results.

[A diagnostic challenge: paraduodenal pancreatitis. Two case reports]. / Egy diagnosztikus kihívás: paraduodenalis pancreatitis. Két eset bemutatása.

The paraduodenal, or groove pancreatitis is a lesser-known type of chronic pancreatitis, often mimicking malignancy, hence resulting in serious differential diagnostic challenges. Herein we report two cases of this entity. Both required analysis of the surgical specimen in order to ensure the diagnosis due to inadequate preoperative histological sampling and a vague clinical presentation. In the first case, strong suspicion of malignancy following imaging, while in the second, severe gastric outlet stenosis indicated the resection. In our report, we give a clinicopathological summary from the literature of this entity, including its epidemiology, clinical presentation and applicable diagnostic methods as well as macroscopic and microscopic pathomorphology. The pathogenesis of this disease is complex. Beside the role of alcohol, anatomic variations of the pancreatic ductal system, pancreatic islets in duodenal wall resulting from incomplete involution of dorsal pancreas, or Brunner gland hyperplasia (often observed as part of the lesion) can all play a role in the disturbance of pancreatic fluid discharge in the minor papilla area, eventually leading to this specific localised inflammation. In addition, recent investigations revealed a susceptible role of genetic polymorphism in the persistent inflammatory disorders of the pancreas. Besides summarizing the differential diagnostic aspects, we also discuss therapeutic possibilities, underlining the conservative methods, which can be used with good efficacy after a successful identification of this entity. Orv Hetil. 2019; 160(22): 873-879.

Evidence Supports Tradition: The in Vitro Effects of Roman Chamomile on Smooth Muscles.

The dried flowers of Chamaemelum nobile (L.) All. have been used in traditional medicine for different conditions related to the spasm of the gastrointestinal system. However, there have been no experimental studies to support the smooth muscle relaxant effect of this plant. The aim of our research was to assess the effects of the hydroethanolic extract of Roman chamomile, its fractions, four of its flavonoids (apigenin, luteolin, hispidulin, and eupafolin), and its essential oil on smooth muscles. The phytochemical compositions of the extract and its fractions were characterized and quantified by HPLC-DAD, the essential oil was characterized by GC and GC-MS. Neuronally mediated and smooth muscle effects were tested in isolated organ bath experiments on guinea pig, rat, and human smooth muscle preparations. The crude herbal extract induced an immediate, moderate, and transient contraction of guinea pig ileum via the activation of cholinergic neurons of the gut wall. Purinoceptor and serotonin receptor antagonists did not influence this effect. The more sustained relaxant effect of the extract, measured after pre-contraction of the preparations, was remarkable and was not affected by an adrenergic beta receptor antagonist. The smooth muscle-relaxant activity was found to be associated with the flavonoid content of the fractions. The essential oil showed only the relaxant effect, but no contracting activity. The smooth muscle-relaxant effect was also detected on rat gastrointestinal tissues, as well as on strip preparations of human small intestine. These results suggest that Roman chamomile extract has a direct and prolonged smooth muscle-relaxant effect on guinea pig ileum which is related to its flavonoid content. In some preparations, a transient stimulation of enteric cholinergic motoneurons was also detected. The essential oil also had a remarkable smooth muscle relaxant effect in this setting. Similar relaxant effects were also detected on other visceral preparations, including human jejunum. This is the first report on the activity of Roman chamomile on smooth muscles that may reassure the rationale of the traditional use of this plant in spasmodic gastrointestinal disorders.

[Appleby procedure - an option for surgical treatment of pancreatic body tumour infiltrating the celiac axis]. / Appleby-mutét − lehetoség truncus coeliacust infiltráló pancreastest tumor sebészi kezelésére.

CASE PRESENTATION: After neoadjuvant oncological therapy the surgical treatment of distal pancreatic tumour - infiltrating the celiac axis and the stomach - was reported. During the operation resection of the trunc, distal pancreatectomy, splenectomy, total gastrectomy, resection of the left adrenal gland and cholecystectomy were carried out. The patient's clinical course was uneventful, only transient alteration of liver functions was detected. Histological work-up revealed R1 resection, so adjuvant oncological therapy was decided. DISCUSSION: Distal pancreatic tumours are frequently inoperable. Infiltration of the celiac axis was similarly considered, however there is a chance for radical operation by the resection of the trunc, when the pancreaticoduodenal arcade will provide the arterial blood supply to the liver. Based on the above case the operative technique and the relevant questions were discussed. In pancreatic tumour and arterial infiltration the preoperative chemotherapy is absolutely recommended, because there is a chance for radical surgery in case of good response.

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).

[Resection of liver and abdominal wall metastasis 11 years after pancreatoduodenectomy. Case report]. / Metasztázis miatt végzett máj- és hasfalreszekció 11 évvel a pancreatoduodenectomia után.

Pancreatic cancer has adverse prognosis. Disease recurrence is typical and it occurs mainly within the first 2 years postoperatively. However late and soliter metastases are rare. This case report shows the history of a male patient, who was radically operated on for pancreatic cancer. 11 years later a solitary liver metastasis has developed and it was completely removed by resection. 1 year postoperatively the patient is doing well. Our case demonstrates that in patients after resection for pancreatic cancer, redo surgery might be justified in case of late and isolated metastasis. Orv Hetil. 2017; 158(28): 1109-1111.

Chronic pancreatitis: Multicentre prospective data collection and analysis by the Hungarian Pancreatic Study Group.

INTRODUCTION: Chronic pancreatitis is an inflammatory disease associated with structural and functional damage to the pancreas, causing pain, maldigestion and weight loss and thus worsening the quality of life. AIMS AND METHODS: Our aim was to find correlations from a multicentre database representing the epidemiological traits, diagnosis and treatment of the disease in Hungary. The Hungarian Pancreatic Study Group collected data prospectively from 2012 to 2014 on patients suffering from chronic pancreatitis. Statistical analysis was performed on different questions. RESULTS: Data on 229 patients (74% male and 26% female) were uploaded from 14 centres. Daily alcohol consumption was present in the aetiology of 56% of the patients. 66% of the patients were previously treated for acute exacerbation. One third of the patients had had previous endoscopic or surgical interventions. Pain was present in 69% of the cases, endocrine insufficiency in 33%, diarrhoea in 13% and weight loss in 39%. Diagnosis was confirmed with US (80%), CT scan (52%), MRI-MRCP (6%), ERCP (39%), and EUS (7,4%). A functional test was carried out in 5% of the patients. In 31% of the cases, an endoscopic intervention was performed with the need for re-intervention in 5%. Further elective surgical intervention was necessitated in 44% of endoscopies. 20% of the registered patients were primarily treated with surgery. The biliary complication rate for surgery was significantly smaller (2%) than endoscopy (27%); however, pancreatic complications were higher in the patients treated with surgery. Patients who smoked regularly needed significantly more surgical intervention following endoscopy (66.7% vs. 26.9%, p = 0.002) than non-smokers, and the ratio of surgical intervention alone was also significantly higher (27.3% vs. 10.8%, p = 0.004). The ratio of surgery in patients who smoked and drank was significantly higher (30.09% vs. 12.5%, p = 0.012) than in abstinent and non-smoking patients, similarly to the need for further surgical intervention after endoscopic treatment (71.43% vs. 27.78%, p = 0.004). CONCLUSIONS: According to the data analysed, the epidemiological data and the aetiological factors in our cohort differ little from European trends. The study highlighted the overuse of ERCP as a diagnostic modality and the low ratio of use of endoscopic ultrasonography. The results proved that alcohol consumption and smoking represent risk factors for the increased need for surgical intervention. Chronic pancreatitis should be treated by multidisciplinary consensus grounded in evidence-based medicine.

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.

The TRPA1 Activator Allyl Isothiocyanate (AITC) Contracts Human Jejunal Muscle: Pharmacological Analysis.

The contractile effect of AITC (300 µM) on human jejunal longitudinal strips was inhibited by the TRPA1 antagonist HC 030031 and atropine or scopolamine, but was insensitive to tetrodotoxin, purinoceptor antagonists or capsaicin desensitization. It is concluded that TRPA1 activation stimulates a cholinergic mechanism in a tetrodotoxin-resistant manner.

Pancreatojejunostomy with modified purse-string suture technique.

PURPOSE: Despite many efforts, pancreatic fistula remains the most troublesome complication following pancreatic resections, especially in case of anastomosis made with soft pancreatic tissue. The purpose of the authors was to show their modification of purse-string pancreatodigestive anastomosis and the results obtained. METHODS: Between January 2013 and June 2015, the technique was applied in 49 patients; one purse-string suture and two U-shaped mattress sutures were used to create the pancreatojejunal anastomosis. In case of soft pancreatic parenchyma, an external stent was temporarily left in the main pancreatic duct. The most frequent pathology was pancreatic cancer, and a pylorus-preserving Whipple procedure was mostly done. RESULTS: Postoperative early morbidity rate was 35 %. There were two fistulas, one grade A fistula from a fibrotic pancreas (4.2 %) and one grade B in case of a soft pancreas (4 %). However, there was no reoperation and mortality. CONCLUSIONS: According to favorable results, the modification of the purse-string suture technique makes this method even safer.

SPINK1 Promoter Variants in Chronic Pancreatitis.

OBJECTIVES: Serine protease inhibitor Kazal type 1 (SPINK1) provides an important line of defense against premature trypsinogen activation within the pancreas. Our aim was to identify pathogenic SPINK1 promoter variants associated with chronic pancreatitis (CP). METHODS: One hundred CP patients (cases) and 100 controls with no pancreatic disease from the Hungarian National Pancreas Registry were enrolled. Direct sequencing of SPINK1 promoter region was performed. Functional characterization of variants was carried out using luciferase reporter gene assay. RESULTS: Two common polymorphisms (c.-253T>C and c.-807C>T) were found in both cases and controls. Variant c.253T>C was enriched in cases relative to controls (odds ratio, 2.1; 95% confidence interval, 1.2-3.8; P = 0.015). Variant c.-215G>A was detected in 3 of 100 cases; always linked with the pathogenic variant c.194+2T>C. Novel promoter variants c.-14G>A, c.-108G>T, and c.-246A>G were identified in 1 case each. Functional analysis showed decreased promoter activity for variants c.-14G>A (80%), c.-108G>T (31%), and c.-246A>G (47%) whereas activity of variant c.-215G>A was increased (201%) and variant c.-253T>C was unchanged compared with wild type. CONCLUSIONS: The common promoter variant c.-253T>C was associated with CP in this cohort. Two of 3 newly identified SPINK1 promoter variants seem to exhibit significant functional defects and should be considered potential risk factors for CP.

Genetic analysis of the bicarbonate secreting anion exchanger SLC26A6 in chronic pancreatitis.

BACKGROUND: Pancreatic ductal HCO3(-) secretion is critically dependent on the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) and the solute-linked carrier 26 member 6 anion transporter (SLC26A6). Deterioration of HCO3(-) secretion is observed in chronic pancreatitis (CP), and CFTR mutations increase CP risk. Therefore, SLC26A6 is a reasonable candidate for a CP susceptibility gene, which has not been investigated in CP patients so far. METHODS: As a first screening cohort, 106 subjects with CP and 99 control subjects with no pancreatic disease were recruited from the Hungarian National Pancreas Registry. In 60 non-alcoholic CP cases the entire SLC26A6 coding region was sequenced. In the Hungarian cohort variants c.616G > A (p.V206M) and c.1191C > A (p.P397=) were further genotyped by restriction fragment length polymorphism analysis. In a German replication cohort all exons were sequenced in 40 non-alcoholic CP cases and variant c.616G > A (p.V206M) was further analyzed by sequencing in 321 CP cases and 171 controls. RESULTS: Sequencing of the entire coding region revealed four common variants: intronic variants c.23 + 78_110del, c.183-4C > A, c.1134 + 32C > A, and missense variant c.616G > A (p.V206M) which were found in linkage disequilibrium indicating a conserved haplotype. The distribution of the haplotype did not show a significant difference between patients and controls in the two cohorts. A synonymous variant c.1191C > A (p.P397=) and two intronic variants c.1248 + 9_20del and c.-10C > T were detected in single cases. CONCLUSION: Our data show that SLC26A6 variants do not alter the risk for the development of CP.