Andrea Szentesi

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

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

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.

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).

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.

Ginger (Zingiber officinale): An alternative for the prevention of postoperative nausea and vomiting. A meta-analysis

BACKGROUND Postoperative nausea and vomiting (PONV) is a distressing outcome related to surgeries. Traditionally, ginger has been used in the treatment of nausea and vomiting for thousands of years. Recently, several randomized, placebo-controlled clinical trials (RCTs) have been conducted to evaluate the efficacy of ginger in PONV. PURPOSE To systematically evaluate the efficacy of ginger on postoperative nausea and vomiting (PONV) compared to placebo, based on RCTs. STUDY DESIGN The meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. METHODS PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for relevant studies. Human, placebo-controlled clinical studies of patients undergoing any types of surgery, receiving pharmacological doses of ginger per os were included. Only clinical trials with explicit description of the ginger preparation used were analysed. No language or publication year restrictions was applied. RESULTS Ten randomized trials including a total of 918 patients were pooled for the statistical analysis. The present meta-analysis supports that ginger has a significant effect on the severity of PONV based on visual analogue scale (VAS) results: in a fixed effects model the pooled standardized mean difference (SMD) was -0.247 (favouring ginger; [LL]: -0.455, [UL]: -0.040, p-value: 0.019). Moreover, our results suggest that ginger reduces the incidence of postoperative nausea and vomiting, as well antiemetic drug demand; however, these effects are not statistically significant compared to placebo, which may be explained by underdosing. CONCLUSIONS According to our thorough meta-analysis ginger is safe and well tolerated, and decreases the severity of PONV, and may lower the incidence of postoperative nausea and vomiting, which in turn may reduce antiemetic drug demand, suggesting that ginger may be a useful alternative to antiemetic medications to alleviate PONV.

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis

BACKGROUND/OBJECTIVES Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP. METHODS We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses. RESULTS Meta-analyses of all AP patients depicted significant (p-value < 0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81-0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07-1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12-1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63-0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07-1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07-1.93, p-value 0.02) in the alcoholic sub-group only. CONCLUSIONS The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP.

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.

Genetic determinants of telomere length and risk of pancreatic cancer: a PANDoRA study: “Teloscore” and PDAC risk

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676‐rs409627, TERT‐rs2736100, CTC1‐rs3027234, DHX35‐rs6028466, PXK‐rs6772228, NAF1‐rs7675998, ZNF208‐rs8105767, OBFC1‐rs9420907, ACYP2‐rs11125529 and TERC‐rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT‐rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1‐rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome‐wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome‐wide candidate SNP for PDAC risk (TERT‐rs2736100), a completely new signal (NAF1‐rs7675998) approaching genome‐wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.