Potential role for probiotics in the prevention of infectious complications during acute pancreatitis

Acute pancreatitis has a high mortality in case of secondary infection of (peri-)pancreatic necrosis. Bacterial translocation is held responsible for the majority of these infectious complications of severe acute pancreatitis. Prophylactic strategies should therefore be directed at the three most important pathophysiological mechanisms of bacterial translocation: disturbed small-bowel motility and bacterial overgrowth, failure of the mucosal barrier function and a disturbed response of the immune system. In-vitro studies and research in experimental animals have shown that specially selected probiotics exert an effect on these mechanisms and can prevent bacterial translocation. Recently, several randomised, double-blind, placebo-controlled trials evaluating prophylactic treatment with enteral probiotics have shown good results. A Dutch multicentre trial, 'Probiotics in pancreatitis trial' (PROPATRIA), is currently underway.     

Transatlantic registries of pancreatic surgery in the United States of America,Germany, the Netherlands,and Sweden: Comparing design,variables, patients,treatment strategies,and outcomes

BackgroundRegistries of pancreatic surgery have become increasingly popular as they facilitate both quality improvement and clinical research. We aimed to compare registries for design, variables collected, patient characteristics, treatment strategies, clinical outcomes, and pathology.MethodsRegistered variables and outcomes of pancreatoduodenectomy (2014–2017) in 4 nationwide or multicenter pancreatic surgery registries from the United States of America (American College of Surgeons National Surgical Quality Improvement Program), Germany (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie - Studien-, Dokumentations- und Qualitätszentrum), the Netherlands (Dutch Pancreatic Cancer Audit), and Sweden (Swedish National Pancreatic and Periampullary Cancer Registry) were compared. A core registry set of 55 parameters was identified and evaluated using relative and absolute largest differences between extremes (smallest versus largest).ResultsOverall, 22,983 pancreatoduodenectomies were included (15,224, 3,558, 2,795, and 1,406 in the United States of America, Germany, the Netherlands, and Sweden). Design of the registries varied because 20 out of 55 (36.4%) core parameters were not available in 1 or more registries. Preoperative chemotherapy in patients with pancreatic ductal adenocarcinoma was administered in 27.6%, 4.9%, 7.0%, and 3.4% (relative largest difference 8.1, absolute largest difference 24.2%, P < .001). Minimally invasive surgery was performed in 7.8%, 4.5%, 13.5%, and unknown (relative largest difference 3.0, absolute largest difference 9.0%, P < .001). Median length of stay was 8.0, 16.0, 12.0, and 11.0 days (relative largest difference 2.0, absolute largest difference 8.0, P < .001). Reoperation was performed in 5.7%, 17.1%, 8.7%, and 11.2% (relative largest difference 3.0, absolute largest difference 11.4%, P < .001). In-hospital mortality was 1.3%, 4.7%, 3.6%, and 2.7% (relative largest difference 3.6, absolute largest difference 3.4%, P < .001).ConclusionConsiderable differences exist in the design, variables, patients, treatment strategies, and outcomes in 4 Western registries of pancreatic surgery. The absolute largest differences of 24.3% for the use of preoperative chemotherapy, 9.0% for minimally invasive surgery, 11.4% for reoperation rate, and 3.4% for in-hospital mortality require further study and improvement. This analysis provides 55 core parameters for pancreatic surgery registries.     

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

Objective: In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients.

Methods and materials: We searched MEDLINE and Embase, supplemented by handsearching, for clinical studies involving hyperthermia in pancreatic cancer patients. The quality of studies was evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Primary outcome was treatment efficacy; we calculated overall response rate and the weighted estimate of the population median overall survival (m_p) and compared these between hyperthermia and control cohorts.

Results: Overall, 14 studies were included, with 395 patients with locally advanced and/or metastatic pancreatic cancer of whom 248 received hyperthermia. Patients were treated with regional (n?=?189), intraoperative (n?=?39) or whole-body hyperthermia (n?=?20), combined with chemotherapy, radiotherapy or both. Quality of the studies was low, with level of evidence 3 (five studies) and 4. The six studies including a control group showed a longer m_p in the hyperthermia groups than in the control groups (11.7 vs. 5.6?months). Overall response rate, reported in three studies with a control group, was also better for the hyperthermia groups (43.9% vs. 35.3%).

Conclusions: Hyperthermia, when added to chemotherapy and/or radiotherapy, may positively affect treatment outcome for patients with pancreatic cancer. However, the quality of the reviewed studies was limited and future randomised controlled trials are needed to establish efficacy.     

Low Inducibility of CYP1A Activity by Polychlorinated Biphenyls (PCBs) in Flounder (Platichthys flesus): Characterization of the Ah Receptor and the Role of CYP1A Inhibition

Several studies have reported a low inducibility of hepaticcytochrome P4501A (CYP1A) activity in European flounder (Platichthysflesus) following exposure to mixtures of polychlorinated biphenyls(PCBs). Here we report on mechanistic studies toward understandingthis low CYP1A inducibility of flounder, involving molecularcharacterization of the Ah receptor (AhR) pathway as well asinhibition of the CYP1A catalytic activity by PCB congeners.Hepatic cytosolk AhR levels in flounder were determined usinghydroxylapatite, protamine sulfate adsorption analysis, or velocitysedimentation on sucrose gradients. AhR levels in flounder ({smalltilde}2–7 fmol/mg protein) were much lower than observedgenerally in rodents ({small tilde}50–300 fmol/mg protein).Molecular characterization of the flounder AhR was providedby first-strand cDNA synthesis and amplification of flounderhepatic poly(A)⁺ RNA using RT-PCR. A 690-bp product was found,similar in size to a Fundulus AhR cDNA. The specificity of the690-bp band was established by Southern blotting and hybridizationwith a degenerate AhR oligonucleotide. The deduced amino acidsequence of the flounder AhR fragment was 59–60% identicalto mammalian AhR sequences. Although the AhR is present in floundercytosol, we were unable to demonstrate detectable amounts ofinducibk TCDD-AhR-DRE complex in gel-retardation assays. Highinduction levels of CYP1A protein and associated EROD activityhave been previously found in flounder following exposure to2,3,7,8-tetrachlorod-ibenzo-p-dioxin (TCDD). In contrast, theinduction of CYP1A catalytic activity by PCB mixtures remainsunexpectedly low. Therefore, we further characterized the inhibitorypotential of PCB congeners on CYP1A activity in flounder andcompared this with inhibitory effects of PCB congeners on ratCYP1A activity. Analysis in vitro demonstrated that 3,3',4,4'-tetraCB,3,3',4,4',5-pentaCB, 2,2',4,4',5,5'-hexaCB, 3,3',4,4',5,5'-hexaCB,and the commercial PCB mixture Clophen A50 are potent competitiveinhibitors of hepatic microsomal CYP1A catalytic activity inflounder and rat The K_m for ethoxyresonifin (0.095 µM)in flounder is strikingly close to K_i's found for the testedPCBs. This emphasizes the possible involvement of PCB congenersin inhibition of EROD activity in PHAH exposed fish. Finally,our data indicate that flounder CYP1A is more efficient in metabolizingethoxyresonifin than that of rat CYP1A.