Synergism interaction between genetic polymorphisms in drug metabolizing enzymes and NSAIDs on upper gastrointestinal haemorrhage: a multicenter case-control study.

BACKGROUND: Interindividual genetic variations contribute to differences in patients' response to drugs as well as to the development of certain disorders. Patients who use non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal disorders, mainly upper gastrointestinal haemorrhage (UGIH). Studies about the interaction between NSAIDs and genetic variations on the risk of UGIH are scarce. Therefore, we investigated the effect of 16 single nucleotide polymorphisms (SNPs) involved in drug metabolism on the risk of NSAIDs-induced UGIH. MATERIALS AND METHODS: We conducted a multicenter case-control study of 326 cases and 748 controls. Participants were sub-grouped into four categories according to NSAID exposure and genetic profile. We estimated odds ratios (ORs) and their 95% confidence intervals (CI) using generalized linear mixed models for dependent binomial variables and then calculated the measures of interaction, synergism index (S), and relative excess risk due to interaction (RERI). We undertook stratified analyses by the type of NSAID (aspirin, non-aspirin). RESULTS: We observed an excess risk of UGIH due to an interaction between any NSAID, non-aspirin NSAIDs or aspirin and carrying certain SNPs. The greatest excess risk was observed for carriers of: rs2180314:C>G [any NSAID: S = 3.30 (95%CI: 1.24-8.80), RERI = 4.39 (95%CI: 0.70-8.07); non-aspirin NSAIDs: S = 3.42 (95%CI: 1.12-10.47), RERI = 3.97 (95%CI: 0.44-7.50)], and rs4809957:A>G [any NSAID: S = 2.11 (95%CI: 0.90-4.97), RERI = 3.46 (95%CI: -0.40-7.31)]. Aspirin use by carriers of rs6664:C>T is also associated with increased risk of UGIH [ORaspirin(+),wild-type: 2.22 (95%CI: 0.69-7.17) vs. ORaspirin(+),genetic-variation: 7.72 (95%CI: 2.75-21.68)], yet larger sample size is needed to confirm this observation. CONCLUSIONS: The joint effect of the SNPs s2180314:C>G and rs4809957:A>G and NSAIDs are more than three times higher than the sum of their individual effects. Personalized prescriptions based on genotyping would permit a better weighing of risks and benefits from NSAID consumption.KEY MESSAGESMulticenter case-control study of the effect of genetic variations involved in drug metabolism on upper gastrointestinal haemorrhage (UGIH) induced by NSAIDs (aspirin and non-aspirin).There is a statistically significant additive synergism interaction between certain genetic polymorphisms and NSAIDs on UGIH: rs2180314:C>G and rs4809957:A>G. The joint effect of each of these single nucleotide polymorphisms and NSAIDs on UGIH is more than three times higher than the sum of their individual effects.Genetic profiling and personalized prescriptions would be useful in managing the risks and benefits associated with NSAIDs.

A multicenter case-control study of the effect of e-nos VNTR polymorphism on upper gastrointestinal hemorrhage in NSAID users.

Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case-control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): -1.35 (95% CI -5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: -2.68 (95% CI -6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype.

Endoscopic drainage with local infusion of antibiotics to avoid necrosectomy of infected walled-off necrosis.

BACKGROUND: Current treatment of infected pancreatic necrosis (IPN) follows a step-up approach. Our group designed a step-up protocol that associates endoscopic drainage with local infusion of antibiotics through transmural nasocystic catheter. Aim of our study was to evaluate our step-up protocol for IPN in terms of proportion of patients avoiding necrosectomy. METHODS: Retrospective analysis of patients admitted with acute pancreatitis (AP) between January 2015 and December 2018. The number of patients who responded to each therapeutic step were analysed: step 1, systemic antibiotics; step 2, endoscopic transmural drainage and local infusion of antibiotics; step 3, endoscopic necrosectomy. RESULTS: 1158 patients with AP were included. 110 patients (8.4%) suffered from necrotising pancreatitis; 48 of them had IPN (42.6% of necrotising pancreatitis) and were treated with systemic antibiotics. Nineteen patients (39.6% of IPN) responded and did not required any invasive therapy. Six patients with IPN on systemic antibiotics died within the first 4 weeks of disease before step 2 could be applied. Urgent surgical necrosectomy in the first 4 weeks was performed in three additional patients. Endoscopic drainage and local antibiotic therapy was performed in the remaining 20 patients; 9 (45% of them) did well and 9 patients underwent necrosectomy (18.7% of IPN). Two patients died on drainage. Overall mortality of the total cohort of AP was 2.53% CONCLUSIONS: Addition of local infusion of antibiotics to endoscopic drainage avoids the need of necrosectomy in half of patients with IPN not responding to systemic antibiotics.

Corrigendum: Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

[This corrects the article DOI: 10.3389/fphar.2020.00860.].

Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study.

Background: Despite the wide benefits of aspirin and its cost-effectiveness, aspirin prescriptions have been reduced due to idiosyncratic responses in susceptible individuals. Low-dose aspirin and single-nucleotide polymorphisms (SNPs) are independently associated with increased risk of gastrointestinal hemorrhage; however, to-date, no studies investigated the SNP-aspirin interaction effect on upper gastrointestinal hemorrhage (UGIH). Therefore, we aimed to evaluate the role of 25 SNPs in multiple genes involved in platelet activation, angiogenesis and inflammatory response in aspirin-related UGIH. Methods: A multicenter, full case-control study was conducted in patients exposed and unexposed to aspirin. Three hundred twenty-six cases diagnosed with UGIH were matched with 748 controls (1:3) by age, gender, health center, and recruitment date. Only adults of European origin were included. Participants were stratified by aspirin exposure and genotype [(Aspirin(-), wild-type), (Aspirin(+), wild-type), (Aspirin(+), genetic variation), (Aspirin(-), genetic variation)]. For each SNP, the Odds Ratio of UGIH and their 95% confidence intervals were estimated in each subgroup by using the generalized linear mixed models for dependent binomial variables. SNP-aspirin interaction effect was estimated through Relative Excess Risk due to Interaction (RERI) measures. Results: We observed two categories of SNPs that might modify the risk magnitude of UGIH in aspirin consumers. Seven SNPs (rs1387180 A > G, rs2238631 T > C, rs1799964 T > C, rs5050 T > C/T > G, rs689466 T > C, rs1799983 T > A/T > G, and rs7756935 C > A) were "positive modifiers" associated with an excess of risk from aspirin exposure and carrying that genetic variation (1.75 ≤ RERI ≤ 4.95). On the contrary, the following nine SNPs (rs2243086 G > T, rs1131882 G > A, rs4311994 C > T, rs10120688 G > A, rs4251961 T > C, rs3778355 G > C, rs1330344 C > T, rs5275 A > G/A > T, and rs3779647 C > T) were "negative modifiers" and associated with a reduced risk in aspirin users (-2.74 ≤ RERI ≤ -0.95). Conclusion: This preliminary study suggests that polymorphisms in genes involved in platelets activity, angiogenesis and inflammatory response might modify the risk of aspirin-related UGIH. Further studies with larger sample size and in different populations are needed to confirm our findings. If confirmed, this might have great impact on public health, thanks to aspirin's prophylactic properties in diseases of high incidence and severity.

Bismuth-containing quadruple therapy versus concomitant quadruple therapy as first-line treatment for Helicobacter Pylori infection in an area of high resistance to clarithromycin: A prospective, cross-sectional, comparative, open trial.

BACKGROUND: Concomitant quadruple (CQT) or bismuth-containing quadruple therapy (BQT) is recommended as first-line treatment for Helicobacter pylori infection depending on antibiotic resistance. AIM: To compare the efficacy, safety, and compliance of CQT and BQT as first-line therapy for H. pylori eradication in real clinical practice in an area of high resistance to clarithromycin. METHODS: A prospective, open, comparative cross-sectional study including dyspeptic patients >18 years with H. pylori infection and with no previous eradication treatment was performed. CQT (omeprazole 20 mg + clarithromycin 500 mg + amoxicillin 1 g + metronidazole 500 mg, all given twice daily, for 14 days) or BQT (omeprazole 20 mg twice daily + 3 capsules of Pylera® 4 times a day, for 10 days) was prescribed at the discretion of the prescribing physician. Eradication was tested by 13 C-urea breath test. Efficacy was assessed by intention-to-treat (ITT) and per-protocol (PP) analyses. RESULTS: One hundred and four consecutive patients were included (64.4% female, age 52.9 years). Fifty patients received CQT and 54 BQT. Eradication rate was similar with both therapies at the PP (CQT 97.9%, 95% CI: 93.9-100 vs BQT 96.2%, 95% CI: 90.9-100, P = 0.605) and ITT analyses (CQT 98.0%, 95% CI: 94-100 vs BQT 94.4%, 95% CI: 88.1-100, P = 0.346). The rate of adverse events was also similar with CQT (56%) and BQT (46.3%). One patient in each group discontinued the treatment due to significant adverse events. CONCLUSION: The use of CQT and BQT as first-line treatment against H. pylori is similarly effective and safe strategy in an area of high clarithromycin resistance.

High primary antibiotic resistance of Helicobacter Pylori strains isolated from dyspeptic patients: A prevalence cross-sectional study in Spain.

BACKGROUND: The rate of H. pylori resistance to different antibiotics is increasing and determines the selection of eradication therapy. The aim of this study was to determine the resistance patterns of H. pylori strains in our area. METHODS: Biopsies from gastric corpus for microbiological culture and antibiotic resistance were obtained in patients undergoing upper gastrointestinal endoscopy for dyspepsia. Selective Agar Pylori for isolation of the bacteria and Agar Mueller-Hinton supplemented with blood to test the sensitivity to antibiotics were used. Presence of H. pylori was confirmed using direct observation with phase-contrast microscopy and/or smears stained with acridine orange. In vitro bacterial susceptibility to amoxicillin, clarithromycin, rifampicin, tetracycline, metronidazole, and levofloxacin was tested using diffusion MIC test strips. Minimum inhibitory concentration values were determined based on the 6th version of the EUCAST (European Committee on Antimicrobial Susceptibility Testing) Clinical Breakpoint (2016). RESULTS: Two hundred and seventeen patients were included (58.1% female, median age 64 years, range 25-92). H. pylori was identified in 108 patients (49.8%); culture and antibiogram were completed in 77 of them (71.3% of H. pylori-positive patients). The resistance rates were as follows: levofloxacin 38.7%, rifampicin 33.3%, metronidazole 27% and clarithromycin 22.4%. No case of amoxicillin or tetracycline resistance was identified. Dual clarithromycin-metronidazole resistance was observed in 10% of strains, whereas multiple drug-resistant was observed in 14.2%. CONCLUSIONS: Resistance rate of H. pylori to antibiotics is high in the northwest of Spain. The high resistance to levofloxacin and clarithromycin advises against their wide empirical use of these antibiotics in eradication regimens.

Theoretical approach to local infusion of antibiotics for infected pancreatic necrosis.

BACKGROUND/OBJECTIVES: Infected pancreatic necrosis is a major complications of acute pancreatitis. If drainage is required, local administration of antibiotics through transmural nasocystic or percutaneous catheter may allow increasing local antibiotic concentrations. Drug diffusion becomes the main factor influencing local drug tissue penetration. The present study aims at providing the rationale for the design of new research protocols evaluating the efficacy of local antibiotics for infected pancreatic necrosis. METHODS: A review of microbiological data was performed for the most common organisms causing the infection, antibiotics spectrum and minimum inhibitory concentrations (MIC). A search of the physico-chemical properties of antibiotics was performed to calculate the diffusion coefficients. An estimation of the antibiotic concentrations in pancreatic tissue was obtained using a mathematical model. Efficacy factors (EF) were calculated and the stability of the antibiotic solutions were evaluated to optimize the dosing regimen. RESULTS: Piperacillin, vancomycin and metronidazole achieve high concentrations in the surrounding tissue very fast. Imipenem, ceftriaxone, ciprofloxacin, gentamicin, linezolid and cloxacillin achieve intermediate concentration values. Tigecycline, showed the lowest concentration values (<2 mg/L). Calculated EF is highest for piperacillin and imipenem short after administration and near to surface diffusion area (0.5 cm), but EF of imipenem is higher at deeper areas and longer time after administration. CONCLUSIONS: Considering obtained results, some solutions are proposed using saline as diluent and 25 °C of temperature during administration. Imipenem has the best theoretical results in empiric local treatment. Linezolid and tigecycline solutions are not recommended.

Update on management of Barrett's esophagus.

Barrett's esophagus (BE) is a common condition that develops as a consequence of gastroesophageal reflux disease. The significance of Barrett's metaplasia is that predisposes to cancer development. This article provides a current evidence-based review for the management of BE and related early neoplasia. Controversial issues that impact the management of patients with BE, including definition, screening, clinical aspects, diagnosis, surveillance, and management of dysplasia and early cancer have been assessed.

A clinical model for predicting lymph node metastasis in submucosal invasive (T1) colorectal cancer.

BACKGROUND: No single histopathological feature of submucosal invasive colorectal cancer (T1-CRC) can reliably predict the risk for lymph node metastasis (LNM). AIM: The purpose of the study was to develop a prediction model of LNM in T1-CRC. METHODS: Ninety-seven surgically resected T1-CRC at our institution were retrospectively evaluated. Morphology, localization, grading, mode of growth, presence of background adenoma, lymphoid infiltration, angiolymphatic invasion, budding, and depth of invasion were assessed. Mortality and morbidity related to surgery were also evaluated. Benefit-risk balance was assessed according to the presence of severe complications and to the presence of LNM. RESULTS: Fourteen cases had LNM (14%). Eight patients (8%) presented severe surgical complications and there were two deaths (2 %). Infiltrative growth pattern (OR 31.91, 95% CI 2.37-428.36; p = 0.009) and the absence of lymphoid infiltrate (OR 28.75; 95% CI 2.13-388.37; p = 0.011) were the only variables independently associated with LNM in the multivariate analysis. Both variables were included in the prediction model together with sessile morphology (OR 4.88; 95% CI 0.81-29.3; p = 0.083) and poorly differentiated carcinoma (OR 11.77; 95% CI 0.77-179.83; p = 0.076). A 0-100 score was developed (infiltrative growth pattern: no = 0, yes = 33; lymphoid infiltrate: no = 29, yes = 0; sessile morphology: no = 0, yes = 15; poorly differentiated: no = 0, yes = 23). Cutoff point to indicate additional surgery was set in 35 points (i.e., 10% risk LNM). Discrimination of the prediction model was excellent (AUC 0.90; 95% CI 0.81-0.99). CONCLUSION: Combined evaluation of infiltrative growth pattern, lymphoid infiltration, poorly differentiated carcinoma, and sessile appearance showed good performance for discriminating T1-CRC patients with LNM. The benefit-risk balance was in favor of surgery when at least two of these criteria were present.

Transhepatic anterograde biliary drainage using a self-expandable metallic stent: A therapeutic alternative after hepaticojejunostomy with Roux-en-Y reconstruction.

Endoscopic drainage is the procedure of choice in cases of obstructive jaundice. However, in patients with a surgical biliary reconstruction, this technique cannot be often satisfactorily used. In these cases, the best alternative has usually been the percutaneous biliary drainage. Since the introduction of endoscopic ultrasoundguided therapy, some new techniques have been proposed to solve these technical problems related to postsurgical disturbed anatomy. In this case report, we describe our successful experience in the performance of a transhepatic anterograde biliary drainage using a self-expandable metallic stent in the context of a patient who previously had undergone a hepaticojejunostomy with Roux-en-Y reconstruction because of a resected hilar cholangiocarcinoma.

Transhepatic anterograde biliary drainage using a self-expandable metallic stent: a therapeutic alternative after hepaticojejunostomy with Roux-en-Y reconstruction / Drenaje biliar transhepático anterógrado usando una prótesis metálica autoexpandible: Una alternativa terapéutica tras la hepaticoyeyunostomía con reconstrucción en Y en Roux

Endoscopic drainage is the procedure of choice in cases of obstructive jaundice. However, in patients with a surgical biliary reconstruction, this technique cannot be often satisfactorily used. In these cases, the best alternative has usually been the percutaneous biliary drainage. Since the introduction of endoscopic ultrasoundguided therapy, some new techniques have been proposed to solve these technical problems related to postsurgical disturbed anatomy. In this case report, we describe our successful experience in the performance of a transhepatic anterograde biliary drainage using a self-expandable metallic stent in the context of a patient who previously had undergone a hepaticojejunostomy with Roux-en-Y reconstruction because of a resected hilar cholangiocarcinoma (AU)

Cholangitis and multiple liver abscesses after percutaneous ethanol injection (PEI) for recurrent hepatocellular carcinoma (HCC).

Percutaneous ablation procedures are minimally invasive treatments for unresectable early stage hepatocellular carcinoma (HCC). These techniques are usually safe, but rare and even fatal complications have been described. We present a fatal result after percutaneous ethanol injection (PEI) for the treatment of a recurrent HCC in a non-cirrhotic liver, with subsequent development of diffuse cholangitis and multiple liver abscesses. Although percutaneous drainage and intensive antibiotic treatment were employed, the patient finally died. We discuss about the etiology and the physiopathology of this rare complication in which the therapeutic options are limited and usually unsuccessful.

Cholangitis and multiple liver abscesses after percutaneous ethanol injection (PEI) for recurrent hepatocellular carcinoma (HCC) / Colangitis y abscesos hepáticos múltiples tras la inyección percutánea de etanol (IPE) en el tratamiento del carcinoma hepatocelular recurrente

Percutaneous ablation procedures are minimally invasive treatments for unresectable early stage hepatocellular carcinoma (HCC). These techniques are usually safe, but rare and even fatal complications have been described. We present a fatal result after percutaneous ethanol injection (PEI) for the treatment of a recurrent HCC in a non-cirrhotic liver, with subsequent development of diffuse cholangitis and multiple liver abscesses. Although percutaneous drainage and intensive antibiotic treatment were employed, the patient finally died. We discuss about the etiology and the physiopathology of this rare complication in which the therapeutic options are limited and usually unsuccessful(AU)

Percutaneous endoscopic suturing is an alternative treatment for persistent gastrocutaneous post-PEG fistula / La sutura endoscópico-percutánea es una alternativa terapéutica en la fístula gastrocutánea persistente post-PEG

Persistent gastrocutaneous fistula after the removal of a gastrostomy tube is an unusual complication associated with percutaneous endoscopic gastrostomy (PEG). Surgical closure has been usually the treatment of choice. Several endoscopic methods have been previously attempted to close the fistula, usually with poor results. We report a successful case of percutaneous endoscopic suturing of a persistent gastrocutaneous post-PEG fistula, using a monofilament absorbable suture. A biopsy forceps was used to deepithelialize both ends of the fistulous tract to promote granulation tissue formation. The gastrocutaneous fistula closed completely after the procedure and there were no complications during the follow-up(AU)

[Adenocarcinoma arising in Meckel's diverticulum: a case report and literature review]. / Adenocarcinoma sobre divertículo de Meckel: presentación de un caso y revisión de la literatura.

Meckel's diverticulum is the most common congenital anomaly of the gastrointestinal tract. The presence of malignant lesions arising in the diverticulum is very rare, the most common malignant lesion being sarcoma, followed by carcinoid tumors, and less frequently by adenocarcinomas. We present the case of an 86-year-old man who developed acute abdomen. Surgery revealed a perforated Meckel's diverticulum. Histology identified a poorly-differentiated adenocarcinoma arising in Meckel's diverticulum. We provide a review of the literature.

Adenocarcinoma sobre divertículo de Meckel: presentación de un caso y revisión de la literatura / Adenocarcinoma arising in Meckel’s diverticulum: a case report and literature review

Resumen El divertículo de Meckel es la anomalía congénita más común del tracto gastrointestinal. La presencia de lesiones malignas sobre el divertículo es muy infrecuente, la más común corresponde a los sarcomas, seguidas del tumor carcinoide y, por último, de los adenocarcinomas. Presentamos el caso de un paciente de 86 años intervenido por un cuadro de abdomen agudo; en la cirugía se identificó un divertículo de Meckel perforado, la histología demostró un adenocarcinoma pobremente diferenciado. Finalmente se ha realizado una revisión de la literatura médica relacionada (AU)

Abstract Meckel’s diverticulum is the most common congenital anomaly of the gastrointestinaltract. The presence of malignant lesions arising in the diverticulum is very rare, themost common malignant lesion being sarcoma, followed by carcinoid tumors, and less frequentlyby adenocarcinomas. We present the case of an 86-year-old man who developed acuteabdomen. Surgery revealed a perforated Meckel’s diverticulum. Histology identified a poorly differentiated adenocarcinoma arising in Meckel’s diverticulum. We provide a review of theliterature