Pancreatitis aguda necrosante secundaria a hernia de hiato grado IV complicada: Presentación de un caso y revisión de la literatura / Acute necrotizing pancreatitis secondary to complicated grade IV hiatal hernia: A case report and literature review

Introducción. En las hernias paraesofágicas tipo IV se produce la herniación del estómago junto a otros órganos abdominales. La herniación del páncreas es muy infrecuente.Caso clínico. Varón de 57 años que acude por dolor torácico, disnea e intolerancia al decúbito. En la tomografía computarizada toracoabdominal se observa hernia diafragmática que contiene colon transverso, intestino delgado y páncreas, con reticulación de la grasa alrededor del mismo, compatible con pancreatitis aguda. Conclusión. La asociación de hernia hiatal con páncreas herniado y pancreatitis es extremadamente infrecuente. El diagnóstico se estableció mediante tomografía computarizada y el tratamiento fue conservador, con cirugía diferida de la hernia de hiato.

Introduction. In type IV paraesophageal hernias, the stomach is herniated along with other abdominal organs. Herniation of the pancreas is very rare. Clinical case. A 57-year-old man presented with chest pain, dyspnea, and intolerance to decubitus. The thoracoabdominal computed tomography shows a diaphragmatic hernia containing the transverse colon, small intestine and pancreas, with reticulation of fat around it, compatible with acute pancreatitis. Conclusion. The association of hiatal hernia with herniated pancreas and pancreatitis is extremely rare. The diagnosis was established by computerized tomography and the treatment was conservative, with delayed surgery for the hiatal hernia.

Diversion Colitis and Probiotic Stimulation: Effects of Bowel Stimulation Prior to Ileostomy Closure.

Background: Diversion colitis is a non-specific inflammation of a defunctionalised segment of the colon after a temporary stoma has been performed. This inflammation is associated with a change in the colonic flora. Aim: To evaluate the efficacy and safety of preoperative stimulation of the efferent loop with probiotics prior to closure of the protective ileostomy in patients operated on colorectal carcinoma and its effect on diversion colitis. A prospective, randomised, double-blind, controlled study is carried out. Methods: Patients who underwent surgery for colorectal carcinoma with protective ileostomy pending reconstructive surgery and with diversion colitis as diagnosis are included. Randomised and divided into two groups. Histological and endoscopic changes were evaluated after stimulation, after restorative surgery and during the short-term follow-up after surgery. Results: Patients in CG were distributed according to the endoscopic index of severity in pre-stimulation/post-stimulation as follows: severe n = 9/9 (25.7%), moderate n = 23/23 (65.7%), and mild n = 3/3 (8.6%); compared to the distribution in SG, severe n = 9/0 (26.5/0%), moderate n = 23/3 (67.6/8.8%), mild n = 2/19 (5.9/55.9%) and normal colonoscopy in 0/12 patients (0/35.3%). Conclusion: Probiotic stimulation of the efferent loop is a safe and effective method, managing to reduce both macroscopic and microscopic colitis, as well as a decrease in symptoms in the short term after reconstructive surgery.

Serological Biomarkers and Diversion Colitis: Changes after Stimulation with Probiotics.

Diversion colitis is a non-specific inflammation of a defunctionalised segment of the colon after a temporary stoma has been performed. This inflammation is associated with an alteration of certain inflammatory serum markers. The aims of this study were, firstly, to evaluate the modification of inflammatory biomarkers after stimulation with probiotics prior to closure of the protective ileostomy. Secondly, to identify if a relationship could be established between the severity of diversion colitis and the alteration of inflammatory biomarkers in the blood. A prospective, randomized, double-blind, controlled study was conducted. Patients who underwent surgery for colorectal carcinoma with protective ileostomy between January 2017 and December 2018 were included, pending reconstructive surgery and with diversion colitis as diagnosis. The sample was randomly divided into a group stimulated with probiotics (SG) (n = 34) and a control group (CG) (n = 35). Histological and endoscopic changes were evaluated after stimulation, after restorative surgery and during the short-term follow-up after surgery, including the correlation with pro-inflammatory biomarkers in blood. As main findings, a significant decrease in C-reactive protein (CRP), Neutrophil/lymphocyte ratio (NLR ratio), and monocyte/lymphocyte ratio (LMR ratio) was observed in the SG versus the CG with a p < 0.001. A significant increase in transferrin values and in the platelet/lymphocyte ratio (PLR) was observed in the SG versus CG after stimulation with probiotics with a p < 0.001. A normalisation of CRP and transferrin levels was observed in the third month of follow-up after closure ileostomy, and NLR, LMR and PLR ratios were equal in both groups. Decreased modified Glasgow prognostic score was found in SG compared to CG after probiotic stimulation (p < 0.001). The endoscopic and histological severity of diversion colitis is associated with a greater alteration of blood inflammatory biomarkers. The stimulation with probiotics prior to reconstructive surgery promotes an early normalization of these parameters.

Diversion Colitis: Macro and Microscopic Findings after Probiotics Stimulation.

The use of a loop ileostomy as the defunctioning procedure of choice to protect a distal colonic anastomosis causes histological and endoscopic changes in the intestinal mucosal architecture, which have been related to chronic inflammation and changes in the microflora that consequently impact the intestinal structure and function following fecal stream diversion. The aim of this study was to evaluate the histological and endoscopic changes on the colonic mucosa in patients with diversion colitis after stimulation of the efferent loop with probiotics prior to closure of the protective ileostomy. A prospective, randomized, double-blind, controlled study was designed. All patients who underwent surgery for colorectal carcinoma with protective ileostomy between January 2017 and December 2018 were included. These patients were pending reconstructive surgery and were diagnosed with endoscopic and histological diversion colitis. Divided into two groups, a group stimulated with probiotics (SG) and a control group (CG). 34 cases and 35 controls were included in the study. Histological and endoscopic changes were evaluated after stimulation, after restorative surgery and during the short-term follow-up after surgery. A decrease in endoscopic pathological findings (mucosal friability, mucous erosions, polyps, edema, erythema and stenosis) and in histological findings (follicular hyperplasia, eosinophils, cryptic abscesses, lymphocyte infiltration, plasma cell infiltration and architecture distortion) was observed in SG. These results were statistically significant with a p < 0.001. The stimulation of the efferent loop of the ileostomy in patients with diversion colitis produced a decrease of the endoscopic and histological severity of colitis in the short term.

Postoperative Ileus after Stimulation with Probiotics before Ileostomy Closure.

Loop ileostomy closure after colorectal surgery is often associated with Postoperative ileus, with an incidence between 13-20%. The aim of this study is to evaluate the efficacy and safety of preoperative stimulation of the efferent loop with probiotics prior to ileostomy closure in patients operated on for colorectal carcinoma. For this, a prospective, randomized, double-blind, controlled study is designed. All patients who underwent surgery for colorectal carcinoma with loop ileostomy were included. Randomized and divided into two groups, 34 cases and 35 controls were included in the study. Postoperative ileus, the need for nasogastric tube insertion, the time required to begin tolerating a diet, restoration of bowel function, and duration of hospital stay were evaluated. The incidence of Postoperative ileus was similar in both groups, 9/34 patients stimulated with probiotics and 10/35 in the control group (CG) with a p = 0.192. The comparative analysis showed a direct relationship between Postoperative ileus after oncological surgery and Postoperative ileus after reconstruction surgery, independently of stimulation. Postoperative ileus after closure ileostomy is independent of stimulation of the ileostomy with probiotics through the efferent loop. There seem to be a relationship between Postoperative ileus after reconstruction and the previous existence of Postoperative ileus after colorectal cancer surgery.

Tumores del estroma gastrointestinal: revisión de nuestra experiencia / Surgery of gastrointestinal stromal tumors: review of our experience in the last five years

Objective: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Surgical resection is the standard treatment for localized primary GISTs. The aim of the study is to present our 5-year surgical experience, as well as the results obtained in terms of survival and disease progression. Material and Method: We conducted a descriptive, retrospective study of primary GISTs treated in our center between 2009-2013. We analyze the most relevant variables, criteria of risk of progression according Fletcher's classification from National Institutes of Health and the Miettinem's classification from the Armed Forces Institute of Pathology, as well as analysis of relapse-free survival (RFS) with Kaplan-Meier survival curves. Results: We present a series of 30 patients. Mean age 65 years (40-84 years). The most common location was the stomach (n = 14, 46.6 percent). The surgery was R0 in 23 cases of 30. The mean tumor diameter was 5.3 cm (0.5-18). 14 patients received adjuvant treatment with Imatinib. After an average follow-up of 31.2 months (6-62 months), it was found relapse in 4 patients, progression and exitus in 1, exitus in 3 and exitus in the immediate postoperative period in 1. RFS at one year was 96.7 percent, and 89.2 percent at 4 years. Mean survival time was 56.2 months (95 percent CI 51.8-60.6). Conclusion: The recommended attitude after radical surgery is follow-up. In selected patients with risk of relapse, adjuvant treatment with Imatinib delays the progression of the disease and increases the survival.

Objetivo: Los tumores del estroma gastrointestinal son las neoplasias mesenquimales más frecuentes del tubo digestivo. La resección quirúrgica es el tratamiento estándar en los GISTs primarios localizados. El objetivo del estudio es presentar nuestra experiencia quirúrgica en 5 años, así como los resultados obtenidos en cuanto supervivencia y progresión de la enfermedad. Material y Método: Serie de casos, estudio observacional descriptivo retrospectivo, que analiza los resultados obtenidos en cuanto al tratamiento quirúrgico de GIST primarios sometidos a resección quirúrgica en nuestro centro entre 2009-2013. Todas las intervenciones fueron realizadas por personal del Staff y dentro de los protocolos de las unidades de cirugía hepato-biliar y esófago-gástrica. Se analizan las variables de mayor relevancia, criterios de riesgo de progresión según la clasificación de Fletcher del National Institutes of Health y la clasificación de Miettinem del Armed Forces Institute of Pathology, así como análisis de la supervivencia libre de recaída (SLR) con curvas de Kaplan-Meier. Resultados: Presentamos una serie de 30 pacientes. Edad media de 65 años (40-84 años). La localización más frecuente fue estómago (n = 14, 46,6 por ciento). La cirugía fue R0 en 23 de los 30 pacientes. El diámetro tumoral medio fue de 5,3 cm (0,5-18, con una mediana de 4 cm. Catorce pacientes recibieron tratamiento adyuvante con Imatinib. Tras un seguimiento medio 31,2 meses (6-62 meses), se detectó recaída en 4 pacientes, progresión y exitus en 1, exitus en 3 y exitus en el postoperatorio inmediato en 1. La SLR al año fue del 96,7 por ciento, siendo del 89,2 por ciento a los 4 años. El tiempo medio de supervivencia fue de 56,2 meses (IC 95 por ciento 51,8-60,6). Conclusiones: La actitud recomendada tras una cirugía radical es el seguimiento. En pacientes seleccionados con riesgo de recaída el tratamiento adyuvante con Imatinib retrasa la progresión de la enfermedad y aumenta la supervivencia.

Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor.

Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.

Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies.

Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only approximately 50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P(3) sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P(3) sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.

Toward second generation hepatitis C virus NS3 serine protease inhibitors: discovery of novel P4 modified analogues with improved potency and pharmacokinetic profile.

Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.

Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease.

The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC(90) by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K(i)* = 4 nM, EC(90) = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K(i)* = 4 nM, EC(90) = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

Proposed biogenetic origin of secu'amamine A from allosecurinine: a model study to support the intermediacy of the putative aziridinium ion.

[reaction: see text] A model study to support the intermediacy of the aziridinium ion in the proposed biogenetic origin of secu'amamine A from allosecurinine is described.