Prognostic factors of hemorrhagic complications after oxaliplatin-based hyperthermic intraperitoneal chemotherapy: Toward routine preoperative dosage of Von Willebrand factor?

BACKGROUND: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC-ox) induces specific morbidity with hemorrhagic complications (HC). The aim of this study was to identify preoperative, intraoperative and postoperative HC predictive factors after HIPEC-ox. METHODS: A prospective single center study that included all consecutive patients treated with curative-intent HIPEC-ox, whatever the origin of peritoneal disease, was conducted. All patients underwent systematic blood tests exploring primary hemostasis and endothelial activation before surgical incision (D0) and on postoperative days 2 (POD2) and 5 (POD5). RESULTS: Between May 2012 and August 2015, 47 patients were enrolled in the study. The overall HC rate was 38%. Major morbidity was significantly higher in patients with HC. Patients presenting HC were significantly more often affected with pseudomyxoma peritonei and had less preoperative chemotherapy. Multivariate analysis showed that a higher plasmatic level of Von Willebrand factor antigen at D0 (D0 VWF:Ag) was a protective predictive factor for HC (p = 0.049, HR: 0.97 CI 95% [0.94-1.00]). A D0 VWF:Ag level below 138% had a sensitivity of 87.5%, a specificity of 67% and an area under the curve of 80.3% (CI 95% [66.5-94], p < 0.01) for predicting HC. CONCLUSIONS: Through the identification of prognostic factors, this study highlighted a subgroup of patients with low risk of HC after HIPEC-ox. Based on these results, we propose a routine preoperative dosage of VWF that would help the surgeon to select the most suitable patients for HIPEC-ox.

Prevention of Barrier Disruption by Heme Oxygenase-1 in Intestinal Bleeding Model.

In this study we investigated the effect of free heme, the local level of which was increased by bleeding, on the intestinal barrier function, using human epithelial colorectal adenocarcinoma cells (Caco-2). Our results show that the addition of hemin to the culture medium markedly disrupted the barrier function, which was significantly improved by glutamine supplementation. Although hemin treatment caused the increased expression of heme oxygenase (HO)-1, the inhibition of HO activity resulted in the aggravation of hemin-induced barrier dysfunction. Up-regulation of HO-1 by pretreatment with a low concentration of hemin almost completely prevented hemin-induced barrier dysfunction. Taken together, these observations indicate that an abnormally high level of intracellular free heme causes barrier dysfunction, probably through the modulation of proteins forming tight junctions.

Hemorragia gastrointestinal, antiinflamatorios no esteroideos, ácido acetilsalicílico y anticoagulantes / Gastrointestinal bleeding, NSAIDs, aspirin and anticoagulants

Los estudios presentados en el reciente congreso de la American Gastroenterological Association, en el campo de la hemorragia digestiva alta no varicosa asociada o no a la toma de antiinflamatorios no esteroideos o de ácido acetilsalicílico, no han sido numerosos pero sí interesantes. Las conclusiones fundamentales son: a) rabeprazol, el único inhibidor de la bomba de protones que tenía escasos estudios en este campo, es eficaz en la prevención de úlceras gastroduodenales; b) famotidina podría ser también eficaz en la prevención de complicaciones por ácido acetilsalicílico; c) los nuevos y potentes inhibidores de ácido competitivos de la bomba de potasio son eficaces (tanto como los inhibidores de la bomba de protones) en la recurrencia de úlceras pépticas por ácido acetilsalicílico; d) la endoscopia precoz (< 8 h) en la hemorragia digestiva alta no varicosa no parece ofrecer mejor resultado que la efectuada en las primeras 24 h; e) la terapia endoscópica en Forrest 1 a no consigue obliterar la arteria sangrante en el 30% de las ocasiones y es la causa de la recurrencia; f) las terapias alternativas con pegamento o productos coagulantes se van abriendo paso en la terapia endoscópica del sangrante; g) la administración liberal de sangre en el sangrante digestivo se asocia a peor pronóstico; h) las lesiones del intestino delgado son causa frecuente de hemorragia digestiva cuando la endoscopia alta no demuestra estigmas positivos, y i) el estudio con cápsula endoscópica tiene un rendimiento alto en la hemorragia digestiva de origen oscuro si se efectúa precozmente en los 2 primeros días tras el inicio del episodio

The studies presented at the recent American Congress of Gastroenterology in the field of non-variceal upper gastrointestinal bleeding (associated or not to NSAIDs or ASA use) have not been numerous but interesting. The key findings are: a) rabeprazole, the only PPI that had few studies in this field, is effective in the prevention of gastric ulcers; b) famotidine could also be effective in the prevention of complications by AAS; c) the new competitive inhibitors of the acid potassium pump are effective (as much as PPIs) on the recurrence of peptic ulcers by ASA; d) early endoscop (<8 h) in non-variceal upper gastrointestinal bleeding seems to offer no better results than those made in the first 24 h; e) endoscopic therapy in Forrest 1a ulcers does not obliterate the bleeding artery in 30% of cases and is the cause of bleeding recurrence; f) alternative therapies with glue or clotting products are being increasingly used in endoscopic therapy of gastrointestinal bleeding; g) liberal administration of blood in the GI bleeding is associated with poor prognosis; h) lesions of the small intestine are frequent cause of gastrointestinal bleeding when upper endoscopy shows no positive stigmata; and i) capsule endoscopy studies have high performance in gastrointestinal bleeding of obscure origin, if performed early in the first two days after the beginning of the bleeding episode

Gastroprotective effects of Corchorus olitorius leaf extract against ethanol-induced gastric mucosal hemorrhagic lesions in rats.

BACKGROUND AND AIM: Corchorus olitorius is a medicinal plant traditionally utilized as an antifertility, anti-convulsive, and purgative agent. This study aimed to evaluate the gastroprotective effect of an ethanolic extract of C. olitorius against ethanol-induced gastric ulcers in adult Sprague Dawley rats. METHODS: The rats were divided into seven groups according to their pretreatment: an untreated control group, an ulcer control group, a reference control group (20 mg/kg omeprazole), and four experimental groups (50, 100, 200, or 400 mg/kg of extract). Carboxymethyl cellulose was the vehicle for the agents. Prior to the induction of gastric ulcers with absolute ethanol, the rats in each group were pretreated orally. An hour later, the rats were sacrificed, and gastric tissues were collected to evaluate the ulcers and to measure enzymatic activity. The tissues were subjected to histological and immunohistochemical evaluations. RESULTS: Compared with the extensive mucosal damage in the ulcer control group, gross evaluation revealed a marked protection of the gastric mucosa in the experimental groups, with significantly preserved gastric wall mucus. In these groups, superoxide dismutase and malondialdehyde levels were significantly increased (P < 0.05) and reduced (P < 0.05), respectively. In addition to the histologic analyses (HE and periodic acid-Schiff staining), immunohistochemistry confirmed the protection through the upregulation of Hsp70 and the downregulation of Bax proteins. The gastroprotection of the experimental groups was comparable to that of the reference control medicine omeprazole. CONCLUSIONS: Our study reports the gastroprotective property of an ethanolic extract of C. olitorius against ethanol-induced gastric mucosal hemorrhagic lesions in rats.

Prophylactic effect of egualen sodium, a stable azulene derivative, on gastrointestinal damage induced by ischemia/reperfusion, double antiplatelet therapy and loxoprofen in rats.

We examined the effect of egualen, a stable azulene derivative, against gastric damage induced by ischemia/reperfusion (I/R), gastric bleeding induced by double antiplatelet therapy with aspirin (ASA) plus clopidogrel, and small intestinal damage generated by loxoprofen, and investigated the possible mechanisms involved in its protective action. Male C57BL/6 mice or SD rats were used under urethane anesthesia (gastric lesions) or in a conscious (intestinal lesions) state. I/R-induced gastric injury was produced in mice by clamping the celiac artery for 30 min, followed by reperfusion for 60 min. Gastric bleeding was induced in rats by luminal perfusion with 25 mM ASA+50 mM HCl for 2 hours in the presence of clopidogrel (30 mg/kg). To produce small intestinal lesions the rats were given loxoprofen (60 mg/kg) p.o. and killed 24 hours later. Egualen was given i.d. 60 min before I/R or ASA perfusion, while given p.o. twice 30 min before and 6 hours after loxoprofen. Egualen significantly prevented the I/R-induced gastric damage, and the effect was equivalent to that of seratrodast (TXA2 antagonist). This agent also significantly suppressed gastric bleeding induced by ASA plus clopidogrel, similar to PGE2. Likewise, egualen significantly prevented loxoprofen-induced damage in the small intestine, accompanied by an increase in the secretion of mucus and suppression of bacterial invasion as well as iNOS expression. These results suggest that egualen has a prophylactic effect against various lesions in the gastrointestinal mucosa, probably through its characteristic pharmacological properties, such as TXA2 antagonistic action, local mucosal protection, and stimulation of mucus secretion.

A bicarbonate-alkaline mineral water protects from ethanol-induced hemorrhagic gastric lesions in mice.

Ingestion of elevated amounts of ethanol in humans and rodents induces hemorrhagic gastric lesions, at least in part by increasing oxidative stress. The present study was undertaken in order to evaluate the influence of a bicarbonate-alkaline mineral water (Uliveto on ethanol-induced hemorrhagic gastric lesions in mice. Lesions were evaluated by both macroscopic and microscopic analysis. In a first set of experiments, mice were allowed to drink Uliveto or reference water ad libitum until 3 h prior to intragastric (i.g.) ethanol (23 ml/kg) administration. Neither Uliveto nor reference water did afford any protection. In a second set of experiments, acute exposure to reference water (35 ml/kg, i.g.), given 30 min before ethanol, did not inhibit gastric lesions. However, administration of the same amount of Uliveto caused a remarkable reduction in ethanol-evoked gastric lesions. Ethanol administration increased 4-hydroxy-2-nonenal levels, a byproduct of oxidative stress, in the luminal part of the gastric mucosa. This response was substantially reduced by about 70% by Uliveto, but not by reference water. Reference water, added with the bicarbonate content, present in the Uliveto water, protected against ethanol-induced lesions. Thus, acute pre-exposure to bicarbonate-alkaline mineral water (Uliveto) protects from both oxidative stress and hemorrhagic gastric lesions caused by ethanol. The elevated bicarbonate content of Uliveto likely accounts for the protection against ethanol-induced gastric injury.

The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage.

The aim of this study was to assess the possible protective effects of Nigella sativa (NS) and its constituent, thymoquinone (TQ) on ethanol-induced gastric mucosal damage in an experimental model. Forty male rats aged four months were divided into four groups (each group containing ten animals); the control group received physiologic saline (10 ml kg(-1)) and the ethanol group had taken 1 ml (per rat) absolute alcohol by gavage. The third and fourth groups also received NS (500 mg kg(-1)) and TQ (10 mg kg(-1)) by gavage 1 h before alcohol administration, respectively. Both drugs (NS and TQ) could protect the gastric mucosa against the injurious effect of absolute alcohol and promote ulcer healing as evidenced from the ulcer index values. Gastric damage was confirmed histomorphometrically by significant increases in the number of mast cells (MC) and gastric erosions in ethanol treated rats. The NS treatment significantly decreased the number of MC and reduced the area of gastric erosions. Likewise, TQ treatment was also able to reduce the number of MC and the gravity of gastric mucosal lesions, but to lesser extent compared to NS. Gastric tissue histamine levels and myeloperoxidase activities were found to be increased in ethanol treated rats, and NS or TQ treatment reversed these increases. Results obtained from this study suggest that both drugs, particularly NS could partly protect gastric mucosa from acute alcohol-induced mucosal injury, and these gastroprotective effects could be due to their antiperoxidative, antioxidant and antihistaminic effects.

Protective effect of teprenone on blood flow and incidence of histologic lesions in rat gastric mucosa after hemorrhage and retransfusion.

BACKGROUND: The effects of teprenone (6,10,14,18-tetramethyl-5,9,13, 17-nonadecatetraen-2-one) on changes in gastric mucosal blood flow, adenosine triphosphate (ATP) content, and incidence of histologic lesions were evaluated in rat gastric mucosa after hemorrhage and retransfusion. METHODS: Teprenone (100 mg/kg) was administered orally once a day for 3 consecutive days. On the 3rd day hemorrhage was induced, withdrawn blood (retransfusion) was returned, and the above variables were determined. RESULTS: Teprenone significantly inhibited the decreases in blood flow and index of mucosal oxygen saturation (ISO2) during hemorrhage in the corpus and antral mucosa. However, no effect of teprenone was observed on systemic blood pressure and ATP levels after hemorrhage and retransfusion. Teprenone significantly (p < 0.05) decreased both the incidence of ischemic lesions and the increase in the severity of lesions after retransfusion in both mucosal regions. CONCLUSION: From these results, it is concluded that the protective effect of teprenone on blood flow was partly responsible for its inhibitory effect on the incidence of lesions in the rat stomach in this hypovolemic shock model, although the former effect might be not a direct effect on systemic vascular tone.

Fatty acid changes in liver choline and ethanolamine glycerophospholipids in aspirin-treated rats fed linoleate, gamma-linolenate and fish oil.

The effects of dietary linoleic acid, gamma-linolenic acid and marine fatty acids on the development of aspirin-induced gastric hemorrhage and the distribution of liver glycerophospholipid fatty acids in fat-deficient growing rats were studied. Aspirin (100 mg/day)-treated and nontreated rats were fed for 7 days, a mixed diet of 2.5% safflower oil and 7.5% hydrogenated coconut oil (SFO/HCO) or 7.5% fish oil (SFO/FO), or 2.5% gamma-linolenate concentrate and 7.5% fish oil (GLA/FO). Gastric hemorrhage was induced in animals by aspirin treatment to various extents. It was not affected by FO feeding, but was significantly alleviated by GLA feeding. Aspirin treatment reduced the proportions of 20:4n-6 in liver phosphatidylcholine. FO feeding (in SFO/FO and GLA/FO rats) further reduced the 20:4n-6 level and replaced it by n-3 fatty acids. GLA feeding, on the other hand, elevated the proportion of 20:4n-6. As a result, the reduction of 20:4n-6 by fish oil feeding, was less significant in GLA/FO rats than in SFO/FO rats. The degree of gastric hemorrhage appeared to relate negatively to the levels of 20:4n-6 in liver phosphatidylcholine, and to the sum of 20:4n-6 and 20:5n-3 when FO was included in the diet. It is suggested that long-chain polyunsaturated fatty acids (20:4n-6 and 20:5n-3) per se in addition to being precursors of prostaglandins, may also affect the development of gastric hemorrhage, possibly by modulating the permeability of cell membranes in the gastric mucosa.

The role of the small intestine in ammonia production after gastric blood administration.

It is commonly believed that the digestion of intraluminal blood by colonic bacteria is the primary cause of increased ammonia production after upper gastrointestinal hemorrhage. To evaluate the role of the small intestine in ammonia production, blood, amino acids, or water (5 mL/kg) was administered as a meal or enema to awake dogs with chronic indwelling catheters. After blood meals, intestinal ammonia production increased rapidly to peak at 60 minutes and returned to basal levels. This response was mimicked by the gastric administration of ammoniagenic amino acids. No change in ammonia production occurred with water administration. In contrast, colonic blood administration resulted in a gradual rise in ammonia production, and peaked at 150 minutes. Amino acid enemas resulted in a similar but somewhat more rapid response. No change occurred with water enemas. After gut decontamination, ammonia production did not increase after blood enemas. However, the rapid increase in ammonia production persisted after blood meals. It is concluded that both the small bowel and colon participate in the augmented ammonia production that occurs after upper gastrointestinal hemorrhage. Gut decontamination reduces ammonia production by altering the colonic microflora, but is not specific therapy directed towards amino acid metabolism by the enterocytes of the small bowel and thus, does not alter the ammonia produced by the small intestine.

The effect of hydrocortisone on immunoglobulin metabolism.

The serum concentration of all subclasses of IgG (gamma(2)A, gamma(2)B, and gamma(1)) as well as IgA and IgM were reduced in normal and low pathogen mice receiving hydrocortisone acetate. Turnover studies using (131)I-labeled gamma(2)A subclass of IgG demonstrated that high dose corticosteroids cause a significantly shortened survival (increased catabolic rate) which contributes to the observed hypogammaglobulinemia. This increase in fractional catabolism is not due to excess loss in the urine or stool but reflects an increase in endogenous catabolism.