Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial.

PURPOSE: The management of perianal fistula in patients with Crohn's disease is an extremely challenging medical problem as many fistulas do not respond to available treatments. The objectives were to assess the safety and efficacy of a suspension of expanded adipose-derived allogeneic mesenchymal stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease METHODS: An open-label, single-arm clinical trial was conducted at six Spanish hospitals. Twenty-four patients were administered intralesionally with 20 million eASCs in one draining fistula tract. A subsequent administration of 40 million eASCs was performed if fistula closure was incomplete at week 12. Subjects were followed until week 24 after the initial administration. RESULTS: Treatment-related adverse events did not indicate any clinical safety concerns after 6 months follow-up. The full analysis of efficacy data at week 24 showed 69.2 % of the patients with a reduction in the number of draining fistulas, 56.3 % of the patients achieved complete closure of the treated fistula achieved, and 30 % of the cases presenting complete closure of all existing fistula tracts. Of note, closure was strictly defined as: absence of suppuration through the external orifice and complete re-epithelization, plus absence of collections measured by magnetic resonance image scan (MRI). Furthermore, MRI Score of Severity showed statistically significant differences at week 12 with a marked reduction at week 24. CONCLUSIONS: Locally injected eASCs appear to be a simple, safe, and beneficial therapy for perianal fistula in Crohn's disease patients. Additional studies are needed to further confirm the efficacy of the eASCs.

Prostacyclin, thromboxane, and oxygen free radicals and postoperative liver function in human liver transplantation.

The aim of this prospective study is to evaluate prostanoid (prostacyclin and thromboxane) and lipid peroxide levels at the portal and hepatic veins, and their relation to immediate postoperative liver function. Nineteen patients with liver cirrhosis undergoing orthotopic liver transplantation were prospectively studied. Blood samples were obtained within 5 min and 1 and 2 hr after reperfusion of the new liver, through a catheter placed at the portal vein in the recipient and another at the left hepatic vein in the donor liver. Plasma prostacyclin and thromboxane were analyzed by HPLC and RIA. The formation of lipid peroxides was determined and expressed in terms of thiobarbituric acid-reacting substances. Immediate postoperative liver function was evaluated using the transaminase levels within the first 48 hr and the early postoperative graft function score, as described previously. After reperfusion, only determinations at 5 min were related with liver function. Either prostacyclin (R = -0.61, P = 0.004) levels at the hepatic vein or prostacyclin production (subtraction between hepatic and portal vein levels) (R = -0.47, P = 0.04) correlated significantly with the early postoperative graft function score. Besides, there was a significant relationship between lipid peroxide production as measured by thiobarbituric acid-reacting substances and a worse early postoperative graft function score (R = 0.61, P = .005). These results suggest that prostacyclin released after liver grafting attenuates preservation and reperfusion damage of the liver, supporting the hypothesis that there is an imbalance of prostanoids within the microvasculature in patients with a compromised postoperative liver function. Our results agree with the involvement of some degree of lipid peroxidation products in the damage of hepatocytes during anoxia and reperfusion.

L-arginine reduces liver and biliary tract damage after liver transplantation from non-heart-beating donor pigs.

BACKGROUND: To evaluate whether L-arginine reduces liver and biliary tract damage after transplantation from non heart-beating donor pigs. METHODS: Twenty-five animals received an allograft from non-heart-beating donors. After 40 min of cardiac arrest, normothermic recirculation was run for 30 min. The animals were randomly treated with L-arginine (400 mg x kg(-1) during normothermic recirculation) or saline (control group). Then, the animals were cooled and their livers were transplanted after 6 hr of cold ischemia. The animals were killed on the 5th day, liver damage was assessed on wedged liver biopsies by a semiquantitative analysis and by morphometric analysis of the necrotic areas, and biliary tract damage by histological examination of the explanted liver. RESULTS: Seventeen animals survived the study period. The histological parameters assessed (sinusoidal congestion and dilatation, sinusoidal infiltration by polymorphonuclear cells and lymphocytes, endothelitis, dissociation of liver cell plates, and centrilobular necrosis) were significantly worse in the control group. The necrotic area affected 15.9 +/- 14.5% of the liver biopsies in the control group and 3.7 +/- 3.1% in the L-arginine group (P<0.05). Six of eight animal in the control group and only one of eight survivors in the L-arginine group developed ischemic cholangitis (P<0.01). L-Arginine administration was associated with higher portal blood flow (676.9 +/- 149.46 vs. 475.2 +/- 205.6 ml x min x m(-2); P<0.05), higher hepatic hialuronic acid extraction at normothermic recirculation (38.8 +/- 53.7% vs. -4.2 +/- 18.2%; P<0.05) and after reperfusion (28.6 +/- 55.5% vs. -10.9 +/- 15.5%; P<0.05) and lower levels of alpha-glutation-S-transferase at reperfusion (1325 +/- 1098% respect to baseline vs. 6488 +/- 5612%; P<0.02). CONCLUSIONS: L-Arginine administration during liver procurement from non heart beating donors prevents liver and biliary tract damage.

Hepatic blood flow and oxygen extraction ratio during normothermic recirculation and total body cooling as viability predictors in non-heart-beating donor pigs.

BACKGROUND: Our aim was to evaluate the hepatic blood flows and oxygen metabolism of non-heart-beating donor (NHBD) pigs, with the use of cardiopulmonary bypass (CPB) and normothermic recirculation (NR) before total body cooling, and its relationship with recipient survival. METHODS: Thirty-five pigs were transplanted with an allograft from NHBDs. After warm ischemia (WI) time (20, 30, or 40 min), CPB and NR were run for 30 min. After this period, the animals were cooled to 15 degrees C. In the control group (20 min of WI), the period of NR was excluded. Liver procurement was then performed. RESULTS: Survival rate was 100% in the 20WI, 70% in the 30WI, and 50% in the 40WI. Control group survival rate was 0%. Hepatic artery blood flow and portal blood flow recovered during NR. Pump blood flow during CPB increased rapidly during NR and was significantly higher in the 20WI. When donors of the livers transplanted in "surviving pigs" (DSP) were compared with donors of the livers transplanted in "nonsurviving pigs" (DNSP), hepatic artery blood flow, portal blood flow, and pump blood flow were higher in the DSP. Hepatic oxygen extraction ratio increased in the three groups with respect to baseline values. Hepatic oxygen extraction ratio was lower in the 20WI than in the other groups and was lower in the DSP than in the DNSP. CONCLUSIONS: The use of a NR period before total body cooling improves survival of liver transplantation in NHBDs. Portal blood flow and pump blood flow measurements can predict the viability of the grafts.

[Asymptomatic pneumoperitoneum after fiber gastroscopy]. / Neumoperitoneo asintomático después de una fibrogastroscopia.

A case of asymptomatic pneumoperitoneum after fiber gastroscopic sclerosis of bleeding gastric erosions is presented. Air bubbles in gastric curvatures without evidence of macroscopic perforation were found at laparotomy. We comment the etiologies of pneumoperitoneum without macroscopic perforation and suggest that the management of patients with asymptomatic pneumoperitoneum with normal clinical examination and blood analysis might be conservative to avoid needless laparotomies.

[Relation of the levels of systemic prostaglandins and hemodynamic changes present during orthotopic transplant of the liver]. / Relación entre los niveles de prostaglandinas sistémicas y los cambios hemodinámicos presentes durante el trasplante ortotópico de hígado.

The aim of this study is to investigate the role of prostaglandins (PGI2 and TXA2) in relation with the hemodynamic alterations occuring after graft reperfusion in patients undergoing OLT. A total of 40 patients with liver cirrhosis were studied. Systemic 6-keto-PGF1 alpha and TXB2, stable metabolites of PGI2 and TXA2 respectively, were determined at the radial artery, at four different surgical stages: basal, hepatectomy, anhepatic, and 10 minutes after graft reperfusion. Overall results showed that 6-keto-PGF1 alpha levels were significantly elevated during hepatectomy (1143 +/- 204) when compared to values in the basal stage (p = 0.007). During hepatectomy, 6-keto-PGF1 alpha levels did not correlate to systemic vascular resistance index (SVRI), neither with the cardiac index (IC) nor with the medial arterial pressure (MAP) in the same stage. During the anhepatic stage, only IRVS was inversely correlated with 6-keto-PGF1 alpha levels (p = 0.004): there was no relation with MAP and CI. During reperfusion no correlations were observed between 6-keto-PGF1 alpha levels and MAP, CI or SVRI. We conclude that systemic PGI2 levels are very high in cirrhotic patients undergoing OLT. The absence of correlation between the magnitude of changes in hemodynamic parameters and 6-keto-PGF1 alpha levels during reperfusion of the new liver suggests that other factors must play a role in these hemodynamic changes.