Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients.

OBJECTIVE: Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. PATIENTS AND METHODS: A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann-Whitney U-nonparametric test. RESULTS: The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients' genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995). CONCLUSION: This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy.

Preliminary results from the use of intraoperative real-time biliary oxygen monitoring in liver transplantation.

BACKGROUND AND AIMS: Biliary anastomosis is a frequent area of complications after liver transplantation (LT) and a potential area of "microangiopathy". The concept of a "marginal bile duct" is unexplored. The main aim was to make a preliminary evaluation of the utility of an innovative real-time oxygen microtension (pO2mt) testing device for the assessment of bile duct viability during LT and to correlate these pO2mt values with microvascular tissue quality by histopathology and outcomes. PATIENTS AND METHODS: Observational prospective cohort study with 23 patients. Oxygen microtension measurements were made placing a micropO2 probe in different areas of recipient and donor's bile duct intraoperative. RESULTS: Mean pO2mt in the graft bile duct at the level of the anastomosis 103.82 (31-157) mm Hg, being 121.52 (55-174) mm Hg 1.5 cm proximal to the hilar plate (P < 0.001). Mean pO2mt in the recipient's bile duct was 117.87 (62-185) mm Hg, while a value of 137.30 (81-198) mm Hg was observed 1.5 cm distal to the anastomosis (P < 0.001). Cystic duct resection (12 cases) was also related with higher pO2mt values at anastomosis [117.8 (93-157) vs 88.54 (31-124) mm Hg] and distal to anastomosis [135.6 (111-174) vs 106.2 (55-133) mm Hg; P < 0.001]. Patients with 1-, 3-, and 12-month biliary complications had significantly lower pO2mt in the intraoperative measurements. CONCLUSION: Our preliminary results show that distal borders of donor and recipient bile ducts may be low-vascularized areas. Tissue pO2mt is significantly higher in areas close to the hilar plate and to the duodenum in donor and recipient's sides, respectively. Bile duct injury and biliary complications are associated with worse tissue pO2mt.

Impact of age on liver regeneration response to injury after partial hepatectomy in a rat model.

BACKGROUND: Liver resection is a feasible treatment for multiple liver diseases. There is no evidence about the impact of age on liver regeneration. OBJECTIVE: To assess the effect of age on liver regeneration in an experimental in vivo animal model of 70%-partial hepatectomy. METHODS: Forty young (Y) and old (O) Wistar male rats (n = 80) were distributed into four groups [controls (C), sham operated (SO), hepatectomy 6 h (H6), and 48 h (H48)]. Different morphometric and biochemical factors, oxidative and nitrosative stress, lipid peroxidation, cytokines kinetics, and histopathologic tissular parameters were determined. RESULTS: Early postoperative mortality was higher in aged rats (P = 0.049). Morphometric determinations, liver regeneration index, and total volume weight were favorable to young rats. Serum transaminase levels were higher in aged rats. Parameters of necrosis (measured by histopathologic injury [HI: 0-I-II-III]), regeneration (measured by bromodeoxyuridine-BrdU incorporation) and apoptosis (determined by the TDT-mediated dUTP nick end labeling-TUNEL) were well-synchronized in young rats. Parameters of oxidative stress such as reduced (GSH), oxidized (GSSG) glutathione and lipid peroxidation (measured by hepatic malondialdehyde -MDA-) were lower in young animals throughout the studied period. Nitrosative stress measured by nitric oxide (NO) end-products was higher in late stages in resected old rats. Pro-inflammatory cytokines (TNF- α) reached higher and earlier levels in aged rats while pro-regenerative cytokines (IL-6) were significantly higher in early stages for young rats and in late stages for aged rats. The levels of TGF-ß were higher in young rats. CONCLUSION: Liver regeneration is delayed and reduced in aged animals submitted to liver resection.

Nitric oxide mimics transcriptional and post-translational regulation during α-tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes.

BACKGROUND & AIMS: Reactive oxygen species (ROS) and nitric oxide (NO) exert a relevant role during bile acid-induced hepatotoxicity. Whether α-Tocopherol regulates oxidative and nitrosative stress, bile acid transporter expression and their NO-dependent post-translational modifications, and cell death were assessed in vitro and in vivo. METHODS: α-Tocopherol and/or NO donors (DETA-NONOate or CSNO, and V-PYRRO/NO) were administered to glycochenodeoxycholic acid (GCDCA)-treated cultured human hepatocytes or to bile duct obstructed rats. Cell injury, superoxide anion (O⁻2) production, as well as inducible nitric oxide synthase (NOS-2), cytochrome P4507A1 (CYP7A1), heme oxygenase-1, (HO-1) and bile acid transporter expression were determined. Cysteine S-nitrosylation and tyrosine nitration of Na(+)-taurocholate co-transporting polypeptide (NTCP), as well as taurocholic acid (TC) uptake were also evaluated. RESULTS: GCDCA-induced cell death was associated with increased (O⁻2) production, NTCP and HO-1 expression, and with a reduction of CYP7A1 and NOS-2 expression. α-Tocopherol reduced cell death, (O⁻2) production, CYP7A1, NTCP, and HO-1 expression, as well as increased NOS-2 expression and NO production in GCDCA-treated hepatocytes. α-Tocopherol and NO donors increased NTCP cysteine S-nitrosylation and tyrosine nitration, and reduced TC uptake in hepatocytes. α-Tocopherol and V-PYRRO/NO reduced liver injury and NTCP expression in obstructed rats. CONCLUSIONS: The regulation of CYP7A1, NTCP, and HO-1 expression may be relevant for the cytoprotective properties of α-Tocopherol and NO against mitochondrial dysfunction, oxidative stress and cell death in GCDCA-treated hepatocytes. The regulation of NO-dependent post-translational modifications of NTCP by α-Tocopherol and NO donors reduces the uptake of toxic bile acids by hepatocytes.

Extended criteria donors in liver transplant candidates with hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a complication of cirrhosis with a poor prognosis without transplantation. The aim of this study is to analyze the influence of extended criteria donors (ECD) on the postoperative outcome of recipients with HRS. The last 498 patients were divided according to pre-transplant type 1 or 2 HRS. Sixty-six (13.25%) recipients fulfilled HRS criteria. Three-month graft survival was 84% with at-listing recipient serum creatinine ranging from 0-0.8 mg/dL; 80% with s-creatinine = 0.9-1.5 mg/dL; 79% with s-creatinine = 1.6-2.5 mg/dL; and 58% with s-creatinine >2.6 mg/dL (log-rank = 18.039; p = 0.001). Recipients with HRS presented higher levels of pre-transplant creatinine and lower levels of sodium, more episodes of hemodialysis and ascitis, and higher model of end-stage liver disease-scores. Three-month graft survival in recipients with HRS relative to ECD-variables showed differences in univariate analysis according to graft steatosis (85% in absent steatosis = 0-10%; 78% in mild steatosis = 10-30%; 76% in moderate steatosis = 30-60%; and 49% when severe steatosis >60%; log-rank = 5.146; p = 0.023). Cox-proportional-hazard-model revealed that graft macrosteatosis per-30%-increments (p = 0.000; HR = 1.303 [1.24-1.33] per-30%-increment) and donors >65 yr (p = 0.089; HR = 1.622 [1.17-1.94]) were independent predictors of graft loss in recipients with HRS. In conclusion, the use of ECD in recipients with cirrhosis and HRS is a good option. However, grafts from moderate-to-severe steatosis and those from aged donors must be carefully allocated in candidates with HRS.

Emergency adrenalectomy due to acute heart failure secondary to complicated pheochromocytoma: a case report.

Pheochromocytomas are catecholamine producing tumors arising mostly from chromaffin cells of the adrenal medulla. The most common clinical presentation is hypertension, mainly in the form of paroxymal episodes. Cardiovascular manifestations include malignant arrhythmia and catecholamine cardiomyopathy, mimicking acute coronary syndromes and acute heart failure.There are reports of pheochromocytomas presenting as acute coronary syndrome and rapidly leading to cardiogenic shock; the failure of intensive medical treatment in these cases has prompted the need for emergency adrenalectomy as the only remaining option. We report on a case of complicated pheochromocytoma presenting as cardiogenic shock, in which emergency adrenalectomy was performed following a total lack of response to intensive medical treatment.

Impact of donor graft steatosis on overall outcome and viral recurrence after liver transplantation for hepatitis C virus cirrhosis.

The aim of this study was to determine the influence of donor graft steatosis on overall outcome, viral recurrence, and fibrosis progression in orthotopic liver transplantation (OLT) for hepatitis C virus (HCV) cirrhosis. One hundred twenty patients who underwent OLT for HCV cirrhosis between 1995 and 2005 were included in the study. Donor steatosis was categorized as absent (0%-10%; n = 40), mild (10%-30%; n = 32), moderate (30%-60%; n = 29), or severe (>60%; n = 19). A Cox multivariate analysis for marginal donor variables and a Model for End-Stage Liver Disease index were performed. Fibrosis evolution was analyzed in liver biopsies (fibrosis < 2 or > or =2) 3, 6, and 12 months post-OLT and in the late post-OLT period. Fifty-six grafts were lost (46%). The survival of the grafts was inversely proportional to donor liver steatosis: 82%, 72%, and 72% at 1, 2, and 3 years post-OLT in the absence of steatosis; 73%, 63%, and 58% with mild steatosis; 74%, 62%, and 43% with moderate steatosis; and 62%, 49%, and 42% with severe steatosis (P = 0.012). HCV recurrence was earlier and more frequent in recipients with steatosis > 30% (46% versus 32% at 3 months, P = 0.017; 58% versus 43% at 6 months, P = 0.020; 70% versus 56% at 12 months, P = 0.058; and 95% versus 69% at 3 years post-OLT, P = 0.0001). Graft survival was lower in alcoholic liver disease recipients versus HCV recipients when steatosis was >30% at 3, 6, and 12 months post-OLT (P = 0.042) but not when steatosis was <30% (P = 0.53). A higher fibrosis score was obtained 3 months post-OLT (P = 0.033), 6 months post-OLT (P = 0.306), 12 months post-OLT (P = 0.035), and in the late post-OLT period (P = 0.009). In conclusion, donor graft steatosis influences the outcome of OLT for HCV cirrhosis. HCV recurrence is more frequent and earlier in recipients of moderately and severely steatotic livers. Fibrosis evolution is higher when graft steatosis is >30%. OLT with >30% steatotic donor livers should be precluded in HCV recipients.

Cytoprotective properties of alpha-tocopherol are related to gene regulation in cultured D-galactosamine-treated human hepatocytes.

Vitamin E (alpha-tocopherol) has demonstrated antioxidant activity and gene-regulatory properties. d-Galactosamine (D-GalN)-induced cell death is mediated by nitric oxide in hepatocytes, and it is associated with hepatic steatosis. The beneficial properties of alpha-tocopherol and their relation to oxidative stress and gene regulation were assessed in D-GalN-induced cell death. Hepatocytes were isolated from human liver resections by a collagenase perfusion technique. alpha-Tocopherol (50 microM) was administered at the advanced stages (10 h) of D-GalN-induced cell death in cultured hepatocytes. Cell death, oxidative stress, alpha-tocopherol metabolism, and NF-kappaB-, pregnane X receptor (PXR)-, and peroxisome proliferator-activated receptor (PPAR-alpha)-associated gene regulation were estimated in the hepatocytes. D-GalN increased cell death and alpha-tocopherol metabolism. alpha-Tocopherol exerted a moderate beneficial effect against apoptosis and necrosis induced by D-GalN. Induction (rifampicin) or inhibition (ketoconazole) of alpha-tocopherol metabolism and overexpression of PXR showed that the increase in PXR-related CYP3A4 expression caused by alpha-tocopherol enhanced cell death in hepatocytes. Nevertheless, the reduction in NF-kappaB activation and inducible nitric oxide synthase expression and the enhancement of PPAR-alpha and carnitine palmitoyl transferase gene expression by alpha-tocopherol may be relevant for cell survival. In conclusion, the cytoprotective properties of alpha-tocopherol are mostly related to gene regulation rather than to antioxidant activity in toxin-induced cell death in hepatocytes.

Strategies to reduce hepatitis C virus recurrence after liver transplantation.

Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.

Impact of donor and recipient CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus dosage requirements and rejection in Caucasian Spanish liver transplant patients.

Studies of liver transplant (LT) patients, mainly in Asians, have evaluated the influence of the CYP3A5*1 allele and P-glycoprotein gene ABCB1 on tacrolimus pharmacokinetics or biopsy-proven acute rejection (BPAR) incidence, with no conclusive results. To investigate these issues, 98 Caucasian Spanish LT patients with tacrolimus, mycophenolate mofetil and steroids and 88 cadaveric donors were genotyped for the SNPs CYP3A5 6986G>A, ABCB1 1236C>T, ABCB1 2677G>A/T and ABCB1 3435C>T;. On day 7 post-LT, patients with a native CYP3A5*1 allele had significantly lower tacrolimus trough concentrations C0 (P = .03) and dose-adjusted concentrations C0 /D (P = .02) than CYP3A5 *3/*3 homozygotes. Three months post-LT, patients carrying a liver with CYP3A5*1 had significantly lower C0 /D (P = .03) and took significantly higher tacrolimus doses (P = .03) than the corresponding *3/*3 homozygotes. ABCB1 SNPs showed no significant association with tacrolimus variables. The 3-month incidence of BPAR was 10.2%, with no statistically significant differences related to CYP3A5 (14.3% in expresser vs. 9.5% in non-expresser) or ABCB1 genotype of either patient or donor. We conclude that in Caucasian Spanish LT patients, a native or graft-borne CYP3A5*1 allele tends to lower tacrolimus concentrations and increase dosage needs, but has no significant impact on the incidence of BPAR.

Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids.

BACKGROUND/PURPOSE: Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis. METHODS: Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined. RESULTS: The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression. CONCLUSIONS: The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.

Neoadjuvant intraperitoneal chemotherapy with paclitaxel for the radical surgical treatment of peritoneal carcinomatosis in ovarian cancer: a prospective pilot study.

PURPOSE: The admitted benefits of intraperitoneal chemotherapy during postoperative administration for the treatment of peritoneal carcinomatosis from ovarian origin are limited by their associated morbidity and restricted diffusion by the presence of multiple intra-abdominal adherences. The purpose of the study was to evaluate the security, effectiveness, and cytoreduction optimization of intraperitoneal paclitaxel administration previously to radical surgery/peritonectomy/HIPEC (hyperthermic intraoperative intraperitoneal chemotherapy) either in monotherapy or combined with intravenous carboplatin. METHODS: Prospective pilot study of 10 patients with ovarian peritoneal carcinomatosis in stage IIIc-FIGO without previous treatment. After staging of the diseases by laparoscopy, five patients received paclitaxel by weekly intraperitoneal administration (60 mg/m(2), 10 cycles), and other five patients additionally received intravenous carboplatin every 21 days (AUC 6, 4 cycles). Subsequently radical surgery/peritonectomy with HIPEC was performed. RESULTS: The presence of moderate abdominal pain was the most common (70%) side effect associated with neoadjuvant paclitaxel intraperitoneal administration. The intravenous carboplatin administration was not associated with significant increase in adverse effects. It boosted intraperitoneal paclitaxel-associated antitumoral activity with a high average decrease in Index Cancer Peritoneal (21.2 vs. 14.4, P = 0.066) and CA 125(1,053 vs. 346, P = 0.043). All the patients who received combined neoadjuvant chemotherapy obtained R0 cytoreduction. Five-year overall survival was 62%. CONCLUSIONS: The intraperitoneal paclitaxel weekly administration combined with intravenous carboplatin administration prior to radical surgery/peritonectomy with HIPEC is a safe and effective option in the treatment of ovarian peritoneal carcinomatosis. This study shows the possibility to investigate other forms of intraperitoneal chemotherapy and their combinations thoroughly.

Prediction of graft dysfunction based on extended criteria donors in the model for end-stage liver disease score era.

BACKGROUND: To explain the influence of recipient status combined with the accumulation of extended criteria donor (ECD) variables on the appearance of severe ischemia-reperfusion injury and graft survival in a model for end-stage liver disease (MELD)-based system, we analyzed our most recent consecutive liver transplantations (LTs), dividing them into two periods: 400 LTs (1992-2002; pre-MELD era) and 275 LTs (2002-2007; post-MELD era). METHODS: Primary dysfunction (PD) was defined as primary graft failure that required emergency retransplantation or as initial poor function. Donor variables were included in a regression model to assess the probability of PD. RESULTS: Donor age, macrovesicular steatosis more than 30%, and cold ischemia time were associated with allograft dysfunction. Mean probability of PD was 14.8%, 19.2%, 27.5%, and 37.4% for ECD 0, 1, 2, and more than or equal to 3, respectively (P=0.003). Distribution of no-mild, moderate, and severe ischemia-reperfusion injuries among MELD categories was 72.53%, 24.17%, and 3.30% (MELD group=12-19); 56.52%, 36.96%, and 6.5% (MELD group=20-28); and 23.91%, 54.35%, and 21.74% (MELD group >or=29), respectively (P=0.043). The development of PD according to ECD variables was 18.8%, 18.1%, 28.0%, and 35.3% for ECD 0, 1, 2, and more than or equal to 3, respectively (P=0.047). These variables were independent predictors of PD (Cox proportional regression model): ECD 2 (relative risk [RR]=1.59; 95% confidence interval [CI]=1.25-1.62), ECD 3 (RR=2.74; 95% CI=2.38-3.13), MELD 21 to 30 (RR=1.89; 95% CI=1.32-2.06), and MELD more than or equal to 30 (RR=3.38; 95% CI=2.43-3.86). Graft survival decreased, whereas MELD and the number of ECD variables increased. CONCLUSION: The combination of three or more ECD variables and an MELD more than or equal to 29 is the worst scenario for graft success after LT.

A prospective study of the efficacy of clinical application of a new carrier-bound fibrin sealant after liver resection.

OBJECTIVE: To examine the effectiveness of fibrin sealants as supportive treatment to improve hemostasis and decrease the incidence of bile leakage and intra-abdominal collections. DESIGN: Prospective, controlled, quasiexperimental study. SETTING: Tertiary referral center, University Hospital Reina Sofía. PATIENTS: A total of 115 patients (58 in the control group and 57 in the collagen sponge group) scheduled for conventional hepatectomies. INTERVENTIONS: Patients were distributed into groups for major and minor hepatectomies with or without application of a carrier-bound collagen sponge on the raw surface of the liver. MAIN OUTCOME MEASURES: The main outcome measures were postoperative mortality, incidence and severity of postoperative surgical complications, and length of hospital stay. The secondary outcome measures were postoperative drainage output volume, transfusion requirements, and changes in biochemical parameters (hemoglobin, bilirubin, alanine aminotransferase, and platelet levels). RESULTS: The fibrin sealant after major liver resection was effective for decreasing drainage volume (mean [SD] volume, 1124.7 [842.8] mL in the control group and 691.2 [499.5] mL in the collagen sponge group; P = .007) with a higher volume of output by drain each postoperative day in the control patients (P = .003); postoperative blood transfusion requirements (18.9% vs 7.0%, respectively; P = .04); moderate to severe postoperative complications (21% vs 8%, respectively; P = .03); and mean (SD) hospital stay (12.6 [6.7] vs 9.6 [5.1] days, respectively; P = .03). CONCLUSION: The use of a new carrier-bound collagen sponge after major liver resection may be recommended because of its clinical and cost-savings effectiveness.

The role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis in recurrent ovarian cancer.

BACKGROUND AND OBJECTIVES: Peritoneal carcinomatosis in women frequently has an ovarian origin. Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) along with radical surgery/peritonectomy could present a new therapeutic approach with curative intention. The purpose of this research is to evaluate the role of the administration of HIPEC. METHODS: A series of patients (N=26) diagnosed with peritoneal carcinomatosis for recurrent epithelial ovarian cancer (stage III) from January 1997 to December 2004 submitted to radical surgery/peritonectomy with optimal cytoreduction (R0-R1) were included in this study, 14 treated with HIPEC and 12 without HIPEC. RESULTS: The variables age, histologic type, peritonectomy procedures, peritoneal cancer index (PCI) and lymph node affectation were similar in both groups. The 5-year global survival was 58% and 17% (p=0.046), and 67% and 29% in patients with maximal cytoreduction (R0) (p=0.264), in the HIPEC- and non-HIPEC-treated patients, respectively. In patients with optimal cytoreduction and partial peritonectomy, 5-year global survival was also superior in the HIPEC group (75% vs. 11%, p=0.011). Average time free of disease was superior in the HIPEC group (48+/-42 vs. 24+/-21 months), with less reinterventions due to a new reappearance during the first three evolutionary years (2/14 vs. 4/12). Postoperative morbidity did not show substantial differences in both groups and there was no surgical mortality. CONCLUSIONS: HIPEC is a complement to radical surgery/ peritonectomy, which has been shown to be a surgical procedure with high tolerability, low morbimortality, enhanced survival and prolonged disease-free interval in patients with peritoneal carcinomatosis for recurrent ovarian cancer.

Radical surgery-peritonectomy and intraoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis in recurrent or primary ovarian cancer.

BACKGROUND AND OBJECTIVES: Advanced ovarian cancer typically spreads in a diffuse intra-abdominal fashion. This characteristic suggests that combined radical surgery and intraperitoneal chemotherapy may be a useful treatment procedure. The purpose of this study was to review patients submitted to surgical debulking and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) and to evaluate the potential prognostic survival factors for advanced epithelial ovarian cancer in our center. METHODS: A series of patients (N = 33) diagnosed of peritoneal carcinomatosis for epithelial ovarian cancer (stage III) from January 1997 to December 2004 submitted to radical surgery-peritonectomy and HIIC with paclitaxel was included in this study; 19 primary ovarian cancer and 14 recurrent ovarian cancer. RESULTS: Cytoreduction R0 (P = 0.018) and negative lymph nodes (P = 0.005) were covariables for major prognostic survival. Patients with optimal cytoreduction R0 obtained survival rates of 63% at 5 years in recurrent ovarian cancer and 60% in primary ovarian cancer, 71% and 63%, respectively with associated subtotal infra-abdominal peritonectomy, and even better results if negative lymph nodes. CONCLUSIONS: Radical surgery-peritonectomy with HIIQ has been shown to be a surgical procedure with high tolerability, low morbimortality, enhanced survival, and prolonged disease-free interval in patients with peritoneal carcinomatosis so much for recurrent or primary ovarian cancer.

Assignment of steatotic livers by the Mayo model for end-stage liver disease.

Prognosis after liver transplantation depends on a combination of recipient and donor variables. The purpose of this study is to define an allocation system of steatotic donor livers relative to recipient model for end-stage liver disease (MELD) score. We reviewed 500 consecutive OLT, computing the MELD score for each recipient. Fatty infiltration in grafts was categorized in no steatosis, 10-30%, 30-60% and > or = 60% steatosis. MELD score did not affect preservation injury and graft dysfunction, which were increased with fat content. Recipient and graft survivals lowered when increasing MELD score. Outcome in low-risk recipients (MELD < or = 9) was not altered with steatosis, except those with > or = 60%. Survival functions in moderate-risk recipients (MELD 10-19) were moderately affected with 10-30% steatosis and severely with those with >30. Exactly 30-60% steatotic grafts work poorly in high-risk recipients (MELD > or = 20), and very poorly with > or = 60% steatosis. Prognosis of candidates is optimally influenced when divergence of recipient-donor risks is presented.