Javier Briceño

Comparative Short-term Benefits of Laparoscopic Liver Resection: 9000 Cases and Climbing.

Objective:To perform a systematic review of worldwide literature on laparoscopic liver resections (LLR) and compare short-term outcomes against open liver resections (OLR) by meta-analyses. Summary Background Data:There are no updated pooled data since 2009 about the current status and short-term outcomes of LLR worldwide. Patients and Methods:All English language publications on LLR were screened. Descriptive worldwide data and short-term outcomes were obtained. Separate analyses were performed for minor-only and major-only resection series, and series in which minor/major resections were not differentiated. Apparent case duplications were excluded. Results:A set of 463 published manuscripts were reviewed. One hundred seventy-nine single-center series were identified that accounted for 9527 LLR cases worldwide. Minor-only, major-only, and combined major–minor series were 61, 18, and 100, respectively, including 32, 8, and 43 comparative series, respectively. Of the total 9527 LLR cases reported, 6190 (65%) were for malignancy and 3337 (35%) were for benign indications. There were 37 deaths reported (mortality rate = 0.4%). From the meta-analysis comparing case-matched LLR to OLR (N = 2900 cases), there was no increased mortality and significantly less complications, transfusions, blood loss, and hospital stay observed in LLR vs OLR. Conclusions:This is the largest review of LLR available to date with over 9000 cases published. It confirms growing safety when performed in selected patients and by trained surgeons, and suggests that LLR may offer improved patient short-term outcomes compared with OLR. Improved levels of evidence, standardized reporting of outcomes, and assuring proper training are the next challenges of laparoscopic liver surgery.

Melatonin reduces apoptosis and necrosis induced by ischemia/reperfusion injury of the pancreas.

Abstract:  The pancreas is highly susceptible to the oxidative stress induced by ischemia/reperfusion (IR) injury leading to the generation of acute pancreatitis. Melatonin has been shown to be useful in the prevention of the damage by ischemia‐reperfusion in liver, brain, myocardium, gut and kidney. The aim of the study was to evaluate the cytoprotective properties of melatonin against injury induced by IR in pancreas. The obstruction of gastro‐duodenal and inferior splenic arteries induced pancreatic IR in male Wistar rats. Melatonin was intraperitoneally administered before or/and after IR injury. The animals were killed at 24 and 48 hr after reperfusion and there were evaluated parameters of oxidative stress (lipoperoxides, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione), glandular endocrine and exocrine function (lipase, amylase, insulin) and cell injury (apoptosis and necrosis). The IR induced a marked enhancement of oxidative stress and impaired pancreatic function. The histological analysis showed that IR induced acute pancreatitis with the accumulation of inflammatory infiltrate, disruption of tissue structure, cell necrosis and hemorrhage. Melatonin administration before or after pancreatic IR prevented all tissue markers of oxidative stress, biochemical and histological signs of apoptosis and necrosis, and restored glandular function. No histological signs of pancreatitis were observed 48 hr after reperfusion in 80% of the animals treated with melatonin, with only a mild edematous pancreatitis being observed in the remaining rats. Preventive or therapeutic administration of melatonin protected against the induction of oxidative stress and tissue injury, and restored cell function in experimental pancreatic IR in rats.

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 ≥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. Liver Transpl 15:37–48, 2009.

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.

Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma

BACKGROUND & AIMS Recurrence of hepatocellular carcinoma (HCC) is a major complication after liver transplantation (LT). The initial immunosuppression protocol may influence HCC recurrence, but the optimal regimen is still unknown. METHODS 219 HCC consecutive patients under Milan criteria, who received an LT at 2 European centres between 2000 and 2010, were included. Median follow-up was 51 months (IQR 26-93). Demographic characteristics, HCC features, and immunosuppression protocol within the first month after LT were evaluated against HCC recurrence by using Cox regression. RESULTS In the explanted liver, 110 patients (50%) had multinodular HCC, and largest nodule diameter was 3±2.1cm. Macrovascular invasion was incidentally detected in 11 patients (5%), and microvascular invasion was present in 41 patients (18.7%). HCC recurrence rates were 13.3% at 3 years and 17.6% at 5 years. HCC recurrence was not influenced by the use/non-use of steroids and antimetabolites (p=0.69 and p=0.70 respectively), and was similar with tacrolimus or cyclosporine (p=0.25). Higher exposure to calcineurin inhibitors within the first month after LT (mean tacrolimus trough concentrations >10ng/ml or cyclosporine trough concentrations >300ng/ml), but not thereafter, was associated with increased risk of HCC recurrence (27.7% vs. 14.7% at 5 years; p=0.007). The independent predictors of HCC recurrence by multivariate analysis were: high exposure to calcineurin inhibitors defined as above (RR=2.82; p=0.005), diameter of the largest nodule (RR=1.31; p<0.001), microvascular invasion (RR=2.98; p=0.003) and macrovascular invasion (RR=4.57; p=0.003). CONCLUSIONS Immunosuppression protocols with early CNI minimization should be preferred in LT patients with HCC in order to minimize tumour recurrence.

Melatonin Prevents Oxidative Stress and Hepatocyte Cell Death Induced by Experimental Cholestasis

The induction of oxidative stress precedes liver injury during experimental obstructive jaundice (OJ). In this sense, different evidences suggest that melatonin (MEL), as antioxidant, may be useful in the protection against apoptosis and necrosis during experimental cholestasis. In addition, we will also assess if MEL-dependent protection is related to a recovery of antioxidant status disturbances induced by OJ. Cholestasis was achieved by double ligature and sectioning of the principal bile duct. MEL was injected intraperitoneally (500 μg/kg/day). Lipid peroxidation was evaluated by the measurement of malondialdehyde (MDA) content in liver. Different parameters related to antioxidant status, such as reduced glutathione (GSH), glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were determined in liver. Liver injury was assessed by alanine aminotransferase (ALT) in serum, histological examination, DNA fragmentation and TUNEL assay. The activation of perisinusoidal stellate cells was evaluated by immunohistochemical measurement of α-smooth muscle actin in liver sections. The induction of OJ increased all the parameters related to apoptosis and necrosis in liver. The induction of liver injury was associated with stellate cell activation, as well as an increase in MDA (p<0.0001) and a reduction in GSH, GPx, catalase and SOD content (p<0.0001) in liver. MEL reduced hepatic apoptosis and necrosis (p<0.004) with a significant improvement in all oxidative stress markers. In conclusion, our results showed that MEL recovered the antioxidant status and reduced apoptosis and necrosis induced by experimental cholestasis.

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 ≥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.

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 ≥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 ≤9) was not altered with steatosis, except those with ≥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 ≥20), and very poorly with ≥60% steatosis. Prognosis of candidates is optimally influenced when divergence of recipient–donor risks is presented.

Melatonin prevents experimental liver cirrhosis induced by thioacetamide in rats

Abstract:  Liver cirrhosis is a critical stage of chronic liver diseases that can produce liver failure, portal hypertension and hepatocarcinoma. Sustained oxidative stress plays a key role in cell damage and fibrosis induced during liver cirrhosis. We evaluated the effect of oxidative stress regulation by melatonin on the development of parenchymal destruction and stellate cell activation in experimental liver cirrhosis. Melatonin was administered to rats with liver cirrhosis induced by thioacetamide (TAA) for 1 or 3 months. Liver injury was assessed by serological analysis, as well as hematoxylin‐eosin staining and the in situ apoptosis detection assay in liver sections. Oxidative stress was evaluated by lipoperoxide and reduced glutathione levels, and by the measurement of catalase and superoxide dismutase activities in liver and serum respectively. The activation of stellate cells was evaluated by α‐smooth muscle actin expression in liver sections. Our results showed that TAA induced oxidative stress with extensive tissue damage and enhanced α‐smooth muscle actin expression in liver. Melatonin prevented the oxidative stress‐related changes associated with TAA toxicity. In conclusion, the study showed that melatonin prevents the tissue damage and fibrosis associated with TAA‐induced liver cirrhosis in rats.

N-acetylcysteine, coenzyme Q10 and superoxide dismutase mimetic prevent mitochondrial cell dysfunction and cell death induced by D-galactosamine in primary culture of human hepatocytes

D-Galactosamine (D-GalN) induces reactive oxygen species (ROS) generation and cell death in cultured hepatocytes. The aim of the study was to evaluate the cytoprotective properties of N-acetylcysteine (NAC), coenzyme Q(10) (Q(10)) and the superoxide dismutase (SOD) mimetic against the mitochondrial dysfunction and cell death in D-GalN-treated hepatocytes. Hepatocytes were isolated from liver resections. NAC (0.5 mM), Q(10) (30 microM) or MnTBAP (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (1mg/mL) were co-administered with D-GalN (40 mM) in hepatocytes. Cell death, oxidative stress, mitochondrial transmembrane potential (MTP), ATP, mitochondrial oxidized/reduced glutathione (GSH) and Q(10) ratios, electronic transport chain (ETC) activity, and nuclear- and mitochondria-encoded expression of complex I subunits were determined in hepatocytes. d-GalN induced a transient increase of mitochondrial hyperpolarization and oxidative stress, followed by an increase of oxidized/reduced GSH and Q(10) ratios, mitochondrial dysfunction and cell death in hepatocytes. The cytoprotective properties of NAC supplementation were related to a reduction of ROS generation and oxidized/reduced GSH and Q(10) ratios, and a recovery of mitochondrial complexes I+III and II+III activities and cellular ATP content. The co-administration of Q(10) or MnTBAP recovered oxidized/reduced GSH ratio, and reduced ROS generation, ETC dysfunction and cell death induced by D-GalN. The cytoprotective properties of studied antioxidants were related to an increase of the protein expression of nuclear- and mitochondrial-encoded subunits of complex I. In conclusion, the co-administration of NAC, Q(10) and MnTBAP enhanced the expression of complex I subunits, and reduced ROS production, oxidized/reduced GSH ratio, mitochondrial dysfunction and cell death induced by D-GalN in cultured hepatocytes.