Safety, Efficacy and Distribution of Doxorubicin Loaded Radiopaque Beads in Chemoembolization in Intermediate Stage Hepatocellular Carcinoma (HCC) with Correlation with Local Response.

PURPOSE: The primary objectives of this study were to evaluate safety, and efficacy of Transarterial Chemoembolization (TACE) using doxorubicin-loaded radiopaque microspheres (DC Bead LUMI™) for the treatment of early and intermediate stage Hepatocellular Carcinoma (HCC) not amenable for curative treatments. Distribution of the microspheres was correlated with results post embolization. MATERIALS AND METHODS: This was a prospective, single arm, open label study. The primary outcome measures were distribution of the radiopaque microspheres as showed by computerized tomography (CT) and local response measured by modified Response Evaluation Criteria (mRECIST) after Magnetic Resonance Imaging (MRI). Secondary measures were Time to Progression (TTP) and Overall Survival (OS). RESULTS: Fifty patients were enrolled over 36 months. Median age was 69.0 years; mean sum of target lesions diameters was 78.6 ± 36.8 mm. There were no Grade 4 or 5 adverse events (AEs). At 6 months Complete Response (CR) (18%), Partial Response (PR) (62%), Objective Response OR (80%) and Stable Disease (SD) (20%) were recorded. Before embolization, Diffusion Weighted Imaging (DWI) showed high signal (restricted diffusion). Post procedure, patients with dense deposition (< 5 mm distance of microsphere aggregations) showed 100% absence of enhancement and no restriction in 30.6%. Median TTP was 8.3 months. TTP for patients with CR was 13.3 months and 7.2 and 5.6 for PR and SD, respectively. At 6 and 36 months, survival was 94% and 34%, respectively. CONCLUSION: DC Bead LUMI™ is well tolerated and effective in early and intermediate stage HCC with maximal necrosis obtained in dense deposition in the target.

Prospective evaluation of two-stage hepatectomy combined with selective portal vein embolisation and systemic chemotherapy for patients with unresectable bilobar colorectal liver metastases.

BACKGROUND: Liver resection is contraindicated in patients with multiple bilobar colorectal liver metastases because of the small liver remnant. An alternative strategy which may be curative is a two-stage hepatectomy in which the cancer is resected from one lobe and regeneration allowed prior to contralateral lobe resection. OBJECTIVE: To assess the feasibility, risks, and outcomes in a prospectively applied strategy for two-stage hepatectomy. METHODS: Over a 6-year period, 14 of 280 patients undergoing liver resection for colorectal liver metastases (5%) were considered for two-stage hepatectomy. Surgery was combined with chemotherapy in all (n = 14) and portal vein embolisation (PVE) selectively (n = 5). Median follow-up was 43 months. RESULTS: Both stages were completed in 11 of 14 patients (78%). There were no deaths. Post-operative complication rates were 0% (1st hepatectomy) and 27% (2nd hepatectomy). The 5-year survival after the second hepatectomy was 50%. The mean disease-free survival was 25 +/- 7.5 months. CONCLUSION: Two-stage hepatectomy combined with systemic chemotherapy and PVE can produce long-term survival in patients with multiple bilobar colorectal liver metastases.

The role of liver resection in the management of intermediate and advanced stage hepatocellular carcinoma. A systematic review.

BACKGROUND: The ideal management for patients with intermediate and advanced stage hepatocellular carcinoma (HCC) is controversial. The main purpose of this systematic review is to examine the role of liver resection in patients with intermediate stage HCC (multinodular HCCs) and in advanced stage HCC [mainly patients with portal vein tumor thrombosis (PVTT)]. METHODS: A systematic search of the literature was performed in Pud Med and the Cochrane Library from 01.01.2000 to 30.06.2016. RESULTS: Twenty-three articles with 2412 patients with multinodular HCCs were selected. Also, 29 studies with 3659 patients with HCCs with macrovascular invasion were selected. In patients with multinodular HCCs the median post-operative morbidity was 25% and the 90-day mortality was 2.7%. The median survival was 37 months and the 5-year survival 35%. The 5-year survival was much better for patients with a number of HCCs ≤3 vs. HCCs >3 (49% vs. 23%). In patients with macrovascular invasion, who underwent hepatic resection, the median post-operative morbidity was 33% and the in-hospital mortality 2.7%. The median survival was 15 months. The 3 and 5year survival was 33% and 20% respectively. Moreover a significant difference in survival was noted according to PVTT stage: 5- year survival for distal PVTT, PVTT of the main intrahepatic PV branch and PVTT extending to the main PV was 45%, 19% and 14.5% respectively. CONCLUSIONS: Liver resection in patients with multinodular HCCs and HCCs with PVTT offers satisfactory long-term survival and should be considered in selected patients.

The role of portal vein embolization in the surgical management of primary hepatobiliary cancers. A systematic review.

BACKGROUND: Primary liver and biliary cancers are very aggressive tumors. Surgical treatment is the main option for cure or long term survival. The main purpose of this systematic review is to underline the indications for portal vein embolization (PVE), in patients with inadequate future liver remnant (FLR) and to analyze other parameters such as resection rate, morbidity, mortality, survival after PVE and hepatectomy for primary hepatobiliary tumors. Also the role of trans-arterial chemoembolization (TACE) before PVE, is investigated. METHODS: A systematic search of the literature was performed in Pub Med and the Cochrane Library from 01.01.1990 to 30.09.2015. RESULTS: Forty articles were selected, including 2144 patients with a median age of 61 years. The median excision rate was 90% for hepatocellular carcinomas (HCCs) and 86% for hilar cholangiocarcinomas (HCs). The main indications for PVE in patients with HCC and presence of liver fibrosis or cirrhosis was FLR <40% when liver function was good (ICGR15 < 10%) and FLR < 50% when liver function was affected (ICGR15:10-20%). The combination of TACE and PVE increased hypertrophy rate and was associated with better overall survival and disease free survival and should be considered in advanced HCC tumors with inadequate FLR. In patients with HCs PVE was performed, after preoperative biliary drainage, when FLR was <40%, in the majority of studies, with very good post-operative outcome. However indications should be refined. CONCLUSION: PVE before major hepatectomy allows resection in a patient group with advanced primary hepato-biliary tumors and inadequate FLR, with good long term survival.

Uric acid and oxidative stress.

Uric acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzing the conversion of hypoxanthine to xanthine and the latter to uric acid are catalysed by the enzyme xanthine oxidoreductase, which may attain two inter-convertible forms, namely xanthine dehydrogenase or xanthine oxidase. The latter uses molecular oxygen as electron acceptor and generates superoxide anion and other reactive oxygen products. The role of uric acid in conditions associated with oxidative stress is not entirely clear. Evidence mainly based on epidemiological studies suggests that increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays an important pathophysiological role. Also, allopurinol, a xanthine oxidoreductase inhibitor that lowers serum levels of uric acid exerts protective effects in situations associated with oxidative stress (e.g. ischaemia-reperfusion injury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant. This review presents the current evidence regarding the antioxidant role of uric acid and suggests that it has an important role as an oxidative stress marker and a potential therapeutic role as an antioxidant. Further well designed clinical studies are needed to clarify the potential use of uric acid (or uric acid precursors) in diseases associated with oxidative stress.

Alterations in plasma oxidative stress markers after laparoscopic operations of the upper and lower abdomen.

The patient's position during laparoscopic surgery can have a clinically relevant effect on lower limb and splanchnic circulation; this factor has not yet been investigated with respect to oxidative stress markers. In order to assess this effect, a prospective clinical trial was designed wherein 2 groups of patients were studied. In group A, 15 patients underwent upper abdominal nonhepatobiliary operations (13 modified Nissen fundoplications and 2 Taylor vagotomies) in the head-up position. In group B, 15 patients underwent lower abdominal operations (10 laparoscopic colectomies and 5 inguinal hernia repairs) in the head-down position. The pneumoperitoneum was maintained at 14 mm Hg in all cases. Plasma concentrations of thiobarbituric-acid reactive substances (TBARS), a marker of lipid peroxidation, plasma total antioxidant status (TAS), and serum uric acid concentrations were measured preoperatively, 5 minutes after deflation of the pneumoperitoneum, and 24 hours postoperatively. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum activities were measured preoperatively and 24 hours postoperatively. In group A, there was a significant increase in TBARS levels (p<0.005) immediately after deflation of the pneumoperitoneum and a significant decrease in TAS and uric acid levels (p<0.005) in the first postoperative day. There was also a significant postoperative elevation in both ALT and AST activities (p<0.001). In group B, no significant increase was found in postoperative TBARS or transaminase levels. TAS and uric acid levels decreased significantly in the first postoperative day (p<0.05) and (p<0.005, respectively). In conclusion, these results show that a combination of pneumoperitoneum and the head-up position causes significant increase in lipid peroxidation, decrease in plasma TAS, and increase in transaminases. The mechanism responsible for these events could be the low-flow ischemia-reperfusion syndrome induced by the pneumoperitoneum and aggravated by the head-up position.

Laparoscopic surgery-induced changes in oxidative stress markers in human plasma.

BACKGROUND: The induction of the pneumoperitoneum increases intraabdominal pressure (IAP), causing splanchnic ischemia, whereas its deflation normalizes IAP and splanchnic blood flow. This procedure appears to represent an ischemia-reperfusion model in humans. METHODS: Thirty laparoscopic cholecystectomies (LC) were performed in 30 patients with a mean age of 54.6 +/- 15.6 years. A group of 20 patients mean age, 57.3 +/- 9.65 who underwent open cholecystectomy (OC) was also studied. Vein plasma levels of thiobarbituric acid-reactive substances (TBARS), a marker of free radical production; plasma total antioxidant status (TAS); and uric acid (UA) levels were measured preoperatively, 5 min after deflation of the pneumoperitoneum or at the end of operation, and 24 h postoperatively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBL) levels were measured preoperatively and 24 h after the operation. RESULTS: In the LC group, significant elevations in the concentration of TBARS were observed in the early postoperative measurements in comparison with the preoperative measurements. TAS and UA levels were decreased significantly 24 h postoperatively compared to preoperative levels. The postoperative levels of AST, ALT, and TBL increased significantly in comparison with the preoperative levels. In the OC group, no alterations in the concentration of TBARS were observed in the postoperative period. The other parameters had changes similar to those recorded for the LC group. CONCLUSIONS: Free radical-induced lipid peroxidation associated with a decrease in plasma antioxidant capacity and UA levels as well as altered hepatic function is observed after deflation of the pneumoperitoneum. These results suggest that free radicals are generated at the end of a laparoscopic procedure, possibly as a result of an ischemia-reperfusion phenomenon induced by the inflation and deflation of the pneumoperitoneum.

Lipid peroxidation and the use of emulsified propofol in laparoscopic surgery.

BACKGROUND: Free radical-induced lipid peroxidation associated with a decrease of antioxidant capacity in plasma is observed after the deflation of the pneumoperitoneum in laparoscopic surgery. In this study, we evaluated the effect of the continuous administration of lipid peroxidation derivatives on emulsified propofol. METHODS: Two groups of 20 patients each who underwent laparoscopic surgery were studied prospectively. Maintenance of anesthesia was achieved with 66% nitrous oxide and either isoflurane or continuous propofol administration. The level of thiobarbituric acid-reactive substances (TBARS) in the plasma was determined as a measure of free radicals before and after surgery. RESULTS: Ten patients in the propofol group had reduced TBARS, as compared to only one in the isoflurane group (p = 0.003). There was a statistically significant difference in age between the patients with reduced TBARS and those without reduced TBARS (p = 0.009) in the propofol group. CONCLUSIONS: Anesthesia with continuous propofol infusion in laparoscopic surgery has a significant scavenging action on the formation of free radicals and exerts its greatest antioxidant effect in patients >/=48 years of age.

Continuous infusion of N-acetylcysteine reduces liver warm ischaemia-reperfusion injury.

BACKGROUND: N-acetylcysteine (NAC) may modulate the initial phase (less than 2 h) of liver warm ischaemia-reperfusion (IR) injury but its effect on the late phase remains unclear. The present study investigated the role of NAC during the early and late phases in a rabbit lobar IR model. METHODS: Liver ischaemia was induced by inflow occlusion to the median and left liver lobes for 60 min, followed by 7 h of reperfusion. In the NAC group (n = 6), NAC was administered intravenously at 150 mg per kg over the 15 min before reperfusion and maintained at 10 mg per kg per h during reperfusion. In the IR group (n = 6), 20 ml 5 per cent dextrose was infused over the 15 min before reperfusion and continued at a rate of 10 ml/h. Animals in a sham operation group (n = 6) underwent laparotomy but no liver ischaemia. All animals were killed at the end of the experiment. RESULTS: Intracellular tissue oxygenation was improved after the second hour of reperfusion in animals treated with NAC compared with that in the IR group (P = 0.023). Hepatic microcirculation improved after 5 h of reperfusion (P = 0.036) and liver injury was reduced after 5 h, as indicated by alanine aminotransferase activity (P = 0.007) and indocyanine green clearance (uptake, P = 0.001; excretion, P = 0.032). CONCLUSION: The main protective effect of NAC becomes apparent 5 h after hepatic ischaemic injury.