Hepatic arterial infusion of chemotherapy for advanced hepatocellular carcinoma

Treatment of advanced hepatocellular carcinoma (HCC) remains a significant problem for clinicians. Sorafenib, the only approved agent, improves survival rate, but is associated with a low tumor response rate. Alternative approaches for the treatment of advanced HCC are urgently needed. Hepatic arterial infusion of chemotherapy (HAIC) is a promising modality for the treatment of advanced HCC. Since its introduction, there have been improvements in implantable pumps, in catheter implantation and in the convenience and safety of HAIC in general. Numerous clinical studies have shown that HAIC provides moderate therapeutic efficacy with substantially favorable toxicity profiles in selected patient groups with advanced HCC. However, the lack of large randomized studies means that HAIC is not yet a well‐established treatment for advanced HCC. We believe there is an urgent need for the further investigation of HAIC for the treatment of advanced HCC.     

Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease

Background and Objective: Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel’s active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. Methods: This was a parallel‐design, open‐label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child‐Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60‐mg loading dose (LD) and daily 10‐mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC_0–t, C_max and t_max) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. Results and Discussion: Exposure to prasugrel’s active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC_0–t and C_max after the LD and last MD ranged from 0·91 to 1·14. MPA to 20 μm ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. Conclusion: Moderate hepatic impairment appears to have no effect on exposure to prasugrel’s active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel.     

Early Hepatic Artery Thrombosis after Liver Transplantation: A Systematic Review of the Incidence, Outcome and Risk Factors

To clarify inconsistencies in the literature we performed a systematic review to identify the incidence, risk factors and outcome of early hepatic artery thrombosis (eHAT) after liver transplantation. We searched studies identified from databases (MEDLINE, EMBASE, Science Citation Index) and references of identified studies. Seventy-one studies out of 999 screened abstracts were eligible for this systematic review. The incidence of eHAT was 4.4% (843/21, 822); in children 8.3% and 2.9% in adults (p < 0.001). Doppler ultrasound screening (DUS) protocols varied from 'no routine' to 'three times a day.' The median time to detection was at day seven. The overall retransplantation rate was 53.1% and was higher in children (61.9%) than in adults (50%, p < 0.03). The overall mortality rate of patients with eHAT was 33.3% (range: 0–80%). Mortality in adults (34.3%) was higher than in children (25%, p < 0.03). The reported risk factors for eHAT were, cytomegalovirus mismatch (seropositive donor liver in seronegative recipient), retransplantation, arterial conduits, prolonged operation time, low recipient weight, variant arterial anatomy, and low volume transplantation centers. eHAT is associated with significant graft loss and mortality. Uniform definitions of eHAT and uniform treatment modalities are obligatory to confirm these results and to obtain a better understanding of this disastrous complication.     

Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3

BACKGROUND AND AIMS: Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade. METHODS: Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA). RESULTS: Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them. CONCLUSIONS: These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.     

原发性肝癌TACE术后严重并发症原因及预防

目的 探讨原发性肝癌行经导管肝动脉化疗栓塞术后严重并发症的原因及预防.方法 2005年1月-2007年7月,573例原发性肝癌患者行1 252次肝动脉化疗栓塞术,术后针对发生的并发症,给予积极治疗,同时结合生化及影像学检查,探讨严重并发症出现的原因及预防措施.结果 并发症有上消化道出血3例、急性肝功能衰竭6例(死亡1例)、肺栓塞1例、胆汁瘤2例、胆囊炎4例、胃穿孔并死亡1例.结论 经导管肝动脉化疗栓塞术治疗原发性肝癌出现的严重并发症与术前肝功能较差、门静脉高压、化疗栓塞药物剂量过大、药物反流及异位栓塞等有关.重视TACE术时机的选择,采用规范化的介入治疗措施,可以避免或减少严重并发症.     

Evaluation of tumour promoting potency of fish borne toxaphene residues, as compared to technical toxaphene and UV-irradiated toxaphene

In this study the potential impact of food chain-based biotransformation and physico-chemical weathering of toxaphene on its tumour promoting potential was investigated in vitro and in vivo. Human exposure to toxaphene is mainly through consumption of contaminated fish, therefore fish-borne residues of toxaphene (cod liver extract, CLE) were prepared by exposing cod to technical toxaphene (TT) for 63 days. UV-irradiated toxaphene (uvT) was included to represent a physico-chemical weathered toxaphene mixture. In vitro, TT, uvT and CLE all showed a dose- and time-dependent inhibition of gap junctional intercellular communication (GJIC) with a relative potency of CLE>TT=uvT. Tumour promoting potency was further studied in vivo in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats, using an increase in altered hepatic foci positive for glutathione-S-transferase-P (AHF-GST-P) as read out. No increase in AHF-GST-P occurred following exposure to either TT, uvT, or CLE, except for the positive control group (2,3,7,8-TCDD). Based on this study the no observed adverse effect level (NOAEL) for tumour promoting potency is at least 12.5mg/kg/week, or higher for CLE. Considering current human exposure levels in Europe it is doubtful that consumption of fish at current levels of toxaphene contamination give rise to human health risk.     

Trafficking of recirculating lymphocytes in the rat liver: rapid transmigration into the portal area and then to the hepatic lymph

Background: We have investigated how recirculating lymphocytes patrol the liver in a normal steady state. Methods: Thoracic duct lymphocytes of congeneic rats were intravenously transferred to host rats and donor cell trafficking in the liver and hepatic lymph was examined. Host hepatic lymph nodes (HLNs) were selectively removed, which allowed liver‐derived donor cells to collect in the thoracic duct without transit in the intervening HLNs. Results: The number of donor cells in the thoracic duct lymph significantly increased over the baseline 3, 5 and 11 h after transfer in the HLN‐removed, non‐pretreated, and HLN‐ligated (in which a lymph efflux was blocked) groups, respectively. Histologically, donor cells appeared in the portal area from 0.5 h after transfer and frequently attached to the basal lamina of portal vein both externally and internally. Three hours after transfer, a few donor cells appeared in the subcapsular sinus of HLNs. Conclusion: The minimal transit time of rat recirculating lymphocytes is 3–4 h in the liver and 5–8 h in the hepatic LNs, in a normal steady state. Recirculating lymphocytes might transmigrate through the portal vein as well as the sinusoid in the periportal zone. This rapid transit might enable an efficient surveillance of the liver portal area by the recirculating lymphocytes.