Delia D'Avola

Radioembolization with Use of Yttrium-90 Resin Microspheres in Patients with Hepatocellular Carcinoma and Portal Vein Thrombosis

PURPOSEnIntraarterial delivery of yttrium-90 ((90)Y)-bound microspheres (ie, radioembolization) is a promising treatment for hepatocellular carcinoma (HCC). An early concern was the embolic nature of the microspheres, and their potential to reduce hepatic arterial blood flow in patients with compromised portal blood flow secondary to portal vein thrombosis/occlusion (PVT). In this situation, the risk of liver failure could be enhanced, particularly in patients with cirrhosis who have increased hepatic arterial blood flow. This retrospective analysis was undertaken to assess the safety and clinical benefits of radioembolization with (90)Y resin microspheres in HCC with branch or main PVT.nnnMATERIALS AND METHODSnA total of 25 patients presenting with unresectable HCC and compromised portal flow received segmental, lobar, or whole-liver infusion of (90)Y resin microspheres. For the analysis of tumor response, changes in target lesions, appearance of new lesions, and changes in portal vein thrombus were studied. Controlled disease was defined by absence of progression in all these components.nnnRESULTSnGlobally, controlled disease was achieved in 66.7% of patients at 2 months and 50% of patients at 6 months. No significant changes were observed in liver-related toxicities according to Common Toxicity Criteria (version 3.0) at 1 and 2 months after treatment. Median survival time was 10 months (95% CI, 6.6-13.3 months).nnnCONCLUSIONSnRadioembolization of unresectable HCC and branch or main PVT with (90)Y resin microspheres was associated with minimal toxicity and a favorable median survival time. Further prospective studies are warranted to validate the findings in this clinically challenging patient population.

Risk factors of lung, head and neck, esophageal, and kidney and urinary tract carcinomas after liver transplantation: the effect of smoking withdrawal.

Liver transplant recipients have an increased risk of malignancy. Smoking is related to some of the most frequent causes of posttransplant malignancy. The incidence and risk factors for the development of neoplasia related to smoking (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were studied in 339 liver transplant recipients. Risk factors for the development of smoking‐related neoplasia were also studied in 135 patients who had a history of smoking so that it could be determined whether smoking withdrawal was associated with a lower risk of malignancy. After a mean follow‐up of 7.5 years, 26 patients were diagnosed with 29 smoking‐related malignancies. The 5‐ and 10‐year actuarial rates were 5% and 13%, respectively. In multivariate analysis, smoking and older age were independently associated with a higher risk of malignancy. In the smoker subgroup, the variables related to a higher risk of malignancy were active smoking and older age. In conclusion, smoking withdrawal after liver transplantation may have a protective effect against the development of neoplasia. Liver Transpl, 2011.

Analysis of Prognostic Factors After Yttrium-90 Radioembolization of Advanced Hepatocellular Carcinoma

PURPOSEnTo analyze which patient-, tumor-, and treatment-related factors may influence outcome after (90)Y radioembolization ((90)Y-RE) for hepatocellular carcinoma (HCC).nnnPATIENTS AND METHODSnSeventy-two consecutive patients with advanced HCC treated with (90)Y-RE were studied to detect which factors may have influenced response to treatment and survival.nnnRESULTSnMedian overall survival was 13 months (95% confidence interval, 9.6-16.3 months). In univariate analysis, survival was significantly better in patients with one to five lesions (19 vs. 8 months, p = 0.001) and in patients with alpha-fetoprotein <52 UI/mL (24 vs. 11 months, p = 0.002). The variation in target tumor size and the appearance of new lesions were analyzed among 50 patients with measurable tumors. A decrease in target tumor size was observed in most patients, and the intensity of such decrease was not associated with any of the factors under study. Patients who developed new lesions in the treated liver (and also in the nontargeted liver) at month 3 more frequently had more than five nodules, bilobar disease, and alpha-fetoprotein >52 UI/mL, and their survival in the multivariate analysis was significantly worse (hazard ratio, 4.7; 95% confidence interval, 13-1.73) (p = 0.002).nnnCONCLUSIONSnYttrium-90 radioembolization results in control of target lesions in the majority of patients with HCC but does not prevent the development of new lesions. Survival of patients treated with (90)Y-RE seems to depend largely on factors related to the aggressiveness of the disease (number of nodules, levels of alpha-fetoprotein, and presence of microscopic disease).

Safety and Liver Transduction Efficacy of rAAV5-cohPBGD in Nonhuman Primates: A Potential Therapy for Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) results from haplo-insufficient activity of porphobilinogen deaminase (PBGD) and is characterized clinically by life-threatening, acute neurovisceral attacks. To date, liver transplantation is the only curative option for AIP. The aim of the present preclinical nonhuman primate study was to determine the safety and transduction efficacy of an adeno-associated viral vector encoding PBGD (recombinant AAV serotype 5-codon-optimized human porphobilinogen deaminase, rAAV5-cohPBGD) administered intravenously as part of a safety program to start a clinical study in patients with AIP. Macaques injected with either 1 × 10(13) or 5 × 10(13) vector genomes/kg of clinical-grade rAAV5-cohPBGD were monitored by standardized clinical parameters, and vector shedding was analyzed. Liver transduction efficacy, biodistribution, vector integration, and histopathology at day 30 postvector administration were determined. There was no evidence of acute toxicity, and no adverse effects were observed. The vector achieved efficient and homogenous hepatocellular transduction, reaching transgenic PBGD expression levels equivalent to 50% of the naturally expressed PBGD mRNA. No cellular immune response was detected against the human PBGD or AAV capsid proteins. Integration site analysis in transduced liver cells revealed an almost random integration pattern supporting the good safety profile of rAAV5-cohPBGD. Together, data obtained in nonhuman primates indicate that rAAV5-cohPBGD represents a safe therapy to correct the metabolic defect present in AIP patients.

Transarterial therapies for hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is often fatal due to local growth inside the liver and its unique arterial vascularization provides the basis for transarterial therapies. Around 35% of patients are diagnosed at stages in which transarterial therapies are indicated as first-line therapy; many others are treated after recurrence or progression to surgery or percutaneous ablation. However, the scientific evidence supporting the use of transarterial therapy is heterogeneous and certainly weak for several subgroups. New developments have emerged in the last decade. Areas covered: This review discusses the scientific evidence supporting the use of transarterial therapies for patients with HCC, including chemoembolization with conventional materials or drug-eluting beads, and internal radiation procedures such as the injection radioactive lipiodol or radioembolization with 90Y-loaded microspheres. The literature on clinical development of transarterial therapies for HCC has been reviewed since 1990. Expert opinion: Transarterial chemoembolization has been shown to improve the survival of those patients with unresectable, mostly viral-related HCC who have a preserved liver function and low tumor burden. Recently developed devices and procedures, particularly drug-eluting beads and radioactive microspheres, may further improve the clinical outcome of patients receiving transarterial therapies. Combination with antiangiogenic agents is an appealing approach that should be explored.

Factors related to increased resting energy expenditure in men with liver cirrhosis.

Objective Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver. Patients and methods We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded. Results REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, &bgr;-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P<0.05), nonprotein respiratory quotient (P<0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P<0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism. Conclusion Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice.

NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma

The identification of new targets for systemic therapy of hepatocellular carcinoma (HCC) is an urgent medical need. Recently, we showed that hNatB catalyzes the N-α-terminal acetylation of 15% of the human proteome and that this action is necessary for proper actin cytoskeleton structure and function. In tumors, cytoskeletal changes influence motility, invasion, survival, cell growth and tumor progression, making the cytoskeleton a very attractive antitumor target. Here, we show that hNatB subunits are upregulated in in over 59% HCC tumors compared to non-tumor tissue and that this upregulation is associated with microscopic vascular invasion. We found that hNatB silencing blocks proliferation and tumor formation in HCC cell lines in association with hampered DNA synthesis and impaired progression through the S and the G2/M phases. Growth inhibition is mediated by the degradation of two hNatB substrates, tropomyosin and CDK2, which occurs when these proteins lack N-α-terminal acetylation. In addition, hNatB inhibition disrupts the actin cytoskeleton, focal adhesions and tight/adherens junctions, abrogating two proliferative signaling pathways, Hippo/YAP and ERK1/2. Therefore, inhibition of NatB activity represents an interesting new approach to treating HCC by blocking cell proliferation and disrupting actin cytoskeleton function.

Prophylaxis and treatment of hepatitis B infection in the setting of liver transplantation

Without any treatment, the prognosis of hepatitis B in liver transplant recipients is very poor. So, antiviral prophylaxis is very important in patients with hepatitis B who undergo liver transplantation. Before liver transplantation, a suppression of viral replication has to be achieved by nucleos(t)ide analogs. Drugs used in the prophylaxis of post-transplant hepatitis B include immunoglobulin against HBV and nucleos(t)ide analogs. Prophylaxis against graft infection must be based on the individual risk of recurrence. When prophylactic measures have failed and graft infection has occurred, treatment of recurrent hepatitis B may be based on the resistance profile of the virus and previous antiviral exposure. Finally, lamivudine seems to be very effective in the prevention of de novo hepatitis B in patients transplanted with a graft from an anti-HBc positive donor.

Locoregional Transarterial Therapies for Hepatocellular Carcinoma: Transarterial Chemoembolization and Radioembolization

Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third most common cause of cancer-related mortality. Despite the widespread implementation of surveillance programs, more than half of the patients with HCC are diagnosed at late stages, when curative treatments (resection or liver transplantation) cannot be applied. For patients presenting with unresectable, non-transplantable HCC and a relatively preserved liver function, locoregional transarterial therapies are the main therapeutic options. Therefore, locoregional transarterial treatments play a key role in the management of HCC. The concept of catheter transarterial therapies is to selectively deliver anticancer treatments to liver tumors. This is possible due to the unique double irrigation of the liver and the predominantly arterial irrigation of liver tumors. Method: An exhaustive analysis of the literature, focused mainly on the last 25 years, has been carried out. Results: This review discusses the scientific evidence supporting the use of transarterial therapies for patients with HCC, including chemoembolization with conventional materials or drug-eluting beads, and internal radiation procedures such as the injection of radiation-loaded microspheres. Conclusion: Transarterial chemoembolization has been shown to improve the survival of those patients with unresectable HCC who have a preserved liver function and a low tumor burden. Recently developed devices and procedures, particularly drug-eluting beads and radioactive microspheres, may further improve the clinical outcome of patients receiving transarterial therapies. The combination with antiangiogenic agents is an appealing approach that should be explored.