Plasmalemmal Vesicle Associated Protein (PLVAP) as a therapeutic target for treatment of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignancy with poor survival outcome. New treatment options for the disease are needed. In this study, we identified and evaluated tumor vascular PLVAP as a therapeutic target for treatment of HCC. METHODS: Genes showing extreme differential expression between paired human HCC and adjacent non-tumorous liver tissue were investigated. PLVAP was identified as one of such genes with potential to serve as a therapeutic target for treatment of HCC. A recombinant monoclonal anti-PLVAP Fab fragment co-expressing extracellular domain of human tissue factor (TF) was developed. The potential therapeutic effect and toxicity to treat HCC were studied using a Hep3B HCC xenograft model in SCID mice. RESULTS: PLVAP was identified as a gene specifically expressed in vascular endothelial cells of HCC but not in non-tumorous liver tissues. This finding was confirmed by RT-PCR analysis of micro-dissected cells and immunohistochemical staining of tissue sections. Infusion of recombinant monoclonal anti-PLVAP Fab-TF into the main tumor feeding artery induced tumor vascular thrombosis and extensive tumor necrosis at doses between 2.5 µg and 12 µg. Tumor growth was suppressed for 40 days after a single treatment. Systemic administration did not induce tumor necrosis. Little systemic toxicity was noted for this therapeutic agent. CONCLUSIONS: The results of this study suggest that anti-PLVAP Fab-TF may be used to treat HCC cases for which transcatheter arterial chemoembolization (TACE) is currently used and potentially avoid the drawback of high viscosity of chemoembolic emulsion for TACE to improve therapeutic outcome. Anti-PLVAP Fab-TF may become a viable therapeutic agent in patients with advanced disease and compromised liver function.

Transcatheter arterial chemoembolization for advanced hepatocellular carcinoma with portal vein invasion: safety, efficacy, and prognostic factors.

PURPOSE: To evaluate the safety and efficacy of transarterial chemoembolization and to identify the prognostic factors associated with survival in patients with hepatocellular carcinoma (HCC) and portal vein (PV) invasion. MATERIALS AND METHODS: From January 2006 to March 2012, 50 patients with HCC invading into the PV (Barcelona Clinic Liver Cancer stage C) were treated with transarterial chemoembolization. The parenchymal tumor and PV tumor were confirmed by multidetector computed tomography (CT) and angiography. There were 14 patients with right PV tumor, 12 patients with left PV tumor, and 24 patients with main PV tumor. The response was evaluated by multidetector CT using Response Evaluation Criteria in Solid Tumors. Patients with residual tumors received repeated transarterial chemoembolization every 6-8 weeks unless the patients achieved complete remission or developed contraindications. RESULTS: The median survival period of the entire group was 6.2 months (range, 1.7-50.9 mo), and the overall response rate was 42% (21 of 50 patients). The 6-month, 12-month, 24-month, and 36-month survival rates were 54%, 22%, 10%, and 8%. There were no instances of 30-day mortality or acute liver failure related to transarterial chemoembolization. The median survival of the 21 responders was 10.5 months, and the median survival of the 29 nonresponders was 5.5 months (P < .001). In both univariate and multivariate analyses, only the response to transarterial chemoembolization (hazard ratio = 0.25, P < .001) and the absence of ascites (hazard ratio = 0.24, P = .01) were significant prognostic factors. CONCLUSIONS: Transarterial chemoembolization is a safe and effective treatment for HCC with major PV invasion. The response to transarterial chemoembolization and the ascites status were the most significant predictive factors for prolonged survival.

Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma.

PURPOSE: To investigate the clinical benefit of additional radiotherapy to patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE) and the molecular effects of radiation on gene expression in hepatoma cells. EXPERIMENTAL DESIGN: Between August 1996 and August 2003, 276 and 64 patients with American Joint Committee on Cancer stage T3N0M0 hepatocellular carcinoma receiving TACE alone and TACE followed by three-dimensional conformal radiotherapy, respectively, at our institution were studied. Clinical outcome and pattern of failure were analyzed for the association of survival benefit with radiotherapy. The molecular effects of radiotherapy were studied in vitro and in vivo using human hepatoma cells with different p53 mutation and hepatitis B virus infection status. RESULTS: Median follow-up and survival time in the TACE alone and TACE + radiotherapy groups were 39 and 19 months, and 51 and 17 months, respectively. Additional radiotherapy to TACE did not improve overall survival (P = 0.65). However, different failure patterns were noted after TACE and after radiotherapy. Although all irradiated tumors regressed substantially, radiotherapy rapidly enhanced both intrahepatic and extrahepatic tumor progression outside the radiotherapy treatment field in a significant portion of patients, which offset the benefit of radiotherapy on overall survival. In molecular analysis of the radiation effects on human hepatoma cells, radiotherapy rapidly induced p53-independent transcriptional up-regulation of vascular endothelial growth factor (VEGF), increased VEGF secretion in a dose-, time-, and cell type-dependent manner, and promoted hepatoma cell growth in vivo with enhanced intratumor angiogenesis, which correlated well with elevated levels of serum VEGF. CONCLUSIONS: Radiotherapy to eradicate a primary hepatocellular carcinoma might result in the outgrowth of previously dormant microtumors not included in the radiotherapy treatment field. Radiotherapy-induced VEGF could be a paracrine proliferative stimulus. Therapeutic implications of the study justify the combination of three-dimensional conformal radiotherapy with anti-VEGF angiogenic modalities for the treatment of unresectable hepatocellular carcinoma to reduce relapses.

Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description.

Twelve patients with hepatocellular carcinoma and chronic hepatitis developed radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy. Six patients died of RILD and six recovered. Mean prescribed dose was 50.6+/-4.3Gy, in a daily fraction of 1.8-2.0Gy. Commonly used dosimetric parameters, such as fraction volume of normal liver with radiation dose >30Gy, prediction score, and normal tissue complication probability, failed to differentiate the fatality and clinical types of this complication. Elevated transaminases are more frequently seen than ascites and elevated alkaline phosphamide are seen in patients with RILD.

Histopathologic correlation of hepatocellular carcinoma after transcatheter arterial chemoembolization with polyvinyl alcohol particle of various sizes.

AIM: Transcatheter arterial chemoembolization (TACE) is one of major treatment for unresectable hepatocellular carcinomas (HCC) and has been used as a neoadjuvant treatment before surgery. This study was to describe the histopathologic features of HCC after TACE with variously sized polyvinyl alcohol (PVA) particles. MATERIALS AND METHODS: Seventeen patients undergoing TACE with PVA followed by surgery for HCC were analyzed. The PVA particles used in TACE were categorized into two groups in respects of particle sizes: the group I, 47-90 µm (n=8) and the group II, >90-250 µm (n=9). The histopathologic features of the resected HCC were characterized with the emphasis on the number of thrombosed vessels and minimal diameter of arterioles/capillaries containing polyvinyl alcohol particles. The clinical results after TACE were also addressed. RESULTS: Histopathologic examinations showed that the median minimal diameters of arterioles containing PVA particles were 0.035 mm in group I and 0.06 mm in group II (p=0.0078). We observed the PVA particle in the sinusoidal spaces of non-tumourous liver in only one patient. However, no sinusoidal infarction was demonstrated in either group. Mean tumour necrosis rate was 67% vs. 61% for the group I and II, respectively. CONCLUSIONS: The smaller PVA particles can reach and occlude more distal arteriolar capillaries, but rarely leak into non-tumourous hepatic sinusoidal spaces. Slightly better tumour necrosis rate after TACE can be achieved.