The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008

Verslype, Chris; Cutsem, Éric Van; Dicato, Mario; Arber, Nadir; Berlin, Jordan; Cunningham, David; Gramont, Aimery de; Díaz-Rubio, Eduardo; Ducreux, Michel; Gruenberger, Thomas; Haller, Daniel G.; Haustermans, Karin; Hoff, PM; Kerr, David; Labianca, Roberto; Moore, Malcolm J.; Nordlinger, Bernard; Ohtsu, Atsushi; Rougier, Philippe; Scheithauer, Werner; Schmoll, Hans‐Joachim; Sobrero, Alberto; Tabernero, Josep; Velde, Cjh van de

doi:10.1093/annonc/mdp281

Cited by 96 publications

(74 citation statements)

References 35 publications

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“…The widely used Barcelona-Clinic-Liver-Cancer (BCLC) staging system links staging of HCC in cirrhosis with treatment modalities [127,128] . The system identifies those patients with early HCC (stage 0 and A) who may benefit form curative therapies (resection, radiofrequency ablation, liver transplantation), those at intermediate or advanced stage (stage B, C) who may benefit from palliative treatments (such as transarterial chemo-or radioembolisation), and the patients with a very poor life expectancy (stage D) where best supportive care is the only option [129] .…”

Section: Treatmentmentioning

confidence: 99%

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Severi¹,

Malenstein²,

Verslype³

et al. 2010

Acta Pharmacol Sin

157

125

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Section: Treatmentmentioning

confidence: 99%

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Severi¹,

Malenstein²,

Verslype³

et al. 2010

Acta Pharmacol Sin

157

125

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“…Risk factors for HCC include hepatitis B and C infections and alcoholism (Blum, 2005). Radical treatments include surgical resection, locoregional ablative techniques (radiofrequency ablation, transarterial chemoembolization, or percutaneous ethanol injection), and liver transplantation or partial hepatectomy, but recurrence rates remain as high as 60% (Kamiyama et al, 2009;Verslype et al, 2009). Factors that determine resectability include the degree of portal hypertension, bilirubin level, tumor size, multiple or bilobar lesions, vascular invasion, and extrahepatic spread.…”

Section: Introductionmentioning

confidence: 99%

Safety Studies on Intrahepatic or Intratumoral Injection of Oncolytic Vesicular Stomatitis Virus Expressing Interferon-β in Rodents and Nonhuman Primates

et al. 2010

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Toxicology studies were performed in rats and rhesus macaques to establish a safe starting dose for intratumoral injection of an oncolytic vesicular stomatitis virus expressing human interferon-b (VSV-hIFNb) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59Â10 9 TCID 50 (50% tissue culture infective dose) of VSV-hIFNb into the left lateral hepatic lobe of Harlan Sprague Dawley rats. Plasma alanine aminotransferase and alkaline phosphatase levels increased and platelet counts decreased in the virus-treated animals on days 1 and 2 but returned to pretreatment levels by day 4. VSV-hIFNb was also injected into normal livers or an intrahepatic McA-RH7777 HCC xenograft established in Buffalo rats. Buffalo rats were more sensitive to neurotoxic effects of VSV; the no observable adverse event level (NOAEL) of VSV-hIFNb in Buffalo rats was 10 7 TCID 50 . Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared with VSV-hIFNb, toxicity of VSV-rIFNb (recombinant VSV expressing rat IFN-b) was greatly diminished in Buffalo rats (NOAEL, >10 10 TCID 50 ). Two groups of two adult male rhesus macaques received 10 9 or 10 10 TCID 50 of VSV-hIFNb injected directly into the left hepatic lobe under computed tomographic guidance. No neurological signs were observed at any time point. No abnormalities (hematology, clinical chemistry, body weights, behavior) were seen and all macaques developed neutralizing anti-VSV antibodies. Plasma interleukin-6, tumor necrosis factor-a, and hIFN-b remained below detection levels by ELISA. On the basis of these studies, we will be proposing a cautious approach to dose escalation in a phase I clinical trial among patients with HCC.

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“…1 HCC develops as a consequence of chronic hepatitis or liver cirrhosis. Key to the malignant outcome is the hypoxic microenvironment, affecting cell death.…”

mentioning

confidence: 99%

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

et al. 2010

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Hypoxia-inducible factors (HIFs) provoke adaptation to hypoxic stress occurring in rapidly growing tumor tissues. Therefore, overexpression of HIF-1 or HIF-2 is a common feature in hepatocellular carcinoma but their specific function is still controversially discussed. To analyze HIF function in hypoxia-induced cell death we created a stable knockdown of HIF-1a and HIF-2a in HepG2 cells and generated tumor spheroids as an in vitro hepatocellular carcinoma model. Knockdown of HIF-1a enhanced expression of HIF-2a and vice versa. Unexpectedly, knockdown of HIF-1a or HIF-2a increased cell viability as well as spheroid size and decreased caspase-3 activity. Antiapoptotic Bcl-X L expression increased in both knockdown spheroids, whereas proapoptotic Bax was only reduced in HIF-1a-knockdown cells. Furthermore, an HIF-2a-knockdown significantly increased Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression in an HIF-1a-dependent manner. Concomitantly, electron microscopy revealed a substantial increase in autophagosomal structures in HIF-2a-knockdown spheroids and mito-/lysotracker costaining confirmed lysosomal activity of these autophagosomes. Blocking autophagosome maturation using 3-methyladenine restored cell death in HIF-2a-knockdown clones comparable to wildtype cells. Conclusion: An HIF-1a-knockdown increases HIF-2a expression and shifts the balance of Bcl-2 family members toward survival. The knockdown of HIF-2a raises autophagic activity and attenuates apoptosis by enhancing HIF-1a expression. Our data indicate that enhanced expression of one HIF-isoform causes a survival advantage in hepatocellular carcinoma development. (HEPATOLOGY 2010;51:2183-2192

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The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008

Cited by 96 publications

References 35 publications

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Safety Studies on Intrahepatic or Intratumoral Injection of Oncolytic Vesicular Stomatitis Virus Expressing Interferon-β in Rodents and Nonhuman Primates

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

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