The predisposition of HCC development and progression might be caused by the genetic diversity of the patients. The Patients with HCC also have quite different clinical presentations and diverse outcomes even in spite of the similar managements. Therefore, by clarifying and exactly understanding the hepatocarcinogenetic mechanisms, we can obtain the insights to establish more effective diagnostic, therapeutic and preventive measures for patients with HCC. Thus, utilizing relevant basic and clinical investigations, we need to set up ‘individualized’ and ‘personalized’ guidelines for early diagnosis, effective treatment and prevention of HCC.

During the past 20 years, my research team has had interests in establishing effective diagnostic, therapeutic and preventive measures for HCC. We have tried to clarify the carcinogenic mechanism of HCC, to improve the efficacies of treatments for HCC, and also to find novel therapeutic and preventive measures of HCC at the laboratory and clinic. Especially, our researches have been focused on the clarification of the diversity of HCC, and thus we have tried to establish useful diagnostic and therapeutic modalities. Also, we have tried to find new molecular targets to be applicable to the managements of HCC patients.

This book is an introduction and summary of our research works for twenty years. I collected and edited the relevant articles, which have been recently published in celebrated medical journals and books. Indeed, I believe this book would be a valuable reference to many clinicians and basic researchers who are interested in HCC.

Foreword viii
 Preface ix
 Part I Hepatocarcinogenesis 1
 Molecular mechanisms of hepatocarcinogenesis
 1.1 Chronic hepatitis B in hepatocarcinogenesis 3
 Effects of hepatitis B virus
 1.2 Synergistic effects of A1896, T1653 and T1762/A1764 mutations in
 genotype C2 hepatitis B virus on development of hepatocellular carcinoma 16
 Aberrant epigenetic modifications
 1.3 Aberrant epigenetic modifications in hepatocarcinogenesis induced by
 hepatitis B virus X protein 23
 Histology of chronic liver diseases
 1.4 Histological characteristics predisposing development of hepatocellular
 carcinoma in patients with chronic hepatitis B 43
 Response to antiviral therapy
 1.5 Biochemical rather than virologic response to interferon therapy may be more closely associated
 with decrease of hepatocellular carcinoma incidence in patients with chronic hepatitis B 53
 Genetic predispositions
 1.6 Genetic variations at loci involved in the immune response are risk factors
 for hepatocellular carcinoma 60
 1.7 Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma
 patients with chronic hepatitis B: Possible implications on survival 71
 1.8 expression of transforming growth factor?α mRNA in livers of patients
 with chronic viral hepatitis and hepatocellular carcinoma 80
 1.9 p16 Hypermethylation in the early stage of hepatitis B virus?associated hepatocarcinogenesis 86
 1.10 expression of DNA methyltransferases in multistep hepatocarcinogenesis 93
 Part II Serologic markers for early diagnosis of hepatocellular carcinoma 101
 Alpha-fetoprotein
 2.1 Specificities of serum α?fetoprotein in HBsAg+ and HBsAg? patients in the
 diagnosis of hepatocellular carcinoma 103
 Transforming growth factor-β1
 2.2 Transforming growth factor ?β1 as a useful serologic marker of small
 hepatocellular carcinoma 109

 Part III Systemic therapy for hepatocellular carcinoma 117
 Interferon therapy
 3.1 Combined therapy consisting of intraarterial cisplatin infusion and systemic
 interferon?α for hepatocellular carcinoma patients with major portal vein
 thrombosis or distant metastasis 119
 Molecular targeted therapy
 3.2 Angiogenic factors as molecular targets for hepatocellular carcinoma 125
 3.3 Clinical trials of molecular targeted therapies in hepatocellular carcinoma:
 Efficacies and toxicities 138
 Combined therapy
 3.4 Interim analysis of START: Study in Asia of the combination of TACE
 (transcatheter arterial chemoembolization) with sorafenib in patients with
 hepatocellular carcinoma trial 150
 3.5 The combination of transcatheter arterial chemoembolization and sorafenib is
 well tolerated and effective in Asian patients with hepatocellular carcinoma:
 Final results of the START trial 164
 Adverse effects of molecular targeted therapy
 3.6 Genetic predisposition of hand?foot skin reaction after sorafenib therapy in
 patients with hepatocellular carcinoma 176
 Part IV Recurrences of hepatocellular carcinoma 185
 Factors associated with recurrence after curative resection
 4.1 Effects of genomic changes in hepatitis B virus on postoperative recurrence and
 survival in patients with hepatocellular carcinoma 187
 Factors associated with recurrence following locoregional therapy
 4.2 Recurrences of hepatocellular carcinoma following initial remission by
 transcatheter arterial chemoembolization 195
 4.3 Predisposing factors of hepatocellular carcinoma recurrence following complete
 remission in response to transarterial chemoembolization 202
 4.4 Recurrences of hepatocellular carcinoma following complete remission by transarterial
 chemoembolization or radiofrequency therapy: Focused on the recurrence patterns 211
 Mediators associated with invasiveness of hepatocellular carcinoma
 4.5 Metastatic tumor antigen 1 is closely associated with frequent postoperative
 recurrence and poor survival in patients with hepatocellular carcinoma 220
 4.6 Clinical implications of arrest?defective protein 1 expression in hepatocellular carcinoma:
 A novel predictor of microvascular invasion 229
 4.7 Association between insulin?like growth factor?2 and metastases after transcatheter arterial
 chemoembolization in patients with hepatocellular carcinoma: A prospective study 235
 Adjuvant therapy to prevent hepatocellular carcinoma recurrence
 4.8 Safety and efficacy of adjuvant pegylated interferon therapy for metastatic
 tumor antigen 1?positive hepatocellular carcinoma 244

 Part V Prognostic indicators of hepatocellular carcinoma 253
 MicroRNAs
 5.1 Roads towards a new tailored therapy for hepatocellular carcinoma: Diagnostic,
 therapeutic and prognostic implications of microRNAs 255
 Metastatic tumor antigens
 5.2 Metastatic tumor antigen in hepatocellular carcinoma: Golden roads toward
 personalized medicine 258
 5.3 Factors predisposing metastatic tumor antigen 1 overexpression in hepatitis B virus
 associated hepatocellular carcinoma 276
 5.4 Single nucleotide polymorphisms associated with metastatic tumour antigen 1
 overexpression in patients with hepatocellular carcinoma 284
 5.5 Overexpression of metastasis?associated protein 2 is associated with hepatocellular
 carcinoma size and differentiation 296
 Tumor necrosis factor-alpha
 5.6 Clinical aspects of tumor necrosis factor?α signaling in hepatocellular carcinoma 303
 Telomerase maintenance gene
 5.7 Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular
 carcinoma patients with chronic hepatitis B 317
 Index 329