Subject Index

A

AAT, see Alpha-1 antitrypsin (AAT)Acute abdomen, 312Acute intermittent porphyria (AIP), 297Adefovir, 235–250Adenosine deaminase deficiency, 301Adjustment disorder, 673–674

DSM-IV definition, 673Adjuvant therapies, 581

resection of HCC, 460–462Adrenal artery, 583Aflatoxin, 33, 530, 644

Aflatoxin B1 (AFB1) fungus,28–45

as HCC risk factor, 11–12in primary HCC development, 58

associated HCC, 292–293Aflatoxin-N7-guanine, 62etiology, 81–82exposure and early effect,

mechanistic basis, 45See also under Biomarkers

AFP, see Alpha-fetoprotein (AFP)AG-3340, 600Age, HCC incidence and, 5–6

age-standardized incidence rate(ASR), 2

China, 5–6female rates, 5high-risk African populations, 5

low-risk populations, 5in men, 29

Agoraphobia, 678Alagille’s syndrome, 299Alcoholic liver disease and HCC,

287–289alcohol as carcinogenic promotor,

288DNA methylation, 288

Methionine adenosyltransferase(MAT) in, 289

S-adenosyl methionine (SAMe)in, 289

ethanol, 288See also Percutaneous ethanol

injectionAlcohol intake, as HCC risk factor, 11,

679etiology, 82–83in primary HCC development,

58–59Algorithm, diagnostic, 318Allelic imbalance determination, 478Alpha-1 antitrypsin (AAT), 86–87

deficiency and HCC, 293–294Alpha-fetoprotein (AFP) as serum

marker for HCC, 42, 156–157,269–272, 314–316, 332

advantage, 269AFP-L3, 339disadvantage, 269

B.I. Carr (ed.), Hepatocellular Carcinoma, Current Clinical OncologyDOI 10.1007/978-1-60327-376-3

C© Humana Press, a part of Springer Science+Business Media, LLC 2009

721

722 Subject Index

American Joint Committee on cancerstaging, 197

for intrahepatic tumors, 197–198American Liver Tumor Study Group

Modified TNM StagingClassification, 472

American Society of Clinical Oncology(ASCO), 607

Anger, 672Angiopoietins (Ang-1 and Ang-2), 161Anticipatory grief, 689Anticipatory nausea, 685

predictors, 685–686treatment, 686

Antiviral therapy, 244–245adefovir dipivoxil (ADV), 245entecavir (ETV), 245for HBV, in United States, 243

FDA approved anti-HBV drugs,245

lamivudine (LVD), 244telbivudine (TLV), 245tenofovir disoproxil fumarate (TDF),

245Anxiety disorders, 676

cognitions, 677GAD, 676–677panic disorder, 677–678PTSD, 677

Anzamet, 545Apoptosis, 595, 600Array comparative genomic

hybridization (aCGH), 134Arterial hypertension, 314Arterial plexus, 630Aryl hydrocarbon receptor (AhR)

agonists, 72–732,3,7,8-tetrachlorodibenzoparadioxin

(TCDD), 72–73ASCO, see American Society of

Clinical Oncology (ASCO)Asian Americans, HCC in, 240–242

Asians, 240California, 240

in males by race/ethnicity,1997–2001, 240

HBV infection among, 241Cambodian, 241China, 241Hong Kong, 241Indonesia, 241Japan, 241Korea, 241Laos, 241Malaysia, 241Philippines, 241Taiwan, 241Thailand, 241Vietnam, 241

non-Asians, 240Asymptomatic clinical feature of HCC,

310–311Australia, 2AZD6244 inhibitor, 121

B

Barcelona Clinic Liver Cancer (BCLC)staging system, 198

Batimastat, 600BAY12-9566, 600Bead Block, 579Benadryl, 545Benefit finding, 672Benign enhancing pseudonodules, 371Benzodiazepines, 683Beta-catenin, 112, 235–250Beta decay, 620Bevacizumab, 599

evaluation in clinical trials, 603Bile acid syntheic disorders, 295Bile salt export protein (BSEP)

deficiency, 294Biliary interface hepatitis, 187Biological Expression Network

Discovery (BLEND), 164–165Biomarkers for HCC, 28–45, 335–343,

606

Subject Index 723

Des-Gamma Carboxy-Prothrombin(DCP), 337–338

glycoprotein, 339, 340Glypican-3, 339–340Golgi protein 73 (GP73), 339, 340human hepatocyte growth factor

(HHGF), 339, 340–341insulin growth factor-1 (IGF-1), 341Lens Culinaris Agglutinin Reactive

Fraction of AFP (AFP-L3),338–339

novel biomarkers, 335–343Osteopontin (OPN), 341–342proteomics, 342–343squamous cellular carcinoma antigen

(SCCA), 341validation, phases of, 338

cancer control, 338clinical assay and validation, 338preclinical exploratory, 338prospective screening, 338retrospective longitudinal, 338

Biomarkers, molecularaflatoxin biomarkers, 30

chlorophyllin, 42as intermediate biomarkers, 41intervention trials using, 41–42structures, 33

biomarker of effect, 29biomarker of susceptibility, 30DNA mutations measured in human

plasma and HCC, 42–44for environmental carcinogens, 29in human investigations, 36–41

aflatoxin studies, 36cross-sectional epidemiological

studies, 37exposure and disease outcome

rrelation, 39longitudinal studies, 37p53 gene analysis in human

HepG2 cells, 37tracking potential of biomarker,

37–38

mechanistic-based biomarkers ofaflatoxin and HBV, 45

methods for measurement, 32–34analytical methods, 33antibody-based methods, 33HPLC, 33HPLC-f, 33IDMS, 33immunoaffinity cleanup/HPLC

procedure, 33immunoassays, 33isotope-dilution mass

spectrometry, 34quantitative measurements, 34

validation, 34–36chemoprevention strategies for

aflatoxin carcinogenesis,34–35

Biopsy, 317–320, 715algorithm, 318decision regarding, 317–320fine-needle aspiration (FNA) biopsy,

319importance of, 319‘Milan criteria’, 317in patients with cirrhosis, 317percutaneous needle core biopsy, 319pitfalls of, 319–320pretransplantation biopsy, 319transjugular needle core biopsy, 319US-guided biopsy, 317, 319

BLEND, see Biological ExpressionNetwork Discovery (BLEND)

BMS214622, 597BMS-500626, 596Body mass index (BMI) and HCC,

14–15Brachytherapy, 620

clinical studies131I-lipiodol, 628–629phase I–II 90Y-microspheres,

633–63590Y-microspheres (yttrium-90),

630–633

724 Subject Index

Brevanib, 599evaluation in clinical trials, 603mechanism of action, 602

Bright-blood images, 375Budd-Chiari syndrome, 372

C

Canada, 2Cancer of the Liver Italian Program

(CLIP) system, 198Candidate serum molecular markers,

156–163diagnostic serum markers, 156–159

complement C3A (C3A), 158cystatin B (CSTB), 158α -fetoprotein (AFP), 156–157Glypican-3 (GPC3), 157insulin-like growth factor

(IGF-II), 158–159Midkine (MDK), 157

prognostic serum markers, 159–163See also individual entry

Carbohydrate metabolism, defects in,and HCC, 295–297

Galactosemia, 295–296hepatic glycogen storage disease,

296–297Glycogen Storage Disease I

(GSD-I), 296Glycogen Storage Disease IV

(GSD-IV), 297Glycogen Storage Disease-III

(GSD-III), 296–297CD24 gene, 339Cediranib, 599

evaluation in clinical trials, 603Celiac axis, 573Cell cycle disruption, 283–301Cell proliferation role in cancer

initiation, 65–66Central sleep apnea, 683Cetuximab, mechanisms of action,

596

CEUS, see Contrast-enhancedultrasound (CEUS)

CHB, see Chronic hepatitis B (CHB)CHC, see Chronic hepatitis C (CHC)Chemical carcinogenesis, 59–74

o-aminoazotoluene, 60aryl hydrocarbon receptor (AhR)

agonists, 72–73cell proliferation role in initiation,

65–66fixation, 65mismatch repair, 66

4-dimethylaminoazobenzene, 60DNA adducts, 61–62ethionine, 74genotoxic carcinogens, 60–66

See also individual entrymutations and their consequences,

62–65non-genotoxic mechanisms, 66–74

alcohol intake, 66–67cirrhosis, 67mutagenic agents in, 66tumor-promoting agents, 67

peroxisome proliferators-activatedreceptors (PPARs), 71–72

See also Estrogenic agents;Phenobarbital; Primary HCC

Chemoembolization, 542results of, 547–551

prognostic factors for survival,548–549

TACE using drug eluting beads,550–551

tumor responses, factorsassociated with, 550

Chemo-occlusion therapy, 545Chemoprevention of HCC, 320–323

HBC treatment and HCC prevention,322

HBV treatment and HCC prevention,321–322

primary, 320–321secondary, 322–323

Subject Index 725

Chemotherapy, 536–537intrahepatic artery, 538–539partial response rate, 536–537response to, 547vs. TACE, 540

Child–Pugh score, 198, 601, 686China, HCC in, 2–4

surveillance, 334–335Chinese University Prognostic Index

(CUPI), 198Cholangiocarcinoma, 28–45Chronic hepatitis, as HCC risk factor, 8Chronic hepatitis B (CHB), 244Chronic hepatitis C (CHC), 259–275Chronic liver disease (CLD) signature,

135–148, 246–248Cigarette smoking and HCC, 16Cirrhosis/Cirrhotic liver, 542

differential diagnosis of nodules in,395–400

etiology, 79–80focal imaging findings in, 371–372focal lesions in cirrhotic liver,

350–355confluent hepatic fibrosis, 351dysplastic nodules, 352–355, See

also individual entryfibrosis, 350–351regenerating nodules, 351–352,

See also individual entrymonitoring cirrhotic patient, 350nodular lesions in, 355in primary HCC development, 59as risk factor for HCC, 8–10, 267,

300Cisplatin (Platinol), 542–543

dose intensity, 544hepatic artery chemoembolization,

548–549prognostic factors for survival,

548–549tumor responses, factors

associated with, 550Citrullinemia, 87–88

Clamp crushing technique, 458Classic triad presentation of HCC, 311Clear cell HCC, 210–211Clinical concerns, in HCC, 132–133Clinical features/presentation of HCC,

310–314, 719–720abdominal pain, 310, 312acute abdomen, 312asymptomatic, 310–311classic triad, 311enucleation sign, 312gastrointestinal hemorrhage, 312gastrointestinal symptoms, 310hepatic decompensation, 312hepatomegaly, 310jaundice, 310rare manifestations, 314swelling, 310tumor rupture/hemoperitoneum,

312–313weakness, 310weight loss, 310See also Diagnostic approach;

Paraneoplastic syndromesClinician’s diagnosis, see Diagnostic

approach to HCCClinicopathologic comments, HCC, 19460Cobalt, 617Coffee consumption and HCC risk, 17

reduction, 17–18Cognitions, 677Colombia, 2Colony stimulating factor-1 (CSF1),

160–161Combined hepatocellu-

lar/cholangiocellularcarcinoma, 212–214

components of, 213immunophenotypic analysis of, 213sarcomatoid change in, 214

Complement C3A (C3A), 158Complications from RFA, 441–443

See also under Radiofrequencyablation (RFA)

726 Subject Index

Computed Tomography (CT), 349–364accuracy of, 361–362helical CT, 364in PEI, 411–412

Confluent fibrosis, 371Congenital intrahepatic porphyria

(CIP), 298Contour SE 579Contrast-enhanced ultrasound (CEUS),

387–404differential diagnosis of nodules in

liver cirrhosis, 395–400Doppler ultrasound, 389–394dysplastic nodules (DN), 389, 401fibrolamellar carcinoma, 393gray-scale, 389–394HCC with autoimmune hepatitis,

396HCC with HCV, 393HCC with portal vein thrombosis,

397hemangioma, 402hyperechogenicity, 389infiltrative HCC, 390–391

with right hepatic veinthrombosis, 392

in PEI, 411–412post-treatment monitoring, 403regenerating nodules (RN), 389–390,

400residual viable tumor, 404techniques, 394–395

contrast-specific imaging mode,395

dual-imaging mode, 395flash-replenishment technique,

395low-MI continuous imaging, 395real-time evaluation of

enhancement, 395‘washout’ during the venous phase,

398–399Conventional hepatic artery anatomy,

574

Copper overload, 86Cox regression analysis, 675C-reactive protein, 339CT, see Computed Tomography (CT)Ctokeratin-19, 339CUPI, see Chinese University

Prognostic Index (CUPI)Cystatin B (CSTB), 158Cystic fibrosis, 299

D

Danazol, 83DC Bead, 5793D-CRT, see Three-dimensional

conformal radiation therapy(3D-CRT)

4D-CRT, see Fourth-dimensionalconformal radiation therapy(4D-CRT)

DDLT, see Deceased donor livertransplantation (DDLT)

Decadron, 545inflammatory response, decrease,

578Deceased donor liver transplantation

(DDLT), 491–492living donor vs., 497, 504, 516–518

A2ALL study, 518advantage of LDLT, 517hepatocyte growth factor (HGF),

519higher recurrence rate in LDLT,

518Hong Kong University Study, 518Korean multicenter study, 517multicenter studies, 517

Delirium, 688definition, 688risk factors, 688

Des-γ-carboxyprothrombin (DCP), 271,412, 337–338, 339, 512–513

Dexamethasone, 545Diabetes mellitus

Subject Index 727

as HCC risk factor, 12–13, 20See also Obesity

type II, 300Diagnostic and Statistical Manual of

Mental Disorders IV(DSM-IV), 673

Diagnostic approach to HCC, 316–317AFP serum level measurement, 316CT, 316literature, 316MRI, 316

washout phase of imaging, 316See also Biopsy

Diagnostic HCC signatures,135–152

See also Chronic liver disease (CLD)signature

Diagnostic serum markers, 156–159α -fetoprotein (AFP), 156–157Glypican-3 (GPC3), 157midkine (MDK), 157

Diet and HCC, 16–18coffee drinking, 17vegetable and fruit consumption,

inverse association between,17

Diffusion weighted images, 374–375Dignity therapy, 689Dimerization, 592Dioxin, in primary HCC development,

58Distress

definition, 642distress thermometer, 644

modified, 645evaluation and treatment, 642psychosocial, 668

DNA adducts, chemical carcinogenesisand, 61–62

Aflatoxin-N7-guanine, 62apoptosis, 64

DNA methylation, 235–250DNA mutations measured in human

plasma and HCC, 42–44

short oligonucleotide mass analysis(SOMA), 43

Doppler ultrasound in CEUS, 389–394See also under Contrast-enhanced

ultrasound (CEUS)Doxorubicin (Adriamycin), 542–543DSM-IV, see Diagnostic and Statistical

Manual of Mental DisordersIV

Dynamic contrast-enhanced series, 376Dynamic multiphasic contrast-enhanced

images, 374–375Dysplasia, hepatocellular, 192–194

cytoplasmic changes, 193differential diagnosis, 193–194

Dysplastic nodules (DN), 352–355,372, 389

T1-weighted MR, 354T2-weighted MR, 354

E

Early Detection Research Network(EDRN), 271

EBRT, see External beam radiationtherapy (EBRT)

ECM, see Extracellular matrix (ECM)Electrons, 617Embogold, 543

microspheres 579Embolization agents, 578–580

Bead Block, 579Contour SE, 579DC Bead, 579Embogold Microspheres, 579gelfoam, 578–579

Endocurietherapy, 620Entecavir, 235–250Enucleation sign, 312Environmental carcinogens, 27–45

age-standardized incidence, 29See also Biomarkers, molecular

Environmental etiology of HCC, 30–32aflatoxin, 31

728 Subject Index

Environmental etiology of HCC (cont.)alcohaol use, 32cigarette smoke, 32HBV, 30HCV, 32hepatitis B surface antigen (HBsAg)

positivity, 30Epidemiology of HCC, 1–21

See also Genetic epidemiologyEpidermal growth factor receptor

(EGFR) and their ligands intargeted therapies for HCC,115–116

Epigenetic dysfunction, 283–301Epithelial glycoprotein-2, 204EPP, see Erythropoietic protoporphyria

(EPP)Erlotinib (Tarceva), 551, 596Erythrocyte-binding polyamine, 339Erythropoietic protoporphyria (EPP),

298Estrogenic agents, as carcinogens,

69–71mechanism of, 70Mestranol, 71

Ethanol injection, 407–417See also Percutaneous ethanol

injectionEthionine, 74Ethnicity, HCC incidence and, 4–5Etiology of primary HCC in human,

79–88aflatoxin and other dietary

carcinogens, 81–82alcohol use, 82–83cirrhosis, 79–80genetic disorders, 84–88non-alcoholic fatty liver disease

(NAFLD), 80non-alcoholic steatohepatitis

(NASH), 80steroids, 83–84tobacco use, 82–83viral hepatitis, 80–81

Europe, 2European Association for the Study of

the Liver (EASL), 363Everolimus, 597

evaluation in clinical trials, 603Expression arrays, in gene expression

profiling, 133External beam radiation therapy

(EBRT), 617–618clinical studies

external beam monotherapy, 626external beam radiation, 624–626for portal vein thrombosis, 626proton radiotherapy, 627

Extracellular matrix (ECM), 595

F

Familial intrahepatic cholestasis,294–295

Bile salt export protein (BSEP)deficiency, 294

multidrug resistance-3 (MDR-3)deficiency, 294

progressive familial intrahepaticcholestasis type I, 294

Fanconi anemia, 300Farnesyl transferase inhibitors (FTIs),

597Fat-containing well-differentiated HCC,

359Fatigue, 680–681

etiology, 681treatment, 681

FDG-PET, see Fluorodeoxyglucosepositron emission tomography(FDG-PET)

Feminization, 314FGF, see Fibroblast growth factor

(FGF)Fibroblast growth factor (FGF), 162Fibrolamellar hepatocellular carcinoma

(FL-HCC), 207–210clinical presenatation, 208

Subject Index 729

microscopic structure, 208Surveillance, Epidemiology, and

End, Results (SEER) program,208

Fibrosis, 268, 350–351See also Cystic fibrosis

FibroTest, 268Fine-needle aspiration (FNA) biopsy,

319, 715FL-HCC, see Fibrolamellar

hepatocellular carcinoma(FL-HCC)

Fluorodeoxyglucose positron emissiontomography (FDG-PET), 272

FNA, see Fine needle aspiration biopsy(FNA)

Focal imaging findings in cirrhotic liver,371–372

Focal nodular hyperplasia (FNH),183–187, 372

clinical aspects, 184–185dystrophic vasculature, 185macroscopic aspects, 185–186microscopic aspects, 186–187needle biopsy, 187

pitfalls, 187in noncirrhotic liver, 185

Fourth-dimensional conformal radiationtherapy (4D-CRT), 619

Free-radical injury, 283–301FTIs, see Farnesyl transferase inhibitors

(FTIs)FUDR, 542, 543, 545Furosemide, 545

G

GAD, see Generalized anxiety disorder(GAD)

Gaiting, 619Galactosemia, 295–296Gastrointestinal hemorrhage, 312Gefitinib (Iressa), 596Gelfoam, 543, 578–579

powder, 546preparation, 580sponge sheets, 546wafer, 579

Gemcitabine (Gemzar), 543Gender, HCC incidence and, 5Gene expression profiling, 131–169Generalized anxiety disorder (GAD),

676–677definition, 676symptoms, 677

Genetic disorders, primary HCC inhuman and, 84–88

alpha-1 antitrypsin (AAT), 86–87citrullinemia, 87–88metal overload disorders, 84–86

copper, 86hereditary hemochromatosis

(HH), 85iron, 84–85

tyrosinemia, 87Genetic epidemiology of HCC,

18–21HCC risk, 18–19lack of reproducibility, 19Mendelian inheritance, 18polymorphisms, 19–20SNPs as HCC risk factor, 20

Genomic arrays (CGH/methylation), ingene expression profiling, 134

Genomic profiling of HCC, 131–169clinical markers defined by HCC

microarray, 166–168early HCC, 166HCC markers, 166HCC risk, 168HCC subtypes, 166markers, 168prognosis, 167recurrence, 168staging, 166

clinical utility, 164gene expression profiling,

133–135

730 Subject Index

Genomic profiling of HCC (cont.)microarray platforms, 133–134,

See also individual entryidentification, 164microarray analysis, 135–156

See also individual entryvalidation, 167See also Candidate serum molecular

markersGenotoxic carcinogens, 60–66Global incidence of HCC, 2–7

age and, 5–6America, 6–7China, 5–6female rates, 5high-risk African populations,

5low-risk populations, 5

age-standardized HCC incidence inmen, 29

age-standardized incidence rate(ASR), 2

America, 2, 6–7Australia, 2Canada, 2China, 2–4Colombia, 2Europe, 2gender, 5

males, 5Greece, 2Hong Kong, 4Korea, 2race/ethnicity, 4–5recent changes in, 4regional variations in, 3Spain, 2sub-Saharan Africa, 1–2Taiwan, 3Thailand, 2United Kingdom, 2See also Risk factors

Glycogen Storage Disease I (GSD-I),296

Glycogen Storage Disease IV(GSD-IV), 297

Glycogen Storage Disease-III(GSD-III), 296–297

Glypicans, 204Glypican-3 (GPC3), 157, 271,

339–340Golgi protein 73 (GP73), 339, 340Gray-scale in CEUS, 389–394

See also under Contrast-enhancedultrasound (CEUS)

Greece, 2Growth factor receptor pathway, 591

mutations, 591targeting, 596

H

HbxAg, see Hepatitis B x antigen(HBxAg)

HCA, see Hepatocellular adenoma(HCA)

HCC-associated gene 1, 339Helical CT detection, 364Hemangioma, 402Hemochromatosis, 291–292Hemoperitoneum, 312–313Hemorrhage, gastrointestinal, 312Hepatectomy, RFA vs., 428–430

See also under Radiofrequencyablation (RFA)

Hepaticangiography, 531–535Hepatic artery, 573

common, 573left, 573proper, 573right, 573

replaced, 575Hepatic artery chemo-occlusion,

546–547safety considerations, 546–547

tailored drug doses, 547unilobar treatments, 546–547vascular slowing, 547

Subject Index 731

Hepatic artery chemotherapy, 542–546chemo-occlusion therapy, protocol

for, 545cisplatin dose intensity, effects of,

544commonly used drugs, 543hepatic arterial occlusion, 543–545results of, 547–551

Hepatic decompensation feature ofHCC, 312

Hepatic glycogen storage disease,296–297

Glycogen Storage Disease I(GSD-I), 296

Glycogen Storage Disease IV(GSD-IV), 297

Glycogen Storage Disease-III(GSD-III), 296–297

Hepatic lesions, 716Hepatic Resection (HR), 414–417

PEI and, 414–415Hepatitis B carriers (HBSAg positive),

315Hepatitis B surface antigen (HBsAg),

28–45Hepatitis B virus (HBV), HCC

associated with, 7–9, 28–45,235–250

antiviral agents in therapy for, inUnited States, 243

lamivudine (LVD), 244HBV-related HCC, 236, 237–239

America, 237in Asian countries, 238China, 238chronic HBV carriers in the

world, 237Europe, 237Hong Kong, 238hyper-endemic regions, 238India, 238Korea, 238Malaysia, 238Philippines, 238

Taiwan, 238Thailand, 238Vietnam, 238

See also under Molecular biologyHepatitis B x antigen (HBxAg), 246

in CLD pathogenesis, 246DNMT1 expression activation, 249Rb inactivation by, 248Smad signaling in presence of, 247TGFβ1 upregulation by, 248in viral replication, 246–250

Hepatitis C virus (HCV) and HCC,8–10, 28–45, 235, 259–275

in Asian Americans, 240–242chronic HCV infection, 8cirrhosis as risk factor, 267cost-effectiveness, 273–274DNA damage by, 263environment/lifestyle in, 9epidemiology, 261–262

Japan, 261–262FibroTest, 268HBV and, 237–239

See also under Hepatitis B virus(HBV); Molecular biology

incidence of, 239–240China, 239

in Japan, incidence according tohistological fibrosis stagereport, 267

Metavir score, 268new serum markers and new

methods, 271AFP-L3, 271des-gamma-carboxyprothrombin

(DCP), 271dynamic CT and dynamic MRI,

detection sensitivities of, 271Early Detection Research

Network (EDRN), 271fluorodeoxyglucose positron

emission tomography(FDG-PET), 272

glypican-3, 271

732 Subject Index

Hepatitis C virus (HCV) and HCC(cont.)

hepatocyte growth factor (HGF),271

insulin-like growth factor(IGF)-1, 271

multi-detector CT (MDCT), 272pathogenesis of, HBV and, 239pathology, 262–264prevention of recurrence, 274–275primary prevention of, 265

screening policies, 265proteins, function and oncogenic

potentials of, 264screening interval, 272–273standardized recall procedures, 272structure of, 263subtyping HCV, importance, 262surveillance/surveillance

methodology, 265–272alpha-fetoprotein (AFP) as serum

marker, 268, 269–272chronic HBV infection,

prevalence, 267combined AFP and US in,

270–271diagnostic imaging, 268Japan, 266target population, 266–268tumor marker determination, 268US imaging modality, 269

transcription of cellular genes,regulating, 264

treatment, 322in United States, 267

Hepatoblastoma, 215–218AFP expression, 217clinical aspects, 215–216macroscopic pathology, 216microscopic pathology and ancillary

studies, 216–218osteoid, 216phenotypic plasticity, 217staging and prognosis, 218

Hepatocarcinogenesis, rodent modelsof, 74–75

Hepatocellular adenoma (HCA),131–169, 188–192, 349–364

architecture, 190clinical aspects, 188hepatocellular carcinoma vs., 189macroscopic pathology, 188–189microscopic pathology, 189–190in a noncirrhotic liver, 189subtypes and ancillary studies,

190–192alpha-fetoprotein positivity, 191glypican-3 expression, 191

Hepatocyte growth factor (HGF), 162,271

Hepatoerythropoietic porphyria (HEP)type II porphyria cutanea, 298

Hepatoma-specificgamma-glutamyltransferase,339

Hereditary coproporphyria (HCP), 298Hereditary fructose intolerance, 300Hereditary hemochromatosis (HFE),

85Hereditary hemorrhagic teleangiectasia,

300–301Hereditary tyrosinemia, 87Histone deacetylases (HDACs),

121–122Hong Kong, 4Hospice care, 691Human hepatocyte growth factor

(HHGF), 339, 340–341Human investigations

biomarkers in, 36–41See also under Biomarkers

HuMV833, 599Hypercalcemia, 313Hypercholesterolemia, 314Hyperechogenicity, 389Hyperplastic nodule, 372Hypervascularization favouring PEI,

409

Subject Index 733

Hypoglycemia, 313Hypo/hypermethylation, 283–301

I

IHC, see Immunohistochemistry (IHC)131I-lipiodol, 628–629Image-guided radiation therapy (IGRT),

620Imaging techniques, 349–364

cirrhotic patient, monitoring, 350CT, 351, 361–362

See also Computed Tomography(CT)

fat-containing well-differentiatedHCC, 359

focal lesions in cirrhotic liver,350–355

See also under CirrhosisHCC, 358MRI, 351, 361–362

See also Magnetic resonanceimaging (MRI)

Multidetector row CT (MDCT)technology, 356

small cavernous hemangioma, 357superparamagnetic iron aramagnetic

oxide (SPIO)-enhanced MRI,354

transient hepatic attenuationdifference (THAD), 357–358

Ultrasonography, 356ultrasound, 351

Immunocytochemical markers of HCC,202–205

alpha-fetoprotein expression,detection, 202

anti-carcinoembryonic antigen(CEA) antibody, 203

β-Catenin translocation, 204epithelial glycoprotein-2, 204Glypicans, 204HepPar 1, 203

lectin-reactive fraction of AFP(AFP-L3), 203

Osteopontin expression, 204serum des-carboxy-prothrombin, 204

Immunohistochemistry (IHC), 474Immunophenotypic analysis,

183–218IMRT, see Intensity-modulated

radiotherapy (IMRT)Incidence of HCC, 2–7

rates, 330See also Global incidence

Indeterminate nodule, using MRI,380

Inducible genetic errors, 283–301In situ hybridization (ISH), 474Insomnia, 682Insulin-like growth factors-I and -II

(IGF-I and -II), 158–159, 271,341

and their ligands in targetedtherapies for HCC, 117

Intensity-modulated radiotherapy(IMRT), 619

Interferon (IFN) therapy, 235, 250,262

Interleukin-6 (IL-6), 162–163International Union against Cancer and

the American Joint Committeeon Cancer (AJCC/UICC), 196

Intra-arterial chemoembolization,569–586

adjuvant therapy, 581–584advanced catheterization techniques,

581–584complications from tace, 581embolization agents, 578–580hepatic arterial anatomy, 573patient selection and preparation,

572procedure, 575–578radioembolization, 584variant arterial anatomy, 573–575

734 Subject Index

Intracellular signal transducers, in HCCtargeted therapy, 117–121

Raf-Mek-Erk/MAPK Pathway,120–121

AZD6244 inhibitor, 121sorafenib inhibitor, 121SPREDs, 120Sprouty (Spry) protein regulator,

120small GTPase superfamily, 118–120

Ras, 118rho, 118

Intrahepatic artery chemotherapy,538–539

Intraoperative ultrasound duringresection, 457

Iron overload, 84–85Ivalon, 543

J

JAK/STAT pathway, 592Japan, 261

HBV and HCV infection in,epidemiology, 261–262

incidence according tohistological fibrosis stagereport, 267

K

Kappa kinase, 593, 598KBR07785, 600KBR-8301, 600Kelly clamp crushing technique, 45890 K/MAC-2BP glycoprotein, 339, 340Korea, 2

multicenter studies for LDLT in,503–506

Kytril, 545

L

Lamivudine (LVD), 244Lapatinib (Tykerb), 596

Lens Culinaris Agglutinin ReactiveFraction of AFP (AFP-L3),338–339

Lesionsbiopsy of, 317, 319with cirrhosis, 716greater than 3 cm, 718greater than 5 cm, 718multiple, 718without cirrhosis, 716

Linked sideroblastic anemia,299–300

Lipiodol (Ethiodol), 543Lipoprotein, 339Liver cancer as an important biological

problem, 57–59See also Primary HCC

Liver transplant, 717clinical evaluation, 719workup, 719

Living donor liver transplantation(LDLT) for HCC, 491–520

advantages, 495extension in transplant

indications, 495minimal damage to liver graft,

495timely manner of performance,

495criteria for, 512–513vs. deceased donor liver

transplantation, 497, 504,516–518

See also under Deceased donorliver transplantation (DDLT)

disadvantages, 495–497donor morbidity, 495donor mortality, 495small-for-size syndrome, 496surgical limitation, 496

ethical issues, 516fall in, reasons, 494history of, 493–495indication of, 498–503

Subject Index 735

multivariate analysis of theindependent predictor foroutcome, 508–510

for recurrence-free survival, 508multicenter studies, 508single-center studies, 508survival, 509

outcomes of, 498–504multicenter studies, 503multicenter study in Japan,

506–507multicenter study in Korea, 504multicenter study in United

States, 504–506single-center studies, 498–503,

508–510outcomes, risk factors for, 508–512

AFP, 511PIVKA II/DCP, 512tumor differentiation, 511tumor distribution, 511tumor number, 508–511tumor size, 508vascular invasion, 511

overestimation, 507perspectives of, 493–497pretransplant treatment, 513–516

PEI, 513rationale for, 513RFA, 513, 515surgical resection, 515–516TACE, 514–515

underestimation, 507in United States (1998–2007), 494

Local regional therapy (LRT), 481–483as a bridge to transplant, 481–483Radiofrequency ablation (RFA),

481–483transarterial chemoembolization

(TACE), 481–483Yttrium-90, 481–483

Lonafarnib, 597Loss of heterozygosity analysis (LOH),

478

LRT, see Local regional therapy (LRT)

M

Macroscopic pathology, 194–196growth patterns, 196portal vein thrombosis, 196

Magnetic resonance imaging (MRI) forHCC evaluation, 316,349–364, 369–381

accuracy of, 361–362capsule or pseudocapsule, 376characteristics of HCC, 375–378dynamic contrast-enhanced series,

376factors affecting, 370focal imaging findings in cirrhotic

liver, 371–372benign enhancing pseudonodules,

371confluent fibrosis, 371dysplastic nodule, 372hyperplastic nodule, 372regenerative nodules, 371

HCC following chemoembolization,378

indeterminate nodule, 380internal nodularity, 376no nodule with high suspicion of

HCC, 380probable HCC, 381pulse sequences, 373–375

bright-blood images, 375diffusion weighted images,

374–375dynamic multiphasic

contrast-enhanced images,374–375

particulate contrast agents, 375perfusion imaging, 375survey images, 373T1-weighted images with lipid

and iron sensitivity, 373T2-weighted images, 374

736 Subject Index

Magnetic resonance imaging (MRI) forHCC evaluation (cont.)

reporting findings, 378–381T1-weighted fat-suppressed image,

377T1-weighted image opposed-phase,

377T1-weighted MR images, 375, 377T2-weighted images, 376–377visible by MRI but not three-phase

CT, 379washout phase of imaging, 316

Major depressive disorder (MDD),674–676

symptoms, 674Mannitol, 545MAPK, see Mitogen-activated protein

kinase (MAPK)Marimastat, 600MDD, see Major depressive disorder

(MDD)Medical therapy, 527–559

chemoembolization, 542future directions 557–559

adjuvant therapy, 558neo-adjuvant therapy, 558newer clinical trials, 558–559TACE standardization, needs for,

557TACE with kinase inhibitors,

557hepatic artery chemo-occlusion,

546–547hepatic artery chemotherapy,

542–546next requirement, 555–557

causes of death, 556earlier diagnosis 555genomics, 557improvements in therapy, 555liver transplantation requirement,

555primary prevention, 555–556proteomics, 557

quantitation of tumor vascularity,556

oncologist, special considerations forthe, 541–542

other systemic therapies, 551–554principles, 528–541

chemotherapeutic agents,resistance to, 536–541

clinical presentation, 528, 529liver disease, underlying,

528–529multifocal disease, 531portal vein invasion, 535vascular tumor, 531–535

systemic chemotherapy, 551treatment options, 530treatments for unresectable HCC,

552MELD, see Model for End-stage Liver

Disease (MELD)Men, HCC among

age-standardized, 29obesity and, 14

Mestranol, 71Metabolic disease and HCC, 283–301

adenosine deaminase deficiency,301

aflatoxin-associated HCC, 292–293Alagille’s syndrome, 299alcoholic liver disease, 287–289alpha 1 antitrypsin deficiency and,

293–294bile acid syntheic disorders, 295cystic fibrosis, 299familial intrahepatic cholestasis,

294–295Bile salt export protein (BSEP)

deficiency, 294multidrug resistance-3 (MDR-3)

deficiency, 294progressive familial intrahepatic

cholestasis type I, 294fanconi anemia, 300hemochromatosis, 291–292

Subject Index 737

hereditary fructose intolerance, 300hereditary hemorrhagic

teleangiectasia, 300–301linked sideroblastic anemia, 299–300nonalcoholic fatty liver disease

(NAFLD), 289–291nonalcoholic steatonecrosis (NASH),

289–291oxidative stress, 286–287steroid-induced HCC, 301type II diabetes mellitus, 300tyrosinemia type I, 297–298Wilson’s disease, 291–292See also Carbohydrate metabolism,

defects in; PorphyriasMetalloproteinase inhibitors, 600Metal overload disorders, 84–86Metastasis signature in HCC tumor or

non-tumor tissues, 152–155Metastat, 600, 716Metavir score, 268Methamphetamine, 262Methionine adenosyltransferase (MAT),

289Methyltestosterone, 83Microarray analysis/studies, 134–156

diagnostic HCC signatures, 135–152See also Chronic liver disease

(CLD) signatureemerging concepts, 135–136HBV and HCV infection altered

genes study, 147hepatic stem cell signatures,

155–156microarray signatures, 136–146

cDNA platform, 137–143genome platform, 136genome/cDNA array, 146microRNA, 143–144proteome/cDNA array, 146ptoteome, 144

OLIGO-based study, 147prognostic HCC signatures, 152–155tumor biomarkers

epigenetic signatures, 151proteomic arrays, 149TMA arrays, 149tumor vs. non-tumor, 148–150

Microarray platforms, in geneexpression profiling, 133–134

array comparative genomichybridization (aCGH), 134

expression arrays, 133(cDNA/OLIGO/noncoding

RNA), 133genomic arrays (CGH/methylation),

134protein arrays (proteome/tissue), 134tissue microarrays (TMA), 134

Microdissection-guided broad panelmutational analysis, 475,476–481

important application, 477cancer recurrence from de novo

second primary cancerformation, discrimination, 477

new primary cancer formation vs.intrahepatic spread of cancer,discrimination between, 477

individual patient liver cancer, 477multiple microdissection targets, 480mutation acquisition, temporal

sequence of, 479tumor suppressor gene loss, steps in,

477Microsatellite DNA analysis, 339Microscopic pathology, 199–202

architectural pattern, 199–200bile pigment, 200–201four-tiered histologic grading

system, 202Kupffer cells, 201Mallory bodies, 201nodules, 202

Midkine (MDK), 157Milan criteria

in biopsy, 317in transplantation, 481

738 Subject Index

Milk thistle, 692Mitogen-activated protein kinase

(MAPK), 120–121Mitomycin C, 543Model for End Stage Liver is Disease

(MELD) score, 198, 317, 432,717

Molecular biology of HCC associatedwith HBV, 245–250

chronic liver disease (CLD) as riskfactor, 246–248

curative therapies, 246cytotoxic drug therapy, 246

Molecular marker, 131–169Molecular mechanisms of HCC,

109–123Beta-catenin in, 112DNA methylation, 112normal hepatocyte to malignant,

transformation, 111p53 dysregulation, 111–112

Molecular pathology, 205–207,591–595

apoptosis, 595inhibition, 206

cell cycle checkpoint proteinsdisruption, 206

challenges to the modification of,595

extracellular matrix changes, 595genetic alterations, 207growth factor receptors, 591JAK/STAT, 592PDGF, 594PI3K/Akt/mTOR, 592proteasome, 593–594Ras/Raf/MAP/ERK, 591–592transcription factor, 593VEGF, 594Wnt/β-Catenin, 593

Molecular profiling of HCC, 131–169,474–476

genetic analysis, 474immunohistochemistry (IHC), 474

microdissection-guided genotyping,476

microdissection targets selection,475

in situ hybridization (ISH), 474slide-based formats, 474See also Genomic profiling

Morphine sulfate, 545embolization, pain reduction in, 578

Mouse models, 78–79MRI, see Magnetic resonance imaging

(MRI)Multi-detector CT (MDCT), 272Multidetector row CT (MDCT)

technologyMultidrug resistance-3 (MDR-3)

deficiency, 294Multifocal disease, 531Multifocal HCC, 718Multisession PEI, 409–410Multistage nature of cancer

development, 76–77Multitargeted kinase inhibitors, 600Mutational analysis, 475, 476–481

See also Microdissection-guidedbroad panel mutationalanalysis

Mutations and their consequences inchemical carcinogenesis,62–65

aneuploidy, 63biological consequence, 64chromosome aberrations, 63endogenous DNA modifications, 65frameshift mutations, 63point mutations, 63

Myelosuppression, 541

N

NAFLD, see Non-alcoholic Fatty LiverDisease (NAFLD)

NASH, see Non-alcoholicsteatohepatitis (NASH)

Subject Index 739

National Comprehensive CancerNetwork (NCCN), 601, 642

Nausea, 685definition, 685

NCCN, see National ComprehensiveCancer Network (NCCN)

Neocarzinostatin (SMANCS), 543Neovastat, 600Neutrons, 617NF-κB, see Nuclear factor-kappa B

(NF-κB)Nodular lesions in cirrhosis, 355‘Nodule-in-nodule appearance’ of

HCC, 354–355Nonalcoholic Fatty Liver Disease

(NAFLD), as HCC risk factor,12, 80, 289–291

Non-alcoholic steatohepatitis (NASH)etiology, 80as HCC risk factor, 12, 289–291

Non-genotoxic mechanisms of chemicalcarcinogenesis, 66–74

See also under Chemicalcarcinogenesis; Estrogenicagents

Nongenotoxins, 55–88Non-hepatitis B cirrhosis, 315NORE1A, 592Nuclear factor-kappa B (NF-κB),

593

O

Obesity, as HCC risk factor, 14–16abdominal, 14body mass index (BMI) and, 14–15Denmark, 14and diabetes, synergism between, 15men, 14Sweden, 14Taiwan, 14United States, 14women, 14

Obstructive sleep apnea, 683

OER, see Oxygen enhancement ratio(OER)

Oncologistsspecial considerations for, 541–542

GI bleeding, 542liver synthetic activity, decreased,

542myelosuppression, 541xenobiotic metabolizing capacity,

542OPB-3206, 600Oral contraceptives use, as HCC risk

factor, 16in primary HCC development, 58

Osteopontin (OPN), 159–160, 339,341–342

Oxidative stress, 286–287Oxygen enhancement ratio (OER), 621Oxymetholone, 83

P

p53 Antibodies, 339p16 Methylation, 339Pain, 681–682

treatment, 682Panic disorder, 677–678Panitumumab, mechanisms of action,

596Paraneoplastic syndromes, 313–314

arterial hypertension, 314feminization, 314hypercalcemia, 313hypercholesterolemia, 314hypoglycemia, 313pityriasis rotunda, 314polycythemia, 313watery diarrhea, 314

Particulate contrast agents, 375Pathogenesis of HCC, 74–79

gene expression analysis, 76mouse models, 78–79multistage nature of development,

76–77

740 Subject Index

Pathogenesis of HCC (cont.)progression, 77promotion stage of development, 77rat models, 75–77rodent models of

hepatocarcinogenesis, 74–75Solt–Farber selection model, 76

Pathologic aspects of HCC, 183–218clinicopathologic comments, 194dysplasia, 192–194focal nodular hyperplasia, 183–187

See also individual entryhepatoblastoma, 215–218hepatocellular adenoma, 188–19

See also individual entryhistopathology, 183–218immunocytochemical markers of,

202–205immunophenotypic analysis,

183–218macroscopic pathology, 194–196microscopic pathology, 199–202molecular pathology, 183–218tumor staging, 183–218See also Molecular pathology

Pathologic variants of HCC, 207–215clear cell HCC, 210–211combined hepatocellu-

lar/cholangiocellularcarcinoma, 212–214

fibrolamellar carcinoma, 207–210Sarcomatoid HCC, 214–215scirrhous (Sclerosing) HCC,

211–212PCT, see Porphyria cutanea tarda (PCT)PDGFR, see Platelet-derived growth

factor receptors (PDGFR)Pegfilgrastrim (Neulasta), 541PEI, see Percutaneous ethanol injection

(PEI)Percutaneous Ablation Therapy (PAT),

407–417Percutaneous ethanol injection (PEI),

407–417

AFP, as tumor marker, 412combined therapies, 414complications, 412–413contrast-enhanced US (CEUS) in,

411–412conventional, 409des-γ-carboxyprothrombin (DCP),

as tumor marker, 412HCC characteistics favouring, 409

hypervascularization, 409neoplastic and cirrhotic tissue,

difference in consistencebetween, 409

indications, 414–417materials used, 409multipronged needle use in, 409–410principles, 408–410RF and, 413–414RFA vs., 430–431‘single session’ procedure, 408–409,

412spiral multislice CT, 411–412techniques, 408–410therapeutic efficacy, evaluation,

410–412Percutaneous needle core biopsy, 319Perfusion imaging, 375Perifosine, 597Peroxisome proliferators-activated

receptors (PPARs) agonists,71–72

Phenobarbital, 67–69constitutive androstane receptor

(CAR) in, 68CYP2B1 induction, 68in primary HCC development, 58

Photons, 617Pityriasis rotunda, 314PIVKA II, see Prothrombin induced by

vitamin K absence factor II(PIVKA II)

Platelet-derived growth factor receptors(PDGFR), 594

signaling pathways, 594

Subject Index 741

Polycythemia, 313Polypharmacy, 604Porphyria cutanea tarda (PCT), 298

familial (autosomal dominant) type,298

familial (rare autosomal recessive)type, 298

sporadic (worldwide) type, 298Porphyrias, 297–299

acute intermittent porphyria (AIP),297

congenital intrahepatic porphyria(CIP), 298

Erythropoietic protoporphyria(EPP), 298

Hepatoerythropoietic porphyria(HEP) type II porphyriacutanea, 298

Hereditary coproporphyria (HCP),298

Variegate porphyria (VP), 298See also Porphyria cutanea tarda

(PCT)Portal hypertension, 541

GI bleeding, 542liver synthetic activity, decreased,

542myelosuppression, 541

Portal vein invasion, 535Portal vein thrombosis, 535Post TACE angiogram, 535Posttraumatic growth (PTG), 672Posttraumatic stress disorder (PTSD),

677definition, 677predictors of, 677

Post-treatment monitoring of HCC,using CEUS, 403

Pre-TACE angiogram, 535Pretransplant treatment, in LDLT,

513–516See also under Living donor liver

transplantation (LDLT)Pretransplantation biopsy, 319

Prevention of HCC, 242–245primary, 242secondary, 242

by anti-HBV therapy, 243–244Primary chemoprevention, 320–321Primary HCC, 55–88

chemicals role in development, 58Aflatoxin B1, 58alcohol abuse, 58–59Dioxin, 58oral contraceptives, 58Phenobarbital, 58tobacco use, 58

cirrhosis in, 59environmental factors on, 56, 59etiology of, 79–88

See also individual entrygenetic factors on, 56hypothesis regarding, 57as an important biological problem,

57–59See also Chemical carcinogenesis

Primary prevention of HCC, 242, 265HCV-related HCC, 265IFN therapy effect on, 265screening policies, 265viral eradication, 265

Pringle maneuver, 458Probable HCC, using MRI, 381Profiling studies, 131–169

See also Genomic profilingPrognostic HCC signatures, 152–155

metastasis/survival/recurrencesignatures, 152–155

Prognostic risk score, 198Prognostic serum markers, 159–163

angiopoietins (Ang-1 and Ang-2),161

colony stimulating factor-1 (CSF1),160–161

fibroblast growth factor (FGF), 162hepatocyte growth factor (HGF), 162interleukin-6 (IL-6), 162–163osteopontin (OPN), 159–160

742 Subject Index

Prognostic serum markers (cont.)vascular endothelial growth factor

(VEGF), 161Progression stage of cancer

development, 77Progressive familial intrahepatic

cholestasis type I, 294Promotion stage of cancer development,

77Proteasomal degradation inhibition,

121Proteasome, 593–594Protein arrays (proteome/tissue), in

gene expression profiling, 134Proteomics, 342–343Prothrombin induced by vitamin K

absence factor II (PIVKA II),512

Prothymosin alpha, 339Protons, 617Psychological disorders, 673Psychosocial issues, 641–692

cancer-related symptoms andtreatment

cognitive impairment, 688fatigue, 680–681nausea, 685–686pain, 681–682sexual dysfunction, 686–687sleep problems, 682–685vomiting, 685

common presenting problems,673–680

adjustment disorder, 673–674agoraphobia, 678anxiety disorders, 676–678major depressive disorder,

674–676psychological disorders, 673substance abuse/dependence,

678–680distress, 642–643role of behavior, 643–644special issues, 688–692

alternative or complementarymedicine, 692

cultural factors, 690end of life issues, 691ethnic factors, 690existential/spiritual issues, 691interpersonal context, 688–690patients with children and

adolescents, 690religious factors, 690

symptoms evaluation, 644–672assessment, 668instruments to assess, 646–667psychosocial distress, 668–672psychosocial history assessment,

669–671PTG, see Posttraumatic growth (PTG)pTNM staging system for HCC, 471Pulse sequences in MRI, 373–375

See also under Magnetic resonanceimaging (MRI)

R

R115777, 597Race, HCC incidence and, 4–5Radiation hepatitis, 622Radiation induced liver disease (RILD),

622Radiation therapy, 615–635

clinical studies, 622–635liver, radiation effects in the,

622–623physics of, 617–620

brachytherapy, 6203D-CRT, 618–6194D-CRT, 619external beam radiation therapy,

617–618IGRT, 620IMRT, 619radiation dose, 618SBRT, 619–620

radioactive microsphere agents, 632

Subject Index 743

radiobiology, 621–622radiation response, modifiers of,

621–622Radiobiology, 621–622Radioembolization, 584Radiofrequency (RF), PEI and,

413–414Radiofrequency ablation (RFA) and

HCC, 421–444AFP as tumor marker, 426, 439Child-Pugh class A cirrhosis, 439complications from, 441–443

general, 442liver-related, 442minor, 442surgical, 442tumor recurrence, 443tumor-related, 442

contraindications for, 427absolute, 427relative, 427

des-γ-carboxyprothrombin (DCP),as tumor marker, 426

equipment, 425–426Radionics, 425RadioTherapeutics Corporation,

425RITA R© Model 1500X, 425

evaluation, 426–427Milan criteria, 426

hepatectomy vs., 428–430historical background, 423–424in living donor liver transplantation

(LDLT), 515in local regional therapy (LRT), 481,

482long-term survival after, 432–441mechanism, 424morality after, 432–441morbidity from

1998–2001, 433–4362003–2008, 437–438

mortality from1998–2001, 433–436

2003–2008, 437–438patient selection, 426–427vs. PEI, 430–431PEI and, 422prior to transplantation, 431–432procedure, 427–428

laparoscopic approach, 427RadioTherapeutics/LeVeen

Needle Electrode system,427

ultrasound guidance, 428recurrence after, 432–441RF thermal ablation, 424TACE and, 422vs. TACE vs. combined RFA+TACE

for HCC, 430–431Raf-Mek-Erk/MAPK Pathway,

120–121Ras pathway, 591–592RASSF1A, 592Rational therapies, 589–611

apoptosis, 600metalloproteinase inhibitors, 600molecularly targeted agents,

combination trials with,605–606

multitargeted kinase inhibitors,600–604

polypharmacy, 604proteasome inhibitors, 598targeting

growth factor receptors,596–597

PDGFR, 599PI3K/Akt/mTOR, 597Ras/Raf/MAP/ERK, 597transcription factors, 598VEGFR, 599Wnt/β-Catenin, 597

unanswered questions, 606–611clinically relevant trials, 609–611drug matching with patient,

607–608future of, 611

744 Subject Index

Rational therapies (cont.)risk population, identification of,

609treatment efficacy, improvement

of, 608–609Rat models, 75–77Receptor tyrosine kinases (RTKs) and

their ligands in targetedtherapies for HCC, 114–117

EGFR, 114, 115–116IGF-I and –II, 117VEGFRs, 114, 116–117

RECIST, see Response evaluationcriteria in solid tumors(RECIST) criteria

Recurrence signatures in HCC tumor ornon-tumor tissues, 152–155

Regenerating nodules (RN), 351–352,371, 389–390, 400

CT for, 351enhanced CT, 352in-phase T1-weighted image, 353MR for, 352out-of-phase T1-weighted gradient

echo, 353T2-weighted image, 353unenhanced CT, 352

Regional variations in HCC incidencerates, 3

Reglan, 545Resection of HCC, 453–462

adjuvant therapies, 460–462Clamp crushing technique, 458indications for, 454–455

bilobar HCC, 455diameter of HCC, 454

Kelly clamp crushing technique,458

long-term survival after, 460preoperative assessment, 455–457

Child’s classification, 456CT scan, 455MELD score, 456

techniques, 457–459

inflow occlusion by clamping,458

intraoperative ultrasound duringoperation, 457

laparoscopic approach, 458Pringle maneuver, 458

tumor recurrence after, risk factorsfor, 461

Respiratory gaiting, 619Response evaluation criteria in solid

tumors (RECIST) criteria, 609Restless legs syndrome, 684–685RFA, see Radiofrequency ablation

(RFA)RILD, see Radiation induced liver

disease (RILD)Risk factors for HCC, 7–18, 242–243,

284–286, 643Aflatoxin B1 (AFB1), 11–12alcohol intake, 11chronic hepatitis, 8cirrhosis, 8–10diabetes, 12–13diet, 16–18

See also individual entrydistribution, 6

Africa, 6Asia, 6Japan, 6

HCV infection, 8–10chronic HCV infection, 8environment/lifestyle in, 9

hepatitis B virus, 7–9Non-alcoholic Fatty Liver Disease

(NAFLD), 12Non-alcoholic Steatohepatitis

(NASH), 12obesity, 14–16

See also individual entryoral contraceptives use, 16Tobacco use, 16

Rodent models ofhepatocarcinogenesis,74–75

Subject Index 745

Roentgen, 618Rupture/hemoperitoneum, tumor,

312–313

S

S-adenosyl methionine (SAMe) in, 289Sarcomatoid HCC, 214–215SBRT, see Stereotactic body

radiotherapy (SBRT)Scirrhous (Sclerosing) HCC, 211–212Screening/Surveillance for HCC,

314–316, 328–333, 714–715AFP, 332–336among cirrhosis patients, 314benefits, 328cost-effectiveness of, 315criteria, 328

acceptability of the tests to targetpopulation and to health-careprofessionals, 331–332

achieving acceptable level ofaccuracy in population,332–333

cost effectiveness, 331disease in question, importance,

329identifiable target population,

329–330standardized recall procedures,

332treatments, effectiveness, 331

current recommendations, 315efficacy of, 334–335hepatitis B carriers (HBSAg

positive), 315high-risk patients, 315how to, 362–364non-hepatitis B cirrhosis, 315objective of, 328risk assessment groups, 315serum AFP testing, 314–315stage distribution, 335survival of patients, 335

treatment, 335ultrasound (US), 314–315, 332–336

performance characteristics, 333when, 362–364why, 362–364See also Imaging techniques;

SurveillanceSecondary chemoprevention, 322–323Secondary prevention of HCC, 242

by anti-HBV therapy, 243–244lamivudine (LVD), 244

Serial analysis of gene expression(SAGE), 133

Serum des-carboxy-prothrombin, 204Sexual dysfunction, 686Short oligonucleotide mass analysis

(SOMA), 43Signs, 310

See also Symptoms‘Single session’ procedure, 408–409,

412Sirolimus, 597Sleep apnea, 682

classification, 683Sleep hygiene, 684Sleep problems, 682–685

insomnia, 682restless legs syndrome, 684–685sleep apnea, 682–683treatment, 683

Slide-based techniques for molecularanalyses, 474

Small-for-size syndrome, 496Small GTPase superfamily, in HCC

targeted therapy, 118–120Smoking and HCC, 16Solt–Farber selection model, 76Sonography, accuracy of, 361–362Sorafenib (Nexavar), 121, 461, 551,

600–601benefits of, 601evaluation in clinical trials, 604mechanism of action, 602

Spain, 2

746 Subject Index

Spherex, 543Spiral multislice CT in PEI, 411SPREDs, in HCC targeted therapy, 120Sprouty (Spry) proteins, in HCC

targeted therapy, 120Squamous cellular carcinoma antigen

(SCCA), 339, 341Staging of HCC, 196–199, 470–473

American Joint Committee on, 197Distant metastases (M), 197for intrahepatic tumors, 197–198Primary tumor (T), 197Regional lymph nodes (N), 197stage grouping, 198

Barcelona Clinic Liver Cancer(BCLC) staging system, 198

Cancer of the Liver Italian Program(CLIP) system, 198

Child–Pugh score, 198Chinese University Prognostic Index

(CUPI), 198Japan integrated staging score, 198Model for End-Stage Liver Disease

(MELD), 198prognostic risk score, 198pTNM staging system, 471

Standardized recall procedures, 272Stem cell signatures, hepatic, 155–156Stereotactic body radiotherapy (SBRT),

619clinical studies, 627–628

Steroid-induced HCC, 301Steroids, etiology, 83–84Sub-Saharan Africa, HCC in, 1–2Substance abuse/dependence, 678–680Sunitinib (Sutent), 551, 601–602

evaluation in clinical trials, 604mechanism of action, 602

Superparamagnetic iron aramagneticoxide (SPIO)-enhanced MRI,354

Surface-enhanced laserdesorption/ionization(SELDI), 342

Surveillance, HCV and HCC, 268–272,360

alpha-fetoprotein (AFP) as serummarker, 268, 269–272

combined AFP and US in, 270–271diagnostic imaging, 268tumor marker determination, 268US imaging modality, 269See also Screening/Surveillance for

HCCSurvival signatures in HCC tumor or

non-tumor tissues, 152–155Symptoms, 310

gastrointestinal symptoms, 310hepatomegaly, 310jaundice, 310pain, 310, 312swelling, 310weakness, 310weight losss, 310

Systemic chemotherapy, 551

T

T1-weighted images with lipid and ironsensitivity, 373

T2-weighted images, 374TACE, see Transhepatic artery

chemoembolization (TACE)Taiwan, 3Tamoxifen, 551Targeted therapies for HCC, evaluation,

113cell cycle modulators, 113DNA modification enzymes, 114histone deacetylases (HDACs) in,

122histone deacetylation inhibition, 121inflammation modulators, 114intracellular signal transducers, 113,

117–121pro-survival molecules, 113proteasomal degradation inhibition,

121

Subject Index 747

proteasome, 114receptor tyrosine kinases (RTKs) and

their ligands, 114–117transcription factors, 113

Telbivudine, 235–250Telomerase activity, 339Temsirolimus, 597Tenofovir, 235–2502,3,7,8-Tetrachlorodibenzoparadioxin

(TCDD), 72–73Thailand, 2TheraSphere, 584Three-dimensional conformal radiation

therapy (3D-CRT), 618–619Time-of-flight mass spectrometry

(TOF-MS), 342Tipifarnib, 597Tissue microarrays (TMA), in gene

expression profiling, 134Tissue polypeptide-specific antigen, 339TNF alpha, 235–250Tobacco use, 644

etiology, 82–83as HCC risk factor, 16in primary HCC development, 58

TOF-MS, see Time-of-flight massspectrometry (TOF-MS)

Trans-activator, 235–250Transarterial chemoembolization

(TACE), 132, 407–417, 528,540

and 3D-CRT/IMRT, 624–626complications from, 581in living donor liver transplantation

(LDLT), 514–515in local regional therapy (LRT),

481–482no treatment controls vs., 541RFA vs. TACE vs. combined

RFA+TACE for HCC,430–431

using drug eluting beads, 550–551Transcription factor, 593Transforming growth factor-beta 1, 339

Transient hepatic attenuation difference(THAD), 357–358

Transjugular needle core biopsy,319

Transplantation, RFA prior to,431–432

Transplantation for HCC, 467–484American Liver Tumor Study Group

Modified TNM StagingClassification, 472

current recommendation for,483–484

historical aspects, 469–470reimbursement for, 469–470risk factors, 470

HCC, 470selection criteria, 470, 472

AFP level, 473CT, 473MELD/PELD score, 473MRI, 473thorough assessment, 472tumor size, 472US assessment, 472–473

staging of HCC, 470–473See also Living donor liver

transplantation (LDLT); Localregional therapy (LRT)

Triple-phase helical CAT scans,531

TSU-68, 599evaluation in clinical trials, 604

Tumor biomarkersepigenetic signatures, 151tumor vs. cirrhosis, 150tumor vs. non-tumor, 148–150

Tumor differentiation, 511Tumor distribution, 511Tumor-Node-Metastasis (TNM) staging

Classification, 471–472Tumor suppressors, 235–250Two-dimensional polyacrylamide gel

electrophoresis (2D-PAGE),342

748 Subject Index

Tyrosinemia, 87type I, 297

U

UDF-1 (manumycin), 597Ultrasonography (US) imaging

modality for HCC detection,269–270, 356

combined AFP and US in HCCsurveillance, 270–271

disadvantage, 270Ultrasound of HCC, 332–335, 387–404

contrast enhancement contributionto, 387–404

See also Contrast-enhancedultrasound (CEUS)

performance characteristics, 333role of, 400–403

Unilobar treatments, 546United Kingdom, 2United Network for Organ Sharing

(UNOS), 317, 467, 471United States, HCC in, 2, 6–7

age-adjusted incidence rates,6–7

multicenter studies for LDLT in,504–506

US-guided biopsy, 317, 319

V

Vandetanib, 601evaluation in clinical trials, 604mechanism of action, 602

Variegate porphyria (VP), 298

Vascular endothelial growth factor(VEGF), 161, 594

and their ligands in targetedtherapies for HCC, 116–117

signaling pathways, 594Vascular invasion, 511Vascular tumor, 531Vatalanib, 601, 602

mechanism of action, 602VEGF, see Vascular endothelial growth

factor (VEGF)Veno-occlusive disease (VOD), 622Viral hepatitis, etiology, 80–81VOD, see Veno-occlusive disease

(VOD)

W

Waltman loop, 577Watery diarrhea, 314Wilson’s disease, 291–292Wnt receptor pathways, 590Women, HCC among, obesity and, 14

Y

Yttrium-90, 528in local regional therapy (LRT), 481,

48390Y-microspheres, 630

delivery of, 631phase I–II, 633–635

Z

Zofran, 545