Time for paradigm change in management of hepatocellular carcinoma: Is a personalized approach on the horizon?

Personalized Medicine

Volumn 13, Issue 5, 2016, Pages 455-467

  Abraham, Jella Andrea ^a   Golubnitschaja, Olga ^a  

^a UNIVERSITY OF BONN   (Germany)

Author keywords

comorbidity; hepatitis; hepatocellular carcinoma; hypoxia; model guided therapy; paradigm change; participatory medicine; predictive preventive personalized medicine; risk factors; therapy monitoring

Indexed keywords

AFLATOXIN; PLACEBO; PROTEIN LYSINE 6 OXIDASE; RAMUCIRUMAB; RESVERATROL; SELENIUM; SORAFENIB; TIVANTINIB;

ALCOHOL CONSUMPTION; CANCER MORTALITY; CANCER RADIOTHERAPY; CANCER SCREENING; CANCER STAGING; CARCINOGENESIS; CHEMOEMBOLIZATION; COHORT ANALYSIS; DELAYED DIAGNOSIS; EARLY DIAGNOSIS; FAT INTAKE; FATTY LIVER; HEPATITIS B VIRUS; HEPATITIS C VIRUS; HUMAN; INFORMATION TECHNOLOGY; INTESTINE FLORA; LIFESTYLE MODIFICATION; LIVER CELL CARCINOMA; MEDICAL DECISION MAKING; METABOLIC SYNDROME X; OVERALL SURVIVAL; PATIENT CARE; PERSONALIZED MEDICINE; PRIORITY JOURNAL; QUALITY OF LIFE; REVIEW; RISK FACTOR; TUMOR MICROENVIRONMENT; UNSPECIFIED SIDE EFFECT; WATCHFUL WAITING;

EID: 84992077669     PISSN: 17410541     EISSN: 1744828X     Source Type: Journal    
DOI: 10.2217/pme-2016-0013     Document Type: Review

References (126)

1. Deng GL, Zeng S, Shen H. Chemotherapy and target therapy for hepatocellular carcinoma: new advances and challenges. World J. Hepatol. 7(5), 787-798 (2015).
2. Ji J, Wang XW. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin. Oncol. 39(4), 461-472 (2012).
3. Scudellari M. Drug development: try and try again. Nature 516(7529), S4-S6 (2014).
4. Berliner L, Lemke HU. An Information Technology Framework for Predictive, Preventive and Personalised Medicine: A Use-Case with Hepatocellular Carcinoma. Springer International Publishing, Cham, Switzerland (2015).
5. Akyol G, Yilmaz G. Stem cell expression profile in hepatocellular carcinoma, small cell dysplasia, cirrhosis. Stem Cell Transl. Investig. 1, e232 (2014).
6. Van Thiel DH, Ramadori G. Non-viral causes of hepatocellular carcinoma. J. Gastrointest. Cancer 42(4), 191-194 (2011).
7. O'Neill S, O'Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes. Rev. 16(1), 1-12 (2015).
8. Cebioglu M, Schild H, Golubnitschaja O. Cancer predisposition in diabetics: risk factors considered for predictive diagnostics and targeted preventive measures. EPMA J. 1(1), 130-137 (2010).
9. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA. Cancer J. Clin. 65(2), 87-108 (2015).
10. Park JW, Chen M, Colombo M et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 35(9), 2155-2166 (2015).
11. Mohanty S, Verma S, Dosik D, Hazin H, Berliner L. Hepatocellular carcinoma and patient assessment. In: An Information Technology Framework for Predictive, Preventive and Personalised Medicine. Berliner L, Lemke HU (Eds. ). Springer International Publishing, Cham, Switzerland, 21-32 (2015).
12. Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: patterns, treatments, prognosis. Annu. Surg. 261(5), 947-955 (2015).
13. Thein HH, Isaranuwatchai W, Campitelli MA et al. Health care costs associated with hepatocellular carcinoma: a population-based study. Hepatology 58(4), 1375-1384 (2013).
14. Llovet JM, Ducreux M, Lencioni R et al. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56(4), 908-943 (2012).
15. Kinoshita A, Onoda H, Fushiya N, Koike K, Nishino H, Tajiri H. Staging systems for hepatocellular carcinoma: current status and future perspectives. World J. Hepatol. 7(3), 406-424 (2015).
16. Berliner L, Lemke HU, vanSonnenberg E et al. Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine. EPMA J. 5(1), 16 (2014).
17. Yamakado K, Hirota S. Sub-classification of intermediatestage (Barcelona Clinic Liver Cancer stage-B) hepatocellular carcinomas. World J. Gastroenterol. 21(37), 10604-10608 (2015).
18. Sinn DH, Cho J-Y, Gwak G-Y et al. Different survival of Barcelona clinic liver cancer stage C hepatocellular carcinoma patients by the extent of portal vein invasion and the type of extrahepatic spread. PLoS ONE 10(4), e0124434 (2015).
19. Yau T, Tang VYF, Yao T-J, Fan S-T, Lo C-M, Poon RTP. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 146(7), 1691. e3-1700. e3 (2014).
20. Pons F, Varela M, Llovet JM. Staging systems in hepatocellular carcinoma. HPB 7(1), 35-41 (2005).
21. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y, Makuuchi M. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13, 772 patients in Japan. Ann. Surg. 245(6), 909-922 (2007).
22. Bester L, Meteling B, Boshell D, Chua TC, Morris DL. Transarterial chemoembolisation and radioembolisation for the treatment of primary liver cancer and secondary liver cancer: a review of the literature. J. Med. Imaging Radiat. Oncol. 58(3), 341-352 (2014).
23. Xie F, Zang J, Guo X et al. Comparison of transcatheter arterial chemoembolization and microsphere embolization for treatment of unresectable hepatocellular carcinoma: a metaanalysis. J. Cancer Res. Clin. Oncol. 138(3), 455-462 (2012).
24. Gramenzi A, Golfieri R, Mosconi C et al. Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis. Liver Int. 35(3), 1036-1047 (2015).
25. Yu SJ, Kim YJ. Effective treatment strategies other than sorafenib for the patients with advanced hepatocellular carcinoma invading portal vein. World J. Hepatol. 7(11), 1553-1561 (2015).
26. Mosconi C, Cappelli A, Pettinato C, Golfieri R. Radioembolization with Yttrium-90 microspheres in hepatocellular carcinoma: role and perspectives. World J. Hepatol. 7(5), 738-752 (2015).
27. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359(4), 378-390 (2008).
28. Gnoni A, Santini D, Scartozzi M et al. Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel? Expert Opin. Ther. Targets 19(12), 1623-1635 (2015).
29. Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J. Hepatol. 5(7), 345-352 (2013).
30. Salem R, Lewandowski RJ. Chemoembolization and radioembolization for hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 11(6), 604-611 (2013).
31. Wong CC, Tse AP, Huang YP et al. Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma. Hepatology 60(5), 1645-1658 (2014).
32. Vanharanta S. A hypoxic ticket to the bone metastatic niche. Breast Cancer Res. 17, 122 (2015).
33. Cox TR, Rumney RMH, Schoof EM et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522(7554), 106-110 (2015).
34. Arzumanyan A, Reis HMGPV, Feitelson MA. Pathogenic mechanisms in HBV-and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer 13(2), 123-135 (2013).
35. Lafaro KJ, Demirjian AN, Pawlik TM. Hepatocellular Cancer, Cholangiocarcinoma, Metastatic Tumors of the Liver. Wagman L (Ed. ). Elsevier Health Sciences, Philadelphia, PA, USA, 1-19 (2014).
36. Welzel TM, Graubard BI, Quraishi S et al. Populationattributable fractions of risk factors for hepatocellular carcinoma in the United States. Am. J. Gastroenterol. 108(8), 1314-1321 (2013).
37. Donato F, Tagger A, Chiesa R et al. Hepatitis B and C virus infection, alcohol drinking, hepatocellular carcinoma: a case-control study in Italy. Brescia HCC Study. Hepatol. Baltim. Md. 26(3), 579-584 (1997).
38. Hassan MM, Hwang LY, Hatten CJ et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 36(5), 1206-1213 (2002).
39. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 127(5), 1372-1380 (2004).
40. McGlynn KA, Quraishi S, Welzel TM, Davila JA, El-Serag HB, Graubard BI. Attributable risks for hepatocellular carcinoma in the United States. Cancer Res. 70(Suppl. 8), Abstract 1816 (2010).
41. Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr. Med. Res. Opin. 26(9), 2183-2191 (2010).
42. Ertle J, Dechêne A, Sowa J-P et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 128(10), 2436-2443 (2011).
43. Trichopoulos D, Bamia C, Lagiou P et al. Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study. J. Natl Cancer Inst. 103(22), 1686-1695 (2011).
44. Anthony PP. Hepatocellular carcinoma: an overview. Histopathology 39(2), 109-118 (2001).
45. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118(12), 3030-3044 (2006).
46. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J. Hepatol. 45(4), 529-538 (2006).
47. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 362(9399), 1907-1917 (2003).
48. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J. Clin. Gastroenterol. 47(Suppl. ), S2-S6 (2013).
49. Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ. Health Perspect. 118(6), 818-824 (2010).
50. Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-medicare database. Hepatology 54(2), 463-471 (2011).
51. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36(6), 1349-1354 (2002).
52. Dyson J, Jaques B, Chattopadyhay D et al. Hepatocellular cancer: the impact of obesity, Type 2 diabetes and a multidisciplinary team. J. Hepatol. 60(1), 110-117 (2014).
53. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 54(4), 533-539 (2005).
54. Connolly GC, Safadjou S, Kashyap R, Orloff M, Khorana AA, Hezel AF. The impact of diabetes mellitus on survival in hepatocellular carcinoma. J. Clin. Oncol. 28(Suppl. 15), e14596 (2010).
55. Hassan MM, Abdel-Wahab R, Kaseb A et al. Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma. Gastroenterology 149(1), 119-129 (2015).
56. Schütte K, Tippelt B, Schulz C et al. Malnutrition is a prognostic factor in patients with hepatocellular carcinoma (HCC). Clin. Nutr. 34(6), 1122-1127 (2015).
57. Wang K. Molecular mechanisms of hepatic apoptosis. Cell Death Dis. 5, e996 (2014).
58. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144(3), 512-527 (2013).
59. Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis-current status and future directions. J. Hepatol. 61(4), 912-924 (2014).
60. El-Serag HB. Hepatocellular carcinoma. N. Engl. J. Med. 365(12), 1118-1127 (2011).
61. Sung W-K, Zheng H, Li S et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 44(7), 765-769 (2012).
62. Ali A, Abdel-Hafiz H, Suhail M et al. Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma. World J. Gastroenterol. 20(30), 10238-10248 (2014).
63. Oikawa T, Ojima H, Yamasaki S, Takayama T, Hirohashi S, Sakamoto M. Multistep and multicentric development of hepatocellular carcinoma: histological analysis of 980 resected nodules. J. Hepatol. 42(2), 225-229 (2005).
64. Hazin H, Dosik D. Personalized chemotherapy for hepatocellular carcinoma. In: An Information Technology Framework for Predictive, Preventive and Personalised Medicine. Berliner L, Lemke HU (Eds. ). Springer International Publishing, Cham, Switzerland, 53-60 (2015)
65. Ferrari C. HBV and the immune response. Liver Int. 35(s1), 121-128 (2015).
66. Barjon C, Dahlqvist G, Calmus Y, Conti F. Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence. Dig. Liver Dis. 47(11), 913-917 (2015).
67. Bhattacharya A, Hegazy AN, Deigendesch N et al. Superoxide dismutase 1 protects hepatocytes from type I interferon-driven oxidative damage. Immunity 43(5), 974-986 (2015).
68. Lu T, Seto WK, Zhu RX, Lai CL, Yuen MF. Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection. World J. Gastroenterol. 19(47), 8887-8894 (2013).
69. Shiffman ML, Benhamou Y. Cure of HCV related liver disease. Liver Int. 35(Suppl. 1), 71-77 (2015).
70. Abdel-Razek W, Waked I. Optimal therapy in genotype 4 chronic hepatitis C: finally cured? Liver Int. 35(Suppl. 1), 27-34 (2015).
71. Walker CM, Grakoui A. Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection? Curr. Opin. Immunol. 35, 137-143 (2015).
72. Ahmed MH, Barakat S, Almobarak AO. Nonalcoholic fatty liver disease and cardiovascular disease: has the time come for cardiologists to be hepatologists? J. Obes. 2012, 483135 (2012).
73. Golubnitschaja O. Gender specific complications in female diabetic patients: an integrative view. EPMA J. 5(Suppl. 1), A78 (2014).
74. Kawada N, Imanaka K, Kawaguchi T et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J. Gastroenterol. 44(12), 1190-1194 (2009).
75. Trovato FM, Catalano D, Musumeci G, Trovato GM. 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicinerecommendations for facing obesity, fatty liver and fibrosis epidemics. EPMA J. 5(1), 21 (2014).
76. Malhi H, Guicciardi ME, Gores GJ. Hepatocyte death: a clear and present danger. Physiol. Rev. 90(3), 1165-1194 (2010).
77. Fujiwara N, Nakagawa H, Kudo Y et al. Sarcopenia, intramuscular fat deposition, visceral adiposity independently predict the outcomes of hepatocellular carcinoma. J. Hepatol. 63(1), 131-140 (2015).
78. Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J. Gastroenterol. 21(13), 3777-3785 (2015).
79. Lam V, Su J, Koprowski S et al. Intestinal microbiota determine severity of myocardial infarction in rats. FASEB J. 26(4), 1727-1735 (2012).
80. Bubnov RV, Spivak MY, Lazarenko LM, Bomba A, Boyko NV. Probiotics and immunity: provisional role for personalized diets and disease prevention. EPMA J. 6(1), 14 (2015).
81. Yoshimoto S, Loo TM, Atarashi K et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499(7456), 97-101 (2013).
82. Son G, Kremer M, Hines IN. Contribution of gut bacteria to liver pathobiology. Gastroenterol. Res. Pract. 2010, 453563 (2010).
83. Miele L, Valenza V, La Torre G et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49(6), 1877-1887 (2009).
84. Zhang H-L, Yu L-X, Yang W et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J. Hepatol. 57(4), 803-812 (2012).
85. Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLoS ONE 9(5), e96864 (2014).
86. Speliotes EK, Yerges-Armstrong LM, Wu J et al. Genomewide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7(3), e1001324 (2011).
87. Trepo E, Nahon P, Bontempi G et al. Association between the PNPLA3 (rs738409 C
88. Gorden A, Yang R, Yerges-Armstrong LM et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum. Hered. 75(1), 34-43 (2013).
89. Bang KB, Cho YK. Comorbidities and metabolic derangement of NAFLD. J. Lifestyle Med. 5(1), 7-13 (2015).
90. Ampuero J, Gallego-Durán R, Romero-Gómez M. Association of NAFLD with subclinical atherosclerosis and coronary-artery disease: meta-analysis. Rev. Esp. Enfermedades Dig. 107(1), 10-16 (2015).
91. Fargion S, Porzio M, Fracanzani AL. Nonalcoholic fatty liver disease and vascular disease: state-of-the-art. World J. Gastroenterol. 20(37), 13306-13324 (2014).
92. Jepsen P. Comorbidity in cirrhosis. World J. Gastroenterol. 20(23), 7223-7230 (2014).
93. Klein J, Dawson LA, Tran TH et al. Metabolic syndromerelated hepatocellular carcinoma treated by volumetric modulated arc therapy. Curr. Oncol. Tor. Ont. 21(2), e340-e344 (2014).
94. Hartleb M, Gutkowski K. Kidneys in chronic liver diseases. World J. Gastroenterol. 18(24), 3035-3049 (2012).
95. Watanabe M, Shibuya A, Minamino T et al. Benefits and problems of transarterial therapy in patients with hepatocellular carcinoma and chronic kidney disease. J. Vasc. Interv. Radiol. 25(12), 1947-1955 (2014).
96. Wiginton CD, Kelly B, Oto A et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, gadolinium detection in tissue. Am. J. Roentgenol. 190(4), 1060-1068 (2008).
97. Grech G, Zhan X, Yoo BC et al. EPMA position paper in cancer: current overview and future perspectives. EPMA J. 6(1), 9 (2015).
98. Hu R, Wang X, Zhan X. Multi-parameter systematic strategies for predictive, preventive and personalised medicine in cancer. EPMA J. 4(1), 2 (2013).
99. Golubnitschaja O, Cebioglu M, Yeghiazaryan K, Pieper C, Schild HH. "Molecular signature" in blood of liver cancer diagnosed patients as a criterion for optimal therapy modalities. EPMA J. 5(Suppl. 1), A38 (2014).
100. Trovato GM. Behavior, nutrition and lifestyle in a comprehensive health and disease paradigm: skills and knowledge for a predictive, preventive and personalized medicine. EPMA J. 3(1), 8 (2012).
101. Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol. Trace Elem. Res. 56(1), 117-124 (1997).
102. Björnstedt M, Fernandes AP. Selenium in the prevention of human cancers. EPMA J. 1(3), 389-395 (2010).
103. Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to selenoproteins: synthesis, identity, their role in human health. Antioxid. Redox Signal. 9(7), 775-806 (2007).
104. Carreras O, Ojeda M, Nogales F. Selenium dietary supplementation and oxidative balance in alcoholism. In: Molecular Aspects of Alcohol and Nutrition. Patel V (Ed. ). Academic Press, San Diego, CA, USA, 133-142 (2016).
105. Assy N, Nassar F, Nasser G, Grosovski M. Olive oil consumption and non-alcoholic fatty liver disease. World J. Gastroenterol. 15(15), 1809-1815 (2009).
106. Yeh C-B, Hsieh M-J, Lin C-W et al. The antimetastatic effects of resveratrol on hepatocellular carcinoma through the downregulation of a metastasis-associated protease by SP-1 modulation. PLoS ONE 8(2), e56661 (2013).
107. Bishayee A, Politis T, Darvesh AS. Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer Treat. Rev. 36(1), 43-53 (2010).
108. Gómez-Zorita S, Fernández-Quintela A, Macarulla MT et al. Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. Br. J. Nutr. 107(2), 202-210 (2012).
109. Abraham J-A, Golubnitschaja O. Predictive and prognostic biomarker panel for targeted application of radioembolisation improving individual outcomes in hepatocellular carcinoma. EPMA J. 7(Suppl. 1), A1 (2016).
110. Lee JH, Kim K-H, Park J-W et al. Low-mass-ion discriminant equation: a new concept for colorectal cancer screening. Int. J. Cancer 134(8), 1844-1853 (2014).
111. Chen T, Xie G, Wang X et al. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol. Cell. Proteomics 10(7), M110. 004945 (2011).
112. Pesta M, Kulda V, Narsanska A, Fichtl J, Topolcan O. May CTC technologies promote better cancer management? EPMA J. 6(1), 1 (2015).
113. Kelley RK, Magbanua MJM, Butler TM et al. Circulating tumor cells in hepatocellular carcinoma: a pilot study of detection, enumeration, next-generation sequencing in cases and controls. BMC Cancer 15, 206 (2015).
114. Dekervel J, van Pelt J, Verslype C. Advanced unresectable hepatocellular carcinoma: new biologics as fresh ammunition or clues to disease understanding? Curr. Opin. Oncol. 25(4), 409-416 (2013).
115. Savic LJ, Chapiro J, Duwe G, Geschwind J-F. Targeting glucose metabolism in cancer: new class of agents for locoregional and systemic therapy of liver cancer and beyond? Hepatic Oncol. 3(1), 19-28 (2016).
116. Delire B, Stärkel P. The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. Eur. J. Clin. Invest. 45(6), 609-623 (2015).
117. Waidmann O, Trojan J. Novel drugs in clinical development for hepatocellular carcinoma. Expert Opin. Investig. Drugs 24(8), 1075-1082 (2015).
118. Bubnov RV, Melnyk IM. Hepatic oncology diagnosis based on imaging fractal analysis: preliminary results. EPMA J. 5(Suppl. 1), A43 (2014).
119. Lemke HU, Golubnitschaja O. Towards personal health care with model-guided medicine: long-term PPPM-related strategies and realisation opportunities within "Horizon 2020. " EPMA J. 5(1), 8 (2014).
120. The European Association for Predictive, Preventive and Personalised Medicine (EPMA). http://epmanet. eu/
121. Golubnitschaja O, Costigliola V, EPMA. General report & recommendations in predictive, preventive and personalised medicine 2012: White Paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J. 3(1), 14 (2012).
122. Shi M, Chen M-S, Sekar K, Tan C-K, Ooi LL, Hui KM. A blood-based three-gene signature for the non-invasive detection of early human hepatocellular carcinoma. Eur. J. Cancer 50(5), 928-936 (2014).
123. Dai M, Chen X, Liu X, Peng Z, Meng J, Dai S. Diagnostic value of the combination of Golgi protein 73 and alphafetoprotein in hepatocellular carcinoma: a meta-analysis. PLoS ONE 10(10), e0140067 (2015).
124. Golubnitschaja O, Watson ID, Topic E, Sandberg S, Ferrari M, Costigliola V. Position paper of the EPMA and EFLM: a global vision of the consolidated promotion of an integrative medical approach to advance health care. EPMA J. 4(1), 12 (2013).
125. WHO/Europe | Vienna conference on nutrition and noncommunicable diseases-Vienna Declaration on Nutrition and Noncommunicable Diseases in the Context of Health 2020. www. euro. who. int/en/health-topics
126. Abraham J-A, Yeghiazaryan K, Golubnitschaja O. Selective internal radiation therapy in treatment of hepatocellular carcinoma: new concepts of personalisation. Pers. Med. 13(4), 347-360 (2016).