Un problema de salud global

Consenso y controversia en el manejo del carcinoma hepatocelular (2º Parte)

El carcinoma hepatocelular (CHC) continúa como una patología en crecimiento en el hemisferio occidental debido a su asociación con el virus de la hepatitis C (VHC).

Autor/a: Dres. Kim RD, Reed AI, Shiro F, Foley DP, Meckel KL, Hemmings AW

Fuente: J Am Coll Surg 2007; 205(1): 108-123

Indice
1. Bibliografía
2. Desarrollo


1. Llovet J.M., Burroughs A., Bruix J.:  Hepatocellular carcinoma.  Lancet 362. 1907-1917.2003;
2.  Moradpour D., Blum H.E.:  Pathogenesis of hepatocellular carcinoma.  Eur J Gastroenterol Hepatol 17. 477-483.2005;
3. Zhou X.D., Tang Z.Y., Yang B.H., et al:  Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma.  Cancer 91. 1479-1486.2001;
4. Trevisani F., D’Intino P.E., Caraceni P., et al:  Etiologic factors and clinical presentation of hepatocellular carcinoma.  Differences between cirrhotic and noncirrhotic Italian patientsCancer 75. 2220-2232.1995;
5. Stroffolini T., Andreone P., Andriulli A., et al:  Characteristics of hepatocellular carcinoma in Italy.  J Hepatol 29. 944-952.1998;
6. Van Roey G., Fevery J., Van Steenbergen W.:  Hepatocellular carcinoma in Belgium: clinical and virological characteristics of 154 consecutive cirrhotic and non-cirrhotic patients.  Eur J Gastroenterol Hepatol 12. 61-66.2000;
7. Bralet M.P., Regimbeau J.M., Pineau P., et al:  Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases.  Hepatology 32. 200-204.2000;
8. Chiesa R., Donato F., Tagger A., et al:  Etiology of hepatocellular carcinoma in Italian patients with and without cirrhosis.  Cancer Epidemiol Biomarkers Prev 9. 213-216.2000;
9. Ming L., Thorgeirsson S.S., Gail M.H., et al:  Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China.  Hepatology 36. 1214-1220.2002;
10. Okuda K., Ohtsuki T., Obata H., et al:  Natural history of hepatocellular carcinoma and prognosis in relation to treatment.  Study of 850 patientsCancer 56. 918-928.1985;
11. American Joint Committee on Cancer:  Liver (including intrahepatic bile ducts).   AJCC cancer staging manual,  SpringerNew York2002: 131-138.
12. Llovet J.M., Bruix J.:  Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.  Hepatology 37. 429-442.2003;
13. Llovet J.M., Bustamante J., Castells A., et al:  Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials.  Hepatology 29. 62-67.1999;
14. Llovet J.M., Fuster J., Bruix J.:  Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.  Hepatology 30. 1434-1440.1999;
15. Mazzaferro V., Regalia E., Doci R., et al:  Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.  N Engl J Med 334. 693-699.1996;
16. Poon R.T., Fan S.T., Lo C.M., et al:  Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database.  Ann Surg 240. 698-708.2004;
17. Llovet J.M., Schwartz M., Mazzaferro V.:  Resection and liver transplantation for hepatocellular carcinoma.  Semin Liver Dis 25. 181-200.2005;
18. Imamura H., Matsuyama Y., Tanaka E., et al:  Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.  J Hepatol 38. 200-207.2003;
19. Shimada M., Gion T., Hamatsu T., et al:  Evaluation of major hepatic resection for small hepatocellular carcinoma.  Hepatogastroenterology 46. 401-406.1999;
20. Llovet J.M.:  Updated treatment approach to hepatocellular carcinoma.  J Gastroenterol 40. 225-235.2005;
21. Bruix J., Castells A., Bosch J., et al:  Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure.  Gastroenterology 111. 1018-1022.1996;
22. Noun R., Jagot P., Farges O., et al:  High preoperative serum alanine transferase levels: effect on the risk of liver resection in Child grade A cirrhotic patients.  World J Surg 21. 390-394.1997;
23. Poon R.T., Fan S.T.:  Assessment of hepatic reserve for indication of hepatic resection: how I do it.  J Hepatobiliary Pancreat Surg 12. 31-37.2005;
24. Hemming A.W., Scudamore C.H., Shackleton C.R., et al:  Indocyanine green clearance as a predictor of successful hepatic resection in cirrhotic patients.  Am J Surg 163. 515-518.1992;
25. Poon R.T., Fan S.T.:  Hepatectomy for hepatocellular carcinoma: patient selection and postoperative outcome.  Liver Transpl 10. S39-S45.2004;
26. Lau H., Man K., Fan S.T., et al:  Evaluation of preoperative hepatic function in patients with hepatocellular carcinoma undergoing hepatectomy.  Br J Surg 84. 1255-1259.1997;
27. Ravaioli M., Grazi G.L., Principe A., et al:  Operative risk by the lidocaine test (MEGX) in resected patients for HCC on cirrhosis.  Hepatogastroenterology 50. 1552-1555.2003;
28. Redaelli C.A., Dufour J.F., Wagner M., et al:  Preoperative galactose elimination capacity predicts complications and survival after hepatic resection.  Ann Surg 235. 77-85.2002;
29. Sugawara Y., Yamamoto J., Higashi H., et al:  Preoperative portal embolization in patients with hepatocellular carcinoma.  World J Surg 26. 105-110.2002;
30. Farges O., Belghiti J., Kianmanesh R., et al:  Portal vein embolization before right hepatectomy: prospective clinical trial.  Ann Surg 237. 208-217.2003;
31. Azoulay D., Castaing D., Krissat J., et al:  Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver.  Ann Surg 232. 665-672.2000;
32. Portolani N., Coniglio A., Ghidoni S., et al:  Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications.  Ann Surg 243. 229-235.2006;
33. Ercolani G., Grazi G.L., Ravaioli M., et al:  Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence.  Ann Surg 237. 536-543.2003;
34. Shirabe K., Kanematsu T., Matsumata T., et al:  Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses.  Hepatology 14. 802-805.1991;
35. Belghiti J., Panis Y., Farges O., et al:  Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis.  Ann Surg 214. 114-117.1991;
36. Shah S.A., Greig P.D., Gallinger S., et al:  Factors associated with early recurrence after resection for hepatocellular carcinoma and outcomes.  J Am Coll Surg 202. 275-283.2006;
37. Vauthey J.N., Lauwers G.Y., Esnaola N.F., et al:  Simplified staging for hepatocellular carcinoma.  J Clin Oncol 20. 1527-1536.2002;
38. Makuuchi M., Belghiti J., Belli G., et al:  IHPBA concordant classification of primary liver cancer: working group report.  J Hepatobiliary Pancreat Surg 10. 26-30.2003;
39. Poon R.T., Fan S.T.:  Evaluation of the new AJCC/UICC staging system for hepatocellular carcinoma after hepatic resection in Chinese patients.  Surg Oncol Clin North Am 12. 35-50.2003;
40. Jonas S., Bechstein W.O., Steinmuller T., et al:  Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.  Hepatology 33. 1080-1086.2001;
41. Yao F.Y., Ferrell L., Bass N.M., et al:  Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria.  Liver Transpl 8. 765-774.2002;
42. Schlitt H.J., Neipp M., Weimann A., et al:  Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.  J Clin Oncol 17. 324-331.1999;
43. Roayaie S., Schwartz J.D., Sung M.W., et al:  Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis.  Liver Transpl 10. 534-540.2004;
44. Bruix J., Llovet J.M.:  Prognostic prediction and treatment strategy in hepatocellular carcinoma.  Hepatology 35. 519-524.2002;
45. Marsh J.W., Dvorchik I.:  Liver organ allocation for hepatocellular carcinoma: are we sure?.  Liver Transpl 9. 693-696.2003;
46. Yao F.Y., Ferrell L., Bass N.M., et al:  Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.  Hepatology 33. 1394-1403.2001;
47. Sarasin F.P., Giostra E., Mentha G., Hadengue A.:  Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepatocellular carcinoma?.  A cost-effectiveness perspectiveHepatology 28. 436-442.1998;
48. Michel J., Suc B., Montpeyroux F., et al:  Liver resection or transplantation for hepatocellular carcinoma?.  Retrospective analysis of 215 patients with cirrhosisJ Hepatol 26. 1274-1280.1997;
49. Bismuth H., Chiche L., Adam R., et al:  Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients.  Ann Surg 218. 145-151.1993;
50. Poon R.T., Fan S.T., Lo C.M., et al:  Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis.  J Clin Oncol 18. 1094-1101.2000;
51. Nagasue N., Ono T., Yamanoi A., et al:  Prognostic factors and survival after hepatic resection for hepatocellular carcinoma without cirrhosis.  Br J Surg 88. 515-522.2001;
52. Yamamoto J., Iwatsuki S., Kosuge T., et al:  Should hepatomas be treated with hepatic resection or transplantation?.  Cancer 86. 1151-1158.1999;
53. Adam R., Azoulay D., Castaing D., et al:  Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?.  Ann Surg 238. 508-518.2003;
54. Lencioni R., Crocetti L.:  A critical appraisal of the literature on local ablative therapies for hepatocellular carcinoma.  Clin Liver Dis 9. 301-314.2005;
55. Hong S.N., Lee S.Y., Choi M.S., et al:  Comparing the outcomes of radiofrequency ablation and surgery in patients with a single small hepatocellular carcinoma and well-preserved hepatic function.  J Clin Gastroenterol 39. 247-252.2005;
56. Wakai T., Shirai Y., Suda T., et al:  Long-term outcomes of hepatectomy vs percutaneous ablation for treatment of hepatocellular carcinoma < or =4 cm.  World J Gastroenterol 12. 546-552.2006;
57. Vivarelli M., Guglielmi A., Ruzzenente A., et al:  Surgical resection versus percutaneous radiofrequency ablation in the treatment of hepatocellular carcinoma on cirrhotic liver.  Ann Surg 240. 102-107.2004;
58. Montorsi M., Santambrogio R., Bianchi P., et al:  Survival and recurrences after hepatic resection or radiofrequency for hepatocellular carcinoma in cirrhotic patients: a multivariate analysis.  J Gastrointest Surg 9. 62-67.2005;
59. Chen M.S., Li J.Q., Zheng Y., et al:  A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma.  Ann Surg 243. 321-328.2006;
60. Porrett P.M., Peterman H., Rosen M., et al:  Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular cancer in the current MELD era.  Liver Transpl 12. 665-673.2006;
61. Mazzaferro V., Battiston C., Perrone S., et al:  Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study.  Ann Surg 240. 900-909.2004;
62. Yamamoto J., Okada S., Shimada K., et al:  Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection.  Hepatology 34. 707-713.2001;
63. Daniele B., De S.I., Izzo F., et al:  Hepatic resection and percutaneous ethanol injection as treatments of small hepatocellular carcinoma: a Cancer of the Liver Italian Program (CLIP 08) retrospective case-control study.  J Clin Gastroenterol 36. 63-67.2003;
64. Khan K.N., Yatsuhashi H., Yamasaki K., et al:  Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection.  J Hepatol 32. 269-278.2000;
65. Koda M., Murawaki Y., Mitsuda A., et al:  Predictive factors for intrahepatic recurrence after percutaneous ethanol injection therapy for small hepatocellular carcinoma.  Cancer 88. 529-537.2000;
66. Huo T.I., Huang Y.H., Wu J.C., et al:  Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for hepatocellular carcinoma in cirrhotic patients: a prospective study.  Scand J Gastroenterol 38. 770-778.2003;
67. Lin S.M., Lin C.J., Lin C.C., et al:  Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.  Gut 54. 1151-1156.2005;
68. Zhou X.D., Tang Z.Y.:  Cryotherapy for primary liver cancer.  Semin Surg Oncol 14. 171-174.1998;
69. Georgiades C.S., Hong K., D’Angelo M., Geschwind J.F.:  Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis.  J Vasc Interv Radiol 16. 1653-1659.2005;
70. Lo C.M., Ngan H., Tso W.K., et al:  Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.  Hepatology 35. 1164-1171.2002;
71. Richard , III , IIIH.M., Silberzweig J.E., Mitty H.A., et al:  Hepatic arterial complications in liver transplant recipients treated with pretransplantation chemoembolization for hepatocellular carcinoma.  Radiology 214. 775-779.2000;
72. Graziadei I.W., Sandmueller H., Waldenberger P., et al:  Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome.  Liver Transpl 9. 557-563.2003;
73. Lau W.Y., Yu S.C., Lai E.C., Leung T.W.:  Transarterial chemoembolization for hepatocellular carcinoma.  J Am Coll Surg 202. 155-168.2006;
74. Lu C.D., Peng S.Y., Jiang X.C., et al:  Preoperative transcatheter arterial chemoembolization and prognosis of patients with hepatocellular carcinomas: retrospective analysis of 120 cases.  World J Surg 23. 293-300.1999;
75. Yamasaki S., Hasegawa H., Kinoshita H., et al:  A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma.  Jpn J Cancer Res 87. 206-211.1996;
76. Liu M.T., Li S.H., Chu T.C., et al:  Three-dimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization.  Jpn J Clin Oncol 34. 532-539.2004;
77. Park W., Lim D.H., Paik S.W., et al:  Local radiotherapy for patients with unresectable hepatocellular carcinoma.  Int J Radiat Oncol Biol Phys 61. 1143-1150.2005;
78. Hata M., Tokuuye K., Sugahara S., et al:  Proton beam therapy for hepatocellular carcinoma with limited treatment options.  Cancer 107. 591-598.2006;
79. Bush D.A., Hillebrand D.J., Slater J.M., Slater J.D.:  High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial.  Gastroenterology 127. S189-S193.2004;
80. Seong J., Park H.C., Han K.H., Chon C.Y.:  Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: a retrospective study of 158 patients.  Int J Radiat Oncol Biol Phys 55. 329-336.2003;
81. Tazawa J., Maeda M., Sakai Y., et al:  Radiation therapy in combination with transcatheter arterial chemoembolization for hepatocellular carcinoma with extensive portal vein involvement.  J Gastroenterol Hepatol 16. 660-665.2001;
82. Yamada K., Izaki K., Sugimoto K., et al:  Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma.  Int J Radiat Oncol Biol Phys 57. 113-119.2003;
83. Bhattacharya S., Novell J.R., Dusheiko G.M., et al:  Epirubicin-lipiodol chemotherapy versus 131iodine-lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma.  Cancer 76. 2202-2210.1995;
84. Raoul J.L., Guyader D., Bretagne J.F., et al:  Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma.  Hepatology 26. 1156-1161.1997;
85. Lau W.Y., Leung T.W., Ho S.K., et al:  Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial.  Lancet 353. 797-801.1999;
86. Carr B.I.:  Hepatic arterial 90yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients.  Liver Transpl 10. S107-S110.2004;
87. Salem R., Lewandowski R., Roberts C., et al:  Use of yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis.  J Vasc Interv Radiol 15. 335-345.2004;
88. Salem R., Lewandowski R.J., Atassi B., et al:  Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival.  J Vasc Interv Radiol 16. 1627-1639.2005;
89. Huang C.C., Wu M.C., Xu G.W., et al:  Overexpression of the MDR1 gene and P-glycoprotein in human hepatocellular carcinoma.  J Natl Cancer Inst 84. 262-264.1992;
90. Olweny C.L., Toya T., Katongole-Mbidde E., et al:  Treatment of hepatocellular carcinoma with adriamycin.  Preliminary communicationCancer 36. 1250-1257.1975;
91. Falkson G., Moertel C.G., Lavin P., et al:  Chemotherapy studies in primary liver cancer: a prospective randomized clinical trial.  Cancer 42. 2149-2156.1978;
92. Chlebowski R.T., Brzechwa-Adjukiewicz A., Cowden A., et al:  Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results.  Cancer Treat Rep 68. 487-491.1984;
93. Morstyn G., Ihde D.C., Eddy J.L., et al:  Combination chemotherapy of hepatocellular carcinoma with doxorubicin and streptozotocin.  Am J Clin Oncol 6. 547-551.1983;
94. Guan Z., Wang Y., Maoleekoonpairoj S., et al:  Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma.  Br J Cancer 89. 1865-1869.2003;
95. Ulrich-Pur H., Kornek G.V., Fiebiger W., et al:  Treatment of advanced hepatocellular carcinoma with biweekly high-dose gemcitabine.  Oncology 60. 313-315.2001;
96. Zhu A.X., Blaszkowsky L.S., Ryan D.P., et al:  Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma.  J Clin Oncol 24. 1898-1903.2006;
97. Lai C.L., Lau J.Y., Wu P.C., et al:  Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial.  Hepatology 17. 389-394.1993;
98. Llovet J.M., Sala M., Castells L., et al:  Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma.  Hepatology 31. 54-58.2000;
99. Ji S.K., Park N.H., Choi H.M., et al:  Combined cis-platinum and alpha interferon therapy of advanced hepatocellular carcinoma.  Korean J Intern Med 11. 58-68.1996;
100. Lin S.M., Lin C.J., Hsu C.W., et al:  Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors.  Cancer 100. 376-382.2004;
101. Hoshida Y., Shiratori Y., Omata M.:  Cost-effectiveness of adjuvant interferon therapy after surgical resection of Hepatitis C-related hepatocellular carcinoma.  Liver 22. 479-485.2002;
102. Ikeda K., Kobayashi M., Saitoh S., et al:  Recurrence rate and prognosis of patients with hepatocellular carcinoma that developed after elimination of hepatitis C virus RNA by interferon therapy.  A closed cohort study including matched control patientsOncology 65. 204-210.2003;
103. Sun H.C., Tang Z.Y., Wang L., et al:  Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial.  J Cancer Res Clin Oncol 132. 458-465.2006;
104. Nishiguchi S., Tamori A., Kubo S.:  Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma.  Intervirology 48. 71-75.2005;
105. Izumi R., Shimizu K., Iyobe T., et al:  Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma.  Hepatology 20. 295-301.1994;
106. Lai E.C., Lo C.M., Fan S.T., et al:  Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial.  Arch Surg 133. 183-188.1998;
107. Ono T., Yamanoi A., Nazmy E.A., et al:  Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials.  Cancer 91. 2378-2385.2001;
108. Mathurin P., Raynard B., Dharancy S., et al:  Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma.  Aliment Pharmacol Ther 17. 1247-1261.2003;
109. Maddala Y.K., Stadheim L., Andrews J.C., et al:  Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization.  Liver Transpl 10. 449-455.2004;
110. Perez S.B., Meneu J.C., Moreno E., et al:  Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma?.  Am J Surg 190. 383-387.2005;
111. Decaens T., Roudot-Thoraval F., Bresson-Hadni S., et al:  Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.  Liver Transpl 11. 767-775.2005;
112. Yao F.Y., Hirose R., LaBerge J.M., et al:  A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation.  Liver Transpl 11. 1505-1514.2005;