Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation

Liver Transplantation

Volumn 20, Issue 3, 2014, Pages 261-269

  Chen, Kan ^a,b   Man, Kwan ^c   Metselaar, Herold J ^b   Janssen, Harry L A ^b,d   Peppelenbosch, Maikel P ^b   Pan, Qiuwei ^b  

^a ZHEJIANG SCI TECH UNIVERSITY   (China)

^b ERASMUS MEDICAL CENTER   (Netherlands)

^c UNIVERSITY OF HONG KONG   (Hong Kong)

^d UNIVERSITY HEALTH NETWORK   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOSUPPRESSIVE AGENT; INOSINATE DEHYDROGENASE INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR;

ANTINEOPLASTIC ACTIVITY; CANCER PATIENT; CANCER RECURRENCE; HUMAN; LIVER CELL CARCINOMA; LIVER GRAFT REJECTION; LIVER TRANSPLANTATION; MAINTENANCE CHEMOTHERAPY; PERSONALIZED MEDICINE; POSTOPERATIVE PERIOD; PRIORITY JOURNAL; REVIEW; TREATMENT OUTCOME;

ANTINEOPLASTIC AGENTS; CALCINEURIN; CARCINOMA, HEPATOCELLULAR; GLUCOCORTICOIDS; GRAFT REJECTION; HUMANS; IMMUNOSUPPRESSION; IMMUNOSUPPRESSIVE AGENTS; IMP DEHYDROGENASE; LIVER NEOPLASMS; LIVER TRANSPLANTATION; NEOPLASM RECURRENCE, LOCAL; NIACINAMIDE; PHENYLUREA COMPOUNDS; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME;

EID: 84896706891     PISSN: 15276465     EISSN: 15276473     Source Type: Journal    
DOI: 10.1002/lt.23806     Document Type: Review

References (96)

1. Davis GL, Dempster J, Meler JD, Orr DW, Walberg MW, Brown B, et al. Hepatocellular carcinoma: management of an increasingly common problem. Proc (Bayl Univ Med Cent) 2008; 21: 266-280.
2. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A,; for OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012; 13: e11-e22.
3. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C,. Cancer after kidney transplantation in the United States. Am J Transplant 2004; 4: 905-913.
4. Tjon AS, Sint Nicolaas J, Kwekkeboom J, de Man RA, Kazemier G, Tilanus HW, et al. Increased incidence of early de novo cancer in liver graft recipients treated with cyclosporine: an association with C2 monitoring and recipient age. Liver Transpl 2010; 16: 837-846.
5. Vivarelli M, Cucchetti A, Piscaglia F, La Barba G, Bolondi L, Cavallari A, Pinna AD,. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl 2005; 11: 497-503.
6. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999; 397: 530-534.
7. Huynh H, Chow KH, Soo KC, Toh HC, Choo SP, Foo KF, et al. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med 2009; 13: 1371-1380.
8. Bilbao I, Sapisochin G, Dopazo C, Lazaro JL, Pou L, Castells L, et al. Indications and management of everolimus after liver transplantation. Transplant Proc 2009; 41: 2172-2176.
9. Schnitzbauer AA, Zuelke C, Graeb C, Rochon J, Bilbao I, Burra P, et al. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 2010; 10: 190.
10. Bialecki ES, Di Bisceglie AM,. Diagnosis of hepatocellular carcinoma. HPB (Oxford) 2005; 7: 26-34.
11. Starzl TE, Marchioro TL, Porter KA, Brettschneider L,. Homotransplantation of the liver. Transplantation 1967; 5 (suppl): 790-803.
12. Henry SD, Metselaar HJ, Van Dijck J, Tilanus HW, Van Der Laan LJ,. Impact of steroids on hepatitis C virus replication in vivo and in vitro. Ann N Y Acad Sci 2007; 1110: 439-447.
13. Pirotte B, Levivier M, Goldman S, Brucher JM, Brotchi J, Hildebrand J,. Glucocorticoid-induced long-term remission in primary cerebral lymphoma: case report and review of the literature. J Neurooncol 1997; 32: 63-69.
14. Leppert W, Buss T,. The role of corticosteroids in the treatment of pain in cancer patients. Curr Pain Headache Rep 2012; 16: 307-313.
15. Mazzaferro V, Rondinara GF, Rossi G, Regalia E, De Carlis L, Caccamo L, et al. Milan multicenter experience in liver transplantation for hepatocellular carcinoma. Transplant Proc 1994; 26: 3557-3560.
16. Chen ZS, He F, Zeng FJ, Jiang JP, Du DF, Liu B,. Early steroid withdrawal after liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2007; 13: 5273-5276.
17. Kim JM, Joh JW, Kim SJ, Kwon CH, Song S, Shin M, et al. Steroid withdrawal in adult liver transplantation: occurrence at a single center. Transplant Proc 2010; 42: 4132-4136.
18. Evans RM,. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-895.
19. Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci U S A 2001; 98: 11318-11323.
20. Wang Z, Malone MH, He H, McColl KS, Distelhorst CW,. Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis. J Biol Chem 2003; 278: 23861-23867.
21. Rogatsky I, Hittelman AB, Pearce D, Garabedian MJ,. Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol 1999; 19: 5036-5049.
22. Lu NZ, Collins JB, Grissom SF, Cidlowski JA,. Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor. Mol Cell Biol 2007; 27: 7143-7160.
23. Schlossmacher G, Stevens A, White A,. Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol 2011; 211: 17-25.
24. Borel JF, Feurer C, Gubler HU, Stähelin H,. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 1976; 6: 468-475.
25. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS,. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63: 977-983.
26. Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, Soulillou JP,. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998; 351: 623-628.
27. Jonas S, Rayes N, Neumann U, Neuhaus R, Bechstein WO, Guckelberger O, et al. De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine-based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer 1997; 80: 1141-1150.
28. Opelz G, Döhler B,. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4: 222-230.
29. McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL,. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transplant 2006; 6: 1578-1585.
30. Frezza EE, Fung JJ, van Thiel DH,. Non-lymphoid cancer after liver transplantation. Hepatogastroenterology 1997; 44: 1172-1181.
31. Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, Sheiner PA,. Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 1998; 83: 1237-1243.
32. Herrero JI, Lorenzo M, Quiroga J, Sangro B, Pardo F, Rotellar F, et al. De novo neoplasia after liver transplantation: an analysis of risk factors and influence on survival. Liver Transpl 2005; 11: 89-97.
33. Vivarelli M, Bellusci R, Cucchetti A, Cavrini G, De Ruvo N, Aden AA, et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation 2002; 74: 1746-1751.
34. Vivarelli M, Cucchetti A, La Barba G, Ravaioli M, Del Gaudio M, Lauro A, et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann Surg 2008; 248: 857-862.
35. Decaens T, Roudot-Thoraval F, Bresson-Hadni S, Meyer C, Gugenheim J, Durand F, et al. Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: a multicenter study of 412 patients. World J Gastroenterol 2006; 12: 7319-7325.
36. Pan Q, Tilanus HW, Metselaar HJ, Janssen HL, van der Laan LJ,. Virus-drug interactions-molecular insight into immunosuppression and HCV. Nat Rev Gastroenterol Hepatol 2012; 9: 355-362.
37. 2+/calcineurin/NFAT signaling. Placenta 2013; 34: 374-380.
38. Rafferty P, Egenolf D, Brosnan K, Makropoulos D, Jordan J, Meshaw K, et al. Immunotoxicologic effects of cyclosporine on tumor progression in models of squamous cell carcinoma and B-cell lymphoma in C3H mice. J Immunotoxicol 2012; 9: 43-55.
39. Schumacher G, Oidtmann M, Rueggeberg A, Jacob D, Jonas S, Langrehr JM, et al. Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth. World J Gastroenterol 2005; 11: 1420-1425.
40. Baksh S, DeCaprio JA, Burakoff SJ,. Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4. Oncogene 2000; 19: 2820-2827.
41. Carr SF, Papp E, Wu JC, Natsumeda Y,. Characterization of human type I and type II IMP dehydrogenases. J Biol Chem 1993; 268: 27286-27290.
42. Manzia TM, De Liguori Carino N, Orlando G, Toti L, De Luca L, D'Andria D, et al. Use of mycophenolate mofetil in liver transplantation: a literature review. Transplant Proc 2005; 37: 2616-2617.
43. Suzuki S, Kimura T, Ando K, Sawada M, Tamura G,. Antitumor activity of mycophenolic acid. J Antibiot (Tokyo) 1969; 22: 297-302.
44. Domhan S, Muschal S, Schwager C, Morath C, Wirkner U, Ansorge W, et al. Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid. Mol Cancer Ther 2008; 7: 1656-1668.
45. Tressler RJ, Garvin LJ, Slate DL,. Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo. Int J Cancer 1994; 57: 568-573.
46. Takebe N, Cheng X, Fandy TE, Srivastava RK, Wu S, Shankar S, et al. IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells. Mol Cancer Ther 2006; 5: 457-466.
47. Inai K, Tsutani H, Yamauchi T, Fukushima T, Iwasaki H, Imamura S, et al. Differentiation induction in non-lymphocytic leukemia cells upon treatment with mycophenolate mofetil. Leuk Res 2000; 24: 761-768.
48. Koehl GE, Wagner F, Stoeltzing O, Lang SA, Steinbauer M, Schlitt HJ, Geissler EK,. Mycophenolate mofetil inhibits tumor growth and angiogenesis in vitro but has variable antitumor effects in vivo, possibly related to bioavailability. Transplantation 2007; 83: 607-614.
49. Guidicelli G, Chaigne-Delalande B, Dilhuydy MS, Pinson B, Mahfouf W, Pasquet JM, et al. The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells. PLoS One 2009; 4: e5493.
50. Sweeney MJ,. Mycophenolic acid and its mechanism of action in cancer and psoriasis. Jpn J Antibiot 1977; 30 (suppl): 85-92.
51. Escobar-Henriques M, Balguerie A, Monribot C, Boucherie H, Daignan-Fornier B,. Proteome analysis and morphological studies reveal multiple effects of the immunosuppressive drug mycophenolic acid specifically resulting from guanylic nucleotide depletion. J Biol Chem 2001; 276: 46237-46242.
52. Takebe N, Cheng X, Wu S, Bauer K, Goloubeva OG, Fenton RG, et al. Phase I clinical trial of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil (CellCept) in advanced multiple myeloma patients. Clin Cancer Res 2004; 10: 8301-8308.
53. Rodríguez-Pascual J, Sha P, García-García E, Rajeshkumar NV, De Vicente E, Quijano Y, et al. A preclinical and clinical study of mycophenolate mofetil in pancreatic cancer. Invest New Drugs 2013; 31: 14-19.
54. Robson R, Cecka JM, Opelz G, Budde M, Sacks S,. Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am J Transplant 2005; 5: 2954-2960.
55. Rostaing L, Kamar N,. mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol 2010; 23: 133-142.
56. van Veelen W, Korsse SE, van de Laar L, Peppelenbosch MP,. The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 2011; 30: 2289-2303.
57. Zhu AX, Abrams TA, Miksad R, Blaszkowsky LS, Meyerhardt JA, Zheng H, et al. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer 2011; 117: 5094-5102.
58. Shiah HS, Chen CY, Dai CY, Hsiao CF, Lin YJ, Su WC, et al. Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. Aliment Pharmacol Ther 2013; 37: 62-73.
59. Chinnakotla S, Davis GL, Vasani S, Kim P, Tomiyama K, Sanchez E, et al. Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl 2009; 15: 1834-1842.
60. Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM,. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 2010; 51: 1237-1243.
61. Rizell M, Andersson M, Cahlin C, Hafström L, Olausson M, Lindnér P,. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 2008; 13: 66-70.
62. Decaens T, Luciani A, Itti E, Hulin A, Roudot-Thoraval F, Laurent A, et al. Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma. Dig Liver Dis 2012; 44: 610-616.
63. Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Skibba A, Kam I,. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008; 14: 633-638.
64. Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Wright F, et al. Predictors of long-term outcome following liver transplantation for hepatocellular carcinoma: a single-center experience. Transpl Int 2007; 20: 747-753.
65. Bjornsti MA, Houghton PJ,. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 335-348.
66. Bhat M, Sonenberg N, Gores GJ,. The mTOR pathway in hepatic malignancies. Hepatology 2013; 58: 810-818.
67. Guertin DA, Sabatini DM,. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353-361.
68. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302.
69. Chung J, Kuo CJ, Crabtree GR, Blenis J,. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 1992; 69: 1227-1236.
70. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22: 159-168.
71. Maes H, Rubio N, Garg AD, Agostinis P,. Autophagy: shaping the tumor microenvironment and therapeutic response. Trends Mol Med 2013; 19: 428-446.
72. Li P, Du Q, Cao Z, Guo Z, Evankovich J, Yan W, et al. Interferon-γ induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1). Cancer Lett 2012; 314: 213-222.
73. Thomas HE, Mercer CA, Carnevalli LS, Park J, Andersen JB, Conner EA, et al. mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Sci Transl Med 2012; 4: 139ra84.
74. Lan SH, Wu SY, Zuchini R, Lin XZ, Su IJ, Tsai TF, et al. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of miR-224. Hepatology; doi: 10.1002/hep.26659.
75. + liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. Cancer Lett 2013; 339: 70-81.
76. Zucman-Rossi J,. Molecular classification of hepatocellular carcinoma. Dig Liver Dis 2010; 42 (suppl 3): S235-S241.
77. Sabatini DM,. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6: 729-734.
78. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.; for SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390.
79. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34.
80. Bhoori S, Toffanin S, Sposito C, Germini A, Pellegrinelli A, Lampis A, Mazzaferro V,. Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle. J Hepatol 2010; 52: 771-775.
81. Tan WF, Qiu ZQ, Yu Y, Ran RZ, Yi B, Lau WY, et al. Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation. Acta Pharmacol Sin 2010; 31: 1643-1648.
82. Weinmann A, Niederle IM, Koch S, Hoppe-Lotichius M, Heise M, Düber C, et al. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis 2012; 44: 432-437.
83. Gomez-Martin C, Bustamante J, Castroagudin JF, Salcedo M, Garralda E, Testillano M, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2012; 18: 45-52.
84. Waidmann O, Hofmann WP, Zeuzem S, Trojan J,. mTOR inhibitors and sorafenib for recurrent hepatocellular carcinoma after orthotopic liver transplantation. J Hepatol 2011; 54: 396-398.
85. Sposito C, Mariani L, Germini A, Flores Reyes M, Bongini M, Grossi G, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013; 59: 59-66.
86. Toso C, Mentha G, Majno P,. Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence. J Hepatol 2013; 59: 3-5.
87. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-7109.
88. Zavaglia C, Airoldi A, Mancuso A, Vangeli M, Viganò R, Cordone G, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. Eur J Gastroenterol Hepatol 2013; 25: 180-186.
89. Staufer K, Fischer L, Seegers B, Vettorazzi E, Nashan B, Sterneck M,. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int 2012; 25: 1158-1164.
90. Finn RS, Poon RT, Yau T, Klümpen HJ, Chen LT, Kang YK, et al. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J Hepatol 2013; 59: 1271-1277.
91. Hanahan D, Weinberg RA,. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674.
92. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008; 135: 1972-1983.
93. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M,. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004; 10: 8421-8425.
94. Sieghart W, Fuereder T, Schmid K, Cejka D, Werzowa J, Wrba F, et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 2007; 83: 425-432.
95. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, et al. Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008; 5: e8.
96. Brouwer C, Vermunt-de Koning DG, Trueworthy RC, Ter Riet PG, Duley JA, Trijbels FJ, et al. Monitoring of inosine monophosphate dehydrogenase activity in mononuclear cells of children with acute lymphoblastic leukemia: enzymological and clinical aspects. Pediatr Blood Cancer 2006; 46: 434-438.