Emerging drugs for neuroblastoma

Expert Opinion on Emerging Drugs

Volumn 18, Issue 2, 2013, Pages 155-171

  Castel, Victoria ^a,b   Segura, Vanessa ^b   Berlanga, Pablo ^a,b  

^a HOSPITAL UNIVERSITARIO LA FE   (Spain)

^b INSTITUTO DE INVESTIGACIÓN SANITARIA DEL HOSPITAL CLÍNICO SAN CARLOS IDISSC   (Spain)

Author keywords

Cancer in children; Drug development; Immunotherapy; Neuroblastoma; Target therapy

Indexed keywords

BEVACIZUMAB; BORTEZOMIB; BUSULFAN; CARBOPLATIN; CELGENE; CISPLATIN; CRIZOTINIB; CYCLOPHOSPHAMIDE; DOXORUBICIN; ETOPOSIDE; GANGLIOSIDE GD2; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IRINOTECAN; ISOTRETINOIN; LESTAURTINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MELPHALAN; NIFURTIMOX; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RECOMBINANT INTERLEUKIN 2; SORAFENIB; TEMOZOLOMIDE; TEMSIROLIMUS; THALIDOMIDE; THIOTEPA; TOPOTECAN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINCRISTINE; VORINOSTAT; XALXORI; ZOLEDRONIC ACID;

ALLERGIC REACTION; CANCER MORTALITY; CANCER PROGNOSIS; CANCER SURVIVAL; CAPILLARY LEAK SYNDROME; CHILDHOOD CANCER; COLORECTAL CANCER; DRUG EFFICACY; EVENT FREE SURVIVAL; GANGLIONEUROMA; HEALTH CARE NEED; HIGH RISK PATIENT; HUMAN; HYPERCALCEMIA; IMMEDIATE TYPE HYPERSENSITIVITY; INDUCTION CHEMOTHERAPY; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; MANTLE CELL LYMPHOMA; MINIMAL RESIDUAL DISEASE; MOLECULARLY TARGETED THERAPY; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NEUROBLASTOMA; OVARY CANCER; OVERALL SURVIVAL; PERITONEUM CANCER; REVIEW; TREATMENT RESPONSE; UTERINE TUBE CARCINOMA;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEUROBLASTOMA;

EID: 84878605600     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728214.2013.796927     Document Type: Review

References (100)

1. Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev 2010;36(4):277-85
2. Spix C, Pastore G, Sankila R, et al. Neuroblastoma incidence and survival in European children (1978-1997): report from the automated childhood cancer information system project. Eur J Cancer 2006;42(13):2081-91
3. Gatta G, Zigon G, Capocaccia R, et al. Survival of European children and young adults with cancer diagnosed 1995-2002. Eur J Cancer 2009;45(6):992-1005
4. Castel V, Villamon E, Canete A, et al. Neuroblastoma in adolescents: genetic and clinical characterisation. Clin Transl Oncol 2010;12(1):49-54
5. Esiashvili N, Goodman M, Ward K, et al. Neuroblastoma in adults: incidence and survival analysis based on SEER data. Pediatr Blood Cancer 2007;49(1):41-6
6. De Bernardi B, Mosseri V, Rubie H, et al. Treatment of localised resectable neuroblastoma. Results of the lnesg1 study by the SIOP Europe neuroblastoma group. Br J Cancer 2008;99(7):1027-33
7. Maris JM. Recent advances in neuroblastoma. N Engl J Med 2010;362(23):2202-11
8. Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report. J Clin Oncol 2009;27(2):289-97
9. Canete A, Gerrard M, Rubie H, et al. Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the international society of paediatric oncology european neuroblastoma experience. J Clin Oncol 2009;27(7):1014-19
10. London WB, Castleberry RP, Matthay KK, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 2005;23(27):6459-65
11. De Bernardi B, Gerrard M, Boni L, et al. Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 2009;27(7):1034-40
12. Evans AE, D'Angio GJ, Randolph J. A proposed staging for children with neuroblastoma. Children's cancer study group a. Cancer 1971;27(2):374-8
13. Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993;11(8):1466-77
14. Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG task force report. J Clin Oncol 2009;27(2):298-303
15. Brodeur GM, Seeger RC, Schwab M, et al. Amplification of n-MYC in untreated human neuroblastomas correlates with advanced disease stage. Science 1984;224(4653):1121-4
16. Mathew P, Valentine MB, Bowman LC, et al. Detection of MYCN gene amplification in neuroblastoma by fluorescence in situ hybridization: a pediatric oncology group study. Neoplasia 2001;3(2):105-9
17. Attiyeh EF, London WB, Mosse YP, et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 2005;353(21):2243-53
18. Schleiermacher G, Mosseri V, London WB, et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer 2012;107(8):1418-22
19. Kumps C, Fieuw A, Mestdagh P, et al. Focal DNA copy number changes in neuroblastoma target MYCN regulated genes. PLoS One 2013;8(1):e52321
20. Caren H, Abel F, Kogner P, Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours. Biochem J 2008;416(2):153-9
21. Shimada H, Umehara S, Monobe Y, et al. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the children's cancer group. Cancer 2001;92(9):2451-61
22. Pearson AD, Pinkerton CR, Lewis IJ, et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol 2008;9(3):247-56
23. Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a Children's Oncology Group study. J Clin Oncol 2009;27(7):1007-13
24. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-gd2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010;363(14):1324-34
25. London WB, Castel V, Monclair T, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 2011;29(24):3286-92
26. Laverdiere C, Liu Q, Yasui Y, et al. Long-term outcomes in survivors of neuroblastoma: a report from the childhood cancer survivor study. J Natl Cancer Inst 2009;101(16):1131-40
27. Kushner BH, LaQuaglia MP, Bonilla MA, et al. Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 1994;12(12):2607-13
28. Castel V, Canete A, Navarro S, et al. Outcome of high-risk neuroblastoma using a dose intensity approach: improvement in initial but not in long-term results. Med Pediatr Oncol 2001;37(6):537-42
29. Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized trial of prophylactic granulocyte colony-stimulating factor during Rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol 2010;28(21):3516-24
30. Cheung NK, Kushner BH, LaQuaglia M, et al. N7: a novel multi-modality therapy of high risk neuroblastoma (NB) in children diagnosed over 1 year of age. Med Pediatr Oncol 2001;36(1):227-30
31. Valteau-Couanet D, Michon J, Boneu A, et al. Results of induction chemotherapy in children older than 1 year with a stage 4 neuroblastoma treated with the NB 97 French society of pediatric oncology (SFOP) protocol. J Clin Oncol 2005;23(3):532-40
32. Kohler JA, Ellershaw C, Machin D; Neuroblastoma Working Group of the Children's Cancer and Leukaemia Group. Response to n7 induction chemotherapy in children more than one year of age diagnosed with metastatic neuroblastoma treated in UKCCSG centers. Pediatr Blood Cancer 2007;49(3):234-9
33. Park JR, Scott JR, Stewart CF, et al. Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study. J Clin Oncol 2011;29(33):4351-7
34. Garaventa A, Luksch R, Biasotti S, et al. A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Cancer 2003;98(11):2488-94
35. Simon T, Langler A, Harnischmacher U, et al. Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 2007;133(9):653-61
36. Ladenstein R, Poetschger U, Luksch R, et al. Busulphan-melphalan as myeloablative therapy (MAT) for high-risk neuroblastoma: results from the HR-NBL1/SIOPEN trial. J Clin Oncol 2011;29(Suppl):abstract 2
37. Matthay KK, Tan JC, Villablanca JG, et al. Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. J Clin Oncol 2006;24(3):500-6
38. Matthay KK, Yanik G, Messina J, et al. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131- metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 2007;25(9):1054-60
39. Gaze MN, Chang YC, Flux GD, et al. Feasibility of dosimetry-based high-dose 131i-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma. Cancer Biother Radiopharm 2005;20(2):195-9
40. Reynolds CP, Wang Y, Melton LJ, et al. Retinoic-acid-resistant neuroblastoma cell lines show altered MYC regulation and high sensitivity to fenretinide. Med Pediatr Oncol 2000;35(6):597-602
41. Castel V, Segura V, Canete A. Treatment of high-risk neuroblastoma with anti-GD2 antibodies. Clin Transl Oncol 2010;12(12):788-93
42. Gilman AL, Ozkaynak MF, Matthay KK, et al. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol 2009;27(1):85-91
43. Hank JA, Robinson RR, Surfus J, et al. Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2. Cancer Res 1990;50(17):5234-9
44. DuBois SG, Chesler L, Groshen S, et al. Phase I study of vincristine, irinotecan, and >1>3>1I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 2012;18(9):2679-86
45. Lode HN, Xiang R, Dreier T, et al. Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. Blood 1998;91(5):1706-15
46. Matthay KK, Quach A, Huberty J, et al. Iodine-131-metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 2009;27(7):1020-5
47. Lau L, Tai D, Weitzman S, et al. Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol 2004;26(4):227-32
48. Beiske K, Burchill SA, Cheung IY, et al. International neuroblastoma Risk Group Task Force. Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Br J Cancer 2009;100(10):1627-37
49. Combaret V, Bergeron C, Noguera R, et al. Circulating MYCN DNA predicts MYCN-amplification in neuroblastoma. J Clin Oncol 2005;23(34):8919-20
50. Yáñez Y, Grau E, Oltra S, et al. Minimal disease detection in peripheral blood and bone marrow from patients with non-metastatic neuroblastoma. J Cancer Res Clin Oncol 2011;137(8):1263-72
51. Blaney SM, Bernstein M, Neville K, et al. Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children's Oncology Group study (advl0015). J Clin Oncol 2004;22(23):4804-9
52. Armstrong MB, Schumacher KR, Mody R, et al. Bortezomib as a therapeutic candidate for neuroblastoma. J Exp Ther Oncol 2008;7(2):135-45
53. Fouladi M, Park JR, Stewart CF, et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children's Oncology Group phase I consortium report. J Clin Oncol 2010;28(22):3623-9
54. Muscal JA, Thompson PA, Horton TM, et al. A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (advl0916). Pediatr Blood Cancer 2013;60(3):390-5
55. More SS, Itsara M, Yang X, et al. Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. Clin Cancer Res 2011;17(8):2339-49
56. Rossler J, Taylor M, Geoerger B, et al. Angiogenesis as a target in neuroblastoma. Eur J Cancer 2008;44(12):1645-56
57. Backman U, Svensson A, Christofferson RH, Azarbayjani F. The bisphosphonate, zoledronic acid reduces experimental neuroblastoma growth by interfering with tumor angiogenesis. Anticancer Res 2008;28(3A):1551-7
58. Russell HV, Groshen SG, Ara T, et al. A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study. Pediatr Blood Cancer 2011;57(2):275-82
59. Kaicker S, McCrudden KW, Beck L, et al. Thalidomide is anti-angiogenic in a xenograft model of neuroblastoma. Int J Oncol 2003;23(6):1651-5
60. Gesundheit B, Moser A, Or R, Klement G. Successful antiangiogenic therapy for neuroblastoma with thalidomide. J Clin Oncol 2007;25(33):5321-4
61. Gilheeney SW, Lyden DC, Sgouros S, et al. A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies. Pediatr Blood Cancer 2007;49(3):261-5
62. Kakodkar NC, Peddinti RR, Tian Y, et al. Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth. Pediatr Blood Cancer 2012;59(4):642-7
63. Widemann BC, Kim A, Fox E, et al. A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children's Oncology Group phase I consortium report. Clin Cancer Res 2012;18(21):6011-22
64. Navid F, Baker SD, McCarville MB, et al. Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. Clin Cancer Res 2013;19(1):236-46
65. George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 2008;455(7215):975-8
66. Carpenter EL, Mosse YP. Targeting ALK in neuroblastoma-preclinical and clinical advancements. Nat Rev Clin Oncol 2012;9(7):391-9
67. De Brouwer S, De Preter K, Kumps C, et al. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res 2010;16(17):4353-62
68. Matthay KK, George RE, Yu AL. Promising therapeutic targets in neuroblastoma. Clin Cancer Res 2012;18(10):2740-53
69. Azarova AM, Gautam G, George RE. Emerging importance of ALK in neuroblastoma. Semin Cancer Biol 2011;21(4):267-75
70. Mosse YP, Balis FM, Lim MS, et al. Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study. J Clin Oncol 2012;30(Suppl):abstract 9500
71. Bresler SC, Wood AC, Haglund EA, et al. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med 2011;3(108):108ra114
72. Sasaki T, Okuda K, Zheng W, et al. The neuroblastoma-associated f1174l ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010;70(24):10038-43
73. Mehra R, Camidge R, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 2012;30(Suppl): abstract 3007
74. Schramm A, Schulte JH, Astrahantseff K, et al. Biological effects of TrkA and TrkB in neuroblastoma. Cancer Lett 2005;228(1-2):143-53
75. Iyer R, Evans AE, Qi X, et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma. Clin Cancer Res 2010;16(5):1478-85
76. Minturn JE, Evans AE, Villablanca JG, et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. Cancer Chemother Pharmacol 2011;68(4):1057-65
77. Opel D, Poremba C, Simon T, et al. Activation of AKT predicts poor outcome in neuroblastoma. Cancer Res 2007;67(2):735-45
78. Johnsen JI, Segerstrom L, Orrego A, et al. Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene 2008;27(20):2910-22
79. Spunt SL, Grupp SA, Vik TA, et al. Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. J Clin Oncol 2011;29(21):2933-40
80. Geoerger B, Kieran MW, Grupp S, et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer 2012;48(2):253-62
81. Coulter DW, Walko C, Patel J, et al. Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors. Anticancer Drugs 2013;24(4):415-21
82. Populo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012;13(2):1886-918
83. Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008;5(1):E8
84. Li Z, Tan F, Liewehr DJ, et al. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst 2010;102(11):758-70
85. Becher OJ, Trippett TM, Kolesar J, et al. Phase I study of single-agent perifosine for recurrent pediatric solid tumors. J Clin Oncol 2010;28:15s
86. Sun W, Modak S. Emerging treatment options for the treatment of neuroblastoma: potential role of perifosine. Oncol Targets Ther 2012;5:21-9
87. Maris JM, Morton CL, Gorlick R, et al. Initial testing of the aurora kinase a inhibitor mln8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer 2010;55(1):26-34
88. Mossé YP, Lipsitz E, Fox E, et al. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of Aurora kinase A: a Children's Oncology Group Phase I Consortium study. Clin Cancer Res 2012;18(21):6058-64
89. Lipsitz EG, Nguyen V, Zhao H, et al. Modeling MLN8237, an aurora kinase a inhibitor, with irinotecan (IRN) and temozolomide (TMZ) in neuroblastoma (NB). J Clin Oncol 2010;28(15s Suppl):abstract 10593
90. Daw NC, Furman WL, Stewart CF, et al. Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study. J Clin Oncol 2005;23(25):6172-80
91. Stewart CF, Leggas M, Schuetz JD, et al. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res 2004;64(20):7491-9
92. Furman WL, Navid F, Daw NC, et al. Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors. J Clin Oncol 2009;27(27):4599-604
93. Furman WL, McGregor LM, McCarville MB, et al. A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma. Investig New Drugs 2012;30(4):1660-70
94. Donfrancesco A, De Ioris MA, McDowell HP, et al. Gefitinib in combination with oral topotecan and cyclophosphamide in relapsed neuroblastoma: pharmacological rationale and clinical response. Pediatr Blood Cancer 2010;54(1):55-61
95. Jakacki RI, Hamilton M, Gilbertson RJ, et al. Pediatric phase I and pharmacokinetic study of erlotinib followed by the combination of erlotinib and temozolomide: a Children's Oncology Group phase I consortium study. J Clin Oncol 2008;26(30):4921-7
96. Zage PE, Zeng L, Palla S, et al. A novel therapeutic combination for neuroblastoma: the vascular endothelial growth factor receptor/epidermal growth factor receptor/rearranged during transfection inhibitor vandetanib with 13-cis-retinoic acid. Cancer 2010;116(10):2465-75
97. Saulnier Sholler GL, Bergendahl GM, Brard L, et al. A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma. J Pediatr Hematol Oncol 2011;33(1):25-30
98. Villablanca JG, London WB, Naranjo A, et al. Phase II study of oral capsular 4-hydroxyphenylretinamide (4-hpr/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group. Clin Cancer Res 2011;17(21):6858-66
99. Children's Oncology G, Villablanca JG, et al. Phase I trial of oral fenretinide in children with high-risk solid tumors: a report from the Children's Oncology Group (COG 09709). J Clin Oncol 2006; 24(21): 3423-30
100. Anderson CP, Reynolds CP. Synergistic cytotoxicity of buthionine sulfoximine (BSO) and intensive melphalan (L-PAM) for neuroblastoma cell lines established at relapse after myeloablative therapy. Bone Marrow Transplant 2002;30(3):135-40