Childhood melanoma

Clinics in Dermatology

Volumn 27, Issue 6, 2009, Pages 529-536

  Jen, Melinda ^a   Murphy, Michael ^a   Grant Kels, Jane M ^a  

^a UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA2B INTERFERON; ANTINEOPLASTIC AGENT; BCG VACCINE; CYCLIN DEPENDENT KINASE INHIBITOR 2A; CYCLOPHOSPHAMIDE; DACARBAZINE; DACTINOMYCIN; GANGLIOSIDE; GANGLIOSIDE GM2; INTERLEUKIN 2; MELANOMA VACCINE; MELPHALAN; PEGINTERFERON ALPHA2B; PEPTIDE VACCINE; VINCRISTINE;

ADJUVANT THERAPY; ADVANCED CANCER; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER IMMUNOTHERAPY; CANCER INCIDENCE; CANCER PREVENTION; CANCER RADIOTHERAPY; CANCER REGRESSION; CANCER RISK; CANCER SIZE; CANCER STAGING; CANCER SURGERY; CANCER SURVIVAL; CARCINOGENESIS; CHILD; CHILDHOOD CANCER; CLINICAL TRIAL; DISEASE FREE SURVIVAL; DRUG MEGADOSE; DYSPLASTIC NEVUS; FAMILY HISTORY; GENE MUTATION; GENETIC SCREENING; HUMAN; IMMUNE DEFICIENCY; IMMUNOSTIMULATION; LOW DRUG DOSE; LYMPH NODE METASTASIS; MAINTENANCE THERAPY; MALIGNANT TRANSFORMATION; MELANOCYTIC NEVUS; MELANOMA; METASTASIS; MONOTHERAPY; OVERALL SURVIVAL; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROGNOSIS; RISK FACTOR; SENTINEL LYMPH NODE BIOPSY; SKIN EXAMINATION; SKIN MANIFESTATION; SKIN PIGMENTATION; SKIN SURGERY; SUN EXPOSURE; SURVIVAL RATE; SURVIVAL TIME; THERAPY DELAY; TUMOR IMMUNITY; UNSPECIFIED SIDE EFFECT; XERODERMA PIGMENTOSUM;

AGE FACTORS; BIOPSY, NEEDLE; CHILD; CHILD, PRESCHOOL; COMBINED MODALITY THERAPY; DISEASE-FREE SURVIVAL; EARLY DETECTION OF CANCER; FEMALE; HUMANS; MALE; MELANOMA; NEOPLASM INVASIVENESS; NEOPLASM STAGING; NEVUS, PIGMENTED; PROGNOSIS; RISK ASSESSMENT; SKIN NEOPLASMS; SURVIVAL ANALYSIS;

EID: 70350351071     PISSN: 0738081X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.clindermatol.2008.09.011     Document Type: Article

References (117)

1. Rao B., Hayes F., Pratt C., et al. Malignant melanoma in children: its management and prognosis. J Pediatr Surg 25 (1990) 198-203
2. Karlsson P., and Fredrikson M. Cutaneous malignant melanoma in children and adolescents in Sweden, 1993-2002: the increasing trend is broken. Int J Cancer 121 (2007) 323-328
3. Saenz N., Saenz-Badillos J., Busam K., et al. Childhood melanoma survival. Cancer 85 (1999) 750-754
4. American Cancer Society. Cancer facts & figures 2008. Available at:. http://www.cancer.org/downloads/STT/2008CAFFfinalsecured.pdf
5. Ries L.A.G., Krapcho M., Stinchcomb D.G., et al. SEER Cancer Statistics Review, 1975-2005 (2008), National Cancer Institute, Bethesda (Md)
6. Ceballos P., Ruiz-Maldonado R., and Mihm M.J. Melanoma in children. N Engl J Med 332 (1995) 656-662
7. Prosdocimo T., Smith M., and Polack E. The diagnosis and treatment of childhood melanoma. W V Med J 98 (2002) 149-151
8. Gibbs P., Moore A., Robinson W., et al. Pediatric melanoma: are recent advances in the management of adult melanoma relevant to the pediatric population. J Pediatr Hematol Oncol 22 (2000) 428-432
9. Strouse J., Fears T., Tucker M., et al. Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology and end results database. J Clin Oncol 23 (2005) 4735-4741
10. Hoang M, Eichenfield L. The rising incidence of melanoma in children and adolescents. Dermatol Nurs 2000;12:188-9, 92-3.
11. Karlsson P., Boeryd B., Sander B., et al. Increasing incidence of cutaneous malignant melanoma in children and adolescents 12-19 years of age in Sweden 1973-92. Acta Derm Venereol 78 (1998) 289-292
12. McWhirter W., Dobson C., and Ring I. Childhood cancer incidence in Australia, 1982-1991. Int J Cancer 65 (1996) 34-38
13. Whiteman D., Valery P., McWhirter W., et al. Incidence of cutaneous childhood melanoma in Queensland, Australia. Int J Cancer 63 (1995) 765-768
14. Berg P., and Lindelöf B. Differences in malignant melanoma between children and adolescents. A 35-year epidemiological study. Arch Dermatol 133 (1997) 295-297
15. Ruiz-Maldonado R., and Orozco-Covarrubias M. Malignant melanoma in children. A review. Arch Dermatol 133 (1997) 363-371
16. Hamre M., Chuba P., Bakhshi S., et al. Cutaneous melanoma in childhood and adolescence. Pediatr Hematol Oncol 19 (2002) 309-317
17. de Vries E., Steliarova-Foucher E., Spatz A., et al. Skin cancer incidence and survival in European children and adolescents (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer 42 (2006) 2170-2182
18. Lange J., Palis B., Chang D., et al. Melanoma in children and teenagers: an analysis of patients from the National Cancer Data Base. J Clin Oncol 25 (2007) 1363-1368
19. Boddie A.J., Smith J.J., and McBride C. Malignant melanoma in children and young adults: effect of diagnostic criteria on staging and end results. South Med J 71 (1978) 1074-1078
20. Fishman C., Mihm M.J., and Sober A. Diagnosis and management of nevi and cutaneous melanoma in infants and children. Clin Dermatol 20 (2002) 44-50
21. Richardson S., Tannous Z., and Mihm M.J. Congenital and infantile melanoma: review of the literature and report of an uncommon variant, pigment-synthesizing melanoma. J Am Acad Dermatol 47 (2002) 77-90
22. Alexander A., Samlowski W., Grossman D., et al. Metastatic melanoma in pregnancy: risk of transplacental metastases in the infant. J Clin Oncol 21 (2003) 2179-2186
23. Conti E., Cercato M., Gatta G., et al. Childhood melanoma in Europe since 1978: a population-based survival study. Eur J Cancer 37 (2001) 780-784
24. Kaplan E. The risk of malignancy in large congenital nevi. Plast Reconstr Surg 53 (1974) 421-428
25. Marghoob A. Congenital melanocytic nevi. Evaluation and management. Dermatol Clin 2002;20:607-16, viii.
26. Ferrari A., Bono A., Baldi M., et al. Does melanoma behave differently in younger children than in adults? A retrospective study of 33 cases of childhood melanoma from a single institution. Pediatrics 115 (2005) 649-654
27. Jafarian F., Powell J., Kokta V., et al. Malignant melanoma in childhood and adolescence: report of 13 cases. J Am Acad Dermatol 53 (2005) 816-822
28. Elwood J., and Jopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 73 (1997) 198-203
29. Roth M., Grant-Kels J., Kuhn M., et al. Melanoma in children. J Am Acad Dermatol 22 (1990) 265-274
30. Downard C., Rapkin L., and Gow K. Melanoma in children and adolescents. Surg Oncol 16 (2007) 215-220
31. Pappo A. Melanoma in children and adolescents. Eur J Cancer 39 (2003) 2651-2661
32. Tromberg J., Bauer B., Benvenuto-Andrade C., et al. Congenital melanocytic nevi needing treatment. Dermatol Ther 18 (2005) 136-150
33. Tannous Z., Mihm M.J., Sober A., et al. Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical management. J Am Acad Dermatol 52 (2005) 197-203
34. Krengel S., Hauschild A., and Schäfer T. Melanoma risk in congenital melanocytic naevi: a systematic review. Br J Dermatol 155 (2006) 1-8
35. Schaffer J, Bolognia J. The clinical spectrum of pigmented lesions. Clin Plast Surg 2000;27:391-408, viii.
36. Kadonaga J., and Frieden I. Neurocutaneous melanosis: definition and review of the literature. J Am Acad Dermatol 24 (1991) 747-755
37. Schmid-Wendtner M., Berking C., Baumert J., et al. Cutaneous melanoma in childhood and adolescence: an analysis of 36 patients. J Am Acad Dermatol 46 (2002) 874-879
38. Novakovic B., Clark W.J., Fears T., et al. Melanocytic nevi, dysplastic nevi, and malignant melanoma in children from melanoma-prone families. J Am Acad Dermatol 33 (1995) 631-636
39. Greene M. Dysplastic nevus syndrome. Hosp Pract (Off Ed) 1984;19:91-103, 7-8.
40. Salopek T. The dilemma of the dysplastic nevus. Dermatol Clin 2002;20:617-28, viii.
41. Whiteman D., Milligan A., Welch J., et al. Germline CDKN2A mutations in childhood melanoma. J Natl Cancer Inst 89 (1997) 1460
42. Soufir N., Ollivaud L., Bertrand G., et al. A French CDK4-positive melanoma family with a co-inherited EDNRB mutation. J Dermatol Sci 46 (2007) 61-64
43. Eliason M., Larson A., Florell S., et al. Population-based prevalence of CDKN2A mutations in Utah melanoma families. J Invest Dermatol 126 (2006) 660-666
44. Gensini F., Sestini R., Piazzini M., et al. The p.G23S CDKN2A founder mutation in high-risk melanoma families from Central Italy. Melanoma Res 17 (2007) 387-392
45. Goldstein A., Chan M., Harland M., et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet 44 (2007) 99-106
46. Helsing P., Nymoen D.A., Ariansen S., et al. Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas. Genes Chromosomes Cancer 47 (2008) 175-184
47. Lang J., Boxer M., and MacKie R. CDKN2A mutations in Scottish families with cutaneous melanoma: results from 32 newly identified families. Br J Dermatol 153 (2005) 1121-1125
48. Ung-Juurlink C. American Academy of Dermatology 1999 Awards for Young Investigators in Dermatology. The prevalence of CDKN2A in patients with atypical nevi and malignant melanoma. J Am Acad Dermatol 41 (1999) 461-462
49. Newton Bishop J., and Gruis N. Genetics: what advice for patients who present with a family history of melanoma?. Semin Oncol 34 (2007) 452-459
50. Tsao H., and Niendorf K. Genetic testing in hereditary melanoma. J Am Acad Dermatol 51 (2004) 803-808
51. Della Torre G., Pasini B., Frigerio S., et al. CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation. Br J Cancer 85 (2001) 836-844
52. Pjanova D., Engele L., Randerson-Moor J., et al. CDKN2A and CDK4 variants in Latvian melanoma patients: analysis of a clinic-based population. Melanoma Res 17 (2007) 185-191
53. Zuo L., Weger J., Yang Q., et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12 (1996) 97-99
54. Molven A., Grimstvedt M., Steine S., et al. A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation. Genes Chromosomes Cancer 44 (2005) 10-18
55. Goldstein A., Chidambaram A., Halpern A., et al. Rarity of CDK4 germline mutations in familial melanoma. Melanoma Res 12 (2002) 51-55
56. Snels D., Hille E., Gruis N., et al. Risk of cutaneous malignant melanoma in patients with nonfamilial atypical nevi from a pigmented lesions clinic. J Am Acad Dermatol 40 (1999) 686-693
57. Garbe C., Büttner P., Weiss J., et al. Risk factors for developing cutaneous melanoma and criteria for identifying persons at risk: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society. J Invest Dermatol 102 (1994) 695-699
58. Holly E., Kelly J., Shpall S., et al. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol 17 (1987) 459-468
59. Bataille V., Bishop J., Sasieni P., et al. Risk of cutaneous melanoma in relation to the numbers, types and sites of naevi: a case-control study. Br J Cancer 73 (1996) 1605-1611
60. MacKie R., Freudenberger T., and Aitchison T. Personal risk-factor chart for cutaneous melanoma. Lancet 2 (1989) 487-490
61. Grob J., Gouvernet J., Aymar D., et al. Count of benign melanocytic nevi as a major indicator of risk for nonfamilial nodular and superficial spreading melanoma. Cancer 66 (1990) 387-395
62. Naldi L., Lorenzo Imberti G., Parazzini F., et al. Pigmentary traits, modalities of sun reaction, history of sunburns, and melanocytic nevi as risk factors for cutaneous malignant melanoma in the Italian population: results of a collaborative case-control study. Cancer 88 (2000) 2703-2710
63. Roush G., Nordlund J., Forget B., et al. Independence of dysplastic nevi from total nevi in determining risk for nonfamilial melanoma. Prev Med 17 (1988) 273-279
64. Grulich A., Bataille V., Swerdlow A., et al. Naevi and pigmentary characteristics as risk factors for melanoma in a high-risk population: a case-control study in New South Wales, Australia. Int J Cancer 67 (1996) 485-491
65. Tucker M., Halpern A., Holly E., et al. Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma. JAMA 277 (1997) 1439-1444
66. Penn I. Development of cancer in transplantation patients. Adv Surg 12 (1978) 155-191
67. Tucker M., Misfeldt D., Coleman C., et al. Cutaneous malignant melanoma after Hodgkin's disease. Ann Intern Med 102 (1985) 37-41
68. Baird E., McHenry P., and MacKie R. Effect of maintenance chemotherapy in childhood on numbers of melanocytic naevi. BMJ 305 (1992) 799-801
69. Melnik M., Urdaneta L., Al-Jurf A., et al. Malignant melanoma in childhood and adolescence. Am Surg 52 (1986) 142-147
70. Wechsler J., Bastuji-Garin S., Spatz A., et al. Reliability of the histopathologic diagnosis of malignant melanoma in childhood. Arch Dermatol 138 (2002) 625-628
71. Roaten J., Partrick D., Bensard D., et al. Survival in sentinel lymph node-positive pediatric melanoma. J Pediatr Surg 40 (2005) 988-992 [discussion 92]
72. Gamblin T., Edington H., Kirkwood J., et al. Sentinel lymph node biopsy for atypical melanocytic lesions with spitzoid features. Ann Surg Oncol 13 (2006) 1664-1670
73. Lohmann C., Coit D., Brady M., et al. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol 26 (2002) 47-55
74. Su L., Fullen D., Sondak V., et al. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 97 (2003) 499-507
75. Balch C. Cutaneous melanoma: prognosis and treatment results worldwide. Semin Surg Oncol 8 (1992) 400-414
76. LeBoit P. "Safe" Spitz and its alternatives. Pediatr Dermatol 19 (2002) 163-165
77. Mones J., and Ackerman A. "Atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus: a critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 26 (2004) 310-333
78. Barnhill R., Flotte T., Fleischli M., et al. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer 76 (1995) 1833-1845
79. Gurbuz Y., Apaydin R., Muezzinoǧlu B., et al. A current dilemma in histopathology: atypical spitz tumor or Spitzoid melanoma?. Pediatr Dermatol 19 (2002) 99-102
80. Bauer J., and Bastian B. Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool. Dermatol Ther 19 (2006) 40-49
81. Sander B., Karlsson P., Rosdahl I., et al. Cutaneous malignant melanoma in Swedish children and teenagers 1973-1992: a clinico-pathological study of 130 cases. Int J Cancer 80 (1999) 646-651
82. Balch C., Buzaid A., Soong S., et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19 (2001) 3635-3648
83. NCCN. NCCN clinical practice guidelines in oncology: melanoma (V.2.2008) (2008), National Comprehensive Cancer Network, Washington, DC
84. Topar G., and Zelger B. Assessment of value of the sentinel lymph node biopsy in melanoma in children and adolescents and applicability of subcutaneous infusion anesthesia. J Pediatr Surg 42 (2007) 1716-1720
85. Bütter A., Hui T., Chapdelaine J., et al. Melanoma in children and the use of sentinel lymph node biopsy. J Pediatr Surg 40 (2005) 797-800
86. Baas P., Hoekstra H., Schraffordt Koops H., et al. Hyperthermic isolated regional perfusion in the treatment of extremity melanoma in children and adolescents. Cancer 63 (1989) 199-203
87. Boddie A.J., and Cangir A. Adjuvant and neoadjuvant chemotherapy with dacarbazine in high-risk childhood melanoma. Cancer 60 (1987) 1720-1723
88. Hayes F., and Green A. Malignant melanoma in childhood: clinical course and response to chemotherapy. J Clin Oncol 2 (1984) 1229-1234
89. Huynh P., Grant-Kels J., and Grin C. Childhood melanoma: update and treatment. Int J Dermatol 44 (2005) 715-723
90. Bernstein I., and Wright P. Immunology and immunotherapy of childhood neoplasia. Pediatr Clin North Am 23 (1976) 93-109
91. Morton D., Eilber F., Malmgren R., et al. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 68 (1970) 158-163 [discussion 63-4]
92. Arons M., and Hurwitz S. Congenital nevocellular nevus: a review of the treatment controversy and a report of 46 cases. Plast Reconstr Surg 72 (1983) 355-365
93. Eilber F., Morton D., Holmes E., et al. Adjuvant immunotherapy with BCG in treatment of regional-lymph-node metastases from malignant melanoma. N Engl J Med 294 (1976) 237-240
94. Kölmel K., Grange J., Krone B., et al. Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients. Eur J Cancer 41 (2005) 118-125
95. Moritz M., and Wallack M. Survival after malignant melanoma in a black child. A case report and review of the literature. Am J Clin Oncol 7 (1984) 545-549
96. Agarwala S., Neuberg D., Park Y., et al. Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer 100 (2004) 1692-1698
97. Kefford R. Adjuvant therapy of cutaneous melanoma: the interferon debate. Ann Oncol 14 (2003) 358-365
98. Kirkwood J., Strawderman M., Ernstoff M., et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1996) 7-17
99. Chiarion-Sileni V., Del Bianco P., Romanini A., et al. Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI - Mel.A.) [ISRCTN75125874]. BMC Cancer 6 (2006) 44
100. Navid F., Furman W., Fleming M., et al. The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma. Cancer 103 (2005) 780-787
101. Rosenberg S., Yang J., White D., et al. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 228 (1998) 307-319
102. Phan G., Attia P., Steinberg S., et al. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19 (2001) 3477-3482
103. Bauer M., Reaman G., Hank J., et al. A phase II trial of human recombinant interleukin-2 administered as a 4-day continuous infusion for children with refractory neuroblastoma, non-Hodgkin's lymphoma, sarcoma, renal cell carcinoma, and malignant melanoma. A Childrens Cancer Group study. Cancer 75 (1995) 2959-2965
104. Osenga K., Hank J., Albertini M., et al. A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group. Clin Cancer Res 12 (2006) 1750-1759
105. Ribeiro R., Rill D., Roberson P., et al. Continuous infusion of interleukin-2 in children with refractory malignancies. Cancer 72 (1993) 623-628
106. Roper M., Smith M., Sondel P., et al. A phase I study of interleukin-2 in children with cancer. Am J Pediatr Hematol Oncol 14 (1992) 305-311
107. Soni S., Lee D., DiVito J.J., et al. Treatment of pediatric ocular melanoma with high-dose interleukin-2 and thalidomide. J Pediatr Hematol Oncol 24 (2002) 488-491
108. Hamm C., Verma S., Petrella T., et al. Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review. Cancer Treat Rev 34 (2008) 145-156
109. Mitchell M., Abrams J., Thompson J., et al. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma. J Clin Oncol 25 (2007) 2078-2085
110. Ives N., Stowe R., Lorigan P., et al. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 25 (2007) 5426-5434
111. Sasse A., Sasse E., Clark L., et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database Syst Rev (2007) CD005413
112. Recchia F., Candeloro G., Necozione S., et al. Multicenter phase II study of chemoimmunotherapy in the treatment of metastatic melanoma. Anticancer Drugs 19 (2008) 201-207
113. Spieth K., Kaufmann R., Dummer R., et al. Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG). Ann Oncol 19 (2008) 801-806
114. Terando A., Faries M., and Morton D. Vaccine therapy for melanoma: current status and future directions. Vaccine 25 Suppl 2 (2007) B4-B16
115. Mitchell M., Jakowatz J., Harel W., et al. Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 12 (1994) 402-411
116. Vaishampayan U., Abrams J., Darrah D., et al. Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin Cancer Res 8 (2002) 3696-3701
117. Livestro D., Kaine E., Michaelson J., et al. Melanoma in the young: differences and similarities with adult melanoma: a case-matched controlled analysis. Cancer 110 (2007) 614-624