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Central Nervous System Effects

  • Nina S. Kadan-Lottick
  • Joseph P. Neglia
Part of the Pediatric Oncology book series (PEDIATRICO)

Keywords

Acute Lymphoblastic Leukemia Clin Oncol Childhood Cancer Acute Lymphoblastic Leukaemia Central Nervous System Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Menkes JH (1990) Textbook of child neurology, 4th edn. Lea and Febiger, PhiladelphiaGoogle Scholar
  2. 2.
    Webb SJ, Monk CS, Nelson CA (2001) Mechanisms of postnatal neurobiological development: implications for human development. Dev Neuropsychol 19:147–171CrossRefPubMedGoogle Scholar
  3. 3.
    Sarnat HB (1992) Cerebral dysgenesis: embryology and clinical expression. Oxford University Press, New YorkGoogle Scholar
  4. 4.
    Corriveau RA, Huh GS, Shatz CJ (1998) Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21:505–520CrossRefPubMedGoogle Scholar
  5. 5.
    Minkowski A, Council for International Organizations of Medical Sciences, France (1967) Dâelâegation gâenâerale áa la recherche scientifique et technique. Regional development of the brain in early life. Davis, PhiladelphiaGoogle Scholar
  6. 6.
    Reiss AL, Abrams MT, Singer HS, Ross JL, Denckla MB (1996) Brain development, gender and IQ in children. A volumetric imaging study. Brain 119:1763–1774PubMedGoogle Scholar
  7. 7.
    Taylor HG, Alden J (1997) Age-related differences in outcomes following childhood brain insults: an introduction and overview. J Int Neuropsychol Soc 3:555–567PubMedGoogle Scholar
  8. 8.
    Robinson K (1998) Implications of developmental plasticity for the language acquisition of deaf children with cochlear implants. Int J Pediatr Otorhinolaryngol 46:71–80CrossRefPubMedGoogle Scholar
  9. 9.
    Bowering ER, Maurer D, Lewis TL, Brent HP (1997) Constriction of the visual field of children after early visual deprivation. J Pediatr Ophthalmol Strabismus 34:347–356PubMedGoogle Scholar
  10. 10.
    Ries LA, Smith MA, Gurney JG, Linet M, Tamra T, et al. (1999) Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. National Cancer Institute SEER Program, NIH Publ no 9904649. National Cancer Institute, Bethesda MDGoogle Scholar
  11. 11.
    Pizzo PA, Poplack DG (2002) Principles and practice of pediatric oncology, 4th edn. Lippincott Williams and Wilkins, Philadelphia, p xv, 1692 ppGoogle Scholar
  12. 12.
    Packer RJ, Sposto R, Atkins TE, Sutton LN, Bruce DA, Siegel KR et al. (1987) Quality of life in children with primitive neuroectodermal tumors (medulloblastoma) of the posterior fossa. Pediatr Neurosci 13:169–175PubMedGoogle Scholar
  13. 13.
    Gelabert-Gonzalez M, Fernandez-Villa J (2001) Mutism after posterior fossa surgery. Review of the literature. Clin Neurol Neurosurg 103:111–114PubMedGoogle Scholar
  14. 14.
    Steinbok P, Cochrane DD, Perrin R, Price A (2003) Mutism after posterior fossa tumour resection in children: incomplete recovery on long-term follow-up. Pediatr Neurosurg 39:179–183CrossRefPubMedGoogle Scholar
  15. 15.
    Sonderkaer S, Schmiegelow M, Carstensen H, Nielsen LB, Muller J, Schmiegelow K (2003) Long-term neurological outcome of childhood brain tumors treated by surgery only. J Clin Oncol 21:1347–1351CrossRefPubMedGoogle Scholar
  16. 16.
    Packer RJ, Gurney JG, Punyko JA, Donaldson SS, Inskip PD, Stovall M et al. (2003) Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study. J Clin Oncol 21:3255–3261CrossRefPubMedGoogle Scholar
  17. 17.
    Brouwers P, Riccardi R, Fedio P, Poplack DG (1985) Long-term neuropsychologic sequelae of childhood leukemia: correlation with CT brain scan abnormalities. J Pediatr 106:723–728PubMedGoogle Scholar
  18. 18.
    Crosley CJ, Rorke LB, Evans A, Nigro M (1978) Central nervous system lesions in childhood leukemia. Neurology 28:678–685PubMedGoogle Scholar
  19. 19.
    Price R (1983) Therapy related central nervous system diseases in children with acute lymphocytic leukemia. In: Mastrangelo R, Poplack D, Riccardi R (eds) Central nervous system leukemia. Nijhoff, AmsterdamGoogle Scholar
  20. 20.
    Price RA, Birdwell DA (1978) The central nervous system in childhood leukemia. III. Mineralizing microangiopathy and dystrophic calcification. Cancer 42:717–728PubMedGoogle Scholar
  21. 21.
    Peylan-Ramu N, Poplack DG, Pizzo PA, Adornato BT, di Chiro G (1978) Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. N Engl J Med 298:815–818PubMedGoogle Scholar
  22. 22.
    Schultheiss TE, Kun LE, Ang KK, Stephens LC (1995) Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31:1093–1112CrossRefPubMedGoogle Scholar
  23. 23.
    Tofilon PJ, Fike JR (2000) The radioresponse of the central nervous system: a dynamic process. Radiat Res 153:357–370PubMedGoogle Scholar
  24. 24.
    Meadows AT, Gordon J, Massari DJ, Littman P, Fergusson J, Moss K (1981) Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet 2:1015–1018CrossRefPubMedGoogle Scholar
  25. 25.
    Cousens P, Waters B, Said J, Stevens M (1988) Cognitive effects of cranial irradiation in leukaemia: a survey and meta-analysis. J Child Psychol Psychiatry 29:839–852PubMedGoogle Scholar
  26. 26.
    Rogers J, Britton PG, Morris RG, Kernahan J, Craft A (1992) Memory after treatment for acute lymphoblastic leukemia. Arch Dis Child 67:266–268PubMedGoogle Scholar
  27. 27.
    Ochs J, Mulhern R, Fairclough D, Parvey L, Whitaker J, Ch'ien L, et al. (1991) Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: a prospective study. J Clin Oncol 9:145–151PubMedGoogle Scholar
  28. 28.
    Brown RT, Madan-Swain A (1993) Cognitive, neuropsychological, and academic sequelae in children with leukemia. J Learn Disabil 26:74–90PubMedGoogle Scholar
  29. 29.
    Stehbens JA, Kaleita TA, Noll RB, MacLean WEJ, O'Brien RT, Waskerwitz MJ et al. (1991) CNS prophylaxis of childhood leukemia: what are the long-term neurological, neuropsychological, and behavioral effects? Neuropsychol Rev 2:147–177CrossRefPubMedGoogle Scholar
  30. 30.
    Radcliffe J, Bunin GR, Sutton LN, Goldwein JW, Phillips PC (1994) Cognitive deficits in long-term survivors of childhood medulloblastoma and other noncortical tumors: age-dependent effects of whole brain radiation. Int J Dev Neurosci 12:327–334CrossRefPubMedGoogle Scholar
  31. 31.
    Mulhern RK, Fairclough D, Ochs J (1991) A prospective comparison of neuropsychologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation. J Clin Oncol 9:1348–1356PubMedGoogle Scholar
  32. 32.
    Rubenstein CL, Varni JW, Katz ER (1990) Cognitive functioning in long-term survivors of childhood leukemia: a prospective analysis. J Dev Behav Pediatr 11:301–305PubMedGoogle Scholar
  33. 33.
    Jankovic M, Brouwers P, Valsecchi MG, van Veldhuizen A, Huisman J, Kamphuis R et al. (1994) Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. ISPACC. International Study Group on Psychosocial Aspects of Childhood Cancer. Lancet 344:224–227CrossRefPubMedGoogle Scholar
  34. 34.
    Robison LL, Nesbit MEJ, Sather HN, Meadows AT, Ortega JA, Hammond GD (1984) Factors associated with IQ scores in long-term survivors of childhood acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 6:115–121PubMedGoogle Scholar
  35. 35.
    Waber DP, Urion DK, Tarbell NJ, Niemeyer C, Gelber R, Sallan SE (1990) Late effects of central nervous system treatment of acute lymphoblastic leukemia in childhood are sex-dependent. Dev Med Child Neurol 32:238–248PubMedGoogle Scholar
  36. 36.
    Bleyer WA, Fallavollita J, Robison L, Balsom W, Meadows A, Heyn R et al. (1990) Influence of age, sex, and concurrent intrathecal methotrexate therapy on intellectual function after cranial irradiation during childhood: a report from the Children's Cancer Study Group. Pediatr Hematol Oncol 7:329–338PubMedGoogle Scholar
  37. 37.
    Kingma A, Rammeloo LA, van der Does-van den Berg A, Rekers-Mombarg L, Postma A (2000) Academic career after treatment for acute lymphoblastic leukaemia. Arch Dis Child 82:353–357CrossRefPubMedGoogle Scholar
  38. 38.
    Fuss M, Poljanc K, Hug EB (2000) Full Scale IQ (FSIQ) changes in children treated with whole brain and partial brain irradiation. A review and analysis. Strahlenther Onkol 176:573–581PubMedGoogle Scholar
  39. 39.
    Moleski M (2000) Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol 15:603–630CrossRefPubMedGoogle Scholar
  40. 40.
    Ruggiero A, Conter V, Milani M, Biagi E, Lazzareschi I, Sparano P et al. (2001) Intrathecal chemotherapy with antineoplastic agents in children. Paediatr Drugs 3:237–246PubMedGoogle Scholar
  41. 41.
    Prassopoulos P, Cavouras D, Golfinopoulos S, Evlogias N, Theodoropoulos V, Panagiotou J (1996) Quantitative assessment of cerebral atrophy during and after treatment in children with acute lymphoblastic leukemia. Invest Radiol 31:749–754CrossRefPubMedGoogle Scholar
  42. 42.
    Raymond-Speden E, Tripp G, Lawrence B, Holdaway D (2000) Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia. J Pediatr Psychol 25:59–68CrossRefPubMedGoogle Scholar
  43. 43.
    Brown RT, Sawyer MB, Antoniou G, Toogood I, Rice M, Thompson N et al. (1996) A 3-year follow-up of the intellectual and academic functioning of children receiving central nervous system prophylactic chemotherapy for leukemia. J Dev Behav Pediatr 17:392–398PubMedGoogle Scholar
  44. 44.
    Orti E, Tornello S, de Nicola AF (1985) Dynamic aspects of glucocorticoid receptors in the spinal cord of the rat. J Neurochem 45:1699–1707PubMedGoogle Scholar
  45. 45.
    Mahoney DH Jr, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick N et al. (1998) Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy — a Pediatric Oncology Group study. J Clin Oncol 16:1712–1722PubMedGoogle Scholar
  46. 46.
    Watterson J, Toogood I, Nieder M, Morse M, Frierdich S, Lee Y, et al. (1994) Excessive spinal cord toxicity from intensive central nervous system-directed therapies. Cancer 74:3034–3041PubMedGoogle Scholar
  47. 47.
    Sapolsky RM (1993) Potential behavioral modification of glucocorticoid damage to the hippocampus. Behav Brain Res 57:175–182CrossRefPubMedGoogle Scholar
  48. 48.
    Waber DP, Carpentieri SC, Klar N, Silverman LB, Schwenn M, Hurwitz CA et al. (2000) Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22:206–213CrossRefPubMedGoogle Scholar
  49. 49.
    Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose GM, Meaney MJ (1995) Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. J Neurosci 15:61–69PubMedGoogle Scholar
  50. 50.
    Bender BG, Lerner JA, Poland JE (1991) Association between corticosteroids and psychologic change in hospitalized asthmatic children. Ann Allergy 66:414–419PubMedGoogle Scholar
  51. 51.
    Drigan R, Spirito A, Gelber RD (1992) Behavioral effects of corticosteroids in children with acute lymphoblastic leukemia. Med Pediatr Oncol 20:13–21PubMedGoogle Scholar
  52. 52.
    Wolkowitz OM (1994) Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids. Psychoneuroendocrinology 19:233–255CrossRefPubMedGoogle Scholar
  53. 53.
    Murphy BP, Inder TE, Huppi PS, Warfield S, Zientara GP, Kikinis R et al. (2001) Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics 107:217–221CrossRefPubMedGoogle Scholar
  54. 54.
    Shinwell ES, Karplus M, Reich D, Weintraub Z, Blazer S, Bader D et al. (2000) Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed 83:F177–F181CrossRefPubMedGoogle Scholar
  55. 55.
    Andre P, Thebaud B, Odievre MH, Razafimahefa H, Zupan V, Dehan M et al. (2000) Methylprednisolone, an alternative to dexamethasone in very premature infants at risk of chronic lung disease. Intensive Care Med 26:1496–1500CrossRefPubMedGoogle Scholar
  56. 56.
    Alexander E 3rd, Loeffler JS (1998) Radiosurgery for primary malignant brain tumors. Semin Surg Oncol 14:43–52CrossRefPubMedGoogle Scholar
  57. 57.
    Pratt CB, Green AA, Horowitz ME, Meyer WH, Etcubanas E, Douglass E et al. (1986) Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna. J Clin Oncol 4:1253–1261PubMedGoogle Scholar
  58. 58.
    Pratt CB, Goren MP, Meyer WH, Singh B, Dodge RK (1990) Ifosfamide neurotoxicity is related to previous cisplatin treatment for pediatric solid tumors. J Clin Oncol 8:1399–1401PubMedGoogle Scholar
  59. 59.
    Kurtzberg J, Keating M, Moore J et al. (1996) 2-amino-9-B-D-arabinosyl-6-methoxy-9H-guanine (GW506U; compound 506U) is highly active in patients with T-cell malignancies; results of a phase I trial in pediatric and adult patients with refractory hematological malignancies (abstract). Blood 88:699aGoogle Scholar
  60. 60.
    Freeman JE, Johnston PG, Voke JM (1973) Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukaemia. Br Med J 4:523–525PubMedGoogle Scholar
  61. 61.
    Miyahara M, Azuma E, Hirayama M, Kobayashi M, Hori H, Komada Y et al. (2000) Somnolence syndrome in a child following 1200-cGy total body irradiation in an unrelated bone marrow transplantation. Pediatr Hematol Oncol 17:489–495CrossRefPubMedGoogle Scholar
  62. 62.
    Van der Kogel A (1991) Central nervous system radiation injury in small animal models. In: Gutin P, Leibel S, Sheline G (eds) Radiation injury to the nervous system. Raven, New York, pp 91–112Google Scholar
  63. 63.
    Priest JR, Ramsay NK, Latchaw RE, Lockman LA, Hasegawa DK, Coates TD et al. (1980) Thrombotic and hemorrhagic strokes complicating early therapy for childhood acute lymphoblastic leukemia. Cancer 46:1548–1554PubMedGoogle Scholar
  64. 64.
    Mulhern RK, Palmer SL (2003) Neurocognitive late effects in pediatric cancer. Curr Probl Cancer 27:177–197CrossRefPubMedGoogle Scholar
  65. 65.
    Palmer SL, Goloubeva O, Reddick WE, Glass JO, Gajjar A, Kun L et al. (2001) Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol 19:2302–2308PubMedGoogle Scholar
  66. 66.
    Schatz J, Kramer JH, Ablin A, Matthay KK (2000) Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy. Neuropsychology 14:189–200CrossRefPubMedGoogle Scholar
  67. 67.
    Mitby PA, Robison LL, Whitton JA, Zevon MA, Gibbs IC, Tersak JM et al. (2003) Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 97:1115–1126CrossRefPubMedGoogle Scholar
  68. 68.
    Rottenberg DA, Chernik NL, Deck MD, Ellis F, Posner JB (1977) Cerebral necrosis following radiotherapy of extracranial neoplasms. Ann Neurol 1:339–357CrossRefPubMedGoogle Scholar
  69. 69.
    New P (2001) Radiation injury to the nervous system. Curr Opin Neurol 14:725–734CrossRefPubMedGoogle Scholar
  70. 70.
    Brouwers P (1987) Neuropsychological abilities of long-term survivors of childhood leukemia. In: Aaronson N, Bechman J (eds) The quality of life of cancer patients. Raven, New York, pp 153–166Google Scholar
  71. 71.
    Baron RM, Kenny DA (1986) The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51:1173–1182CrossRefPubMedGoogle Scholar
  72. 72.
    Mulhern RK, Kepner JL, Thomas PR, Armstrong FD, Friedman HS, Kun LE (1998) Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol 16:1723–1728PubMedGoogle Scholar
  73. 73.
    Hack M, Breslau N, Aram D, Weissman B, Klein N, Borawski-Clark E (1992) The effect of very low birth weight and social risk on neurocognitive abilities at school age. J Dev Behav Pediatr 13:412–420PubMedGoogle Scholar
  74. 74.
    Kaleita TA (2002) Central nervous system-directed therapy in the treatment of childhood acute lymphoblastic leukemia and studies of neurobehavioral outcome: Children's Cancer Group trials. Curr Oncol Rep 4:131–141PubMedGoogle Scholar
  75. 75.
    Bates E (1999) Language and the infant brain. J Commun Disord 32:195–205CrossRefPubMedGoogle Scholar
  76. 76.
    Stiles J (2000) Neural plasticity and cognitive development. Dev Neuropsychol 18:237–272CrossRefPubMedGoogle Scholar
  77. 77.
    Vicari S, Albertoni A, Chilosi AM, Cipriani P, Cioni G, Bates E (2000) Plasticity and reorganization during language development in children with early brain injury. Cortex 36:31–46PubMedGoogle Scholar
  78. 78.
    Riccardi R, Brouwers P, Di Chiro G, Poplack DG (1985) Abnormal computed tomography brain scans in children with acute lymphoblastic leukemia: serial long-term follow-up. J Clin Oncol 3:12–18PubMedGoogle Scholar
  79. 79.
    Jannoun L (1983) Are cognitive and educational development affected by age at which prophylactic therapy is given in acute lymphoblastic leukaemia? Arch Dis Child 58:953–958PubMedGoogle Scholar
  80. 80.
    Waber DP, Tarbell NJ, Fairclough D, Atmore K, Castro R, Isquith P et al. (1995) Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 13:2490–2496PubMedGoogle Scholar
  81. 81.
    McGlone J (1977) Sex differences in the cerebral organization of verbal functions in patients with unilateral brain lesions. Brain 100:775–793PubMedGoogle Scholar
  82. 82.
    Briellmann RS, Berkovic SF, Jackson GD (2000) Men may be more vulnerable to seizure-associated brain damage. Neurology 55:1479–1485PubMedGoogle Scholar
  83. 83.
    Farace E, Alves WM (2000) Do women fare worse: a meta-analysis of gender differences in traumatic brain injury outcome. J Neurosurg 93:539–545PubMedGoogle Scholar
  84. 84.
    Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD (1998) Gender-linked brain injury in experimental stroke. Stroke 29:159–165; discussion 166PubMedGoogle Scholar
  85. 85.
    Brady MT, McGrath N, Brouwers P, Gelber R, Fowler MG, Yogev R et al. (1996) Randomized study of the tolerance and efficacy of high-versus low-dose zidovudine in human immunodeficiency virus-infected children with mild to moderate symptoms (AIDS Clinical Trials Group 128). Pediatric AIDS Clinical Trials Group. J Infect Dis 173:1097–1106PubMedGoogle Scholar
  86. 86.
    Roof RL, Hall ED (2000) Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 17:367–388PubMedGoogle Scholar
  87. 87.
    Yeates KO, Taylor HG, Drotar D, Wade SL, Klein S, Stancin T et al. (1997) Preinjury family environment as a determinant of recovery from traumatic brain injuries in school-age children. J Int Neuropsychol Soc 3:617–630PubMedGoogle Scholar
  88. 88.
    Wade S, Drotar D, Taylor HG, Stancin T (1995) Assessing the effects of traumatic brain injury on family functioning: conceptual and methodological issues. J Pediatr Psychol 20:737–752PubMedGoogle Scholar
  89. 89.
    Nesbit ME,Jr., Sather HN, Robison LL, Ortega J, Littman PS, D'Angio GJ et al. (1981) Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: comparison of 1800 rad and 2400 rad. A report for Children's Cancer Study Group. Lancet 1:461–466CrossRefPubMedGoogle Scholar
  90. 90.
    Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME et al. (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725–1731CrossRefPubMedGoogle Scholar
  91. 91.
    Butler RW, Mulhern RK (2004) Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol (in press)Google Scholar
  92. 92.
    Butler RW, Copeland DR (2002) Attentional processes and their remediation in children treated for cancer: a literature review and the development of a therapeutic approach. J Int Neuropsychol Soc 8:115–124CrossRefPubMedGoogle Scholar
  93. 93.
    Thompson SJ, Leigh L, Christensen R, Xiong X, Kun LE, Heideman RL et al. (2001) Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer. J Clin Oncol 19:1802–1808PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Nina S. Kadan-Lottick
  • Joseph P. Neglia

There are no affiliations available

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