• Secondary CNS tumours in children initially treated from ALL according to the treatment protocols of chemotherapy and radiotherapy

Secondary CNS tumours in children initially treated from ALL according to the treatment protocols of chemotherapy and radiotherapy

SOVREMENNAYA PEDIATRIYA.2018.3(91):74-85; doi 10.15574/SP.2018.91.74

Dorosh О. І., Troyanovska O. O., Abramyuk А. М., Melko I. P., Tsymbalyuk-Voloshin I. P., Polishchuk R. S.
ME of Lviv Oblast Council "Western Ukrainian Specialized Children's Medical Centre", Lviv, Ukraine
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
Institute and Polyclinic for Diagnostic and Interventional Neuroradiology, Dresden, Germany
University Hospital Carl Gustav Carus, Dresden, Germany
Technische Universitaet, Dresden, Germany
Institution under public law of Saxony, Dresden, Germany
Medical Centre "NOVO", Lviv, Ukraine

The history of 3 children with secondary CNS tumours (fibrotic astrocytoma, oligodendroglioma, benign meningioma), diagnosed in 6 years 1 month, 7 years and 7.5 years, respectively, after the completion of a 2-year course of protocol treatment for acute lymphoblastic leukaemia (ALL), is presented. This made up 1.01% of 298 alive children under the age of 18 years with newly diagnosed ALL, treated at the Haematological Department of the Western Ukrainian Specialized Children's Medical Centre for the period from February 1993 to December 2017 in accordance with the ALL-BFM and Interfant-99/06 treatment protocols. In accordance with the treatment protocols, all children were administered chemotherapy and some of them — also cranial irradiation. The analysis showed that due to the implication of modern ALL treatment protocols based on risk assessment, the incidence of secondary malignancies associated with ALL in childhood remained low for 25 years among the followed-up living patients. We compared our results with investigations in the other oncohaematological centres.

Key words: children, acute lymphoblastic leukaemia, secondary CNS tumours, chemotherapy, radiotherapy.


1. Aloi D, Belgioia L, Barra S, Giannelli F, Cavagnetto F, Gallo F, Milanaccio C, Garre M, Di Profio S, Di Iorgi N, Corvo R. (2017). Neuroendocrine late effects after tailored photon radiotherapy for children with low grade gliomas: Long term correlation with tumour and treatment parameters. Radiother Oncol. Nov. 125(2): 241—247.

2. Anderson VA, Godber T, Smibert E, Weiskop S, Ekert H. (2000, Jan). Cognitive and academic outcome following cranial irradiation and chemotherapy in children: a longitudinal study. Br J Cancer. 82(2): 255—262. https://doi.org/10.1054/bjoc.1999.0912; PMid:10646874 PMCid:PMC2363266

3. Aung L, Khyne T, Yeoh AE, Quah TC, Tan AM. (2009, Aug). A report from the Singapore Childhood Cancer Survivor Study (SG-CCSS): a multi-institutional collaborative study on long-term survivors of childhood cancer, initial analysis reporting for the SG-CCSS. Ann Acad Med Singapore. 38(8): 684—689. PMid:19736571

4. Bhatia S, Sather HN, Pabustan OB, Trigg ME, Gaynon PS, Robison LL. (2002). Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood. 99(12): 4257—4264. https://doi.org/10.1182/blood.V99.12.4257; PMid:12036851

5. Bien E, Stachowicz-Stencel T, Szalewska M, Krawczyk M, Synakiewicz A, Dubaniewicz-Wybieralska M, Zielinski P, Adamkiewicz-Drozynska E, Balcerska A. (2009, May). Poor-risk high-grade gliomas in three survivors of childhood acute lymphoblastic leukaemia — an overview of causative factors and possible therapeutic options. Childs Nerv Syst. 25(5): 619—626. https://doi.org/10.1007/s00381-009-0838-2; PMid:19301014

6. Blatt J, Poplack D, Sherins R. (1981). Testicular function in boys following chemotherapy for acute lymphoblastic leukemia. N Engl J Med. 304: 1121—1124. https://doi.org/10.1056/NEJM198105073041901; PMid:6783900

7. Borgmann A, Zinn C, Hartmann R, Herold R, Kaatsch P, Escherich G, Moricke A, Henze G, von Stackelberg A; ALL-REZ BFM Study Group. (2008). Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer. 44(2): 257—268. https://doi.org/10.1016/j.ejca.2007.09.019; PMid:17981026

8. Brouwers P, Poplack O. (1990). Memory and learning sequelae in long-term survivors of acute lymphoblastic leukemia: association with attention deficits. Pediatr Hematol Oncol. 12: 174—181. https://doi.org/10.1097/00043426-199022000-00009

9. Conklin HM, Ogg RJ, Ashford JM, Scoggins MA, Zou P, Clark KN, Martin-Elbahesh K, Hardy KK, Merchant TE, Jeha S, Huang L, Zhang H. (2015, Nov 20). Computerized cognitive training for amelioration of cognitive late effects among childhood cancer survivors: a randomized controlled trial. J Clin Oncol. 33(33): 3894—3902. https://doi.org/10.1200/JCO.2015.61.6672; PMid:26460306 PMCid:PMC4652013

10. Das U, Appaji L, Kumari BS, Sirsath NT, Padma M, Kavitha S, Avinash T, Lakshmaiah KC. (2014, Oct). Spectrum of pediatric brain tumors: a report of 341 cases from a tertiary cancer center in India. Indian J Pediatr. 81(10): 1089—1091. https://doi.org/10.1007/s12098-014-1387-6; PMid:24733618

11. Essig S, Li Q, Chen Y, Hitzler J, Leisenring W, Greenberg M, Sklar C, Hudson MM, Armstrong GT, Krull KR, Neglia JP, Oeffinger KC, Robison LL, Kuehni CE, Yasui Y, Nathan PC. (2014, Jul). Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 15(8): 841—851. https://doi.org/10.1016/S1470-2045(14)70265-7

12. Fisher J, Aur R. (1982). Endocrine assessment in childhood acute lymphocytic leukemia. Cancer. 49: 145—151. https://doi.org/10.1002/1097-0142(19820101)49:1<145::AID-CNCR2820490128>3.0.CO;2-O

13. Fontana M, Stanton C, Pompili A, Amadori S, Mandelli F, Meloni G, Riccio A, Rubinstein LJ. (1987). Late multifocal gliomas in adolescents previously treated for acute lymphoblastic leukemia. Cancer. 60: 1510. https://doi.org/10.1002/1097-0142(19871001)60:7<1510::AID-CNCR2820600718>3.0.CO;2-V

14. Goel NJ, Abdullah KG, Lang SS. (2018). Outcomes and Prognostic Factors in Pediatric Oligodendroglioma: A Population-Based Study. Pediatr Neurosurg. 53(1): 24—35. https://doi.org/10.1159/000481458; PMid:29131101

15. Goshen Y, Stark B, Kornreich L, Michowiz S, Feinmesser M, Yaniv I. (2007, Sep). High incidence of meningioma in cranial irradiated survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 49(3): 294—297. https://doi.org/10.1002/pbc.21153; PMid:17243137

16. Gurney JG, Severson RK, Davis S, Robison LL. (1995). Incidence of cancer in children in the United States: sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 75: 2186—2195. https://doi.org/10.1002/1097-0142(19950415)75:8<2186::AID-CNCR2820750825>3.0.CO;2-F

17. Hawkins MM, Draper GJ, Kingston JE. (1987). Incidence of second primary tumour among childhood cancer survivors. Br J Cancer. 56: 339—347. https://doi.org/10.1038/bjc.1987.200; PMid:2822073 PMCid:PMC2002190

18. Hijiya N, Ness KK, Ribeiro RC, Hudson MM. (2009). Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer. 115(1): 23—35. https://doi.org/10.1002/cncr.23988; PMid:19072983 PMCid:PMC2767267

19. Iyer RS, Soman CS, Nair CN, Pai SK, Kurkure PA, Pande SC, Advani SH. (1994, Mar). Brain tumors following cure of acute lymphoblastic leukemia. Leuk Lymphoma. 13(1—2): 183—186. https://doi.org/10.3109/10428199409051670; PMid:8025519

20. J Wu CT, Tsay PK, Jaing TH, Chen SH, Tseng CK, Jung SM. (2016, Oct). Oligodendrogliomas in Children: Clinical Experiences With 20 Patients. Pediatr Hematol Oncol. 38(7): 555—558. https://doi.org/10.1097/MPH.0000000000000610; PMid:27299589

21. Jazbec J, Todorovski L, Jereb B. (2007, Feb 2). Classification tree analysis of second neoplasms in survivors of childhood cancer. BMC Cancer. 7: 27. https://doi.org/10.1186/1471-2407-7-27; PMid:17270060 PMCid:PMC1802085

22. Jenkinson H, Hawkins M. (1999). Secondary brain tumors in children with ALL. Lancet. 354: 1126. https://doi.org/10.1016/S0140-6736(05)76922-1; https://doi.org/10.1016/S0140-6736(05)76923-3

23. Kaatsch P, Reinisch I, Spix C, Berthold F, Janka-Schaub G, Mergenthaler A, Michaelis J, Blettner M. (2009). Case-control study on the therapy of childhood cancer and the occurrence of second malignant neoplasms in Germany. Cancer Causes Control. 20(6): 965—980. https://doi.org/10.1007/s10552-009-9315-1; PMid:19263232

24. Kowalczyk J, Nurzynska-Flak J, Armata J, Boguslawska-Jaworska J, Rokicka-Milewska R, Sonta-Jakimczyk D, Balwierz W, Chybicka A, Kaczmarek-Kanold M, Wachowiak J, Matysiak M, Pawelec K. (2004, Mar). Incidence and clinical characteristics of second malignant neoplasms in children: a multicenter study of a polish pediatric leukemia/lymphoma group. Med Sci Monit. 10(3): CR117—22. PMid:14976453

25. Kowalczyk JR, Nurzynska J, Armata J, Boguslawska-Jaworska J, Rokicka-Milewska R, Sonta-Jakimczyk D, Balwierz W, Chybicka A, Kaczmarek-Kanold M, Kolecki P, Matysiak M, Pawelec K. (2002). Second malignant neoplasms in children: a multicenter study of the Polish Pediatric Leukemia/Lymphoma Group. Med Pediatr Oncol. 38: 421—423. https://doi.org/10.1002/mpo.1356; PMid:11984804

26. Krawczuk-Rybak M, Panasiuk A, Stachowicz-Stencel T, Zubowska M, Skalska-Sadowska J, Sega-Pondel D, Czajnska-Deptula A, Slawinska D, Badowska W, Kamienska E, Pobudejska-Pieniazek A, Wieczorek M. (2018). Health status of Polish children and adolescents after cancer treatment. Eur J Pediatr.177(3): 437—447. https://doi.org/10.1007/s00431-017-3066-x; https://doi.org/10.1007/s00431-018-3094-1

27. Kubota M, Akiyama Y, Koishi S, Sawada M, Usami I, Lin YW, Watanabe K, Takimoto T. (1998, Jun). Second malignancy following treatment of acute lymphoblastic leukemia in children. Int J Hematol. 67(4): 397—401. https://doi.org/10.1016/S0925-5710(98)00023-1

28. Landier W, Armenian S, Bhatia S. (2015, Feb). Late effects of childhood cancer and its treatment. Pediatr Clin North Am. 62(1): 275—300. https://doi.org/10.1016/j.pcl.2014.09.017; PMid:25435123

29. Langer T, Grabow D, Steinmann D, Wormann B, Calaminus G. (2017). Late effects and long-term follow-up after cancer in childhood. Oncol Res Treat.40(12): 746—750. https://doi.org/10.1159/000484936; PMid:29183026

30. Late Effects of Treatment for Childhood Cancer (PDQ®): Health Professional Version. PDQ Pediatric Treatment Editorial Board. PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); 2002—2018. Jan 2.

31. Leung J, Guiney M. (1996, Feb). Secondary tumours after prophylactic cranial irradiation. Australas Radiol. 40(1): 43—44. https://doi.org/10.1111/j.1440-1673.1996.tb00343.x; PMid:8838887

32. Littman P, Coccia P, Bleyer WA, Lukens J, Siegel S, Miller D, Sather H, Hammond D. (1987). Central nervous system (CNS) prophylaxis in children with low risk acute lymphoblastic leukemia (ALL). Int J Radiat Oncol Biol Phys. 3: 1443—1449. https://doi.org/10.1016/0360-3016(87)90308-7

33. Loning L, Zimmermann M, Reiter A, Kaatsch P, Henze G, Riehm H, Schrappe M. (2000). Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood. 95(9): 2770—2775. PMid:10779419

34. Malone M, Lumley H, Erdohazi M. (1986). Astrocytoma as a second malignancy in patients with acute lymphoblastic leukemia. Cancer. 57: 1979—1985. https://doi.org/10.1002/1097-0142(19860515)57:10<1979::AID-CNCR2820571016>3.0.CO;2-R

35. Maniar TN, Braunstein I, Keefe S, Hussen S, Abrams T, De Michele A, El-Deiry WS. (2007, Oct). Childhood ALL and second neoplasms. Cancer Biol Ther. 6(10): 1525—1531. https://doi.org/10.4161/cbt.6.10.4928; PMid:17952026

36. Matsuda R, Nikaido Y, Yamada T, Mishima H, Tamaki R. (2005, Mar). High-dose radiation-induced meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia. No Shinkei Geka. 33(3): 277—280. PMid:15773318

37. Maule M, Scelo G, Pastore G, Brennan P, Hemminki K, Tracey E, Sankila R, Weiderpass E, Olsen JH, McBride ML, Brewster DH, Pompe-Kirn V, Kliewer EV, Chia KS, Tonita JM, Martos C, Jonasson JG, Merletti F, Boffetta P. (2007). Risk of second malignant neoplasms after childhood leukemia and lymphoma: an international study. JNCI J Natl Cancer Inst. 99(10): 790—800. https://doi.org/10.1093/jnci/djk180; PMid:17505074

38. Mike V, Meadows AT, D'Angio GJ. (1982). Incidence of second malignant neoplasm in children: results of an international study. Lancet. 2(8311): 1326—1331. https://doi.org/10.1016/S0140-6736(82)91524-0

39. Moss SD, Rockswold GL, Chou SN, Yock D, Berger MS. (1988, Apr). Radiation-induced meningiomas in pediatric patients. Neurosurgery. 22(4): 758—61. https://doi.org/10.1227/00006123-198804000-00026; https://doi.org/10.1097/00006123-198804000-00026; PMid:3163779

40. Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, Donaldson SS, Meadows AT, Robison LL. (2001). Second malignant neoplasms in five-year survivors of childhood cancer: Childhood Cancer Survivor Study. JNCI J Natl Cancer Inst. 93(8): 618—629. https://doi.org/10.1093/jnci/93.8.618; PMid:11309438

41. Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, Sather HN, Hammond GD. (1991). Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med. 325(19): 1330—1336. https://doi.org/10.1056/NEJM199111073251902; PMid:1922234

42. Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD. (2006). New Primary Neoplasms of the Central Nervous System in Survivors of Childhood Cancer: a Report From the Childhood Cancer Survivor Study. JNCI J Natl Cancer Inst. 98(21): 1528—1537. https://doi.org/10.1093/jnci/djj411; PMid:17077355

43. Pasqualini T, Escobar ME, Domene H, Muriel FS, Pavlovsky S, Rivarola MA. (1987). Evaluation of gonadal function following long-term treatment for acute lymphoblastic leukemia in girls. J Pediatr Hematol Oncol. 9: 15—22. https://doi.org/10.1097/00043426-198721000-00004

44. Pui CH, Relling MV, Behm FG, Hancock ML, Boyett JM, Raimondi SC, Krance RA, Mahmoud HH, Ribeiro RC, Sandlund JT et al. (1995). L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins. Leukemia. 9(10): 1680—1684. PMid:7564509

45. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC, Head DR, Behm FG, Mahmoud MH, Sandlund JT et al. (1991). Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 325(24): 1682—1687. https://doi.org/10.1056/NEJM199112123252402; PMid:1944468

46. Quigley C, Cowell C, Jimenez M, Burger H, Kirk J, Bergin M, Stevens M, Simpson J, Silink M. (1989). Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med. 321: 143—151. https://doi.org/10.1056/NEJM198907203210303; PMid:2501681

47. Rangwala SD, Tobin MK, Birk DM, Butts JT, Nikas DC, Hahn YS. (2017). Pica in a child with anterior cingulate gyrus oligodendroglioma: case report. Pediatr Neurosurg. 52(4): 279—283. https://doi.org/10.1159/000477816; PMid:28704833

48. Relling MV, Boyett JM, Blanco JG, Raimondi S, Behm FG, Sandlund JT, Rivera GK, Kun LE, Evans WE, Pui CH. (2003). Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment. Blood. 101(10): 3862—3867. https://doi.org/10.1182/blood-2002-08-2405; PMid:12531808

49. Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui CH. (1999). High incidence of secondary brain tumors after radiotherapy and antimetabolites. Lancet. 354: 34—39. https://doi.org/10.1016/S0140-6736(98)11079-6

50. Renard M, Suciu S, Bertrand Y, Uyttebroeck A, Ferster A, van der Werff Ten Bosch J, Mazingue F, Plouvier E, Robert A, Boutard P, Millot F, Munzer M, Mechinaud F, Lescoeur B, Baila L, Vandecruys E, Benoit Y, Philippet P; EORTC Children Leukaemia Group (CLG). (2011, Jul 15). Second neoplasm in children treated in EORTC 58881 trial for acute lymphoblastic malignancies: low incidence of CNS tumours. Pediatr Blood Cancer. 57(1): 119—125. https://doi.org/10.1002/pbc.23083; PMid:21412967

51. Rimm IJ, Li FC, Tarbell NJ, Winston KR, Sallan SE. (1987). Brain tumors after cranial irradiation for childhood acute lymphoblastic leukemia. A 13-year experience from the Dana-Farber Cancer Institute and the Children's Hospital. Cancer. 59: 1506—1508. https://doi.org/10.1002/1097-0142(19870415)59:8<1506::AID-CNCR2820590819>3.0.CO;2-P

52. Sanchez Fernandez I, Loddenkemper T. (2017, Jan). Seizures caused by brain tumors in children. Seizure. 44: 98—107. https://doi.org/10.1016/j.seizure.2016.11.028; PMid:28017579

53. Schmiegelow K, Al-Modhwahi I, Andersen MK, Behrendtz M, Forestier E, Hasle H, Heyman M, Kristinsson J, Nersting J, Nygaard R, Svendsen AL, Vettenranta K, Weinshilboum R; Nordic Society for Paediatric Haematology and Oncology. (2009). Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood. 113(24): 6077—6084. https://doi.org/10.1182/blood-2008-11-187880; PMid:19224761 PMCid:PMC2699230

54. Signorelli C, Wakefield CE, Fardell JE, Wallace WHB, Robertson EG, McLoone JK, Cohn RJ. (2017, Jun). The impact of long-term follow-up care for childhood cancer survivors: A systematic review. Crit Rev Oncol Hematol. 114: 131—138. https://doi.org/10.1016/j.critrevonc.2017.04.007; PMid:28477741

55. Skinner R, Mulder RL, Kremer LC, Hudson MM, Constine LS, Bardi E, Boekhout A, Borgmann-Staudt A, Brown MC et al. (2017, Feb). Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Lancet Oncol. 18(2): 75—90. https://doi.org/10.1016/S1470-2045(17)30026-8

56. Soffer D, Gomori JM, Siegal T, Shalit MN. (1989, Apr 15). Intracranial meningiomas after high-dose irradiation. Cancer. 63(8): 1514—1519. https://doi.org/10.1002/1097-0142(19890415)63:8<1514::AID-CNCR2820630810>3.0.CO;2-Y

57. Sorge C, Li R, Singh S, Reddy AT, Solomon DA, Perry A, Friedman GK. (2017, Dec). Complete durable response of a pediatric anaplastic oligoden-droglioma to temozolomide alone: Case report and review of literature. Pediatr Blood Cancer. 64(12). https://doi.org/10.1002/pbc.26708; PMid:28696020

58. Stanulla M, Loning L, Welte K, Schrappe M. (1999). Secondary brain tumors in children with ALL. Lancet. 354: 1126—1127. https://doi.org/10.1016/S0140-6736(05)76922-1; https://doi.org/10.1016/S0140-6736(05)76923-3

59. Stein ME, Drumea K, Guilbord JN, Ben_Itzhak O, Kuten A. (1995). Case report: late aggressive meningioma following prophylactic cranial irradiation for acute lymphoblastic leukemia. Br J Radiol. 68: 1123—1125. https://doi.org/10.1259/0007-1285-68-814-1123; PMid:7496718

60. Trott KR. (2017, Oct). Special radiobiological features of second cancer risk after particle radiotherapy. Phys Med. 42: 221—227. https://doi.org/10.1016/j.ejmp.2017.05.002; PMid:29103987

61. Van der Plas E, Schachar RJ, Hitzler J, Crosbie J, Guger SL, Spiegler BJ, Ito S, Nieman BJ. (2016, Dec 29). Brain structure, working memory and response inhibition in childhood leukemia survivors. Brain Behav. 7(2): e00621. https://doi.org/10.1002/brb3.621; PMid:28239531 PMCid:PMC5318374

62. Vancura RW, Kepes JJ, Newell KL, Ha TM, Arnold PM. (2006, May). Secondary intracranial neoplasms exhibiting features of astrocytoma and neuroblastoma in 2 children treated for acute lymphoblastic leukemia: report of 2 cases. Surg Neurol. 65(5): 490—494. https://doi.org/10.1016/j.surneu.2005.06.047; PMid:16630913

63. Vowels MR, Tobias V, Mameghan H. (1991). Second intracranial neoplasms following treatment of childhood acute lymphoblastic leukemia. J Paediatr Child Health. 27: 43—46. https://doi.org/10.1111/j.1440-1754.1991.tb00344.x; PMid:2043390

64. Winick NJ, McKenna RW, Shuster JJ, Schneider NR, Borowitz MJ, Bowman WP, Jacaruso D, Kamen BA, Buchanan GR. (1993). Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. J Clin Oncol. 11(2): 209—217. https://doi.org/10.1200/JCO.1993.11.2.209; PMid:8426196

65. Wojcik D, Dyrda T, Pietras W. (1998). Astrocytoma in a 6-year-old girl after the treatment for acute lymphoblastic leukemia. Wiad Lek. 51; Suppl 4: 318—321. PMid:10731992