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Journal of Neuro-Oncology

, Volume 97, Issue 1, pp 137–141 | Cite as

Hepatic Sinusoidal Obstruction Syndrome in a child after chemotherapy for medulloblastoma

  • M. Kashif Ishaqi
  • A. Jamil
  • M. Khanani
  • M. Baroudi
  • Omar Trad
  • M. El-Hayek
  • Eric Bouffet
Case Report

Abstract

Hepatic Sinusoidal Obstruction Syndrome (HSOS), the new name given to veno-occlusive disease (VOD) of the liver, is a well-known complication of high-dose chemotherapy employed with hematopoietic stem cell transplantation, but it has rarely been observed in children who receive conventional chemotherapy. HSOS following standard chemotherapy has been reported in patients receiving vincristine, actinomycin D, and cyclophosphamide for the treatment of Wilms tumor and more rarely rhabdomyosarcoma. We report a 14-year-old boy with high risk medulloblastoma treated with craniospinal radiation followed by chemotherapy, who experienced severe HSOS after only one course of chemotherapy including carboplatin, vincristine, and cyclophosphamide. To our knowledge, this is the second report of HSOS after standard dose chemotherapy for brain tumor in childhood.

Keywords

Chemotherapy Hepatic Sinusoidal Obstruction Syndrome Medulloblastoma Veno-occlusive disease 

Introduction

Hepatic Sinusoidal Obstruction Syndrome (HSOS) is a multi-system disorder that has been associated with high-dose chemotherapy and/or radiotherapy for hematopoietic stem cell transplant (HSCT) [1] and less commonly with antineoplastic agents outside the transplant setting [2]. HSOS is a clinical syndrome characterized by tender hepatomegaly, weight gain caused by fluid retention, and hyperbilirubinemia in the absence of other causes [3, 4]. The diagnostic criteria for HSOS have been standardized by two groups of investigators. The Jones criteria (Baltimore) require hyperbilirubinemia (total bilirubin of 34.2 μmol/l or more) and the presence of at least two of the following symptoms: hepatomegaly, ascites, and weight gain >5% over baseline [3]. The McDonald criteria (modified Seattle) stipulate the presence of at least two of the following symptoms: hyperbilirubinemia (total bilirubin of 34.2 μmol/l or more), hepatomegaly with right upper quadrant pain, and ascites or unexplained weight gain >2% over baseline [5]. It is characterized by the obstruction of small intrahepatic venules and injury to sinusoidal endothelial cells and hepatocytes by high-dose alkylating chemotherapy agents which appear to be the primary event in the pathogenesis [6] (Table 1). A characteristic feature seen in many of these patients is thrombocytopenia refractory to platelet transfusions, although clinically severe bleeding related to thrombocytopenia is uncommon [1]. In brain tumor patients, HSOS has mostly been reported after high dose chemotherapy and stem cell transplant [7]. We report an unusual case of HSOS in an adolescent treated with conventional chemotherapy for medulloblastoma.
Table 1

Diagnostic criteria for HSOS

Jones criteria (Baltimore)

McDonald criteria (Seattle)—modified

Elevated total serum bilirubin (≥34.2 μmol/l) before day 21 after SCT, plus two of the three following criteria:

1. Tender hepatomegaly

2. Weight gain >5% from baseline

3. Ascites

Occurrence of two of the following events within 20 days of SCT:

1. Hyperbilirubinemia (total serum bilirubin ≥34.2 μmol/l)

2. Hepatomegaly or right upper quadrant pain of liver origin

3. Unexplained weight gain (>2% of baseline body weight)

HSOS Hepatic Sinusoidal Obstruction Syndrome, SCT stem cell transplantation

Case report

A 14-year-old boy presented with 2-week history of headache, vomiting, and ataxia. Brain MRI scans showed a posterior fossa tumor. Sub-total excision of cerebellar tumor that involved the vermis was performed at another center. Postoperative imaging showed a residual mass that measured more than 1.5 cm in diameter. Histopathologic evaluation was consistent with medulloblastoma. The patient had a negative spinal MRI for drop metastasis. CSF examination did not show any malignant cells. His postoperative management was given according to the institutional high risk protocol. He received 36 Gy to the craniospinal axis with a 20-Gy boost to the posterior fossa with 3D conformal technique with Photon. In addition, he received six doses of vincristine (1.5 mg/m2 per dose) weekly during his radiation treatment. Six weeks later, a pre-Cisplatin audiometric evaluation revealed severe hearing loss equivalent to grade III toxicity Brock criteria [8]. For this reason, Cisplatin was replaced with carboplatin. His first chemotherapy cycle included vincristine 1.5 mg/m2 and carboplatin 560 mg/m2 on day 1 followed by cyclophosphamide 1,000 mg/m2/day on days 2 and 3 along with Mesna. G-CSF was initiated 1 day after completion of chemotherapy. Four days after his discharge, he presented to the emergency room oozing gums and excess bruising. He was afebrile and his general and systemic physical examination was otherwise unremarkable. Laboratory workup indicated Hb: 9.1 g/dl, absolute neutrophil count (ANC): 0.01 × 109/l, platelets: 20 × 109/l, creatinine 53 μmol/l, AST: 224 IU/l, ALT: 165 IU/l, LDH 254 IU/l, total bilirubin: 34 μmol/l, direct bilirubin: 17 μmol/l, total protein: 5.7 g/dl, albumin: 3.1 g/dl. Empirical treatment was immediately started for febrile neutropenia with ceftazidime and amikacin with a presumptive diagnosis of sepsis or DIC. Over the subsequent 48-h period, he continued to have gum bleeding that was refractory to platelet transfusions, and he developed mild respiratory distress, severe oral mucositis, and watery diarrhea. On the third day of admission, his physical examination revealed jaundice, a weight gain of 14%, tender hepatomegaly, and ascites. His chest X-ray revealed bilateral interstitial infiltration. IV fluconazole and metronidazole were initiated, and his antibiotics were changed to meropenem and vancomycin. At that time, hepatic function tests and coagulation tests were as follows: total bilirubin 102 μmol/l, direct bilirubin 72 μmol/l, AST 1,954 IU/l, ALT 1,339 IU/l, LDH 1,085 IU/l, PT 17.0 s (normal 8.7–14.2), aPTT 42.4 s (normal 22.7–40.3), fibrinogen 4.6 (normal 1.5–3.8). Abdominal ultrasonography (US) revealed enlarged liver with moderate ascites. Serologic tests for viral hepatitis were negative. Clinical and laboratory findings were strongly suggestive of HSOS secondary to conventional chemotherapy. During this acute phase, the patient was hydrated with intravenous saline and 5% dextrose solution and received regular fresh frozen plasma, pack red blood cells and platelet transfusions. As defibrotide was not available, the patient was treated with oral ursodiol at a dose of 10 mg/kg/dose TID for 7 days and IV N-acetylcysteine (NAC) 65 mg/kg/dose q 12 h for 3 days [9]. Over a period of 2 weeks, he showed progressive clinical improvement with gradual normalization of blood counts and liver function tests. He was given one cycle of carboplatin followed by vincristine a week later with the plan to continue these alternating with cyclophosphamide. He tolerated this well.

Discussion

HSOS was first described in South Africa and was linked to the ingestion of pyrrolizidine alkaloids contained in herbal tea [10]. HSOS occurring after allogeneic HSCT was first described in 1979, and now most cases of HSOS in the Western world are seen with allogeneic HSCT [11, 12]. HSOS has also been reported after autologous bone marrow transplant, particularly in relation to busulfan conditioning regimen [7, 13].

However, HSOS is not a common complication of conventional chemotherapy. Outside the transplant setting, HSOS has been observed in children with Wilm’s tumor following vincristine and actinomycin D administration [14, 15, 16, 17]. However, sporadic cases in children treated for Rhabdomyosarcoma with escalating doses of cyclophosphamide (2.2 g/m2) have been reported [18, 19, 20].

In medulloblastoma patients, HSOS has essentially been reported in the context of high dose chemotherapy regimens. In a series of 23 patients treated with high dose chemotherapy followed by bone marrow transplant for recurrent medulloblastoma, Dunkel et al. [21] reported grade 3-4 hepatic toxicity in 13 patients and one toxic death related to HSOS. In a review paper on 50 recurrent medulloblastoma patients treated with a combination of busulfan and thiotepa, Valteau-Couanet et al. [7] observed symptoms of HSOS in 22 patients. In this experience, previous treatment with craniospinal radiation was associated with a higher risk of hepatic disease. The role of busulfan in the induction of liver toxicity seems to be significant, and in a series of 9 patients with supratentorial PNET treated with sequential high-dose thiotepa alone and stem cell transplant after craniospinal radiation, Massimino et al. [22] did not observe any occurrence of HSOS. Likewise, no case of HSOS has been observed in the St Jude Study SJMB96, which uses craniospinal radiation followed by intensive chemotherapy with cyclophosphamide, cisplatin, and vincristine [23]. However, this may be related to the use of amifostine in this protocol, as this agent has shown hepatoprotective properties in pre-clinical studies [24]. Our case is remarkable, as HSOS occurred in a teenager who received chemotherapy for medulloblastoma in a non-transplant setting. To our knowledge, this is the second case reported in that context [25]. Our patient developed HSOS after one course of post-radiation chemotherapy with vincristine 1.5 mg/m2 and carboplatin 560 mg/m2 on day 1 followed by Cyclophosphamide 1,000 mg/m2/day on days 2 and 3. HSOS has been observed at a younger age with use of vincristine and cyclophosphamide for rhabdomyosarcoma [19]. The use of cyclophosphamide as a conditioning regimen in HSCT setting is a known risk factor for developing HSOS [4].

Our patient did not have any identified risk factor such as young age, pre-existing liver disease, abdominal or total body irradiation, or fungal infection as reported earlier [4, 5, 27]. Aside from previous craniospinal radiation; age may be another risk factor in that context, as previous work has suggested that toxicity of chemotherapy is more pronounced in teenagers and young adults treated for medulloblastoma [28].

The occurrence of severe unexpected hearing and liver toxicity also raises the possibility of an underlying predisposing condition, including chromosomal instability syndromes such as Fanconi anemia or Nijmegen syndrome [26, 27, 28]. Both conditions are associated with hypersensitivity to DNA cross-linking agents and/or radiation. No specific testing has been performed on our patient, and in particular no chromosome breakage analysis. However, our patient did not show any of the dysmorphic features associated with these syndromes. Toxicity in these patients is mostly hematological rather than hepatic. In addition, all reports of medulloblastoma associated with Fanconi anemia concern infants and young children below the age of 6 years [28, 29, 30, 31, 32, 33, 34]. Similarly, the two reports on medulloblastoma associated with Nijmegen syndrome involved young children aged 3 and 7, respectively [26, 27]. The role of craniospinal radiation in the occurrence of HSOS is possible. Even if our patient was treated with a 3D photon technique, there is little doubt that megavoltage photon beams delivered to the spinal axis result in scattered doses to the liver. In a comparative dosimetric study of standard megavoltage photon treatment and proton therapy, Miralbell et al. [35] showed that the former technique delivers at least 50% of the prescribed dose to almost one-third of the liver whereas the proton plan is able to completely avoid both the heart and the liver.

The prognosis of HSOS is variable and depends on the severity of the disease with mortality ranging from 3 to 60%, and death is uniformly inevitable in severe cases [4, 12]. In our case, the course of HSOS was favorable after symptomatic treatment.

This observation suggests that both vincristine and cyclophosphamide may play a role in the development of HSOS outside the transplant setting. HSOS should be considered in children receiving conventional chemotherapy who develop unexplained thrombocytopenia refractory to platelet transfusion, weight gain, tender hepatomegaly, and alteration of liver enzymes. A high index of suspicion is required to identify this complication. Aggressive supportive measures should be instituted and if necessary other options like defibrotide or N-acetylcysteine needs to be considered, as patients surviving the acute phase can expect to make a full recovery. The main issue in such situations concerns further chemotherapeutic management, as the risk of recurrence of symptoms of HSOS is significant, even after chemotherapy dose reduction [14]. In our experience, chemotherapy was successfully resumed after a modification of the protocol.

In summary, HSOS may occur as a consequence of craniospinal radiation and chemotherapy in the management of patients with medulloblastoma. The respective role of hepatic radiation injury and drug related liver toxicity cannot be determined in this context. However, this case report reinforces the potential benefit of advanced techniques of radiotherapy, such as protons that deliver superior target dose coverage and maximize sparing of normal structures [35, 36].

References

  1. 1.
    Kumar S, DeLeve LD, Kamath PS, Tefferi A (2003) Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 78:589–598CrossRefPubMedGoogle Scholar
  2. 2.
    Tack DK, Letendre L, Kamath PS, Tefferi A (2001) Development of hepatic veno-occlusive disease after Mylotarg infusion for relapsed acute myeloid leukemia. Bone Marrow Transpl 28:895–897CrossRefGoogle Scholar
  3. 3.
    Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, Vogelsang GB, Sensenbrenner LL, Santos GW, Saral R (1987) Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 44:778–783CrossRefPubMedGoogle Scholar
  4. 4.
    McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118:255–267PubMedGoogle Scholar
  5. 5.
    McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED (1984) Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 4:116–122CrossRefPubMedGoogle Scholar
  6. 6.
    Shulman HM, Fisher LB, Schoch HG, Henne KW, McDonald GB (1994) Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology 19:1171–1181CrossRefPubMedGoogle Scholar
  7. 7.
    Valteau-Couanet D, Fillipini B, Benhamou E, Grill J, Kalifa C, Couanet D, Habrand JL, Hartmann O (2005) High-dose busulfan and thiotepa followed by autologous stem cell transplantation (ASCT) in previously irradiated medulloblastoma patients: high toxicity and lack of efficacy. Bone Marrow Transpl 36:939–945CrossRefGoogle Scholar
  8. 8.
    Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J (1991) Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol 19:295–300CrossRefPubMedGoogle Scholar
  9. 9.
    Ringden O, Remberger M, Lehmann S, Hentschke P, Mattsson J, Klaesson S, Aschan J (2000) N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation. Bone Marrow Transpl 25:993–996CrossRefGoogle Scholar
  10. 10.
    Wilmot FC, Robertson GW (1920) Senecio disease, or cirrhosis of the liver due to senecio poisoning. Lancet 2:848–849CrossRefGoogle Scholar
  11. 11.
    Berk PD, Popper H, Krueger GR, Decter J, Herzig G, Graw RG Jr (1979) Veno-occlusive disease of the liver after allogeneic bone marrow transplantation: possible association with graft-versus-host disease. Ann Intern Med 90:158–164PubMedGoogle Scholar
  12. 12.
    Kalayoglu-Besisik S, Yenerel MN, Caliskan Y, Ozturk S, Besisik F, Sargin D (2005) Time-related changes in the incidence, severity, and clinical outcome of hepatic veno-occlusive disease in hematopoietic stem cell transplantation patients during the past 10 years. Transpl Proc 37:2285–2289CrossRefGoogle Scholar
  13. 13.
    Shih CS, Hale GA, Gronewold L, Tong X, Laningham FH, Gilger EA, Srivastava DK, Kun LE, Gajjar A, Fouladi M (2008) High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors. Cancer 112:1345–1353CrossRefPubMedGoogle Scholar
  14. 14.
    Bisogno G, de Kraker J, Weirich A, Masiero L, Ludwig R, Tournade MF, Carli M (1997) Veno-occlusive disease of the liver in children treated for Wilms tumor. Med Pediatr Oncol 29:245–251CrossRefPubMedGoogle Scholar
  15. 15.
    Czauderna P, Katski K, Kowalczyk J, Kurylak A, Lopatka B, Skotnicka-Klonowicz G, Sawicz-Birkowska K, Godzinski J (2000) Venoocclusive liver disease (VOD) as a complication of Wilms’ tumour management in the series of consecutive 206 patients. Eur J Pediatr Surg 10:300–303CrossRefPubMedGoogle Scholar
  16. 16.
    Green DM, Norkool P, Breslow NE, Finklestein JZ, D’Angio GJ (1990) Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms’ Tumor Study. J Clin Oncol 8:1525–1530PubMedGoogle Scholar
  17. 17.
    Tornesello A, Piciacchia D, Mastrangelo S, Lasorella A, Mastrangelo R (1998) Veno-occlusive disease of the liver in right-sided Wilms’ tumours. Eur J Cancer 34:1220–1223CrossRefPubMedGoogle Scholar
  18. 18.
    Cecen E, Uysal KM, Ozguven A, Gunes D, Irken G, Olgun N (2007) Veno-occlusive disease in a child with rhabdomyosarcoma after conventional chemotherapy: report of a case and review of the literature. Pediatr Hematol Oncol 24:615–621CrossRefPubMedGoogle Scholar
  19. 19.
    Kanwar VS, Albuquerque ML, Ribeiro RC, Kauffman WM, Furman WL (1995) Veno-occlusive disease of the liver after chemotherapy for rhabdomyosarcoma: case report with a review of the literature. Med Pediatr Oncol 24:334–340CrossRefPubMedGoogle Scholar
  20. 20.
    Ortega JA, Donaldson SS, Ivy SP, Pappo A, Maurer HM (1997) Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Childrens Cancer Group, the Pediatric Oncology Group, and the Pediatric Intergroup Statistical Center. Cancer 79:2435–2439CrossRefPubMedGoogle Scholar
  21. 21.
    Dunkel IJ, Boyett JM, Yates A, Rosenblum M, Garvin JH Jr, Bostrom BC, Goldman S, Sender LS, Gardner SL, Li H, Allen JC, Finlay JL (1998) High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma Children’s Cancer Group. J Clin Oncol 16:222–228PubMedGoogle Scholar
  22. 22.
    Massimino M, Gandola L, Spreafico F, Luksch R, Collini P, Giangaspero F, Simonetti F, Casanova M, Cefalo G, Pignoli E, Ferrari A, Terenziani M, Podda M, Meazza C, Polastri D, Poggi G, Ravagnani F, Fossati-Bellani F (2006) Supratentorial primitive neuroectodermal tumors (S-PNET) in children: a prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy. Int J Radiat Oncol Biol Phys 64:1031–1037PubMedGoogle Scholar
  23. 23.
    Strother D, Ashley D, Kellie SJ, Patel A, Jones-Wallace D, Thompson S, Heideman R, Benaim E, Krance R, Bowman L, Gajjar A (2001) Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study. J Clin Oncol 19:2696–2704PubMedGoogle Scholar
  24. 24.
    Borowska H, Arciszewska E, Czauderna P, Sawicki B (2004) Dactinomycin-induced veno-occlusive disease in rats. The hepatoprotective action of amifostine. Evaluation in a light and electron microscope. Folia Morphol 63:91–93Google Scholar
  25. 25.
    Elli M, Pinarli FG, Dagdemir A, Acar S (2006) Veno-occlusive disease of the liver in a child after chemotherapy for brain tumor. Pediatr Blood Cancer 46:521–523CrossRefPubMedGoogle Scholar
  26. 26.
    Bakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti RA, Bhambhani K (2003) Medulloblastoma with adverse reaction to radiation therapy in Nijmegen breakage syndrome. J Pediatr Hematol Oncol 25:248–251CrossRefPubMedGoogle Scholar
  27. 27.
    Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G (2003) Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol 41:44–48CrossRefPubMedGoogle Scholar
  28. 28.
    Hirsch B, Shimamura A, Moreau L, Baldinger S, Hag-alshiekh M, Bostrom B, Sencer S, D’Andrea AD (2004) Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 103:2554–2559CrossRefPubMedGoogle Scholar
  29. 29.
    de Chadarevian JP, Vekemans M, Bernstein M (1985) Fanconi’s anemia, medulloblastoma, Wilms’ tumor, horseshoe kidney, and gonadal dysgenesis. Arch Pathol Lab Med 109:367–369PubMedGoogle Scholar
  30. 30.
    Frappart PO, McKinnon PJ (2007) BRCA2 function and the central nervous system. Cell Cycle 6:2453–2457PubMedGoogle Scholar
  31. 31.
    Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95:1548–1551PubMedGoogle Scholar
  32. 32.
    Ruud E, Wesenberg F (2001) Microcephalus, medulloblastoma and excessive toxicity from chemotherapy: an unusual presentation of Fanconi anaemia. Acta Paediatr 90:580–583CrossRefPubMedGoogle Scholar
  33. 33.
    Sari N, Akyuz C, Aktas D, Gumruk F, Orhan D, Alikasifoglu M, Aydin B, Alanay Y, Buyukpamukcu M (2009) Wilms tumor, AML and medulloblastoma in a child with cancer prone syndrome of total premature chromatid separation and Fanconi anemia. Pediatr Blood Cancer 53(2):208–210CrossRefPubMedGoogle Scholar
  34. 34.
    Tischkowitz MD, Chisholm J, Gaze M, Michalski A, Rosser EM (2004) Medulloblastoma as a first presentation of Fanconi anemia. J Pediatr Hematol Oncol 26:52–55CrossRefPubMedGoogle Scholar
  35. 35.
    Miralbell R, Lomax A, Bortfeld T, Rouzaud M, Carrie C (1997) Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume. Int J Radiat Oncol Biol Phys 38:477–484CrossRefPubMedGoogle Scholar
  36. 36.
    Lee CT, Bilton SD, Famiglietti RM, Riley BA, Mahajan A, Chang EL, Maor MH, Woo SY, Cox JD, Smith AR (2005) Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 63:362–372CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • M. Kashif Ishaqi
    • 1
  • A. Jamil
    • 1
  • M. Khanani
    • 1
  • M. Baroudi
    • 1
  • Omar Trad
    • 1
  • M. El-Hayek
    • 1
  • Eric Bouffet
    • 2
  1. 1.Division of Pediatric Hematology/OncologyTawam Hospital, Johns Hopkins MedicineAl-AinUnited Arab Emirates
  2. 2.Division of Hematology and OncologyHospital for Sick ChildrenTorontoCanada

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