Annie Huang

SickKids, Toronto, Ontario, Canada

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Publications (56)402.85 Total impact

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    ABSTRACT: Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10−8). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
    Acta Neuropathologica 10/2015; · 9.73 Impact Factor
  • Patrick Sin-Chan, Annie Huang
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    ABSTRACT: Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.
    Expert Opinion on Therapeutic Targets 08/2014; · 4.90 Impact Factor
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    ABSTRACT: Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.
    Acta Neuropathologica 07/2014; · 9.73 Impact Factor
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    ABSTRACT: Childhood CNS-PNETs comprise a heterogeneous spectrum of diseases with poorly defined biology. The embryonic stem cell enriched C19MC OncomiR cluster is frequently amplified in one sub-group of CNS-PNETs (group 1 CNS-PNETs) with distinctly aggressive clinic-pathologic features. However, the specific oncogenic role of C19MC in group 1 CNS-PNETs, and mechanisms by which C19MC effects cellular transformation remains unknown. In this study we used exome and RNA-sequencing of C19MC associated tumors, and functional studies of the C19MC OncomiRs in human neural stem cell to define oncogenic partners and downstream effectors of the C19MC locus.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii29. · 6.18 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
    Nature Genetics 04/2014; · 35.21 Impact Factor
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    ABSTRACT: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
    Nature 02/2014; · 38.60 Impact Factor
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    ABSTRACT: Background Supratentorial primitive neuroectodermal tumor (sPNET) is a malignant brain tumor with poor prognosis. New model systems that replicate sPNET's molecular subtype(s) and maintain cancer stem cell (CSC) pool are needed.MethodsA fresh surgical specimen of a pediatric sPNET was directly injected into the right cerebrum of Rag2/SCID mice. The xenograft tumors were serially sub-transplanted in mouse brains, characterized histopathologically, and subclassified into molecular subtype through qRT-PCR and immunohistochemical analysis. CSCs were identified through flow cytometric profiling of putative CSC markers (CD133, CD15, CD24, CD44, and CD117), functional examination of neurosphere forming efficiency in vitro, and tumor formation capacity in vivo. To establish a neurosphere line, neurospheres were propagated in serum-free medium.ResultsFormation of intracerebral xenograft tumors was confirmed in 4 of the 5 mice injected with the patient tumor. These xenograft tumors were sub-transplanted in vivo 5 times. They replicated the histopathological features of the original patient tumor and expressed the molecular markers (TWIST1 and FOXJ1) of group 3 sPNET. CD133(+) and CD15(+) cells were found to have strong neurosphere-forming efficiency in vitro and potent tumor-forming capacity (with as few as 100 cells) in vivo. A neurosphere line BXD-2664PNET-NS was established that preserved stem cell features and expressed group 3 markers.Conclusion We have established a group 3 sPNET xenograft mouse model (IC-2664PNET) with matching neurosphere line (BXD-2664PNET-NS) and identified CD133(+) and CD15(+) cells as the major CSC subpopulations. This novel model system should facilitate biological studies and preclinical drug screenings for childhood sPNET.
    Neuro-Oncology 01/2014; · 6.18 Impact Factor
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    ABSTRACT: Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
    Acta Neuropathologica 01/2014; · 9.73 Impact Factor
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    ABSTRACT: Medulloblastoma and central nervous system (CNS)-primitive neuro-ectodermal tumors (PNETs) are a diverse group of entities which encompasses different pathological and clinical pictures. Initially divided based on histology and location, molecular insight is leading to new definitions and a change in the borders delineating these diseases, such that they become more divergent. Current treatment approaches consist of surgical resection, radiotherapy and intensive chemotherapy, dependent on age. Stratification is one risk factor shown to be prognostic and is divided into high- and average-risks. Outcomes with modern treatment regimens are good, particularly in average-risk medulloblastoma patients, but the cost of cure is high, with high rates of neurocognitive, endocrine and social dysfunction. The changing biological landscape, however, may allow for clearer prediction of tumor behavior, to better identify "good" and "bad" players within these groups. Discovery of subgroups with changes in dependent molecular pathways will also lead to the development of new specific targeted therapies. Presenting exciting opportunities, these advances may transform the treatment for some patients, revolutionizing therapy in the future. Several challenges, however, are yet to be faced and caution is needed not to abandon previously defined prognostic factors on the strength of thus far retrospective evidence. We are witnessing a new era of trials with biological stratification involving multiple subgroups and treatment arms, based on specific tumor-related targets. This review discusses the changing face of medulloblastoma and CNS-PNETs and how we move molecular advances into clinical trials that benefit patients.
    F1000prime reports. 01/2014; 6:56.
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    ABSTRACT: Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.
    Acta Neuropathologica 12/2013; · 9.73 Impact Factor
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    ABSTRACT: Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.
    Nature Genetics 12/2013; · 35.21 Impact Factor
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    ABSTRACT: Background Embryonal tumor with multilayered rosettes (ETMR) is an aggressive central nervous system primitive neuroectodermal tumor (CNS-PNET) variant. ETMRs have distinctive histology, amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, expression of the RNA binding protein Lin28, and dismal prognosis. Functional and therapeutic studies of ETMR have been limited by a lack of model systems.Methods We have established a first cell line, BT183, from a case of ETMR and characterized its molecular and cellular features. LIN28 knockdown was performed in BT183 to examine the potential role of Lin28 in regulating signaling pathway gene expression in ETMR. Cell line findings were corroborated with immunohistochemical studies in ETMR tissues. A drug screen of 73 compounds was performed to identify potential therapeutic targets.ResultsThe BT183 line maintains C19MC amplification, expresses C19MC-encoded microRNAs, and is tumor initiating. ETMRs, including BT183, have high LIN28 expression and low let-7 miRNA expression, and show evidence of mTOR pathway activation. LIN28 knockdown increases let-7 expression and decreases expression of IGF/PI3K/mTOR pathway components. Pharmacologic inhibition of the mTOR pathway reduces BT183 cell viability.ConclusionsBT183 retains key genetic and histologic features of ETMR. In ETMR, Lin28 is not only a diagnostic marker but also a regulator of genes involved in growth and metabolism. Our findings indicate that inhibitors of the IGF/PI3K/mTOR pathway may be promising novel therapies for these fatal embryonal tumors. As the first patient-derived cell line of these rare tumors, BT183 is an important, unique reagent for investigating ETMR biology and therapeutics.
    Neuro-Oncology 12/2013; · 6.18 Impact Factor
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    ABSTRACT: Diencephalic syndrome (DS) is a clinical disorder of metabolism associated with poor outcome in children with low-grade gliomas (LGGs). Since survival has been primarily reported with aggressive therapy, we report outcome data for these patients using a current, contrasting chemotherapy-driven approach. We performed a population-based review of DS patients treated with chemotherapy from 1997-2012. Metabolic rate was assessed in selected cases using open-circuit calorimetry to generate resting energy expenditure (REE) data. Tumor tissue was analyzed for BRAF alterations. Survival was compared with an age-related, radiotherapy naïve cohort of non-DS children with location-matched LGGs. Nine children (1.7 % of 520 LGG diagnoses) fulfilled DS criteria. The median diagnostic age was 1.49 years (0.55-2.69 years), although neurofibromatosis Type-I patients were older (p = 0.005). All tumors analyzed exhibited either NF1 mutation or BRAF fusion. Seven tumors were histologically confirmed as low grade astrocytomas, one demonstrated neurocytic features, and one NF1 case was diagnosed using imaging and clinical criteria. All patients received chemotherapy, with seven cases also receiving initial nutritional supplementation. All nine gained weight after only 6 months of treatment. Two DS patients had serial REE measurements, revealing a hypermetabolic state (over 200 % of predicted REE) at diagnosis which reduced to normal range with therapy. First-line chemotherapy treatment resulted in one minor response, stable disease in four cases, with progression in the remaining four patients. Although DS patients demonstrated inferior initial progression-free survival when compared to non-DS counterparts (5 years: 22 versus 60 %, p = 0.015), all DS children remain alive at a median follow up of 5.3 years (1.2-14.9 years) with none requiring radiotherapy. Long-term sequelae included pituitary and visual dysfunction, learning difficulties and paradoxical, inappropriate weight gain. DS can be managed with non-aggressive chemotherapeutic, radiation-sparing strategies supplemented by temporary nutritional support. Multiple lines of therapy may be required to overcome disease progression but excellent survival and metabolic outcomes can be achieved. Continued surveillance is mandatory to prevent significant weight gain and support affected children with clinical sequelae.
    Journal of Neuro-Oncology 11/2013; · 3.12 Impact Factor
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    ABSTRACT: Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
    Acta Neuropathologica 10/2013; · 9.73 Impact Factor
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    ABSTRACT: In a retrospective review of 24 metastatic medulloblastoma patients whose treatment included craniospinal irradiation, 5 patients presented with gross residual abnormalities at completion of therapy. This report describes 2 medulloblastoma patients with persistent residual abnormalities on serial follow-up imaging studies. The patients aged 2 and 2.5 years old at the time of diagnosis underwent surgery followed by multiagent chemotherapy. One patient progressed on therapy and underwent salvage craniospinal radiation. The second showed residual tumor on end of treatment imaging and received low-dose craniospinal irradiation. Despite persistent magnetic resonance imaging findings, the patients are alive and well 13 and 7 years after diagnosis with no further treatment applied. The nature of these residual abnormalities is discussed.
    Journal of Pediatric Hematology/Oncology 03/2013; · 0.97 Impact Factor
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    ABSTRACT: Choroid plexus carcinoma (CPC) is a rare central nervous system malignant tumor with a dismal prognosis, especially in the case of incomplete resection or recurrence. The authors report long-term survival of a 1-year-old patient with recurrent CPC and Li-Fraumeni syndrome with surgical resection and high-dose chemotherapy (HDC) consisting of single cycle of Busulfan and Thiotepa followed by autologous stem cell rescue without the use of radiation therapy. Remarkably the patient remains without evidence of recurrence 5 years after completion of therapy. Additional studies are necessary to determine the role of HDC and stem cell rescue in patients with recurrent CPC.
    Pediatric Hematology and Oncology 01/2013; · 0.90 Impact Factor
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    ABSTRACT: Background Optimal management of optic pathway/hypothalamic glioma (OPHG) remains an ongoing challenge. Little is known about the natural history, management strategies, and outcomes in adolescents. Carboplatin-based chemotherapy is a useful modality in younger children, delaying radiation to their immature brains. National trials have focused on younger children and excluded adolescents from studies evaluating the role of chemotherapy.Methods This retrospective study describes clinical characteristics, treatment regimens, and outcomes in adolescents (aged ≥10 years) with OPHG (diagnosis during 1990-2006). Progression-free survival was compared with that in a cohort of younger children (aged <10 years).ResultsThirty-three adolescents (19 females, 6 with neurofibromatosis type 1) with OPHG were identified within 2 Canadian pediatric oncology institutions. The majority presented with visual symptoms (82%). More than 55% (18 of 33) involved the posterior tract and/or hypothalamus (modified Dodge classification 3/4). Seventeen were initially observed; 8 remained progression free. Of the 25 of 33 adolescents who required active treatment, 9 (36%) needed second-line therapy. The progression-free survival for any first active treatment at age <10 years (52 of 102) or ≥10 years (25 of 33) was similar (46.9 vs 46.8 months; P = .60). In those who received chemotherapy as first-line treatment or after prior nonchemotherapy treatment failure, the progression-free survival trend was superior (62.9 vs 38.9 months) in those aged ≥10 years although not statistically significant (P = .16).Conclusions Chemotherapy is a valuable treatment modality for the achievement of disease control even in adolescents; their progression-free survival compares favorably with that in younger children. We propose that chemotherapy be considered as a first-line modality in adolescents, avoiding potential radiation-associated morbidities.
    Neuro-Oncology 01/2013; · 6.18 Impact Factor
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    ABSTRACT: Embryonal tumor with multilayered rosettes (ETMR, previously known as ETANTR) is a highly aggressive embryonal CNS tumor, which almost exclusively affects infants and is associated with a dismal prognosis. Accurate diagnosis is of critical clinical importance because of its poor response to current treatment protocols and its distinct biology. Amplification of the miRNA cluster at 19q13.42 has been identified previously as a genetic hallmark for ETMR, but an immunohistochemistry-based assay for clinical routine diagnostics [such as INI-1 for atypical teratoid rhabdoid tumor (AT/RT)] is still lacking. In this study, we screened for an ETMR-specific marker using a gene-expression profiling dataset of more than 1,400 brain tumors and identified LIN28A as a highly specific marker for ETMR. The encoded protein binds small RNA and has been implicated in stem cell pluripotency, metabolism and tumorigenesis. Using an LIN28A specific antibody, we carried out immunohistochemical analysis of LIN28A in more than 800 childhood brain-tumor samples and confirmed its high specificity for ETMR. Strong LIN28A immunoexpression was found in all 37 ETMR samples tested, whereas focal reactivity was only present in a small (6/50) proportion of AT/RT samples. All other pediatric brain tumors were completely LIN28A-negative. In summary, we established LIN28A immunohistochemistry as a highly sensitive and specific, rapid, inexpensive diagnostic tool for routine pathological verification of ETMR.
    Acta Neuropathologica 11/2012; · 9.73 Impact Factor
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    ABSTRACT: Tandem cycles of high-dose chemotherapy are an increasingly popular alternative to radiation treatment in the management of infants and young children with central nervous system (CNS) tumors. Most of these protocols have a carboplatin and thiotepa backbone. The toxicities of these regimens have been reported extensively; however, pulmonary arterial vasculopathy (PAV) with pulmonary arterial hypertension (PAH) has not been previously documented in patients treated with this approach. PAH is a disorder of the pulmonary vasculature characterized by a progressive increase in pulmonary vascular resistance, leading to right heart failure and potentially death. We evaluated PAH as a complication after high-dose chemotherapy and autologous stem cell transplantation (SCT). We performed a retrospective evaluation of all pediatric patients diagnosed with a CNS tumor between 2001 and 2010 scheduled to receive 3 cycles of high-dose chemotherapy with carboplatinum (17 mg/kd/day for 2 days) and thiotepa (10 mg/kg/day for 2 days), followed by autologous SCT. Our primary objective was to evaluate the incidence of PAV and PAH in this population, as well as patient outcomes after the development of PAH. Our cohort comprised 20 patients with a median age at diagnosis of 28 months (range, 3-131 months). Three patients developed biopsy-confirmed PAV with PAH, and 1 patient developed respiratory distress after the third cycle, with an enlarged right ventricle detected on radiography. This latter patient did not meet the criteria for PAH. The 2 patients who developed PAV with PAH at the end of the third cycle succumbed to PAH. Death due to PAV and PAH was the sole toxic mortality observed during the study period. PAV with PAH is a major and possibly fatal complication after high-dose chemotherapy and sequential autologous SCT using carboplatinum and thiotepa in a tandem fashion. There is an urgent need to evaluate PAH as a potential complication after each cycle of high-dose chemotherapy when using such regimens in pediatric patients with CNS tumors.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2012; · 3.15 Impact Factor
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    ABSTRACT: BACKGROUND: Cisplatin (CDDP) ototoxicity is a significant side effect of the current treatment of medulloblastoma (MB). Cumulative dose of CDDP and age are recognized risk factors for hearing loss, but inter-individual susceptibility limits our ability to identify patients at risk for hearing loss. We describe the kinetics of early audiometric changes during therapy and identify profiles associated with a higher risk of needing hearing aids. PROCEDURE: Serial audiometric evaluations were performed during and after completion of therapy in children with average risk (AR) and high-risk (HR) MB. Each audiogram was scored according to five grading systems. Variations of pure tone thresholds were analyzed at each frequency for each consecutive audiogram. CDDP dose modifications and hearing outcome were recorded. RESULTS: A total of 258 audiograms from 35 patients (22 AR, 13 HR) were analyzed. Eighteen AR patients (81.3%) required dose reduction and the median cumulative dose of CDDP administered was 412.5 mg/m(2) (150-600), corresponding to 68% of the intended dose. Three HR patients (23.0%) required dose reduction. At a median follow-up of 67 months (11-117), nine patients (25.7%) required hearing support: After two cycles of CDDP (150 mg/m(2) ), the average hearing loss at 8,000 Hz was twice higher in the group that eventually required hearing support. CONCLUSION: Early alteration of high-frequency thresholds may help identify individuals who will require hearing support. In the MB population, alternative strategies should be developed to limit the cumulative dose of CDDP to prevent significant ototoxicity.
    Pediatric Blood & Cancer 09/2012; · 2.35 Impact Factor

Publication Stats

616 Citations
402.85 Total Impact Points

Institutions

  • 2005–2014
    • SickKids
      • Division of Hematology/Oncology
      Toronto, Ontario, Canada
  • 2010–2013
    • University of Toronto
      • Hospital for Sick Children
      Toronto, Ontario, Canada
  • 2009
    • McMaster University
      • Division of Hematology/Oncology
      Hamilton, Ontario, Canada
  • 2008
    • Children's Hospital of Eastern Ontario
      Ottawa, Ontario, Canada