Cynthia Hawkins

SickKids, Toronto, Ontario, Canada

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Publications (232)1612.36 Total impact

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    ABSTRACT: Background: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. Methods: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. Results: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53 % of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13 % for unithalamic tumors compared to 37 ± 32 % for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. Conclusion: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.
    Child s Nervous System 11/2015; DOI:10.1007/s00381-015-2968-z · 1.11 Impact Factor
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    ABSTRACT: OBJECT Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care. METHODS This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation. RESULTS Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8-17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3-7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6-8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9-17.9 years) after treatment. CONCLUSIONS In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes.
    Journal of Neurosurgery Pediatrics 11/2015; DOI:10.3171/2015.6.PEDS14709 · 1.48 Impact Factor

  • Neuro-Oncology 11/2015; 17(suppl 5):v148-v148. DOI:10.1093/neuonc/nov223.10 · 5.56 Impact Factor
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    Acta Neuropathologica 10/2015; DOI:10.1007/s00401-015-1492-2 · 10.76 Impact Factor
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    ABSTRACT: Pediatric high-grade astrocytomas (pHGA) and diffuse-intrinsic-pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of Poly-(ADP-Ribose)-Polymerase-1 (PARP1) inhibition in pre-clinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors, Veliparib, Olaparib, and Niraparib, as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of Niraparib was examined in an orthotopic xenograft model of pHGA. 85% of pHGAs and 76% of DIPG TMA samples expressed PARP1. 6 of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines some PARP1 protein expression was required for response to PARP inhibition, however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pre-treatment of pHGA cells with sub-lethal dose of Niraparib (1µM) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA-damage-repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo, and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 days vs. 25 days). Our data provide in vitro and in vivo evidence that Niraparib may be an effective radiosensitizer for pHGA and DIPG.
    Molecular Cancer Therapeutics 09/2015; DOI:10.1158/1535-7163.MCT-15-0282 · 5.68 Impact Factor
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    ABSTRACT: Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.
    Child s Nervous System 08/2015; DOI:10.1007/s00381-015-2883-3 · 1.11 Impact Factor
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    ABSTRACT: Germline biallelic mismatch repair deficiency (bMMRD) results in a unique cancer predisposition syndrome in which the affected children are susceptible to the development of malignancies, especially brain, gastrointestinal, and lymphoid cancers. Acute myeloblastic leukemia is rarely reported in this syndrome. Here we report the decision-making challenges in a bMMRD child with acute myeloblastic leukemia. Our experience should alert physicians to include bMMRD in the differential diagnosis of a child with hyper/hypopigmented spots and leukemia. Furthermore, the presence of the above and consanguinity emphasizes the need to rule out bMMRD when an allogeneic bone marrow transplant is considered and to enable the surveillance of other family members for earlier detection of cancers in these children.
    Journal of Pediatric Hematology/Oncology 08/2015; DOI:10.1097/MPH.0000000000000415 · 0.90 Impact Factor
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    ABSTRACT: Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of café au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty-two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients. © 2015 UICC.
    International Journal of Cancer 08/2015; DOI:10.1002/ijc.29724 · 5.09 Impact Factor
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    ABSTRACT: Bifocal pineal and suprasellar tumors have only been described in the context of germ cell tumors in the pediatric age group. We report 2 patients with radiologic findings of bifocal pineal and suprasellar lesions, with a histologic diagnosis of supratentorial primitive neuroectodermal tumor. The absence of diabetes insipidus and other endocrine abnormalities was noteworthy in both cases. This observation challenges previous reports on the pathognomonic value of this clinico-radiologic entity.
    Journal of Pediatric Hematology/Oncology 08/2015; DOI:10.1097/MPH.0000000000000402 · 0.90 Impact Factor
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    Pawel Buczkowicz · Cynthia Hawkins ·
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30 years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity’s unique mutational landscape, copy number alterations and structural variants as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues.
    Frontiers in Oncology 06/2015; 5(147):1-9. DOI:10.3389/fonc.2015.00147
  • Sylvia Cheng · Cynthia Hawkins · Michael D. Taylor · Ute Bartels ·
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    ABSTRACT: Tuberous sclerosis complex is a heritable multisystem disorder associated with genes involved in the formation of a tumor-suppressor complex acting through the Ras homologue enriched in brain protein to limit activation of the mammalian target of rapamycin complex I. Mutations in these genes result in enhanced mammalian target of rapamycin signaling and may cause neurological manifestations including brain tubers, subependymal nodules, and subependymal giant cell astrocytomas. These astrocytomas are tumors that arise near the foramen of Monro and may lead to obstructive hydrocephalus. Standard therapy has been surgical resection. More recently, mammalian target of rapamycin inhibitor, everolimus, has been approved for treatment after demonstration of efficacy in prospective clinical trials.
    Pediatric Neurology 06/2015; 53(3). DOI:10.1016/j.pediatrneurol.2015.05.020 · 1.70 Impact Factor

  • Koichi Ichimura · Yoshitaka Narita · Cynthia E Hawkins ·
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    ABSTRACT: Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies.
    Acta Neuropathologica 05/2015; 129(6). DOI:10.1007/s00401-015-1439-7 · 10.76 Impact Factor
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    ABSTRACT: Myxopapillary ependymoma (MPE) is a distinct histological variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumour lysates consisting of assays measuring Pyruvate Kinase M activity (PKM), Hexokinase activity (HK), and lactate production. At a gene expression level, we demonstrate that spinal Grade II and MPE are molecularly and biologically distinct. These findings are supported by specific copy number alterations occurring in each histological variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with up-regulation of HIF-1α. These findings were validated by western blot analysis demonstrating increased protein expression of HIF-1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; 21(16). DOI:10.1158/1078-0432.CCR-14-2650 · 8.72 Impact Factor
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    ABSTRACT: Pediatric gliomas are the most commonly diagnosed brain cancer in children, accounting for approximately 50% of all cases. Recently, we conducted genome-analysis of diffuse intrinsic pontine glioma (DIPG), which specifically arises in the brainstem. Through this, we identified a histone H3.3 mutation (a lysine-methionine substitution at position 27 [K27M]) in approximately 70% of cases. We then showed that H3.3K27M is a negative prognostic marker for DIPG patients independent of histology. We hypothesized a similar prognostic role for H3.3K27M in thalamic gliomas. Utilizing a newly optimized, ultra-sensitive digital droplet PCR assay, we analyzed 38 radiologically confirmed thalamic gliomas (13 low grade and 25 high grade gliomas). Median survival for patients with high grade thalamic gliomas was 1.35 years vs 8.71 years for low grade thalamic glioma patients. Three (23%) low grade and 11 (44%) high grade gliomas tested positive for the H3.3K27M mutation. 31 patients, clinically annotated for treatment, extent of resection, age and outcome were used to determine the prognostic implications of H3.3-K27M. Kaplan-Meier survival analysis revealed significantly worse overall survival of thalamic glioma patients harbouring the H3.3-K27M mutation versus wild type samples (log rank p < 0.001) with a median survival of 1.04 vs 5.81 years for H3.3K27M vs WT thalamic gliomas, respectively. Multivariate cox analysis demonstrated H3.3K27M mutation status to be independent of WHO grade as a predictor of overall survival with a hazard ratio of 6.5 (95% confidence intervals 1.78-24.4, p = 0.005). These findings provide the first evidence that H3.3K27M status is a negative prognostic indicator for thalamic pediatric glioma. Furthermore, we have optimized a digital droplet PCR assay to assess mutation status in small samples, including formalin-fixed paraffin embedded, with high sensitivity and specificity in a clinical setting.
    3rd Biennial Conference on Pediatric Neuro-Oncology Basic and Translational Research; 05/2015
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.
    Nature medicine 05/2015; 21(7). DOI:10.1038/nm.3855 · 27.36 Impact Factor
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    ABSTRACT: OBJECT Choroid plexus carcinomas (CPCs) are rare brain tumors originating from the ventricular choroid plexus. They account for 2%-4% of all pediatric brain tumors and are most frequently seen in very young children. This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss. Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue. At the Hospital for Sick Children in Toronto, this empirical finding led to the strategy of neoadjuvant chemotherapy to minimize blood loss and maximize cytoreduction. The authors undertook this study to assess the potentially beneficial effect of neoadjuvant chemotherapy on blood loss during surgery for CPCs. METHODS In this retrospective cohort review, the demographic, clinical, and treatment parameters of 22 consecutive patients diagnosed with CPC are presented. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit. RESULTS Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2-5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy. CONCLUSIONS In children with CPC, the administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival.
    Journal of Neurosurgery Pediatrics 05/2015; 16(2):1-8. DOI:10.3171/2014.12.PEDS14372 · 1.48 Impact Factor

  • Neuro-Oncology 04/2015; 17(suppl 3):iii13-iii13. DOI:10.1093/neuonc/nov061.51 · 5.56 Impact Factor

  • Neuro-Oncology 04/2015; 17(suppl 3):iii9-iii9. DOI:10.1093/neuonc/nov061.33 · 5.56 Impact Factor
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    Neuro-Oncology 04/2015; 17(suppl 3):iii18-iii19. DOI:10.1093/neuonc/nov061.72 · 5.56 Impact Factor

Publication Stats

10k Citations
1,612.36 Total Impact Points


  • 2004-2015
    • SickKids
      • • Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC)
      • • Department of Paediatric Laboratory Medicine (DPLM)
      • • Division of Pathology
      • • Division of Neurology
      • • Division of Hematology/Oncology
      • • Division of Neurosurgery
      Toronto, Ontario, Canada
  • 2014
    • Brain Canada
      Montréal, Quebec, Canada
  • 2004-2014
    • University of Toronto
      • • Laboratory Medicine Program
      • • Hospital for Sick Children
      • • Department of Medical Biophysics
      Toronto, Ontario, Canada
  • 2011
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands