Cynthia Hawkins

University of Toronto, Toronto, Ontario, Canada

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Publications (221)1540.66 Total impact

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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 · 1.16 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 · 0.96 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 · 5.01 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 · 0.96 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. We report a 15 year-old girl with tuberous sclerosis complex who proceeded to surgical resection of her subependymal giant cell astrocytoma after 3 months of treatment with mammalian target of rapamycin inhibition. We compared her subependymal giant cell astrocytoma tissue specimen with 12 untreated subependymal giant cell astrocytomas accessed from The Hospital for Sick Children in Toronto, Canada. This girl's histopathological findings were consistent with subependymal giant cell astrocytomas with no exposure to mammalian target of rapamycin inhibitors. There were no major differences identified on immunohistochemistry at targets downstream of mammalian target of rapamycin complex 1 or in neighboring signaling pathways. The majority of cells were reactive to glial fibrillary acidic protein, mitogen-activated protein kinase, phospho-S6, caspase 3 (95% positivity), and NP-1. In this one individual, rapamycin therapy did not change the histopathological characteristics of subependymal giant cell astrocytoma. Mammalian target of rapamycin inhibition involves complex signaling pathways inducing subependymal giant cell astrocytoma shrinkage. However, its effect is not easily characterized within tumor tissue. Copyright © 2015 Elsevier Inc. All rights reserved.
    Pediatric Neurology 06/2015; DOI:10.1016/j.pediatrneurol.2015.05.020 · 1.50 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; DOI:10.1158/1078-0432.CCR-14-2650 · 8.19 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 · 28.05 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; DOI:10.3171/2014.12.PEDS14372 · 1.37 Impact Factor
  • Neuro-Oncology 04/2015; 17(suppl 3):iii13-iii13. DOI:10.1093/neuonc/nov061.51 · 5.29 Impact Factor
  • Neuro-Oncology 04/2015; 17(suppl 3):iii9-iii9. DOI:10.1093/neuonc/nov061.33 · 5.29 Impact Factor
  • Neuro-Oncology 04/2015; 17(suppl 3):iii18-iii19. DOI:10.1093/neuonc/nov061.72 · 5.29 Impact Factor
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    ABSTRACT: Lynch syndrome, the most common inherited colorectal cancer syndrome in adults, is an autosomal dominant condition caused by heterozygous germ-line mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Inheriting biallelic (homozygous) mutations in any of the MMR genes results in a different clinical syndrome termed biallelic mismatch repair deficiency (BMMR-D) that is characterised by gastrointestinal tumours, skin lesions, brain tumours and haematologic malignancies. This recently described and under-recognised syndrome can present with adenomatous polyps leading to early-onset small bowel and colorectal adenocarcinoma. An important clue in the family history that suggests underling BMMR-D is consanguinity. Interestingly, pedigrees of BMMR-D patients typically show a paucity of Lynch syndrome cancers and most parents are unaffected. Therefore, a family history of cancers is often non-contributory. Detection of BMMR-D can lead to more appropriate genetic counselling and the implementation of targeted surveillance protocols to achieve earlier tumour detection that will allow surgical resection. This review describes an approach for diagnosis and management of these patients and their families. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 04/2015; 51(8). DOI:10.1016/j.ejca.2015.02.008 · 4.82 Impact Factor
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    ABSTRACT: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 04/2015; DOI:10.1016/S1470-2045(15)70114-2 · 24.73 Impact Factor
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    ABSTRACT: Co-expression of ERBB2 and ERBB4, reported in 75 % of pediatric ependymomas, correlates with worse overall survival. Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with ependymoma in a phase I study. Bevacizumab exposure in ependymoma xenografts leads to ablation of tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of bevacizumab and lapatinib in children with recurrent ependymomas. Patients ≤21 years of age with recurrent ependymoma received lapatinib orally twice daily (900 mg/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/dose) and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course. Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of bevacizumab and 24-48 h following dose 2 of bevacizumab. Twenty-four patients with a median age of 10 years (range 2-21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥4 courses (range 4-14). Grade 3 toxicities included rash, elevated ALT, and diarrhea. Grade 4 toxicities included peri-tracheostomy hemorrhage (n = 1) and elevated creatinine phosphokinase (n = 1). The median lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of bevacizumab and lapatinib was well tolerated in children with recurrent ependymoma, it proved ineffective.
    Journal of Neuro-Oncology 04/2015; 123(1). DOI:10.1007/s11060-015-1764-7 · 2.79 Impact Factor
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    ABSTRACT: OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell-specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI-guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.
    Journal of Neurosurgery 04/2015; 122(6):1-10. DOI:10.3171/2015.2.JNS132507 · 3.15 Impact Factor
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    ABSTRACT: Solid tumors arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumor-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumors. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase inhibitor nilotinib as a therapeutic option for the management of pediatric gliomas. We have utilized two independent pediatric high-grade glioma cell lines with either high platelet-derived growth factor receptor alpha (PDGFRα) or high PDGFRβ expression in in vitro assays to investigate the specific downstream effects of nilotinib treatment. Using in vitro cell-based assays we show that nilotinib inhibits PDGF-BB-dependent activation of PDGFRα. We further show that nilotinib is able to decrease cell proliferation and anchorage-independent growth via suppression of AKT and ERK1/2 signaling pathways. Our results suggest that nilotinib may be effective for management of a PDGFRα-dependent group of pediatric gliomas.
    Journal of Neuro-Oncology 03/2015; 122(3). DOI:10.1007/s11060-015-1744-y · 2.79 Impact Factor
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    ABSTRACT: Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.
    Acta Neuropathologica 03/2015; 129(3):449-57. DOI:10.1007/s00401-015-1389-0 · 10.76 Impact Factor

Publication Stats

10k Citations
1,540.66 Total Impact Points

Institutions

  • 2004–2015
    • University of Toronto
      • • Laboratory Medicine Program
      • • Department of Medical Biophysics
      • • Hospital for Sick Children
      Toronto, Ontario, Canada
    • 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
  • 2011
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2009
    • McMaster University
      • Division of Hematology/Oncology
      Hamilton, Ontario, Canada