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  • Tabori, Uri  (41)
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  • 1
    In: Neuro-Oncology, 2014, Vol. 16(suppl5), pp.v102-v102
    Description: OBJECTIVES: The advent of integrated genomics has fundamentally changed our understanding of medulloblastoma. Although survival differences have been shown to exist between the four principle subgroups, treatment related differences have yet to be elucidated. We sought to delineate these differences at a large referral centre. METHODS: All patients over age 3 treated with surgery, craniospinal irradiation and adjuvant chemotherapy were identified at the Hospital for Sick Children in Toronto from 1998-2012. RESULTS: Ninety-four patients were identified who met our inclusion criteria. Two periods were identified, those patients treated prior to 2006 as per the open protocols of the Children's Oncology Group (CCG9961, POG9631), and patients treated after 2006 treated as per the SJMB03 protocol. Five-year progression free survival over the entire cohort was 78%. When stratified by treatment, 5 year survival pre and post 2006 were identical (76.8% pre-2006 and 79.3% post-2006). When re-analysed in a subgroup specific manner, we find no significant differences in progression-free survival pre and post 2006. Strikingly, we found that Group 3 and 4 patients have excellent survivals compared to those previously reported, with 5 year progression-free survival in average risk Group 4 patients of over 90% and over 75% in average risk Group 3 patients regardless of treatment protocol. SHH patients did relatively poorly across both treatment protocols with 5 year progression free survival of 60% likely owing to a high proportion of TP53 mutated patients. CONCLUSIONS: In a cohort of homogenously treated patients over age 3, progression free survival appears to be improved compared to initial reports based on retrospective cohorts. The impact of subgroup affiliation in children over age 3 needs to assessed in large prospectively treated cooperative protocols to determine the subgroup specificity of treatment regiments.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Pediatric Blood & Cancer, July, 2014, Vol.61(7), p.1190(5)
    Keywords: Medulloblastoma -- Diagnosis ; Children'S Hospitals
    ISSN: 1545-5009
    ISSN: 20450907
    E-ISSN: 20450915
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  • 3
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.3552-3552
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Cancer Research, 07/01/2017, Vol.77(13 Supplement), pp.NG05-NG05
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.1432-1432
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    In: Nature, 2012, Vol.488(7409), p.49
    Description: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4a. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-[beta] signalling in Group 3, and NF-[kappa]B signalling in Group 4, suggest future avenues for rational, targeted therapy.
    Keywords: Medulloblastoma – Physiological Aspects ; Medulloblastoma – Genetic Aspects ; Genetic Variation – Research ; Cancer Genetics – Research ; Cancer Metastasis – Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 7
    Language: English
    In: Journal of neurosurgery. Pediatrics, March 2015, Vol.15(3), pp.236-42
    Description: While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups.
    Keywords: Etv = Endoscopic Third Ventriculostomy ; FOR = Frontal and Occipital Horn Ratio ; Endoscopic Third Ventriculostomy ; Hydrocephalus ; Mcpprh ; Mcpprh = Modified Canadian Preoperative Prediction Rule for Hydrocephalus ; Medulloblastoma ; Molecular Subgroups ; Oncology ; Pediatric ; Posterior Fossa ; Shunt ; Biomarkers, Tumor -- Analysis ; Cerebellar Neoplasms -- Complications ; Hedgehog Proteins -- Analysis ; Hydrocephalus -- Surgery ; Medulloblastoma -- Complications ; Ventriculostomy -- Statistics & Numerical Data ; Wnt Proteins -- Analysis
    ISSN: 19330707
    E-ISSN: 1933-0715
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  • 8
    Language: English
    In: Cell, 20 January 2012, Vol.148(1-2), pp.59-71
    Description: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. ► Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ► Cancers with such alterations harbor TP53 mutations ► Context-specific link between the status of p53 and likelihood of chromothripsis ► p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia Connecting p53 status and chromothripsis in specific types of cancer provides a genetic basis for the more aggressive forms of medulloblastoma and leukemia.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 9
    In: Nature Genetics, 2015
    Description: DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (〉250/Mb), which was greater than all childhood and most cancers (〉7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P 〈 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in 〈6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.
    Keywords: Base Pair Mismatch ; DNA Mismatch Repair ; Brain Neoplasms -- Genetics ; DNA Replication -- Genetics;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 10
    In: Pediatric Blood & Cancer, July 2014, Vol.61(7), pp.1190-1194
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/pbc.25002/abstract Byline: Vijay Ramaswamy, Marc Remke, David Shih, Xin Wang, Paul A. Northcott, Claudia C. Faria, Charles Raybaud, Uri Tabori, Cynthia Hawkins, James Rutka, Michael D. Taylor, Eric Bouffet Background Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. Procedure We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. Results The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4-12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P=0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P=0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P=0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P=0.02), however is no longer significant when controlling for subgroup (P=0.07). Conclusions The duration of the pre-diagnostic interval in childhood medulloblastoma is highly subgroup dependent, further highlighting the clinical heterogeneity and biological relevance of the four principle subgroups of medulloblastoma. Pediatr Blood Cancer 2014;61:1190-1194. [c] 2014 Wiley Periodicals, Inc. Article Note: Conflict of interest: Nothing to declare. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Fig. S1. Pre-diagnostic interval for the onset of symptoms as a function of percentage of patients diagnosed. A: Pre-diagnostic interval in weeks plotted as a function of the percentage of patients at initial diagnosis for all medulloblastoma's (n=126). B: Subgroup specific pre-diagnostic interval in weeks plotted as a function of the percentage of patients at initial diagnosis by subgroup. WNT (n=16), SHH (n=31), Group 3 (n=27), Group 4 (n=52), P=0.0001 (Kruskal-Wallis test). Fig. S2. A: Linear regression of the pre-diagnostic interval as a function of age at diagnosis. The solid line represents the best-fit regression line and dashed lines represent 95% confidence intervals. B: Subgroup specific linear regression of the pre-diagnostic interval as a function of age at diagnosis. Significant P-values 〈0.05 in bold. Fig. S3. Subgroup specific survival analysis. Survival stratified by median pre-diagnostic interval within each subgroup for (A) SHH, (B) Group 3, and (C) Group 4. Survival stratified by a pre-diagnostic interval above and below 12 weeks for (D) WNT, (E) Group 3, and (F) Group 4. No SHH cases had a pre-diagnostic c interval above 12 weeks. Table SI. Median Duration of Symptoms by Subgroup Divided by Weeks Table SII. Frequency of Presenting Symptoms by Subgroup in Children 〈3
    Keywords: Genomics ; Medulloblastoma ; Pediatric Brain Tumor ; Pre‐Diagnostic Interval ; Subgroups
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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