Publications by authors named "Annie Huang"

132 Publications

Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

Lancet Child Adolesc Health 2021 Sep 29. Epub 2021 Sep 29.

Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada; Division of Haematology/Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease.

Methods: Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors.

Findings: 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18-36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47-68) at 6 months and 31% (21-42) at 2 years; overall survival was 29% (20-38) at 2 years and 27% (18-37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28-0·80; p=0·0057) and non-brainstem location (0·42 [0·22-0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16-0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19-0·67; p=0·0020), and radiotherapy (0·21, 0·10-0·41; p<0·0001) on multivariable analysis. 2-year event-free and overall survival was 0% at 2 years in patients treated with conventional chemotherapy without radiotherapy (regardless of surgery extent), and 21% (95% CI 1-41) and 30% (6-54), respectively, in patients treated with high-dose chemotherapy, and gross total resection without radiotherapy. 2-year event-free survival in patients treated with high-dose chemotherapy and radiotherapy was 66% (95% CI 39-93) for patients with gross total resection and 44% (7-81) for patients with sub-total resection. 2-5-year overall survival was 66% (95% CI 33-99, p=0·038) for patients with gross total resection and 67% (36-98, p=0·0020) for patients with sub-total resection.

Interpretation: Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival.

Funding: Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.
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http://dx.doi.org/10.1016/S2352-4642(21)00245-5DOI Listing
September 2021

Hearing Loss After Radiation and Chemotherapy for CNS and Head-and-Neck Tumors in Children.

J Clin Oncol 2021 Sep 27:JCO2100899. Epub 2021 Sep 27.

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Purpose: Hearing loss (HL) is a serious secondary effect of treatment for CNS and head-and-neck tumors in children. The goal of this study was to evaluate incidence and risk factors for HL in patients with multiple ototoxic exposures.

Patients And Methods: We evaluated 340 ears from 171 patients with CNS or head-and-neck tumors treated with radiation, with or without chemotherapy, who had longitudinal audiologic evaluation. International Society of Pediatric Oncology-Boston grades were assigned to 2,420 hearing assessments. Multivariable weighted ordinal logistic regression was fitted to evaluate the effect of clinicopathologic features on HL.

Results: Mean cochlea dose (odds ratio [OR] 1.04 per Gy, < .001), time since radiotherapy (RT; OR 1.21 per year, < .001), cisplatin dose (OR 1.48 per 100 mg/m, < .001), and carboplatin dose (OR 1.41 per 1,000 mg/m, = .002) were associated with increasing International Society of Pediatric Oncology-Boston grade of HL. There was no synergistic effect of RT and cisplatin (interaction term, = .53) or RT and carboplatin (interaction term, = .85). Cumulative incidence of high-frequency HL (> 4 kHz) was 50% or greater at 5 years after RT if mean cochlea dose was > 30 Gy, while incidence of HL across all frequencies continued to increase beyond 5 years after RT.

Conclusion: Children treated with radiation and chemotherapy experience a high incidence of HL over time, with associations found between more severe HL and cisplatin or carboplatin dose as well as mean cochlea dose. Mean cochlea dose of ≤ 30 Gy is proposed as a goal to reduce the risk of HL; a lower threshold (20-25 Gy) may be considered in patients receiving platinum chemotherapy to reduce cumulative HL burden.
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http://dx.doi.org/10.1200/JCO.21.00899DOI Listing
September 2021

Paediatric atypical choroid plexus papilloma: is adjuvant therapy necessary?

J Neurooncol 2021 Sep 16. Epub 2021 Sep 16.

Division of Paediatric Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Introduction: Choroid Plexus Tumours (CPTs) account for 1-4% of all brain tumours in children. Atypical choroid plexus papillomas (aCPPs) are a subset of these tumours, defined over a decade ago, yet no consensus exists on the optimal approach to their management.

Methods: We conducted a retrospective analysis of all patients treated for CPTs at the Hospital for Sick Children between January 1, 2000, and December 31, 2018, and focused on patients with aCPP. Data extracted from the patient records for analysis included: demographic and clinical features, radiological imaging, surgical and adjuvant therapies, key pathological features, immunohistochemical staining for TP53 and tumour karyotype. Six of seven aCPP samples were profiled using Illumina HumanMethylationEPIC arrays and the top 10,000 most variably methylated probes were visualized using tSNE. Copy number inferencing was also performed.

Results: Twenty-nine patients were diagnosed with CPT, seven of whom had a diagnosis of aCPP as confirmed by histological review. Methylation profiling demonstrated that aCPPs clustered with both choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). Complete resection of the tumour was pursued in all cases of aCPP and no patient received adjuvant therapy. All aCPP patients were alive at last follow up.

Conclusions: This limited case series suggests that paediatric aCPP can be successfully managed with surgical resection alone, followed by a 'watch and wait' approach thus avoiding adjuvant therapies. A deeper understanding of the biology of aCPP is required to identify objective markers which can help provide robust risk stratification and inform treatment strategies.
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http://dx.doi.org/10.1007/s11060-021-03843-2DOI Listing
September 2021

Hearing loss and intellectual outcome in children treated for embryonal brain tumors: Implications for young children treated with radiation sparing approaches.

Cancer Med 2021 Oct 4;10(20):7111-7125. Epub 2021 Sep 4.

Program in Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.

Purpose: We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation.

Methods: Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard-dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced-dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately.

Results: Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05).

Conclusions: Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.
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http://dx.doi.org/10.1002/cam4.4245DOI Listing
October 2021

CLAMP and Zelda function together to promote zygotic genome activation.

Elife 2021 08 3;10. Epub 2021 Aug 3.

Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, United States.

During the essential and conserved process of zygotic genome activation (ZGA), chromatin accessibility must increase to promote transcription. is a well-established model for defining mechanisms that drive ZGA. Zelda (ZLD) is a key pioneer transcription factor (TF) that promotes ZGA in the embryo. However, many genomic loci that contain GA-rich motifs become accessible during ZGA independent of ZLD. Therefore, we hypothesized that other early TFs that function with ZLD have not yet been identified, especially those that are capable of binding to GA-rich motifs such as chromatin-linked adaptor for male-specific lethal (MSL) proteins (CLAMP). Here, we demonstrate that embryonic development requires maternal CLAMP to (1) activate zygotic transcription; (2) increase chromatin accessibility at promoters of specific genes that often encode other essential TFs; and (3) enhance chromatin accessibility and facilitate ZLD occupancy at a subset of key embryonic promoters. Thus, CLAMP functions as a pioneer factor that plays a targeted yet essential role in ZGA.
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http://dx.doi.org/10.7554/eLife.69937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367384PMC
August 2021

Evaluation of vitamin D protocol in the neonatal intensive care unit at Rush University Medical Center.

JPEN J Parenter Enteral Nutr 2021 Jun 14. Epub 2021 Jun 14.

Division of Neonatology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois, USA.

Background: In 2017, the neonatal intensive care unit (NICU) at Rush University Medical Center (RUMC) implemented a protocol to provide individualized vitamin D supplementation dosing for very low-birth-weight (VLBW) and very preterm infants. This study evaluated the association of demographic and socioeconomic factors, vitamin D dose, and health indicators, including bone mineral status, measured by alkaline phosphatase and phosphorus levels; linear growth velocity; and occurrence of fractures.

Method: This retrospective cross-sectional study included 227 VLBW or very preterm infants (34 VLBW, 12 very preterm, and 181 VLBW and very preterm) born in and discharged from the RUMC NICU between February 1, 2017, and October 31, 2019. Vitamin D dose was classified as adjusted (supplemental dose of 800 IU/day, n = 169) or standard (recommended dose of 400 IU/day, n = 58), per the protocol. Binary logistic and linear regression models were constructed to test the associations between infant and maternal characteristics and vitamin D dose group and between vitamin D dose group and health indicators.

Results: The analysis found a statistically significant association between maternal age, gestational age, infant birth weight, and race/ethnicity and receipt of an adjusted vitamin D dose. No significant associations were found between health indicators and vitamin D dose.

Conclusion: Sociodemographic factors may influence vitamin D deficiency in VLBW and very preterm infants in the NICU. At this time, there is insufficient evidence to support a tailored approach, but further research in this area is warranted.
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http://dx.doi.org/10.1002/jpen.2138DOI Listing
June 2021

Ventricular size determination and management of ventriculomegaly and hydrocephalus in patients with diffuse intrinsic pontine glioma: an institutional experience.

J Neurosurg 2021 Mar 5:1-7. Epub 2021 Mar 5.

1Division of Haematology Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada.

Objective: There is no consensus on the optimal clinical management of ventriculomegaly and hydrocephalus in patients with diffuse intrinsic pontine glioma (DIPG). To date, the impact on survival in patients with ventriculomegaly and CSF diversion for hydrocephalus in this population remains to be elucidated. Herein, the authors describe their institutional experience.

Methods: Patients diagnosed with DIPG and treated with up-front radiation therapy (RT) at The Hospital for Sick Children between 2000 and 2019 were identified. Images at diagnosis and progression were used to determine the frontal/occipital horn ratio (FOR) as a method to measure ventricular size. Patients with ventriculomegaly (FOR ≥ 0.36) were stratified according to the presence of symptoms and categorized as follows: 1) asymptomatic ventriculomegaly and 2) symptomatic hydrocephalus. For patients with ventriculomegaly who did not require CSF diversion, post-RT imaging was also evaluated to assess changes in the FOR after RT. Proportional hazards analyses were used to identify clinical and treatment factors correlated with survival. The Kaplan-Meier method was used to perform survival estimates, and the log-rank method was used to identify survival differences between groups.

Results: Eighty-two patients met the inclusion criteria. At diagnosis, 28% (n = 23) of patients presented with ventriculomegaly, including 8 patients who had symptomatic hydrocephalus and underwent CSF diversion. A ventriculoperitoneal shunt was placed in the majority of patients (6/8). Fifteen asymptomatic patients were managed without CSF diversion. Six patients had resolution of ventriculomegaly after RT. Of 66 patients with imaging at the time of progression, 36 (55%) had ventriculomegaly, and 9 of them required CSF diversion. The presence of ventriculomegaly at diagnosis did not correlate with survival on univariate analysis. However, patients with symptomatic hydrocephalus at the time of progression who underwent CSF diversion had a survival advantage (p = 0.0340) when compared to patients with ventriculomegaly managed with conservative approaches.

Conclusions: Although ventriculomegaly can be present in up to 55% of patients with DIPG, the majority of patients present with asymptomatic ventriculomegaly and do not require surgical interventions. In some cases ventriculomegaly improved after medical management with steroids and RT. CSF diversion for hydrocephalus at the time of diagnosis does not impact survival. In contrast, our results suggest a survival advantage in patients who undergo CSF diversion for hydrocephalus at the time of progression, albeit that advantage is likely to be confounded by biological and individual patient factors. Further research in this area is needed to understand the best timing and type of interventions in this population.
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http://dx.doi.org/10.3171/2020.10.JNS203257DOI Listing
March 2021

Thrombospondin-1 mimetics are promising novel therapeutics for MYC-associated medulloblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab002. Epub 2021 Feb 18.

Department of Pediatrics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Background: Medulloblastoma (MB) comprises four subtypes of which group 3 MB are the most aggressive. Although overall survival for MB has improved, the outcome of group 3 MB remains dismal. C- amplification or MYC overexpression which characterizes group 3 MB is a strong negative prognostic factor and is frequently associated with metastases and relapses. We previously reported that MYC expression alone promotes highly aggressive MB phenotypes, in part via repression of thrombospondin-1 (TSP-1), a potent tumor suppressor.

Methods: In this study, we examined the potential role of TSP-1 and TSP-1 peptidomimetic ABT-898 in amplified human MB cell lines and two distinct murine models of MYC-driven group 3 MBs.

Results: We found that TSP-1 reconstitution diminished metastases and prolonged survival in orthotopic xenografts and promoted chemo- and radio-sensitivity via AKT signaling. Furthermore, we demonstrate that ABT-898 can recapitulate the effects of TSP-1 expression in MB cells in vitro and specifically induced apoptosis in murine group 3 MB tumor cells.

Conclusion: Our data underscore the importance of TSP-1 as a critical tumor suppressor in MB and highlight TSP-1 peptidomimetics as promising novel therapeutics for the most lethal subtype of MB.
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http://dx.doi.org/10.1093/noajnl/vdab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890793PMC
February 2021

Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study.

Acta Neuropathol 2021 05 22;141(5):771-785. Epub 2021 Feb 22.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.
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http://dx.doi.org/10.1007/s00401-021-02284-5DOI Listing
May 2021

Targeted disruption of galectin 3 in mice delays the first wave of spermatogenesis and increases germ cell apoptosis.

Cell Mol Life Sci 2021 Apr 28;78(7):3621-3635. Epub 2021 Jan 28.

Department of Anatomy and Cell Biology, Justus-Liebig-University of Giessen, Aulweg 123, 35385, Giessen, Germany.

Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3) exhibited significantly decreased testicular weight in adulthood compared to controls. The transgenic mice also exhibited a delay to the first wave of spermatogenesis, a decrease in the number of germ cells at postnatal day 5 (P5) and P15, and defective Sertoli cell maturation. Mechanistically, we found that Insulin-like-3 (a Leydig cell marker) and enzymes involved in steroid biosynthesis were significantly upregulated in adult Lgals3 testes. These observations were accompanied by increased serum testosterone levels. To determine the underlying causes of the testicular atrophy, we monitored cellular apoptosis. Indeed, adult Lgals3 testicular cells exhibited an elevated apoptosis rate that is likely driven by downregulated Bcl-2 and upregulated Bax and Bak expression, molecules responsible for live/death cell balance. Moreover, the percentage of testicular macrophages within CD45 cells was decreased in Lgals3 mice. These data suggest that galectin 3 regulates spermatogenesis initiation and Sertoli cell maturation in part, by preventing germ cells from undergoing apoptosis and regulating testosterone biosynthesis. Going forward, understanding the role of galectin 3 in testicular physiology will add important insights into the factors governing the development of germ cells and steroidogenesis and delineate novel biomarkers of testicular function.
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http://dx.doi.org/10.1007/s00018-021-03757-2DOI Listing
April 2021

Embryonal Tumor With Multilayered Rosettes of the Parietooccipital Region: A Case Report.

J Pediatr Hematol Oncol 2021 Jan 11. Epub 2021 Jan 11.

Faculty of Medicine, University of Ottawa Divisions of Pediatric Neurosurgery Pediatric Hematology/Oncology, Children's Hospital of Eastern Ontario Divisin of Anatomical Pathology, Eastern Ontario Regional Laboratory Association, Ottawa, ON Division of Pediatric Hematology/Oncology, Hospital for Sick Children, Toronto, Canada.

Embryonal tumor with multilayered rosettes is a rare and highly malignant early childhood brain tumor. We report a case of embryonal tumor with multilayered rosettes in the parietooccipital region of a 2-year-old girl. Histopathology of the tumor demonstrated amplification of the 19q13.42 locus and strong positivity for LIN28A. Treatment was multimodal and included 3 surgical resections, adjuvant chemotherapy with autologous stem cell rescue, and focal radiotherapy. The use of the agents vorinostat and isotretinoin, and the addition of focal radiation have not been extensively described in this patient population, but may attribute to our patient's sustained remission at 2.5-years follow-up.
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http://dx.doi.org/10.1097/MPH.0000000000002048DOI Listing
January 2021

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Cancer Discov 2021 05 18;11(5):1176-1191. Epub 2020 Dec 18.

Department of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223607PMC
May 2021

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases.

Acta Neuropathol 2021 02 17;141(2):291-301. Epub 2020 Dec 17.

Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.
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http://dx.doi.org/10.1007/s00401-020-02250-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847432PMC
February 2021

Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer.

Nat Commun 2020 12 4;11(1):6216. Epub 2020 Dec 4.

Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.

Histone H3 lysine 27 (H3K27M) mutations represent the canonical oncohistone, occurring frequently in midline gliomas but also identified in haematopoietic malignancies and carcinomas. H3K27M functions, at least in part, through widespread changes in H3K27 trimethylation but its role in tumour initiation remains obscure. To address this, we created a transgenic mouse expressing H3.3K27M in diverse progenitor cell populations. H3.3K27M expression drives tumorigenesis in multiple tissues, which is further enhanced by Trp53 deletion. We find that H3.3K27M epigenetically activates a transcriptome, enriched for PRC2 and SOX10 targets, that overrides developmental and tissue specificity and is conserved between H3.3K27M-mutant mouse and human tumours. A key feature of the H3K27M transcriptome is activation of a RAS/MYC axis, which we find can be targeted therapeutically in isogenic and primary DIPG cell lines with H3.3K27M mutations, providing an explanation for the common co-occurrence of alterations in these pathways in human H3.3K27M-driven cancer. Taken together, these results show how H3.3K27M-driven transcriptome remodelling promotes tumorigenesis and will be critical for targeting cancers with these mutations.
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http://dx.doi.org/10.1038/s41467-020-19972-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718276PMC
December 2020

Embryonal tumors with multi-layered rosettes: a disease of dysregulated miRNAs.

J Neurooncol 2020 Oct 22;150(1):63-73. Epub 2020 Oct 22.

Division of Hematology-Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G1X8, Canada.

Introduction: ETMRs are highly lethal, pediatric embryonal brain tumors, previously classified as various histologic diagnoses including supratentorial primitive neuroectodermal tumors (sPNET) and CNS PNET. With recognition that these tumors harbor recurrent amplification of a novel oncogenic miRNA cluster on chr19, C19MC, ETMRs were designated as a distinct biological and molecular entity with a spectrum of histologic and clinical manifestations.

Methods: We reviewed published literature describing clinical presentation, the genetic and epigenetic drivers of oncogenesis, and recent therapeutic strategies adopted to combat these aggressive tumors.

Results: As a consequence of C19MC amplification, ETMRs upregulate several oncogenic and pluripotency proteins, including LIN28A, DNMT3B and MYCN, that confer a unique epigenetic signature reminiscent of nascent embryonic stem cells. In this review, we focus on the dysregulation of miRNAs in ETMR, the major pathogenic mechanism identified in this disease.

Conclusion: Despite the use of multi-modal therapeutic regimens, ETMR patients have dismal survival. Understanding the unique biology of these tumors has provided new insights towards novel therapeutic targets.
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http://dx.doi.org/10.1007/s11060-020-03633-2DOI Listing
October 2020

Atypical teratoid rhabdoid tumor: molecular insights and translation to novel therapeutics.

J Neurooncol 2020 Oct 6;150(1):47-56. Epub 2020 Oct 6.

Department of Neurological Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Introduction: Atypical teratoid rhabdoid tumor (ATRT) is a rare, often lethal brain tumor of childhood characterized by a complex epigenetic landscape amongst a simple genetic background. Recent molecular studies have defined key biologic events that contribute to tumorigenesis and molecular subtypes of ATRT.

Methods: Seminal studies on ATRT are reviewed with an emphasis on molecular pathogenesis and its relevance to novel therapeutics.

Results: In this review, we summarize the key clinicopathologic and molecular features of ATRT, completed and ongoing clinical trials and outline the translational potential of novel insights into the molecular pathogenesis of this tumor.

Conclusions: SMARCB1 loss is the key genetic event in ATRT pathogenesis that leads to widespread epigenetic dysregulation and loss of lineage-specific enhancers. Current work is defining subtype-specific treatments that target underlying molecular derangements that drive tumorigenesis.
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http://dx.doi.org/10.1007/s11060-020-03639-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230985PMC
October 2020

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

JCO Precis Oncol 2020 20;4. Epub 2020 May 20.

Semmelweis University, Budapest, Hungary.

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors.

Patients And Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries.

Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( = .02).

Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.
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http://dx.doi.org/10.1200/PO.19.00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446502PMC
May 2020

Household spraying in cholera outbreaks: Insights from three exploratory, mixed-methods field effectiveness evaluations.

PLoS Negl Trop Dis 2020 08 31;14(8):e0008661. Epub 2020 Aug 31.

Department of Civil and Environmental Engineering, Tufts University, Medford, Massachusetts, United States of America.

Household spraying is a commonly implemented, yet an under-researched, cholera response intervention where a response team sprays surfaces in cholera patients' houses with chlorine. We conducted mixed-methods evaluations of three household spraying programs in the Democratic Republic of Congo and Haiti, including 18 key informant interviews, 14 household surveys and observations, and 418 surface samples collected before spraying, 30 minutes and 24 hours after spraying. The surfaces consistently most contaminated with Vibrio cholerae were food preparation areas, near the patient's bed and the latrine. Effectiveness varied between programs, with statistically significant reductions in V. cholerae concentrations 30 minutes after spraying in two programs. Surface contamination after 24 hours was variable between households and programs. Program challenges included difficulty locating households, transportation and funding limitations, and reaching households quickly after case presentation (disinfection occurred 2-6 days after reported cholera onset). Program advantages included the concurrent deployment of hygiene promotion activities. Further research is indicated on perception, recontamination, cost-effectiveness, viable but nonculturable V. cholerae, and epidemiological coverage. We recommend that, if spraying is implemented, spraying agents should: disinfect surfaces systematically until wet using 0.2/2.0% chlorine solution, including kitchen spaces, patients' beds, and latrines; arrive at households quickly; and, concurrently deploy hygiene promotion activities.
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http://dx.doi.org/10.1371/journal.pntd.0008661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485970PMC
August 2020

Causes of death in pediatric neuro-oncology: the sickkids experience from 2000 to 2017.

J Neurooncol 2020 Aug 14;149(1):181-189. Epub 2020 Aug 14.

Division of Hematology/Oncology, the Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 2M9, Canada.

Purpose: Primary benign and malignant central nervous system (CNS) tumors are the most frequent solid tumors in the pediatric age and represent the leading cause of death by cancer in children in high income countries. However, information regarding specific causes of death in this population is still limited. The objective of this work was to investigate mortality in a large cohort of children diagnosed at our institution.

Methods: We identified patients consecutively diagnosed with CNS tumor and treated at a Tertiary Care Canadian Children's Hospital between January 2000 and December 2017. Patient charts were reviewed and different variables such as tumor diagnosis, location, gender, age at diagnosis, age at death and cause of death collected.

Results: Of 1274 patients, 306 (24%) succumbed to their disease. Mortality rate varied significantly according to tumor subtype, ranging from 3.1% in low grade glioma (LGG) to 97.8% in diffuse intrinsic pontine glioma (DIPG). While high grade gliomas (HGG) and DIPG represented only 6.3 and 7.1% of total diagnoses respectively, together they accounted for 49.3% of total deaths (n = 151). Median time from diagnosis to death was 15 months (4 days to 15 years) and shortest for DIPG (11 months). Two hundred and ninety patients (94.8%) died as a result of the primary disease, 4 of treatment-related toxicity, two patients' deaths were unrelated to the primary disease (idiopathic encephalopathy and domestic fire) whereas 10 patients succumbed to a secondary malignancy. Of note, four of these ten patients had a confirmed underlying cancer predisposition syndrome.

Conclusion: Disease progression is the main cause of death in children with brain tumor, while treatment related mortality is low in this series. Research should continue to focus on improving treatment strategies for patients whose prognosis remains dismal.
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http://dx.doi.org/10.1007/s11060-020-03590-wDOI Listing
August 2020

Bevacizumab for pediatric radiation necrosis.

Neurooncol Pract 2020 Jul 20;7(4):409-414. Epub 2020 Jan 20.

Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.

Background: Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described.

Methods: We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation.

Results: We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients.

Conclusions: Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials.
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http://dx.doi.org/10.1093/nop/npz072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393279PMC
July 2020

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Cell Rep Med 2020 Jun;1(3)

Departments of Pediatrics, Anatomy, and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
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http://dx.doi.org/10.1016/j.xcrm.2020.100038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394286PMC
June 2020

Reply to S.A. Upadhyaya.

J Clin Oncol 2020 10 30;38(28):3353-3354. Epub 2020 Jul 30.

Alyssa T. Reddy, MD, University of California San Francisco, CA; Mark D. Krailo, PhD, Keck School of Medicine, University of Southern California, Los Angeles, CA; Allen B. Buxton, MS, Children's Oncology Group, Monrovia, CA; Douglas R. Strother, MD, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Annie Huang, MD, PhD, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada; Tianni Zhou, PhD, California State University at Long Beach, Long Beach, CA; Alexander R. Judkins, MD, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA; Peter C. Burger, MD, Johns Hopkins University, Baltimore, MD; Ian F. Pollack, MD, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, Pittsburgh, PA; Chris Williams-Hughes, BS, Children's Oncology Group, Monrovia, CA; Maryam Fouladi, MD, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Ben Ho, MSc, Hospital for Sick Children, Toronto, ON, Canada; Claire M. Mazewski, MD, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA; Victor A. Lewis, MD, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Louis-Gilbert Vezina, MD, The George Washington University School Medicine and Health Sciences, Washington, DC; Timothy N. Booth, MD, University of Texas Southwestern, Dallas, TX; and Anita Mahajan, MD, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1200/JCO.20.01573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526718PMC
October 2020

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.

Cancer Cell 2020 04;37(4):569-583.e5

Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.
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http://dx.doi.org/10.1016/j.ccell.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169997PMC
April 2020

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy.

Nat Commun 2020 04 14;11(1):1825. Epub 2020 Apr 14.

Toronto General Research Institute, University Health Network, 67 College Street, Toronto, ON, M5G 2M1, Canada.

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.
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http://dx.doi.org/10.1038/s41467-020-15585-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156401PMC
April 2020

Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas.

Neuro Oncol 2020 10;22(10):1474-1483

Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear.

Methods: We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers.

Results: Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma-like tumors could stratify these tumors into low and high risk (P = 0.0014).

Conclusion: The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.
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http://dx.doi.org/10.1093/neuonc/noaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566385PMC
October 2020

Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors.

Neuro Oncol 2020 07;22(7):944-954

Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.
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http://dx.doi.org/10.1093/neuonc/noaa046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339881PMC
July 2020

Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333.

J Clin Oncol 2020 04 27;38(11):1175-1185. Epub 2020 Feb 27.

Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.

Purpose: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT.

Patients And Methods: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored.

Results: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort ( < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients.

Conclusion: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
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http://dx.doi.org/10.1200/JCO.19.01776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145589PMC
April 2020

Pediatric embryonal brain tumors in the molecular era.

Expert Rev Mol Diagn 2020 03 15;20(3):293-303. Epub 2020 Jan 15.

Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.

: Embryonal brain tumors (EBTs) are highly aggressive malignancies predominantly affecting children. They include medulloblastoma (MB), atypical rhabdoid/teratoid tumors (ATRT), pineoblastoma (PB), embryonal tumor multiple rosettes (ETMR)/-altered tumors, and newly recognized embryonal tumors with activation or alteration.: This review will provide a comprehensive overview and updated of the literature on each of these EBTs. The evolution from location- and histopathology-based diagnosis to more specific and robust molecular-based classification schemes, as well as treatment modalities, will be discussed.: The subgrouping of EBTs with multi-omic profiling has had important implications for risk stratification and discovery of targetable driver pathways. However, these innovations are unlikely to significantly improve survival among high-risk patients until robust preclinical studies are conducted, followed by validation in biology-informed clinical trials.
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http://dx.doi.org/10.1080/14737159.2020.1714439DOI Listing
March 2020
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