Publications by authors named "Eric Bouffet"

387 Publications

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

Childhood head trauma and the risk of childhood brain tumours: a case-control study in Ontario, Canada.

Int J Cancer 2021 Sep 14. Epub 2021 Sep 14.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population- and hospital-based case-control study of children 0-15 years with newly diagnosed CBTs from 1997-2003 recruited across Ontario through pediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education, and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, nor head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33805DOI Listing
September 2021

Pediatric cancer care in Africa: SIOP Global Mapping Program report on economic and population indicators.

Pediatr Blood Cancer 2021 Sep 14:e29345. Epub 2021 Sep 14.

Paediatric Hematology and Oncology Unit of Rabat, Mohamed V University, Rabat, Morocco.

Introduction: Inalignment with the World Health Organization (WHO) Global Initiative for Childhood Cancer (GICC), the International Society of Pediatric Oncology initiated a program to map global pediatric oncology services. As survival rates in Africa are low and data are scant, this continent was mapped first to identify areas with greatest need.

Methods: Beginning November 2018, an electronic survey was sent to all known stakeholders, followed by email communications and internet searches to verify data. Availability of pediatric oncologists, chemotherapy, surgical expertise, and radiotherapy was correlated with geographic region, World Bank income status, Universal Health Coverage, population < 15 and < 24 years, percentage of gross domestic product spent on healthcare, and Human Development Index (HDI).

Results: Responses were received from 48/54 African countries. All three treatment modalities were reportedly available in 9/48 countries, whereas seven countries reported no pediatric oncology services. Negative correlations were detected between provision of all three services and geographic region (P = 0.01), younger median population age (P = 0.002), low-income country status (P = 0.045), and lower HDI (P < 0.001).

Conclusion: This study provides a comprehensive overview of pediatric oncology care in Africa, emphasizing marked disparities between countries: some have highly specialized services, whereas others have no services. A long-term strategy to eliminate disparities in African pediatric cancer care should be aligned with the WHO GICC aims and facilitated by SIOP Africa.

Meeting Abstracts: SIOP maps pediatric oncology services in Africa to address inequalities in childhood cancer services. Geel J, Ranasinghe N, Davidson A, Challinor J, Howard S, Wollaert S, Myezo K, Renner L, Hessissen L, Bouffet E. 51st Annual Congress of the International Society of Paediatric Oncology (SIOP), Lyon, France, October 2019. Pediatric Blood and Cancer Vol 66 S219-S219. Pediatric cancer care in Africa: SIOP Global Mapping Program report on economic and population indicators.
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http://dx.doi.org/10.1002/pbc.29345DOI 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 Sep 4. 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
September 2021

Pediatric cancer care in Africa: SIOP Global Mapping process.

Pediatr Blood Cancer 2021 Aug 29:e29315. Epub 2021 Aug 29.

School of Nursing, University of California San Francisco, San Francisco, California, USA.

In November 2018, theInternational Society of Paediatric Oncology (SIOP) launched a project to map African facilities providing pediatric oncology treatment. A 55-item digital survey was created in English, piloted in India, translated to French and Portuguese, and distributed by email, social media, or personal contacts. December 2019, 48/54 African countries responded (72% surveys completed and analyzed). Issues included incomplete responses, multiple entries for one facility with conflicting data for key services, and repeated entries with varied answers by the same respondent. The facility mapping project, now on-going program will serve as a global registry of global pediatric cancer centers.
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http://dx.doi.org/10.1002/pbc.29315DOI Listing
August 2021

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study.

Lancet Oncol 2021 Aug 26. Epub 2021 Aug 26.

Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer.

Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection.

Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p<0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm (2·5 [1·8-3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm (1·8 [1·3-2·4]; p=0·0001), and intensive treatment (1·8 [1·3-2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3-0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3-0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3-2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1-2·3]; p=0·020).

Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness.

Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(21)00454-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389979PMC
August 2021

COVID-19 in pediatric cancer: Where are the brain tumors?

Neuro Oncol 2021 Aug 20. Epub 2021 Aug 20.

Division of Hematology and Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1093/neuonc/noab189DOI Listing
August 2021

Recommendations for Age-Appropriate Testing, Timing, and Frequency of Audiologic Monitoring During Childhood Cancer Treatment: An International Society of Paediatric Oncology Supportive Care Consensus Report.

JAMA Oncol 2021 Aug 12. Epub 2021 Aug 12.

Department of Audiovestibular Medicine and Cochlear Implant, Great Ormond Street Hospital for Children National Health Service Trust, London, United Kingdom.

Importance: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on.

Objective: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice.

Methods: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel.

Findings: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources.

Conclusions And Relevance: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.
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http://dx.doi.org/10.1001/jamaoncol.2021.2697DOI Listing
August 2021

Establishing a pediatric radiation oncology department in a low- and middle-income country: Major challenge in implementing the Global Initiative for Childhood Cancer.

Pediatr Blood Cancer 2021 Oct 6;68(10):e29233. Epub 2021 Aug 6.

Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/pbc.29233DOI Listing
October 2021

Case Report: Visual Rehabilitation in Hemianopia Patients. Home-Based Visual Rehabilitation in Patients With Hemianopia Consecutive to Brain Tumor Treatment: Feasibility and Potential Effectiveness.

Front Neurol 2021 21;12:680211. Epub 2021 Jul 21.

Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.

Visual field loss is frequent in patients with brain tumors, worsening their daily life and exacerbating the burden of disease, and no supportive care strategies exist. In this case series, we sought to characterize the feasibility and potential effectiveness of a home-based visual rehabilitation program in hemianopia patients using immersive virtual-reality stimulation. Two patients, one with homonymous hemianopia and the other with bitemporal hemianopia, consecutive to pediatric brain tumors, with no prior visual rehabilitation performed 15 min of home-based audiovisual stimulation every 2 days for 6 weeks (case 2) and 7 weeks (case 1) between February and August 2020. Patients used a virtual-reality, stand-alone, and remotely controlled device loaded with a non-commercial audiovisual stimulation program managed in real time from the laboratory. Standard visual outcomes assessed in usual care in visual rehabilitation were measured at the clinic. Following a mixed method approach in this pragmatic study of two cases, we collected quantitative and qualitative data on feasibility and potential effectiveness and compared the results pre- and post-treatment. Implementation and wireless delivery of the audiovisual stimulation, remote data collection, and analysis for cases 1 and 2 who completed 19/20 and 20/20 audiovisual stimulation sessions at home, respectively, altogether indicated feasibility. Contrast sensitivity increased in both eyes for cases 1 and 2. Visual fields, measured by binocular Esterman and monocular Humphrey full-field analyses, improved in case 1. A minor increase was observed in case 2. Cases 1 and 2 enhanced reading speed. Case 2 strongly improved quality of life scores. This is the first report of a home-based virtual-reality visual rehabilitation program for adult patients with hemianopia consecutive to a pediatric brain tumor. We show the feasibility in real-world conditions and potential effectiveness of such technology on visual perception and quality of life.
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http://dx.doi.org/10.3389/fneur.2021.680211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333276PMC
July 2021

Posterior fossa syndrome-time to unmute the silence on cerebellar mutism.

Neuro Oncol 2021 Sep;23(9):1427-1428

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

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http://dx.doi.org/10.1093/neuonc/noab147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408842PMC
September 2021

An Audiovisual 3D-Immersive Stimulation Program in Hemianopia Using a Connected Device.

Am J Case Rep 2021 Jun 9;22:e931079. Epub 2021 Jun 9.

Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

BACKGROUND Homonymous hemianopia is a loss of conscious vision in one hemifield, strongly affecting everyday life. Audiovisual stimulation programs improve visual perception in the blind hemifield; however, they use large equipment operated in clinical settings. Such treatments require frequent visits at the clinic, hampering the patient's adherence and compliance. In one hemianopia patient, we tested a 4-week dynamic audiovisual rehabilitation program in the stand-alone, remotely controlled, virtual-reality, head-mounted display Oculus Go and measured the effect on visual perception. CASE REPORT A 15-year-old Caucasian male was diagnosed with a right homonymous hemianopia with splitting of central fixation after a traumatic occipital contusion at age 7 months. Visual assessment showed impaired binocular contrast sensitivity and retinal sensitivity. Fixation stability and visual fields were strongly affected. After a 4-week audiovisual rehabilitation program, including 3 hours 20 minutes of stimulation, the contrast sensitivity, fixation stability, and paracentral visual perception were significantly enhanced, improving quality of life. CONCLUSIONS This pioneering work reports the use of virtual-reality in a head-mounted display to provide an audiovisual stimulation protocol for low-vision rehabilitation in a hemianopia patient. Real-time data recording and remote control of the stimulation program demonstrate that such rehabilitation treatment can be performed by the patient at home without interruption of care, decreasing the burden of disease. Beneficial effects on visual function were measured according to clinical guidelines of low-vision assessment. Improvement in visual function and quality of life challenge the prevailing belief that post-acute vision loss is both permanent and unchangeable.
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http://dx.doi.org/10.12659/AJCR.931079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202419PMC
June 2021

Bridging the Gap: Exploring the Impact of Hospital Isolation on Peer Relationships Among Children and Adolescents with a Malignant Brain Tumor.

Child Adolesc Social Work J 2021 May 18:1-15. Epub 2021 May 18.

The Hospital for Sick Children, Toronto, ON Canada.

Children and adolescents with complex medical conditions are often uprooted from their environments and isolated in hospital while undergoing treatment. Little is known about how they perceive this isolation and its subsequent impact on their relationships with peers, both during and after isolation for treatment. This study describes the experience of hospital isolation from the perspectives of children and adolescents with a malignant brain tumor. The use and impact of information and communication technologies (ICT) as a possible bridge for contact is also explored. Following a qualitative approach utilizing interpretive phenomenological analysis, in-depth interviews were conducted with eight youth participants who had undergone treatment for medulloblastoma. Data analysis generated three main themes: (1) transforming children and relationships, (2) hospitalization in a digital world, and (3) ICTs as a promising bridge back to school. Study findings provide insight into the experience of hospital isolation for children and adolescents, while highlighting the positive social as well as academic outcomes of frequent, open ended ICT use throughout hospital isolation. This is timely, given the context of the COVID-19 pandemic and its resulting isolation. Considerations for hospital social workers to promote relationships and connection, while facilitating a smooth transition as these children return to school are included.
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http://dx.doi.org/10.1007/s10560-021-00764-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130807PMC
May 2021

Treatment abandonment and refusal among children with central nervous system tumors in Jordan.

Pediatr Blood Cancer 2021 Aug 22;68(8):e29054. Epub 2021 May 22.

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

Background: Treatment abandonment and refusal are reported to contribute significantly to poor survival of children with cancer in low- and middle-income countries. We aimed to assess this phenomenon among children diagnosed with central nervous system (CNS) tumors in Jordan.

Methods: We retrospectively reviewed the medical charts of children <18 years diagnosed with CNS tumors (2010-2020). Patients who abandoned or refused part of treatment were reviewed for their clinical characteristics, social circumstances, and possible reasons. We excluded patients referred for second opinion, radiotherapy only, or who traveled abroad for treatment.

Results: Four hundred seventy-three Jordanian children were identified; 12 families (2.5%) abandoned treatment, and 15 refused part of therapy (3%). Most patients were females (67%) and most had good or moderate performance status (89%). Most families (93%) lived within 2 hours from King Hussein Cancer Center. Most parents were university graduates (71%) and all fathers were employed, while 71% of mothers were housewives. The most common reasons to abandon or refuse therapy were treatment intensity in view of poor tumor outcome or bad quality of life, conflicting recommendations from other health care providers, "personal beliefs" against chemotherapy, and preference to use alternative medicine.

Conclusions: Treatment abandonment and refusal in Jordanian children with CNS tumors is low. Universal cancer insurance, high level of education in the country, centralized cancer care in one institution, and the twinning program likely contributed to our low incidence. Improving knowledge on CNS tumors and better community rehabilitation and supportive services may help further decrease the abandonment and treatment refusal rate.
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http://dx.doi.org/10.1002/pbc.29054DOI Listing
August 2021

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

J Clin Oncol 2021 Sep 4;39(25):2779-2790. Epub 2021 May 4.

Lebanese American University Medical Center-Rizk, Beirut, Lebanon.

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.

Patients And Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.

Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years.

Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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http://dx.doi.org/10.1200/JCO.20.02636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407605PMC
September 2021

Diffuse intrinsic pontine glioma: a clinic in Mexico, social media, and unpublishable data.

Lancet Oncol 2021 05;22(5):595-596

Department of Pediatric Oncology, La Timone Children's Hospital, AP-HM, Marseille, France; Metronomics Global Health Initiative, Marseille, France.

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http://dx.doi.org/10.1016/S1470-2045(21)00009-7DOI Listing
May 2021

The threat of the COVID-19 pandemic on reversing global life-saving gains in the survival of childhood cancer: a call for collaborative action from SIOP, IPSO, PROS, WCC, CCI, St Jude Global, UICC and WHPCA.

Ecancermedicalscience 2021 15;15:1187. Epub 2021 Feb 15.

Paediatric Oncology in Developing Countries (PODC) Committee, International Society of Paediatric Oncology (SIOP), Industriestrasse 25, 6312 Steinhausen, Switzerland.

The COVID-19 pandemic poses an unprecedented health crisis in all socio-economic regions across the globe. While the pandemic has had a profound impact on access to and delivery of health care by all services, it has been particularly disruptive for the care of patients with life-threatening noncommunicable diseases (NCDs) such as the treatment of children and young people with cancer. The reduction in child mortality from preventable causes over the last 50 years has seen childhood cancer emerge as a major unmet health care need. Whilst survival rates of 85% have been achieved in high income countries, this has not yet been translated into similar outcomes for children with cancer in resource-limited settings where survival averages 30%. Launched in 2018, by the World Health Organization (WHO), the Global Initiative for Childhood Cancer (GICC) is a pivotal effort by the international community to achieve at least 60% survival for children with cancer by 2030. The WHO GICC is already making an impact in many countries but the disruption of cancer care during the COVID-19 pandemic threatens to set back this global effort to improve the outcome for children with cancer, wherever they may live. As representatives of the global community committed to fostering the goals of the GICC, we applaud the WHO response to the COVID-19 pandemic, in particular we support the WHO's call to ensure the needs of patients with life threatening NCDs including cancer are not compromised during the pandemic. Here, as collaborative partners in the GICC, we highlight specific areas of focus that need to be addressed to ensure the immediate care of children and adolescents with cancer is not disrupted during the pandemic; and measures to sustain the development of cancer care so the long-term goals of the GICC are not lost during this global health crisis.
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http://dx.doi.org/10.3332/ecancer.2021.1187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987488PMC
February 2021

The transcriptional landscape of Shh medulloblastoma.

Nat Commun 2021 03 19;12(1):1749. Epub 2021 Mar 19.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-21883-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819PMC
March 2021

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

Clin Cancer Res 2021 May 18;27(10):2879-2889. Epub 2021 Mar 18.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.

Materials And Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; = 52) and children (SJMB03: age 3-21 years; = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.

Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR ( = 21), SHH ( = 30), and MYC ( = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. GLAs were not associated with PFS.

Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127412PMC
May 2021

Brainstem gliomas … the devil is in the details.

Neuro Oncol 2021 06;23(6):869-871

Division of Haematology Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada (A.F., E.B.).

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http://dx.doi.org/10.1093/neuonc/noab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168808PMC
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

Challenges in the Management of Childhood Intracranial Germ Cell Tumors in Middle-Income Countries: A 20-Year Retrospective Review From a Single Tertiary Center in Malaysia.

J Pediatr Hematol Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Pediatrics, Division of Hematology-Oncology Department of Surgery, Division of Neurosurgery Departments of Pathology Radiology Clinical-Radiation Oncology, University Malaya Medical Center, Kuala Lumpur, Malaysia Department of Pediatric Hematology-Oncology, Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, TN Department of Pediatric and Adolescent Oncology/Hematology, Perth Children's Hospital, Nedlands, WA, Australia Department of Pediatric Hematology-Oncology, Division of Neuro-oncology, Hospital for Sick Children, Toronto, ON, Canada.

Background: A higher incidence of pediatric intracranial germ cell tumors (iGCTs) in Asian countries compared with Western countries has been reported. In Malaysia, the literature regarding pediatric iGCTs have been nonexistent. The aim of this study was to review the management, survival, and long-term outcomes of pediatric iGCTs at a single tertiary center in Malaysia.

Patients And Methods: We retrospectively reviewed data from patients aged below 18 years with iGCTs treated at the University Malaya Medical Center (UMMC) from 1998 to 2017.

Results: Thirty-four patients were identified, with a median follow-up of 3.54 years. Sixteen (47%) patients had pure germinoma tumors (PGs), and the remaining patients had nongerminomatous germ cell tumors (NGGCTs). The median age was 12 years, with a male:female ratio of 4.7:1. Abnormal vision, headache with vomiting, and diabetes insipidus were the commonest presenting symptoms. Twenty-eight patients received initial surgical interventions, 24 were treated with chemotherapy, and 28 received radiotherapy. Eight patients experienced relapses. The 5- and 10-year event-free survival rates were similar at 61.1%±12.6% and 42.9%±12.1% for PG and NGGCT, respectively. The 5- and 10-year overall survival rates were the same at 75.5%±10.8% and 53.3%±12.3% for PG and NGGCT, respectively. Four patients died of treatment-related toxicity. Most of the survivors experienced good quality of life with satisfactory neurological status.

Conclusions: The survival rate of childhood iGCTs in UMMC was inferior to that reported in developed countries. Late diagnosis, poor adherence to treatment, and treatment-related complications were the contributing factors. Although these results highlight a single institution experience, they most likely reflect similar treatment patterns, outcomes, and challenges in other centers in Malaysia.
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http://dx.doi.org/10.1097/MPH.0000000000002116DOI Listing
February 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

[Formula: see text]Family environment as a predictor and moderator of cognitive and psychosocial outcomes in children treated for posterior fossa tumors.

Child Neuropsychol 2021 Jul 17;27(5):641-660. Epub 2021 Feb 17.

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

. The current study examined the effects of clinical factors (i.e., treatment type, history of cerebellar mutism) as well as environmental factors (i.e., family environment) as predictors of cognitive and psychosocial outcomes in children treated for posterior fossa tumors.. Twenty-seven children/adolescents treated for posterior fossa tumors (treatment type: radiation [ = 12], surgery [ = 15]; history of mutism: yes [ = 7], no [ = 20]) and = 13 healthy controls, aged 8-17 years, and their caregivers completed measures assessing cognitive and psychosocial functioning, as well as the family environment (i.e., parental education, family functioning, family psychiatric history). Hierarchical linear regression analyses were conducted to examine the role of clinical factors and the family environment as predictors of cognitive and psychosocial outcomes. Family environment was also examined as a moderator of clinical factor group differences in outcomes.. Regression analyses revealed lower intelligence scores among the radiation group compared to the control group, lower verbal memory scores among both treatment groups compared to the control group, and a significant positive effect of parental education on verbal memory scores. Further, history of cerebellar mutism predicted poorer performance on a speeded naming task, and this relationship was moderated by family functioning, with a greater effect of mutism present among those with poorer family functioning.. Interventions aimed at improving the family environment may help to mitigate negative cognitive effects of pediatric brain tumors, particularly among those most at-risk for poor outcomes.
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http://dx.doi.org/10.1080/09297049.2021.1885639DOI Listing
July 2021

Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q.

Neuro Oncol 2021 08;23(8):1360-1370

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

Background: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification.

Methods: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival.

Results: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group.

Conclusions: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.
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http://dx.doi.org/10.1093/neuonc/noab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328032PMC
August 2021

Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition.

Cancer Discov 2021 Jun 9;11(6):1454-1467. Epub 2021 Feb 9.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for mutations ( = 10). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition and . Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406556PMC
June 2021

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

J Clin Oncol 2021 03 27;39(7):807-821. Epub 2021 Jan 27.

Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX.

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving , , and . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
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http://dx.doi.org/10.1200/JCO.20.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078396PMC
March 2021

Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03).

J Clin Oncol 2021 03 6;39(7):822-835. Epub 2021 Jan 6.

Hartwell Center, St Jude Children's Research Hospital, Memphis, TN.

Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma.

Patients And Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories.

Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( = .74) or when patients were stratified by clinical risk ( = .71). Mutations in (96%), (37%), and (24%) were most common in WNT tumors and (38%), (21%), and (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%).

Conclusion: These results establish a new risk stratification for future medulloblastoma trials.
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http://dx.doi.org/10.1200/JCO.20.01372DOI Listing
March 2021

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

Cancer Discov 2021 May 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
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