Incidence trends in pediatric central nervous system tumors in Canada: a 15 years report from Cancer and Young People in Canada (CYP-C) registry

Abstract Background The aim of this study is to present a national surveillance report on pediatric central nervous system (CNS) tumors in Canada during the period between 2001 and 2015. Methods All pediatric patients with a diagnosis of primary CNS tumors were collected by the Cancer in Young People in Canada (CYP-C) surveillance system that includes every patient less than 15 years of age with a tumor seen in one of the 17 pediatric oncology centres in Canada. This registry included malignant and benign CNS tumors. We calculated the age-adjusted incidence rates (AAIRs) per 100 000 person-years for CNS tumors overall and by age group, major histology subgroups, and geographical distribution over the country. Results Overall, 3306 patients less than 15 years old had been diagnosed with a CNS tumor in Canada in 2001–2015 with a 1.23:1 male to female ratio. The overall AAIR is 3.80. The three most frequent groups of tumors were low-grade gliomas (36.4%), high-grade gliomas (22.3%), and embryonal tumors (18.7%) with incidence rates of 1.41, 0.86, and 0.72 per 100 000 person-years, respectively. The incidence rate of pediatric CNS tumors is stable during the period 2001–2015 in Canada and no significant differences were seen between malignant and benign tumors over the country. Conclusions These data represent all the pediatric patients 0–14 years old with a CNS tumor in the Canadian population. Incidence rates by age group, sex, and subgroups of tumors are similar to those seen in the literature.

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Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2002 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2002-2002

Author(s):

Sébastien Perreault ◽

Cornelis Martinus van Tilburg ◽

Birgit Geoerger ◽

Karsten Nysom ◽

Ingrid Ora ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Disease Control ◽

Pediatric Patients ◽

Disease Control Rate ◽

Cns Tumors ◽

Low Grade ◽

Gene Fusions ◽

Receptor Kinase

2002 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types, including central nervous system (CNS) tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across 175 adult and pediatric patients with various non-CNS cancers (McDermott et al, ESMO 2020). We report data on patients with TRK fusion-positive primary CNS tumors. Methods: Patients with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, and 1 small round blue cell tumor. The patients had gene fusions involving NTRK2 (n = 24; 73%), NTRK1 (n = 5; 15%), and NTRK3 (n = 4; 12%). Median age was 8.9 years (range 1.3–79.0); 26 patients were pediatric ( < 18 years). Patients were heavily pre-treated with 45% having 2 or more prior lines of systemic therapy. The ORR in all patients was 30% (95% CI 16–49): 3 complete responses (all in pediatric patients), 7 partial responses (2 pending confirmation), 20 stable disease (including 15 pts > 6 months), and 3 progressive disease. The ORR in patients with HGG and LGG were 26% (95% CI 9–51) and 38% (95% CI 9–76), respectively. In all patients, the 24-week disease control rate was 73% (95% CI 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months. Median duration of response (DoR) was not reached (95% CI 3.8–not estimable [NE]) at a median follow-up of 12.0 months. The 12-month DoR rate was 75% (95% CI 45–100). Median PFS was 18.3 months (95% CI 6.7–NE) at a median follow-up of 16.5 months. Median overall survival (OS) was not reached (95% CI 16.9–NE) at a median follow-up of 16.5 months, with a 12-month OS rate of 85% (95% CI 71–99). Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events (TRAE) were reported by 20 patients and were Grade 3–4 in 3 patients (9%). There were no treatment discontinuations due to TRAEs. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile. These results support testing for NTRK gene fusions in patients of all ages with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

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QOL-36. USE OF CANNABINOIDS IN THE PEDIATRIC CENTRAL NERVOUS SYSTEM TUMOR POPULATION

Neuro-Oncology ◽

10.1093/neuonc/noaa222.695 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii438-iii438

Author(s):

Kathleen Dorris ◽

Jessica Channell ◽

Ashley Mettetal ◽

Molly Hemenway ◽

Natalie Briones ◽

...

Keyword(s):

Quality Of Life ◽

Central Nervous System ◽

Nervous System ◽

Cell Activity ◽

Cns Tumors ◽

Low Grade ◽

Tumor Type ◽

Central Nervous System Tumor ◽

The Impact

Abstract BACKGROUND Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are a class of compounds found in marijuana. Numerous studies in adults have examined cannabinoid use in management of cancer-related symptoms such as nausea, anorexia, and pain. Less is known about the use in the pediatric oncology population. METHODS A prospective observational study has been ongoing since 2016 at Children’s Hospital Colorado to evaluate cannabinoids’ impact using PedsQL™ modules on quality of life of pediatric patients with central nervous system (CNS) tumors who are 2–18 years old. Laboratory assessments of T-cell activity and pharmacokinetics of CBD, THC and associated metabolites are in process. Diaries with exploratory information on cannabinoid use patterns are being collected. RESULTS Thirty-three patients (14:19; male:female) have been enrolled with a median age of 6.4 years (range, 2.9–17.7 years). The most common tumor type in enrolled patients is embryonal tumors (13/33; 39%). Nine (27%) patients have low-grade glial/glioneuronal tumors, and eight (24%) had high-grade/diffuse midline gliomas. The remaining patients had ependymoma or craniopharyngioma. The median time on cannabinoids is 9 months. Most (n=20) patients have used oral products with CBD and THC. One patient continues on cannabinoid therapy in follow up. Preliminary immune function analyses identified impaired neutrophil superoxide anion production and chemotaxis in patients taking cannabinoids at early time points on therapy. CONCLUSIONS Families of children with various CNS tumors are pursuing cannabinoid therapy for both antitumor and supportive care purposes. Analysis of the impact of cannabinoids on patients’ quality of life is ongoing.

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PATH-27. MUTATION DETECTION USING PLASMA CELL-FREE DNA IN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.662 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii430-iii430

Author(s):

Ross Mangum ◽

Jacquelyn Reuther ◽

Koel Sen Baksi ◽

Ryan C Zabriskie ◽

Ilavarasi Gandhi ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Plasma Cell ◽

Pediatric Patients ◽

Cns Tumors ◽

Cell Free Dna ◽

Pilot Studies ◽

Dna And Rna ◽

Free Dna ◽

Initial Cohort

Abstract BACKGROUND The role of plasma cell-free DNA (cfDNA) as a cancer biomarker for tracking treatment response and detecting early relapse has been well described for solid tumors outside the central nervous system (CNS). However, the presence of a blood-brain barrier complicates the application of plasma cfDNA analysis for patients with CNS malignancies. METHODS cfDNA was extracted from plasma of pediatric patients with CNS tumors utilizing a QIAmp® MinElute® kit and quantitated with Qubit 2.0 Fluorometer. Extensive genomic testing, including targeted DNA and RNA solid tumor panels, exome and transcriptome sequencing, as well as copy number array, was performed on matched tumor samples as part of the Texas KidsCanSeq study. An Archer® Reveal ctDNA28 NGS kit was then used for assaying the sensitivity of detecting tumor-specific mutations in the plasma of these patients. RESULTS A median of 10.7ng cfDNA/mL plasma (Interquartile range: 6.4 – 15.3) was extracted from 78 patients at time of study enrollment. Longitudinal samples from 24 patients exhibited a median yield of 7.7ng cfDNA/mL plasma (IQR: 5.9 – 9.1). An initial cohort of 6 patients was identified with 7 somatic variants covered by the Archer® Reveal kit. Four of seven mutations identified in matched tumor specimens were detected in patient plasma at variant allele frequencies ranging from 0.2–1%. CONCLUSIONS While challenging, detection of cfDNA in the plasma of pediatric patients with CNS tumors is possible and is being explored in a larger patient cohort along with pilot studies investigating cerebrospinal fluid as an additional source for tumor-specific cfDNA.

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Co-Deregulated miRNA Signatures in Childhood Central Nervous System Tumors: In Search for Common Tumor miRNA-Related Mechanics

Cancers ◽

10.3390/cancers13123028 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3028

Author(s):

George I. Lambrou ◽

Apostolos Zaravinos ◽

Maria Braoudaki

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cns Tumors ◽

Normal Brain ◽

Cns Tumor ◽

Different Types ◽

Receiver Operator Curve Analysis ◽

The Central Nervous System ◽

Tumor Types ◽

Operator Curve

Despite extensive experimentation on pediatric tumors of the central nervous system (CNS), related to both prognosis, diagnosis and treatment, the understanding of pathogenesis and etiology of the disease remains scarce. MicroRNAs are known to be involved in CNS tumor oncogenesis. We hypothesized that CNS tumors possess commonly deregulated miRNAs across different CNS tumor types. Aim: The current study aims to reveal the co-deregulated miRNAs across different types of pediatric CNS tumors. Materials: A total of 439 CNS tumor samples were collected from both in-house microarray experiments as well as data available in public databases. Diagnoses included medulloblastoma, astrocytoma, ependydoma, cortical dysplasia, glioblastoma, ATRT, germinoma, teratoma, yoc sac tumors, ocular tumors and retinoblastoma. Results: We found miRNAs that were globally up- or down-regulated in the majority of the CNS tumor samples. MiR-376B and miR-372 were co-upregulated, whereas miR-149, miR-214, miR-574, miR-595 and miR-765 among others, were co-downregulated across all CNS tumors. Receiver-operator curve analysis showed that miR-149, miR-214, miR-574, miR-595 and miR765 could distinguish between CNS tumors and normal brain tissue. Conclusions: Our approach could prove significant in the search for global miRNA targets for tumor diagnosis and therapy. To the best of our knowledge, there are no previous reports concerning the present approach.

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LINC-39. PERFORMANCE STATUS OF PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS TREATED IN MEXICO, A SINGLE-CENTER EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noaa222.472 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii385-iii386

Author(s):

Claudia Madrigal-Avila ◽

Alfonso Perez-Bañuelos ◽

Rafael Ruvalcaba-Sanchez ◽

Lourdes Vega-Vega ◽

Gabriela Escamilla-Asiain

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Multidisciplinary Approach ◽

Pediatric Patients ◽

Performance Status ◽

Retrospective Chart Review ◽

Cns Tumors ◽

Surgical Morbidity ◽

Tertiary Center

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age, they comprise about a quarter of all cancers at this age. Little is known about the specific epidemiology of this group in Mexico and there are no reports of results focused on the Performance Status of patients who are treated in a multidisciplinary setting. OBJECTIVE To describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center. METHODS We report a retrospective chart review of all pediatric patients who presented to the Neuro-Oncology Clinic at Teleton Pediatric Oncology Hospital in Queretaro, Mexico, from December 2014 to January 2020. We analyzed age, gender, the extent of surgical resection and histopathology. Performance Status was assessed using ECOG and Karnofsky/Lansky scores during every patient’s last follow-up visit. RESULTS A total of 56 patients were treated, epidemiology and histopathology variants are similar to those described in the international literature. With a median follow-up of 33 months, 35 patients are alive (62.5%), 28 of them (74.2%) have an excellent Performance Status (ECOG score 0 or Lansky/Karnofsky ≥ 90), 5 (14.2%) scored ECOG 1–2 and only 4 (11.4%) scored ECOG 3–4. CONCLUSIONS A multidisciplinary approach with a focus on Performance Status and the potential for neurological recovery is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term.

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Long-term medical imaging use in children with central nervous system tumors

PLoS ONE ◽

10.1371/journal.pone.0248643 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0248643

Author(s):

Erin J. A. Bowles ◽

Diana L. Miglioretti ◽

Marilyn L. Kwan ◽

Ute Bartels ◽

Adam Furst ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Medical Imaging ◽

Tumor Grade ◽

Tumor Diagnosis ◽

Cns Tumors ◽

Cns Tumor ◽

Longitudinal Imaging ◽

The U.S

Background Children with central nervous system (CNS) tumors undergo frequent imaging for diagnosis and follow-up, but few studies have characterized longitudinal imaging patterns. We described medical imaging in children before and after malignant CNS tumor diagnosis. Procedure We conducted a retrospective cohort study of children aged 0–20 years diagnosed with CNS tumors between 1996–2016 at six U.S. integrated healthcare systems and Ontario, Canada. We collected computed topography (CT), magnetic resonance imaging (MRI), radiography, ultrasound, nuclear medicine examinations from 12 months before through 10 years after CNS diagnosis censoring six months before death or a subsequent cancer diagnosis, disenrollment from the health system, age 21 years, or December 31, 2016. We calculated imaging rates per child per month stratified by modality, country, diagnosis age, calendar year, time since diagnosis, and tumor grade. Results We observed 1,879 children with median four years follow-up post-diagnosis in the U.S. and seven years in Ontario, Canada. During the diagnosis period (±15 days of diagnosis), children averaged 1.10 CTs (95% confidence interval [CI] 1.09–1.13) and 2.14 MRIs (95%CI 2.12–2.16) in the U.S., and 1.67 CTs (95%CI 1.65–1.68) and 1.86 MRIs (95%CI 1.85–1.88) in Ontario. Within one year after diagnosis, 19% of children had ≥5 CTs and 45% had ≥5 MRIs. By nine years after diagnosis, children averaged one MRI and one radiograph per year with little use of other imaging modalities. Conclusions MRI and CT are commonly used for CNS tumor diagnosis, whereas MRI is the primary modality used during surveillance of children with CNS tumors.

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An Integrated Analysis of Tumor Purity of Common Central Nervous System Tumors in Children Based on Machine Learning Methods

Frontiers in Genetics ◽

10.3389/fgene.2021.707802 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jian Yang ◽

Jiajia Wang ◽

Shuaiwei Tian ◽

Qinhua Wang ◽

Yang Zhao ◽

...

Keyword(s):

Machine Learning ◽

Central Nervous System ◽

Nervous System ◽

Random Forest ◽

Cns Tumors ◽

Integrated Analysis ◽

Immune Microenvironment ◽

Cns Tumor ◽

Tumor Sample ◽

Tumor Purity

Background: Tumor purity is defined as the proportion of cancer cells in the tumor tissue, and its effects on molecular genetics, the immune microenvironment, and the prognosis of children’s central nervous system (CNS) tumors are under-researched.Methods: We applied random forest machine learning, the InfiniumPurify algorithm, and the ESTIMATE algorithm to estimate the tumor purity of every child’s CNS tumor sample in several published pediatric CNS tumor sample datasets from Gene Expression Omnibus (GEO), aiming to perform an integrated analysis on the tumor purity of children’s CNS tumors.Results: Only the purity of CNS tumors in children based on the random forest (RF) machine learning method was normally distributed. In addition, the children’s CNS tumor purity was associated with primary clinical pathological and molecular indicators. Enrichment analysis of biological pathways related to the purity of medulloblastoma (MB) revealed some classical signaling pathways associated with MB biology and development-related pathways. According to the correlation analysis between MB purity and the immune microenvironment, three immune-related genes, namely, CD8A, CXCR2, and TNFRSF14, were negatively related to MB purity. In contrast, no significant correlation was detected between immunotherapy-associated markers, such as PD-1, PD-L1, and CTLA4; most infiltrating immune cells; and MB purity. In the tumor purity–related survival analysis of MB, ependymoma (EPN), and children’s high-grade glioma, we discovered a minor effect of tumor purity on the survival of the aforementioned pediatric patients with CNS tumors.Conclusion: Our purity pediatric pan-CNS tumor analysis provides a deeper understanding and helps with the clinical management of pediatric CNS tumors.

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A Comparison of Epidemiological Characteristics of Central Nervous System Tumours in China and Globally from 1990 to 2019

Neuroepidemiology ◽

10.1159/000519463 ◽

2021 ◽

Vol 55 (6) ◽

pp. 460-472

Author(s):

Bo Zhu ◽

Xiaomei Wu ◽

Haozhe Piao ◽

Shuang Xu ◽

Bing Yao

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Epidemiological Data ◽

Incidence Rates ◽

Older Age ◽

Age Group ◽

Central Nervous System Tumours ◽

Life Years ◽

Epidemiological Characteristics ◽

Incident Cases

Background: Despite their great disease burden, there have been few studies on the epidemiology of central nervous system tumours (CNSTs) in China. We used the latest data updated by GBD to analyse the trends of incidence, mortality, and disability-adjusted life years (DALYs) for CNSTs in China versus globally. Methods: Epidemiological data on CNSTs were extracted from GBD 2019. We used Joinpoint regression analysis to calculate the magnitude and direction of the trends and the age-period-cohort method to analyse the age, period, and cohort effects of the trend. Results: From 1990 to 2019, the 106.52% increase in Chinese incident cases was higher than the global increase (94.35%). The 67.32% increase in cancer deaths and 16.03% increase in DALYs were lower than the global increases (cancer death: 76.36%; DALYs: 40.06%). The age-standardized incidence rates (ASIRs) in China were higher than the global ASIRs, and the increase in China was higher than that globally. Although the age-standardized mortality rates and age-standardized DALY rates in China were higher, their increases in China were less than those globally. Both in China and globally, the number and incidence, mortality, and DALYs by age group showed a bimodal distribution (younger than 5 years and older), and the peak in the older age group showed a backwards trend. The proportion of incident cases, cancer deaths, and DALYs also increased in the older age group. In the age-period-cohort model, the local drifts in the older age group were above zero. Conclusions: The burden of CNSTs is very serious in China, and we should pay attention to the key populations, early diagnosis technology, improvements in medical technology, and ways to reduce medical costs. We believe our results could help policymakers allocate resources efficiently to reduce the burden of CNSTs.

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Practical Neuropathology Synoptic Reporting for Central Nervous System Tumors

Archives of Pathology & Laboratory Medicine ◽

10.5858/2010-0193-ra.1 ◽

2011 ◽

Vol 135 (6) ◽

pp. 789-792

Author(s):

Mark W. Becher

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Data Extraction ◽

Tnm Classification ◽

Cns Tumors ◽

Imaging Data ◽

Cns Tumor ◽

Narrative Report ◽

Laboratory Information Systems ◽

Synoptic Reporting

Abstract Context.—Synoptic reporting for central nervous system (CNS) tumors has never been formally addressed, and neuropathologists lack practical templates that they can adapt to their laboratory information system to be compliant with College of American Pathologists (CAP) standards. Objectives.—To provide practical synoptic report templates designed for CNS tumors that allow for easy data extraction and CAP compliance and improve the reporting of CNS tumors. Data Sources.—Review of literature and synoptic report format experience in our practice. Conclusions.—Synoptic reporting of required elements is a recently introduced standard for CNS tumors. It is difficult to use a universal non-CNS tumor synoptic report template for CNS tumors because they are heavily weighted to include items not important or required for CNS tumors, such as margins and the TNM classification system. In addition, the CAP CNS protocol, published in 2008, is an immense comprehensive document that is not conducive to simple inclusion in a narrative report. We describe our experience using a synoptic template for CNS tumors that includes all required elements, is tailored to the practice of neuropathology, and can easily be adapted to other laboratory information systems. Because of the multidisciplinary nature of CNS tumor diagnoses, neuropathologists typically collect clinical, demographic, and imaging data on all CNS tumor cases. These data can readily be entered into a primary synoptic report that could replace our standard narrative report.

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PATH-21. CLINICAL UTILITY OF DNA METHYLATION PROFILING FOR DIAGNOSIS OF CHALLENGING CENTRAL NERVOUS SYSTEM TUMORS: THE TORONTO EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noz175.617 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi147-vi147

Author(s):

Shirin Karimi ◽

Jeffrey Zuccato ◽

Yasin Mamatjan ◽

Sheila Mansouri ◽

Suganth Suppiah ◽

...

Keyword(s):

Dna Methylation ◽

Central Nervous System ◽

Nervous System ◽

Clinical Utility ◽

Cns Tumors ◽

Cns Tumor ◽

Dna Methylation Profiling ◽

Diffuse Gliomas ◽

Methylation Profiling

Abstract The update on the WHO classification of central nervous system (CNS) tumors incorporated molecular signatures for a more accurate diagnosis. Recently, DKFZ has demonstrated the utility of DNA methylation profiling(MP) for molecular classification of CNS tumors. We performed a prospective clinical study over the last three years to evaluate the clinical utility ofDNA MP on FFPE samples of 66 challenging CNS tumor cases using online DKFZ classifier. Eleven samples were excluded due to low tumor DNA content or low calibration(predictive) scores(CS)< 0.3.DNA MP confirmed the original pathology diagnoses in 15(27%)cases. The integrated molecular diagnoses were changed in 38/55(70%) including establishment of a new diagnostic entity, change in molecular signature and subtyping. TheWHO grades were changed in 16(27%) of the tumors; about two-thirds resulted in upgrading. We detected non-canonical IDH mutations in 9 diffuse gliomas and the CNV plots revealed false positive FISH results for 1p/19q co-deletion in two diffuse gliomas. The CNV plots contributed to the final diagnosis in 40(72%) patients. The molecular subtypes of medulloblastoma, ependymoma and glioblastoma subclasses were determined in 36(65%) cases. Seventy-five percent of cases with confirmation of initial diagnosis or change in molecular diagnosis had CS > 0.5, among which 51% had a CS >0.9. The median and range CS of cases with new diagnostic entity and confirmed cases were 0.86(0.37–0.99) and 0.98(0.42–0.99), respectably. Furthermore, we detected higher CS in IDH-mutant gliomas in comparison to glioblastoma IDH-wild type(P=0.04). We also observed lower CS in mesenchymal glioblastoma in comparison to other subclasses. The MGMT promoter methylation was determined in 17/20(85%) glioblastoma cases. While the DKFZ group established CS of 0.9 as a cut-off for matching to methylation classes, our findings suggest lower threshold values in challenging CNS tumor cases. Our experience indicates clinical utility of MP of challenging CNS tumors as a reliable ancillary diagnostic tool in routine neuropathology practice.

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