Disease Evolution Monitored by Serial Cerebrospinal Fluid Liquid Biopsies in Two Cases of Recurrent Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in childhood. Initial treatment generally includes surgery, irradiation, and chemotherapy. Approximately 20-30% of patients will experience a recurrence, which portends a very poor prognosis. The current standard of care for evaluation for relapse includes radiographic surveillance with magnetic resonance imaging at regular intervals. The presence of circulating tumor DNA in the cerebrospinal fluid has been demonstrated to be a predictor of a higher risk of progression in a research setting for patients with medulloblastoma treated on a prospective single institution clinical trial. We have previously published and clinically validated a liquid-biopsy-based genetic assay utilizing low-pass whole genome sequencing to detect copy number alterations in circulating tumor DNA. Here, we present two teenage patients with posterior fossa medulloblastoma with recurrent disease who have been monitored with serial liquid biopsies showing tumor evolution over time, demonstrating the clinical utility of these approaches.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods: A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results: A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions: GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Use of External Control Cohorts in Pediatric Brain Tumor Clinical Trials.

Why, when, and how to consider external control cohorts in pediatric brain tumor clinical trials.

OpenPBTA: The Open Pediatric Brain Tumor Atlas.

Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.

Low-pass whole-genome and targeted sequencing of cell-free DNA from cerebrospinal fluid in pediatric patients with central nervous system tumors.

Background: Central nervous system tumors are the most common pediatric solid tumors and the most frequent cause of cancer-related morbidity in childhood. Significant advances in understanding the molecular features of these tumors have facilitated the development of liquid biopsy assays that may aid in diagnosis and monitoring response to therapy. In this report, we describe our comprehensive liquid biopsy platform for detection of genome-wide copy number aberrations, sequence variants, and gene fusions using cerebrospinal fluid (CSF) from pediatric patients with brain, spinal cord, and peripheral nervous system tumors. Methods: Cell-free DNA was isolated from the CSF from 55 patients, including 47 patients with tumors and 8 controls. Results: Abnormalities in cell-free DNA were detected in 24 (51%) patients including 11 with copy number alterations, 9 with sequence variants, and 7 with KIAA1549::BRAF fusions. Positive findings were obtained in patients spanning histologic subtypes, tumor grades, and anatomic locations. Conclusions: This study demonstrates the feasibility of employing this platform in routine clinical care in upfront diagnostic and monitoring settings. Future studies are required to determine the utility of this approach for assessing response to therapy and long-term surveillance.

Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor.

Atypical teratoid rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors that occur mostly in young children and have historically carried a very poor prognosis. While recent clinical trial results show that this tumor is curable, outcomes are still poor compared to other central nervous system embryonal tumors. We here review prior AT/RT clinical trials and highlight promising pre-clinical results that may inform novel clinical approaches to this aggressive cancer.

Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

MR multitasking-based dynamic imaging for cerebrovascular evaluation (MT-DICE): Simultaneous quantification of permeability and leakage-insensitive perfusion by dynamic T 1 / T 2 * mapping.

PURPOSE: To develop an MR multitasking-based dynamic imaging for cerebrovascular evaluation (MT-DICE) technique for simultaneous quantification of permeability and leakage-insensitive perfusion with a single-dose contrast injection. METHODS: MT-DICE builds on a saturation-recovery prepared multi-echo fast low-angle shot sequence. The k-space is randomly sampled for 7.6 min, with single-dose contrast agent injected 1.5 min into the scan. MR multitasking is used to model the data into six dimensions, including three spatial dimensions for whole-brain coverage, a saturation-recovery time dimension, and a TE dimension for dynamic T 1 $$ {\mathrm{T}}_1 $$ and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ quantification, respectively, and a contrast dynamics dimension for capturing contrast kinetics. The derived pixel-wise T 1 / T 2 * $$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$ time series are converted into contrast concentration-time curves for calculation of kinetic metrics. The technique was assessed for its agreement with reference methods in T 1 $$ {\mathrm{T}}_1 $$ and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ measurements in eight healthy subjects and, in three of them, inter-session repeatability of permeability and leakage-insensitive perfusion parameters. Its feasibility was also demonstrated in four patients with brain tumors. RESULTS: MT-DICE T 1 / T 2 * $$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$ values of normal gray matter and white matter were in excellent agreement with reference values (intraclass correlation coefficients = 0.860/0.962 for gray matter and 0.925/0.975 for white matter ). Both permeability and perfusion parameters demonstrated good to excellent intersession agreement with the lowest intraclass correlation coefficients at 0.694. Contrast kinetic parameters in all healthy subjects and patients were within the literature range. CONCLUSION: Based on dynamic T 1 / T 2 * $$ {\mathrm{T}}_1/{\mathrm{T}}_2^{\ast } $$ mapping, MT-DICE allows for simultaneous quantification of permeability and leakage-insensitive perfusion metrics with a single-dose contrast injection.

Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics.

BACKGROUND: The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. METHODS: We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. RESULTS: Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. CONCLUSIONS: A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Quantitative Nuclear Histomorphometry Predicts Molecular Subtype and Clinical Outcome in Medulloblastomas: Preliminary Findings.

Molecular subtypes of medulloblastoma [Sonic Hedgehog (SHH), Wingless/INT (WNT), Group 3, and Group 4] are defined by common patterns of gene expression. These differential gene expression patterns appear to result in different histomorphology and prognosis. Quantitative histomorphometry is a well-known method of computer-aided pathology image analysis. The hypotheses we sought to examine in this preliminary proof of concept study were whether computer extracted nuclear morphological features of medulloblastomas from digitized tissue slide images could independently: (1) distinguish between molecularly determined subgroups and (2) identify patterns within these subgroups that correspond with clinical outcome. Our dataset was composed of 46 medulloblastoma patients: 16 SHH (5 dead, 11 survived), 3 WNT (0 dead, 3 survived), 12 Group 3 (4 dead, 8 survived), and 15 were Group 4 (5 dead, 10 survived). A watershed-based thresholding scheme was used to automatically identify individual nuclei within digitized whole slide hematoxylin and eosin tissue images. Quantitative histomorphometric features corresponding to the texture (variation in pixel intensity), shape (variations in size, roundness), and architectural rearrangement (distances between, and number of connected neighbors) of nuclei were subsequently extracted. These features were ranked using feature selection schemes and these top-ranked features were then used to train machine-learning classifiers via threefold cross-validation to separate patients based on: (1) molecular subtype and (2) disease-specific outcomes within the individual molecular subtype groups. SHH and WNT tumors were separated from Groups 3 and 4 tumors with a maximum area under the receiver operating characteristic curve (AUC) of 0.7, survival within Group 3 tumors was predicted with an AUC of 0.92, and Group 3 and 4 patients were separated into high- and low-risk groups with p = 0.002. Model prediction was quantitatively compared with age, stage, and histological subtype using univariate and multivariate Cox hazard ratio models. Age was the most statistically significant variable for predicting survival in Group 3 and 4 tumors, but model predictions had the highest hazard ratio value. Quantitative nuclear histomorphometry can be used to study medulloblastoma genetic expression phenotypes as it may distinguish meaningful features of disease pathology.

Safety of Tumor Treating Fields (TTFields) therapy in pediatric patients with malignant brain tumors: Post-marketing surveillance data.

There is an unmet need to develop effective and tolerable treatments for pediatric patients with malignant central nervous system tumors. This is especially essential for pediatric patients with aggressive brain tumors such as high-grade gliomas, which have a typical survival rate of under 2 years. Tumor Treating Fields (TTFields) are locoregional, noninvasive electric fields that produce an antimitotic effect on cancerous cells when applied to the skin via arrays. TTFields therapy (200 kHz) is currently approved in adult patients with newly diagnosed glioblastoma (GBM), with temozolomide, and recurrent GBM as monotherapy. Positive preclinical and clinical data have encouraged off-label use of TTFields therapy in pediatric patients with brain tumors, and this study aims to explore the safety of TTFields therapy in pediatric patients (0-18 years of age) based on data from an unsolicited post-marketing surveillance safety database. The real-world data reported here demonstrate that TTFields therapy has a favorable safety profile for pediatric patients with brain tumors, with no new safety signals observed. Findings from this study warrant further research into the efficacy of TTFields therapy, as well as its potential impact on the quality of life in pediatric patients.

Multi-institutional analysis of central nervous system germ cell tumors in patients with Down syndrome.

PURPOSE: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard of care has not been established due to paucity of data. METHODS: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. RESULTS: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n = 13; 31.7%), followed by posterior fossa (n = 7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from postsurgery cardiopulmonary failure, one from pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. CONCLUSION: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

BACKGROUND: The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

Novel MRI deformation-heterogeneity radiomic features are associated with molecular subgroups and overall survival in pediatric medulloblastoma: Preliminary findings from a multi-institutional study.

Introduction: Medulloblastoma (MB) is a malignant, heterogenous brain tumor. Advances in molecular profiling have led to identifying four molecular subgroups of MB (WNT, SHH, Group 3, Group 4), each with distinct clinical behaviors. We hypothesize that (1) aggressive MB tumors, growing heterogeneously, induce pronounced local structural deformations in the surrounding parenchyma, and (b) these local deformations as captured on Gadolinium (Gd)-enhanced-T1w MRI are independently associated with molecular subgroups, as well as overall survival in MB patients. Methods: In this work, a total of 88 MB studies from 2 institutions were analyzed. Following tumor delineation, Gd-T1w scan for every patient was registered to a normal age-specific T1w-MRI template via deformable registration. Following patient-atlas registration, local structural deformations in the brain parenchyma were obtained for every patient by computing statistics from deformation magnitudes obtained from every 5mm annular region, 0 < d < 60 mm, where d is the distance from the tumor infiltrating edge. Results: Multi-class comparison via ANOVA yielded significant differences between deformation magnitudes obtained for Group 3, Group 4, and SHH molecular subgroups, observed up to 60-mm outside the tumor edge. Additionally, Kaplan-Meier survival analysis showed that the local deformation statistics, combined with the current clinical risk-stratification approaches (molecular subgroup information and Chang's classification), could identify significant differences between high-risk and low-risk survival groups, achieving better performance results than using any of these approaches individually. Discussion: These preliminary findings suggest there exists significant association of our tumor-induced deformation descriptor with overall survival in MB, and that there could be an added value in using the proposed radiomic descriptor along with the current risk classification approaches, towards more reliable risk assessment in pediatric MB.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

IDH-mutant brainstem gliomas in adolescent and young adult patients: Report of three cases and review of the literature.

Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH-mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.

Clinical utility of comprehensive genomic profiling in central nervous system tumors of children and young adults.

BACKGROUND: Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. METHODS: OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. RESULTS: NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. CONCLUSIONS: Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

Primary Primitive Neuroectodermal Tumor of the Spine With t(11;22): Report of 3 Cases and Review of Literature.

Intradural extramedullary peripheral primitive neuroectodermal tumor (pPNET) with t(11;22) is a rare clinical finding in the pediatric population with few published cases in the literature. The authors report 3 cases of intradural primary pPNET and discuss the clinical presentation, treatment, and survival of the patients. Clinicians should be vigilant in considering pPNET in the differential diagnosis of extradural masses. The authors also compare the clinical course and outcome of therapy with primary PNET of the central nervous system and Ewing sarcoma family of tumors. In addition, this report highlights the risk for leptomeningeal dissemination at recurrence and discusses the importance of central nervous system-targeted therapy for durable disease control.