Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults.

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15-39 years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages.

Treatment of NF1-Associated Optic Pathway/Hypothalamic Gliomas in Patients With Diencephalic Syndrome.

Diencephalic syndrome is usually associated with tumors in the hypothalamic region, rarely occurring in patients with neurofibromatosis type 1 (NF1)-associated gliomas. We describe the clinical presentation and response to treatment in 3 patients with NF1 presenting with diencephalic syndrome as first symptom of optic pathway/hypothalamic glioma (OPHG). Because of the rarity of this constellation, knowledge about the clinical course and best treatment options for patients with NF1-associated OPHG and diencephalic syndrome is still limited. All 3 patients showed good response to treatment with normalization of body mass index and decrease in tumor volume within 6 months.

Real-time drug testing of paediatric diffuse midline glioma to support clinical decision making: The Zurich DIPG/DMG centre experience.

BACKGROUND: Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9-12 months from diagnosis with currently no curative treatment options. Given DMG molecular heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich. METHOD: Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel). Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing. RESULTS: Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1-4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib. CONCLUSION: We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame.

Educational Attainment and Employment Outcome of Survivors of Pediatric CNS Tumors in Switzerland-A Report from the Swiss Childhood Cancer Survivor Study.

BACKGROUND: Childhood cancer survivors diagnosed with a central nervous system (CNS) tumor are at risk for educational and vocational challenges. This study compared educational attainment and employment outcome in survivors of CNS tumors to survivors of other malignancies. METHODS: The questionnaire-based Swiss Childhood Cancer Survivor Study (SCCSS) included cancer patients diagnosed between 1976 and 2010, aged ≤20 years, who survived ≥5 years after diagnosis. We classified participants aged ≥16 years into three groups: CNS tumor and non-CNS malignancy with and without CNS-directed treatment. We analyzed educational attainment, employment outcome and special schooling. Subgroup analyses included survivors aged ≥25 years. RESULTS: We analyzed 2154 survivors, including 329 (15%) CNS tumor survivors, 850 (40%) non-CNS tumor survivors with and 975 (45%) without CNS-directed treatment. Fewer CNS tumor survivors aged ≥25 years reached tertiary education (44%) compared to those without CNS-directed treatment (51%) but performed similar to survivors with CNS-directed treatment (42%). Among CNS tumor survivors, 36 (14%) received special schooling. Higher parental education was associated with higher levels in survivors. Employment outcome did not significantly differ between the three diagnostic groups. A higher proportion of CNS tumor survivors received disability pension or were unemployed. CONCLUSIONS: Our findings suggest that CNS tumor survivors need more time to achieve their highest educational level. This should influence clinical care of these survivors by offering vocational counseling.

Central nervous system tumors in children under 5 years of age: a report on treatment burden, survival and long-term outcomes.

PURPOSE: The challenges of treating central nervous system (CNS) tumors in young children are many. These include age-specific tumor characteristics, limited treatment options, and susceptibility of the developing CNS to cytotoxic therapy. The aim of this study was to analyze the long-term survival, health-related, and educational/occupational outcomes of this vulnerable patient population. METHODS: Retrospective study of 128 children diagnosed with a CNS tumor under 5 years of age at a single center in Switzerland between 1990 and 2019. RESULTS: Median age at diagnosis was 1.81 years [IQR, 0.98-3.17]. Median follow-up time of surviving patients was 8.39 years [range, 0.74-23.65]. The main tumor subtypes were pediatric low-grade glioma (36%), pediatric high-grade glioma (11%), ependymoma (16%), medulloblastoma (11%), other embryonal tumors (7%), germ cell tumors (3%), choroid plexus tumors (6%), and others (9%). The 5-year overall survival (OS) was 78.8% (95% CI, 71.8-86.4%) for the whole cohort. Eighty-seven percent of survivors > 5 years had any tumor- or treatment-related sequelae with 61% neurological complications, 30% endocrine sequelae, 17% hearing impairment, and 56% visual impairment at last follow-up. Most patients (72%) attended regular school or worked in a skilled job at last follow-up. CONCLUSION: Young children diagnosed with a CNS tumor experience a range of complications after treatment, many of which are long-lasting and potentially debilitating. Our findings highlight the vulnerabilities of this population, the need for long-term support and strategies for rehabilitation, specifically tailored for young children.

Response and resistance to BRAFV600E inhibition in gliomas: Roadblocks ahead?

BRAFV600E represents the most common BRAF mutation in all human cancers. Among central nervous system (CNS) tumors, BRAFV600E is mostly found in pediatric low-grade gliomas (pLGG, ~20%) and, less frequently, in pediatric high-grade gliomas (pHGG, 5-15%) and adult glioblastomas (GBM, ~5%). The integration of BRAF inhibitors (BRAFi) in the treatment of patients with gliomas brought a paradigm shift to clinical care. However, not all patients benefit from treatment due to intrinsic or acquired resistance to BRAF inhibition. Defining predictors of response, as well as developing strategies to prevent resistance to BRAFi and overcome post-BRAFi tumor progression/rebound growth are some of the main challenges at present in the field. In this review, we outline current achievements and limitations of BRAF inhibition in gliomas, with a special focus on potential mechanisms of resistance. We discuss future directions of targeted therapy for BRAFV600E mutated gliomas, highlighting how insights into resistance to BRAFi could be leveraged to improve outcomes.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

Cerebellar tumors.

The cerebellum is the most common site of presentation of central nervous system tumors in children but exceedingly rare in adults. Children often present with acute symptoms related to increased intracranial pressure, requiring urgent surgical intervention. The differential diagnosis is broad and includes a variety of benign and malignant entities. Cerebellar low-grade gliomas are the most common and benign, slow-growing tumors, for which surgical resection alone is curative. Embryonal tumors, on the other hand - most commonly medulloblastomas - are highly aggressive and treatment includes intensive postsurgical radiotherapy and chemotherapy. Driven by multiple genomewide profiling studies, the field of neuro-oncology is making great strides towards understanding how different tumors develop and embarking on a new generation of molecularly informed clinical trials.

TGF-ß Determines the Pro-migratory Potential of bFGF Signaling in Medulloblastoma.

The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo. TGF-ß regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-ß pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-ß counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-ß signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling.

Review of molecular classification and treatment implications of pediatric brain tumors.

PURPOSE OF REVIEW: Brain tumors are the most common solid tumors and leading cause of cancer-related death in children. The advent of large-scale genomics has resulted in a plethora of profiling studies that have mapped the genetic and epigenetic landscapes of pediatric brain tumors, ringing in a new era of precision diagnostics and targeted therapies. In this review, we highlight the most recent findings, focusing on studies published after 2015, and discuss how new evidence is changing the care of children with brain tumors. RECENT FINDINGS: Genome-wide and epigenome-wide profiling data have revealed distinct tumor entities within, virtually, all pediatric brain tumor groups including medulloblastoma; ependymoma; high-grade and low-grade gliomas; atypical teratoid/rhabdoid tumors; and other embryonal tumors, previously called CNS primitive neuroectodermal tumors. Whenever integrated with clinical information, many molecular alterations emerge as powerful prognostic markers and should thus be used to stratify patients and tailor therapies. SUMMARY: Optimal integration of this newly emerging knowledge in a timely and meaningful way into clinical care is a remarkable task and a matter of active debate. The historical morphology-based classification of tumors is being replaced by a genetic-based classification, and the first generation of molecularly informed clinical trials is underway.

Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.

BACKGROUND: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. METHODS: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTS: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONS: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.

The Changing Landscape of Pediatric Low-Grade Gliomas: Clinical Challenges and Emerging Therapies.

Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions--mostly young children with midline tumors--experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes--especially neurofibromatosis type 1 and tuberous sclerosis--have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets--in particular alterations of the Ras/MAPK pathway--are rapidly changing our approach to PLGG.