A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

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.

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.

Tailoring Medulloblastoma Treatment Through Genomics: Making a Change, One Subgroup at a Time.

After more than a decade of genomic studies in medulloblastoma, the time has come to capitalize on the knowledge gained and use it to directly improve patient care. Although metastatic and relapsed disease remain poorly understood, much has changed in how we define medulloblastoma, and it has become evident that with conventional therapies, specific groups of patients are currently under- or overtreated. In this review, we summarize the latest insights into medulloblastoma biology, focusing on how genomics is affecting patient stratification, informing preclinical studies of targeted therapies, and shaping the new generation of clinical trials.

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.

Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma.

Infants with low-grade glioma (LGG) have a poor survival. BRAFV600E mutation has been identified in pediatric LGG; however, the use of BRAF inhibitors in infants has never been reported. A 2-month-old with V600E mutant hypothalamic/chiasmatic glioma progressed on chemotherapy resulting in profound visual loss, massive ascites, and diencephalic syndrome. Initiation of dabrafenib resulted in rapid and sustained disappearance of clinical symptoms and a profound sustained cytoreduction. BRAF inhibition was safely tolerated with dramatic clinicoradiological response, suggesting early targeted therapy is a viable option in infants with LGG. A re-evaluation of current management paradigms in this population is warranted to leverage the potential benefit of upfront-targeted therapies.