Childhood Central Nervous System Research Articles

Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9–11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM). We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b + macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.

Association between parental occupational exposure to extremely low frequency magnetic fields and childhood nervous system tumors risk: A meta-analysis

Background and objectivePrevious epidemiological studies suggested association between parental occupational exposure to extremely low frequency magnetic fields (ELF-MF) and risk of childhood nervous system tumors, but the results were inconsistent. We conducted a meta-analysis of case-control and cohort studies to re-evaluate this association. MethodsRelevant studies were identified by searching PubMed and Web of Science databases as well as by manual searching. Summary odds ratio (OR) with 95% confidence interval (CI) were pooled with a fixed-effects or random-effects model. ResultsA total of 22 eligible articles (21 case-control studies and 1 cohort study) were included for the quantitative analysis. The results showed that parental occupational ELF-MF exposure was significantly associated with an increased risk of childhood nervous system tumors (OR = 1.11, 95% CI = 1.02–1.21), and this association remained in studies on central nervous system (CNS) tumors (OR = 1.13, 95% CI = 1.02–1.27) but not neuroblastoma (OR = 1.02, 95% CI = 0.92–1.14). Furthermore, maternal (OR = 1.14, 95% CI = 1.05–1.23) but not paternal (OR = 1.05, 95% CI = 0.98–1.13) occupational ELF-MF exposure significantly increased risk of childhood nervous system tumors. Increased risk of childhood CNS tumors was significant associated with maternal (OR = 1.16, 95% CI = 1.06–1.26) but not paternal (OR = 1.15, 95% CI = 0.98–1.34) occupational ELF-MF exposure. ConclusionIn conclusion, our results provide limited evidence for the association between maternal occupational exposure to ELF-MF and increased risk of childhood CNS tumors, which should be explained with cautions. Future studies are needed to further evaluate the association of paternal occupational ELF-MF exposure with risk of childhood CNS tumors.

Neuroimmune disorders of the central nervous system in children in the molecular era.

Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal ofprecision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.

Purification and Characterization of α-Mannosidase from Moss Hyophilla nymaniana (Fleish.) Menzel

α-Mannosidase EC: (3.2.1.24) is the major post-translational modifications enzyme which catalyzes the cleavage of the alpha form of mannose. Lysosomal α-mannosidase assists in the processing of complex sugars from glycoproteins. Defective or deficient α-mannosidase activity causes α-mannosidosis and leads to deterioration of the central nervous system in children. In the present study, plant α-mannosidase was purified 39-fold in a stepwise manner by ammonium sulfate precipitation, dialysis, gel filtration chromatography and DEAE ion exchange chromatography. The purified mannosidase was a heterodimer consisting of approximately 72 and 50 kDa molecular mass subunits under reducing conditions. Optimum pH and temperature reported for mannosidase activity were 4.5 and 40 °C respectively. Among the various metal ions tested for the assessment of the enzyme activity, 2 mM Zn2+ strongly activated the enzyme while Hg2+and Ag2+ caused enzyme inhibition at the same concentration. The Km and Vmax values calculated from Lineweaver plot against the substrate p-nitrophenyl α-mannopyranoside were 5.4 mM and 8.4 U/ml, respectively. To the author’s knowledge, the data presented here is the first report on purification and characterization of α-mannosidase from the moss H. nymaniana.

Neurologic disorders in 4858 survivors of central nervous system tumors in childhood-an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study.

A comprehensive overview of neurologic complications among survivors of central nervous system (CNS) tumors in childhood is lacking. We aimed to investigate the risk for these disorders in a large, population-based study with outcome measures from nationwide hospital registries. We identified 4858 five-year survivors with diagnoses of CNS tumor in childhood in Denmark, Iceland, Finland, and Sweden in 1943-2007, and 166658 matched population comparison subjects. Inpatient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was verified in 1309 survivors, while 92.4 were expected, yielding an overall RR of 14.2 (95% confidence interval [CI]: 13.3-15.1) and an AER of 20 hospitalizations per 1000 persons per year. The risks remained increased more than 20 years after diagnosis (RR: 6.3, 95% CI: 5.6-7.2; AER: 11, 9-12). The most frequent diagnoses were epilepsy (affecting 14.1% of all survivors) followed by hydrocephalus (9.5%) and paralytic syndromes (4.2%), with RRs of 28.7 (95% CI: 26.0-31.6), 243 (95% CI: 190-311), and 40.3 (95% CI: 33.1-49.2), respectively. Of these outcomes, 30%-40% were diagnosed prior to or synchronously with the CNS tumor. The survivors had highly increased RRs for infectious diseases of the CNS, disorders of cranial nerves, and degenerative diseases of the nervous system. Survivors of childhood CNS tumors are at markedly increased risk for neurologic disorders throughout their lives. Health care professionals must be aware of survivors who might benefit from preventive interventions and intensive follow-up.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study

IntroductionAcquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands.MethodsChildren < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments.ResultsBetween 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28–84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%).ConclusionThe reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

Delays in diagnosis for children with newly diagnosed central nervous system tumors.

United States studies documenting time interval from symptom onset to definitive diagnosis for childhood central nervous system (CNS) tumors are more than a quarter-century old. The purpose of this study is to establish an accurate and contemporary Ohio baseline of the diagnostic interval for children with newly diagnosed CNS tumors. Medical records were retrospectively reviewed for 301 children with newly diagnosed CNS tumors from January 2004 to August 2015 at Nationwide Children's Hospital. We obtained comprehensive data on 171 patients (56.8%). Records were reviewed for age, gender, tumor type, presenting symptoms, number of health care visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis, and any associated genetic syndromes. Of the 171 patients with newly diagnosed CNS tumors, 25 children (14.6%) had a known cancer predisposition syndrome (all with neurofibromatosis type 1). Among the remaining 146 children, the median and mean time intervals from symptom onset to definitive diagnosis were 42 days and 138 days (range < 1 to 2190 days), respectively. We have documented and quantified the contemporary delays in diagnosis of childhood brain tumors in central Ohio to serve as a benchmark for our future planned interventions to reduce the time interval from symptom onset to diagnosis through adaptation of the United Kingdom HeadSmart program throughout the state of Ohio and ultimately throughout the United States.

Increased incidence of inguinal hernia in offspring of female survivors of childhood central nervous system tumors.

Female survivors of childhood central nervous system (CNS) tumors experience an increased risk of infertility and various pregnancy complications. We aimed to explore whether the incidence of inguinal hernia could be higher in offspring of female CNS tumor survivors as compared to the general population. Girls who were younger than 15 years of age and diagnosed with CNS tumors between 1958 and 2013 were identified from the Swedish Cancer Registry. By linking with the Swedish Medical Birth Registry, we identified 580 children who were born to mothers of CNS tumor survivors. After 9,662 person-years of follow-up, 23 of them were diagnosed with inguinal hernia, giving an incidence rate (IR) of 2.4 per 1,000 person-years, whereas the IR was 1.2 for the matched controls. Cox regression analysis was used to calculate the hazard ratio (HR) of inguinal hernia. After adjusting for some confounding factors, the incidence of inguinal hernia was significantly increased with an HR of 1.92 (95%CI 1.08-3.41). The association was predominant in offspring whose mothers were diagnosed with CNS tumors at the age of 10 and older, and with CNS tumors located in the brain.

Unequal Cumulative Incidence and Mortality Outcome in Childhood Brain and Central Nervous System Malignancy in the USA.

While survival in overall pediatric malignancy has improved during recent decades, brain/central nervous system (CNS) tumors has not demonstrated comparable survival advantage. Incidence and mortality data in this malignancy continue to illustrate race and sex differences; however, there are few data in the pediatric setting. This study sought to characterize brain/CNS tumors by socio-demographic and assess racial and sex variances in both cumulative incidence and mortality. A retrospective cohort design with Surveillance, Epidemiology and End Results (SEER) 1973-2014 was used for the assessment of children aged < 1-19years diagnosed with brain/CNS tumors. The age-adjusted incidence rates were used for temporal trends, percent change, and annual percent change. We utilized binomial regression model to determine the exposure effect of race and sex on cancer mortality, adjusting for potential confounders. Childhood brain/CNS tumor cumulative incidence (CmI) continues to rise in annual percent change, and mortality varied by race, sex, and year of diagnosis. The CmI was highest among whites, intermediate among blacks, and lowest among Asians, as well as lower in females relative to that in males. Compared to whites, blacks were 21% more likely to die from brain/CNS tumors [risk ratio (RR) 1.21, 95% confidence interval (C.I.) 1.13-1.28], while males were 4% more likely to die relative to females (RR 1.04, 95% C.I. 1.00-1.08). After controlling for age, sex, and tumor grade, racial disparities persisted, with 16% increased risk of dying among blacks relative to whites [adjusted risk ratio 1.16, (99% C.I.) 1.08-1.25, p < 0.001]. The cumulative incidence of brain/CNS malignancy is higher among whites relative to that in blacks; however, blacks experienced survival disadvantage even after adjustment for potential tumor prognostic and predisposing factors.

Bacterial Infections of the CentralNervous System.

Bacterial infections of the central nervous system (CNS) continue to be an important cause of morbidity and mortality in children. The spectrum of bacterial infection of CNS includes; focal or multifocal infections like brain abscesses or subdural empyema; or more generalized or diffuse infections like pyogenic meningitis or ventriculitis. Focal and generalized infections may co-exist in an individual patient. Prompt and adequate antibiotic therapy and occasionally neurosurgical interventions are the cornerstone of effective management. The recent emergence of several multidrug-resistant bacteria poses a threat to the effective management of bacterial CNS infections. Several adjunctive anti-inflammatory and neuroprotective therapies are being tried, however; none has made a remarkable impact on the outcome. Consequently, bacterial CNS infections in children still remain a challenge to manage. In this review, authors discuss the current updates on the diagnostic and therapeutic aspects of bacterial infections of the CNS in children (post-neonatal age group).

Hyperexcitability of the Central Nervous System in Children with Chronic Pain: A Systematic Review.

Hyperexcitability of the central nervous system plays an important role in the development and maintenance of chronic pain in adults. This knowledge has led to improved treatment strategies within this population. In children, however, research on the presence of central hyperexcitability is scarce. To further investigate this topic in children with chronic pain, there is a need for a clear literature overview. Systematic review. The literature search was performed using the electronic databases PubMed and Web of Science. An article was considered eligible if it included children (age two to 12 years) diagnosed with chronic pain. Articles had to report original research outcomes related to central hyperexcitability, and a comparison with a healthy control group was necessary. Characteristics of the study sample, the assessment, and conclusions regarding central hyperexcitability were extracted from each included article. Twelve case-control studies were included with moderate to good methodological quality (510 children with chronic pain and 670 healthy controls). After summarizing the articles' results on indices of central hyperexcitability, we concluded that secondary hyperalgesia might be present in children with recurrent abdominal pain, juvenile fibromyalgia, and juvenile idiopathic arthritis. Preliminary evidence exists for altered cortical nociceptive processing in children with migraine and recurrent abdominal pain. Based on the results of this review, central hyperexcitability might be present in in several pediatric chronic pain conditions. Further research on other manifestations of central hyperexcitability (e.g., bottom-up and top-down mechanisms and nociceptive brain changes) is necessary to provide firm evidence about its presence in children with chronic pain.

Gene Therapy Approaches to Treat the Neurodegeneration and Visual Failure in Neuronal Ceroid Lipofuscinoses.

Neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, inherited lysosomal storage disorders mostly affecting the central nervous system of children. Symptoms include vision loss, seizures, motor deterioration and cognitive decline ultimately resulting in premature death. Studies in animal models showed that the diseases are amenable to gene supplementation therapies, and over the last decade, major advances have been made in the (pre)clinical development of these therapies. This mini-review summarises and discusses current gene therapy approaches for NCL targeting the brain and the eye.

Socioeconomic Factors and Ninth Grade School Performance in Childhood Leukemia and CNS Tumor Survivors.

BackgroundChildhood cancer survivors can experience deficits in school performance in adolescence. Few studies have investigated how social and socioeconomic factors influence and modify school performance. This study investigates the hypothesis that social and parental socioeconomic factors influence ninth grade school performance in childhood leukemia and central nervous system (CNS) tumor survivors and that the effect is different from that in healthy peers.MethodsWe analyzed data from nationwide Danish registers on school grades for children who finished ninth grade during 2002–2015 in Denmark. Using a unique within-school matched design, we compared grades from childhood cancer survivors with grades from healthy peers. Social factors were maternal/paternal civil status, immigrant status, and country of origin. Parental socioeconomic factors were measured by education and income. The study consisted of 36 426 children, of whom 460 and 289 were leukemia and CNS tumor survivors, respectively.ResultsSchool grades varied considerably across social strata. However, the grades among CNS tumor survivors varied notably less in the following effect modifiers: parental educational attainment, income, and immigrant status. On the contrary, no significant effect modifiers were found among leukemia survivors as compared with healthy peers.ConclusionThere is a strong effect of social and parental socioeconomic factors on school performance in healthy adolescence in Denmark. The same pattern is seen in survivors of leukemia, but a different pattern is seen in survivors of CNS tumors. This finding suggests that impairment of school-related functions differ between leukemia and CNS tumor survivors. This study contributes to knowledge on learning in adolescence in childhood cancer survivors by investigating several social and socioeconomic effect modifiers with nationwide register data and a unique statistical method particularly suitable for comparing school grades. Improved insight could make it possible to identify high-risk groups that may need different means of help.

Information needs of survivors and families after childhood CNS tumor treatment: a population-based study

Background: This study examines information needs and satisfaction with provided information among childhood central nervous system (CNS) tumor survivors and their parents.Material and methods: In a population-based sample of 697 adult survivors in Sweden, 518 survivors and 551 parents provided data. Information needs and satisfaction with information were studied using a multi-dimensional standardized questionnaire addressing information-related issues.Results: Overall, 52% of the survivors and 48% of the parents reported no, or only minor, satisfaction with the extent of provided information, and 51% of the survivors expressed a need for more information than provided. The information received was found useful (to some extent/very much) by 53%, while 47% did not find it useful, or to a minor degree only. Obtaining written material was associated with greater satisfaction and usefulness of information. Dissatisfaction with information was associated with longer time since diagnosis, poorer current health status and female sex. The survivors experienced unmet information needs vis-à-vis late effects, illness education, rehabilitation and psychological services. Overall, parents were more dissatisfied than the survivors.Conclusion: These findings have implications for improvements in information delivery. Information in childhood CNS tumor care and follow-up should specifically address issues where insufficiency was identified, and recognize persistent and with time changing needs at the successive stages of long-term survivorship.

Predominance of girls with cancer in families with multiple childhood cancer cases

BackgroundRecent studies indicate that one of four childhood cancers can be attributed to hereditary genetic abnormalities.MethodsThe Lund Childhood Cancer Genetic study includes newly diagnosed childhood cancer patients as well as childhood cancer survivors visiting the Department of Pediatrics or the Late Effect Clinic at Skåne University Hospital, Lund, Sweden. Questionnaires regarding family history of cancer and blood samples were provided. Reported data were validated and extended by use of the Swedish Population- and Cancer Registries. Demographics in families with one case of childhood cancer (FAM1) were investigated and compared to families with multiple cases of childhood cancer (FAM > 1) as well as to childhood cancer in the general population.ResultsForty-one out of 528 families (7.8%) had more than one case of childhood cancer. In 23 families the affected children were relatives up to a 3rd degree (4.4%). In FAM > 1, 69.2% of the children with leukemia and 60% of those with tumors in the central nervous system (CNS) had a childhood relative with matching diagnosis, both significantly higher than expected. Significantly more female than male patients were observed in FAM > 1 compared to FAM1. This female predominance was most striking in childhood leukemia (77% female) and also, yet to a lesser extent, in CNS tumors (68% female).ConclusionsWe conclude that the high proportion of children with leukemia or CNS tumors in FAM > 1 having a childhood relative with the same diagnosis suggests a hereditary background. Moreover, we report a female predominance in childhood leukemia and childhood CNS tumors in FAM > 1, which may indicate a hereditary gender-specific risk factor in these families.

Antifungal azoles itraconazole and posaconazole exhibit potent in vitro antiviral activity against clinical isolates of parechovirus A3 (Picornaviridae)

Parechovirus A3 (Par-A3, formerly human parechovirus 3) is an emerging viral infection of the central nervous system in children. We used an automated, homogeneous, cell based assay to identify itraconazole and posaconazole as inhibitors of Par-A3, with antiviral activity below concentrations clinically attainable in pediatric patients. Currently, there is no approved antiviral treatment for Par-A3 infection, despite numerous reports of serious Par-A3 disease in neonates and infants.

The association between high birth weight and the risks of childhood CNS tumors and leukemia: an analysis of a US case-control study in an epidemiological database

BackgroundHigh birth weight (BW), 4000 g or larger, is an established risk factor for childhood leukemia. However, its association with central nervous system (CNS) tumor risk is yet unclear. The present study examined it, analyzing data obtained from a case-control study conducted among three states from the US. The association with childhood leukemia risk was also further examined.MethodsIn this study, a data set provided by the Comprehensive Epidemiologic Data Resource was analyzed with an official permission. The original case-control study was conducted to examine the association between paternal preconception exposure to ionizing radiation and childhood cancer risk. Cases with childhood cancer were mainly ascertained from local hospitals, and controls were selected, matched with birth year (1-year category), county of residence, sex, ethnicity and maternal age (+/−2 years). Since the ID numbers were unavailable, conventional logistic analyses were conducted adjusting for those matching variables except for the county of residence. In addition to those variables, gestational age, age at diagnosis and study sites as covariables were included in the logistic models.ResultsAnalyzed subjects were 72 CNS tumor cases, 124 leukemia cases and 822 controls born from 1945 to 1989. The odds ratios (ORs) of CNS tumor risk for children with low BWs (<2500 g) and high BWs (>4000 g) were 2.0 (95% confidence interval [CI]) = 0.7, 5.9) and 2.5 (95%CI = 1.2, 5.2)], respectively. When high-BW children were restricted to those who were large for gestational age (LGA), the OR for high-BW children remained similar (OR = 2.7; 95%CI = 1.1, 6.2). On the other hand, the ORs of leukemia risk for children with low and high BWs were 0.8 (95%CI = 0.2, 3.0) and 1.4 (95%CI = 0.7, 2.6), respectively. In the normal range of BW (2500–4000 g), higher BW was positively associated with CNS tumor risk (beta = 0.0011, p for trend = 0.012). However, the association with leukemia risk was not significant (beta = −0.0002, p for trend = 0.475).ConclusionHigh-BW and LGA children had an elevated childhood CNS tumor risk. In the normal BW range, the BW itself was positively related to CNS tumor risk. No significant association between BW and childhood leukemia risk was observed in this study.

P 22 Defining the role of imaging methods in diagnostics symptomatic epilepsy in children

Introduction Defining the role of MRI and CT in the comprehensive assessment of the state of the central nervous system in children with symptomatic epilepsy. Subjects and Methods The object of the study were 28 patients with symptomatic epilepsy aged from 1 to 14 years. Debut of seizures observed in a wide range of ages from 1 month to 10 years (mean 6.3 ± 4.9). All patients underwent EEG (electroencephalography) studies, magnetic resonance imaging and computed tomography. Results Structural changes of brain were found in 45.6% of all examined patients in MRI and CT. Pathological changes in the EEG were found in 77.2% of patients. Regional epileptiform activity, represented by a complex-acute or slow waves recorded in 51.9% of cases. Changes on MRI were detected in 44.6% of patients. CT allowed us to determine the state of the ventricular system and subarachnoid spaces. The following MRI signs were found, in 5 (14.3%) cases it was midline shift of the brain, in 12 (34.3%) cases it was asymmetry of the lateral ventricles. Subarachnoid perivascular space expansion was found in 22 (62.9%) cases, which often revealed in the fronto-temporal region of the brain. Conclusion Thus, at present, CT and MRI are the main methods of neuroimaging in the diagnostics of symptomatic epilepsy in children. However, it should be noted that only the focused research, knowledge-based clinics, medical history, EEG findings, MRI and CT scans in total identifies epileptogenic focus.

Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report.

Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown. Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1-38.9), median age at last evaluation 30.3 years (range, 6.1-56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs. From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6-16.7; motor impairment HR: 7.6; 95% CI: 5.8-9.9; hearing loss HR: 18.4; 95% CI: 13.1-25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2-3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8-3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9-5.4), and stroke (HR: 14.9; 95% CI: 10.4-21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6-3.2), meningioma (HR: 2.6; 95% CI: 1.1-6.5), and stroke (HR: 2.0; 95% CI: 1.1-3.4). CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.

Diffuse intrinsic pontine gliomas: the future of combination therapy with mTORC1/2 inhibitors and radiation

DIPGs, even though rare in adults, account for 10 percent of all childhood central nervous system tumors and comprise 75–80% of brainstem tumors in children.