Childhood Primary Central Nervous System Research Articles

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

Treatments associated with all-cause mortality among children with primary brain and central nervous system tumors: a retrospective cohort study from the SEER database.

Evidence on treatment modalities and survival in childhood primary brain and central nervous system (CNS) tumors remains contradictory, with previous studies often lacking sufficient patient cohort sizes to assess the differences in histological subtypes. This cohort study based on a large population investigated the effects of various treatments on the mortality of patients with different histological types of primary brain and CNS tumors from the Surveillance, Epidemiology, and End Results (SEER) database. Data of demography, primary tumor site, histology, tumor grade and treatments from all pediatric patients with primary brain and CNS tumors were extracted in this retrospective cohort. The outcomes were overall, 1-, 5-, and 10-year all-cause mortality. Multivariate Cox proportional hazards models were to explore the associations of treatment with overall, 1-, 5-, and 10-year all-cause mortality, with hazard ratios (HRs) and 95% confidence intervals (CIs). Totally 10,994 children were included, with the mean age at diagnosis of 7.3 years, and the median follow-up time of 5.0 years. Of which, 2,003 (18.2%) were diffuse astrocytoma, 3,188 (29.0%) were embryonal tumors, and 3,691 (33.5%) were malignant glioma. Then 4,333 (39.41%) children died during the follow-up. For diffuse astrocytomas and malignant gliomas, patients who received all other treatments were associated with overall, 1-, 5- and 10-year all-cause mortality compared to those only received resection. Embryonal tumors patients receiving resection with radiation only and those receiving resection with both chemotherapy and radiation were associated with lower odds of overall, 1-, 5- and 10-year all-cause mortality compared to patients who only received resection. For ependymal tumors, no surgery/only biopsy with chemotherapy, resection with chemotherapy only, resection with both chemotherapy and radiation, and other treatments had increased risks of overall all-cause mortality compared with resection. The risk of 1-year all-cause mortality increased in ependymal tumors with treatment involving resection and radiation. However, resection with both chemotherapy and radiation was not significantly associated with the 1- nor 5-year all-cause mortality. Resection may be recommended for children with diffuse astrocytoma, ependymal tumors, and malignant glioma, while resection with radiotherapy or chemoradiation may be recommended for children with embryonal tumors.

H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.

Mycophenolate mofetil as induction and long-term maintaining treatment in childhood: Primary angiitis of the central nervous system

ObjectiveTo report our single centre experience in treating 4 children affected by childhood primary central nervous system vasculitis (cPACNS) using mycophenolate mofetil (MMF). MethodsFrom December 2011 to August 2015, 4 patients (3 males; age range: 9 months–13 years) affected by cPACNS were collected. Enrolled children received the following treatment protocol: acetylsalicylic acid and/or anticoagulant therapy with low molecular weight heparin (LMWH) 100 U/k BID replaced by acenocoumarol; methyl-prednisolone (30mg/kg/day for 3–5 days) followed by prednisone (2mg/kg/day), tapered and discontinued over 7–8 months; MMF used for induction therapy and subsequent maintenance phase (750–1000mg/m2 BID, half-dose for the first 10–15 days followed by full-dose). ResultsIn all children, no relapse of cerebral vasculitis occurred during the whole follow-up period and all of them improved while in MMF treatment. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), performed at 6, 9 or 12 months intervals, showed no progression or even improvement of the typical radiological findings. Medium period of MMF treatment was 29 months (range: 10–42 months). No major drug-related adverse events were documented. ConclusionWe report for the first time on the efficacy and safety of MMF in the induction and maintenance of clinical remission in cPACNS. Our single centre experience of MMF use in treating cPACNS seems represent an appealing, alternative and safe option in this clinical setting over a long-term follow-up.

MRI and clinicopathological correlation of childhood primary central nervous system angiitis

To review the long-term clinical and imaging follow-up of eight children with histopathologically proven childhood primary central nervous system angiitis (cPACNS). Eight children (5-17 years, five female and three male patients) with biopsy-proven cPACNS vasculitis were reviewed retrospectively. All children were followed at the Children's Hospital of Eastern Ontario. Magnetic resonance imaging (MRI) images of the brain parenchyma and vessel pattern of the arteries of the circle of Willis were reviewed at baseline and follow-up(s). All MRI images were correlated with clinical and histopathological findings. Seven (87.5%) children demonstrated parenchymal abnormalities: five of the seven (71.4%) presented with non-haemorrhagic lesions, one (14.3%) presented with a parenchymal bleed, and one (14.3%) showed diffuse oedema. One child remained negative for brain parenchymal abnormality at baseline and follow-up. Of the seven children with a parenchymal abnormality, parenchymal enhancement was seen in two (28.5%) and leptomeningeal enhancement was seen in one child. Only two children had positive diffusion-weighted imaging (DWI) restriction at baseline. Five of the seven children (71.4%) showed no magnetic resonance angiography (MRA) abnormalities at baseline. In one, MRA detected complete absence of flow. Follow-up MRA (24-74 months) demonstrated that five of the seven (71.4%) children had progressive paucity of the peripheral vascularity. Two children (28.5%) with shorter-term follow-up (7 and 13 months) did not demonstrate MRA changes. Long-term follow-up MRA demonstrated progressive paucity of peripheral vessels, which could be secondary to the inflammation affecting the peripheral vasculature causing reduction in vessel lumen size beyond the resolution of the maximum intensity projection (MIP) reconstruction.

Late Cerebrovascular Complications After Radiotherapy for Childhood Primary Central Nervous System Tumors

BackgroundBrain radiotherapy plays a central role in the treatment of certain types of childhood primary central nervous system tumors. However, damage to surrounding normal brain tissue causes different acute and chronic medical and neurological complications. Despite the expected increase in number of childhood primary central nervous system tumor survivors, studies assessing the occurrence of late cerebrovascular complications, such as cavernoma, moyamoya, microbleeds, superficial siderosis, and stroke are sparse. MethodsWe undertook a retrospective consecutive case series review describing the occurrence and characteristics of late cerebrovascular complications in 100 survivors of childhood primary central nervous system tumors treated with radiotherapy. Demographic, clinical, and radiological findings including gradient echo brain magnetic resonance data were retrieved. ResultsLate cerebrovascular complications were found in 36 (36%) of the patients included in the study. Mean age at radiotherapy was 8.6 years (3-17) and at diagnosis was 23.9 years (3-38). The majority were males (21; 58%). The most common complications were microbleeds (29/36; 80.6%) and cavernomas 19 (52.8%). In seven (19.4%), late cerebrovascular complications were symptomatic: epilepsy (two), motor and language deficit (two), and sensorineural hearing loss and progressive ataxia (three) associated with cavernomas, stroke, and superficial siderosis, respectively. Follow-up length was associated with an increased diagnosis of late cerebrovascular complications (P < 0.0001). Late cerebrovascular complications occurred more commonly in children treated with whole-brain radiation therapy (P = 0.046). Factors such as sex, chemotherapy, and histological type of tumor were not correlated with the occurrence of late cerebrovascular complications. ConclusionAlthough not usually symptomatic, late cerebrovascular complications occur frequently in survivors of childhood primary central nervous system tumors treated with radiotherapy. Prolonged follow-up increases the probability of diagnosis. The impact and prognostic value of these late cerebrovascular complications is yet to be clarified.

Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011.

The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

Primary and Secondary Central Nervous System Vasculitis

Central nervous system vasculitis is an increasingly recognized inflammatory brain disease causing devastating neurological deficits and psychiatric manifestations in previously healthy children. Primary central nervous system vasculitis represents an isolated inflammatory attack targeting the cerebral vessels. In contrast, in children with secondary central nervous system vasculitis, an underlying condition can be identified. The spectrum of childhood primary and secondary central nervous system vasculitis is rapidly expanding, as is the differential diagnosis including nonvasculitic inflammatory brain diseases and noninflammatory vasculopathies. Early recognition, rapid diagnostic evaluation, and initiation of treatment have led to improved morbidity and mortality. This review focuses on clinical, laboratory, and neuroimaging characteristics of the distinct subtypes of primary childhood central nervous system vasculitis, reports the etiology of secondary central nervous system vasculitis, provides an overview of the differential diagnosis, and reviews the current approaches in treatment.

Outcome of Primary Childhood Central Nervous System Tumors: Results from a Single Center in Iran

Childhood primary central nervous system (CNS) malignancies are one of the most important concerns in pediatric oncology. In this historical cohort, 82 patients treated in Ali-Asghar Children's Hospital between 1996 and 2005 were evaluated for age, gender, type of treatment, tumor pathology, and survival. The records of 38 female (46.3%) and 44 male (53.7%) patients were included. The mean age was 6.8 ± 3.39 years (6 months to 14 years); the frequency of medulloblastoma was significantly more than others (p = 0.012). Complete resection, radiotherapy, and chemotherapy were done in 47.5, 82.9, and 97.56%, respectively. Estimated 5 years overall and event-free survivals (EFSs) were approximately 68.5 and 35%, respectively. The patients with complete resected tumors had significantly better outcome (p = 0.013). Also, low-grade versus high-grade astrocytoma was significantly a better outcome (p = 0.01). The poor EFS with consideration of high number of progressive disease among our patients (50% unresectable tumor) suggests that children in Iran with CNS tumors had high quality of care but availability of advanced treatment protocol and sharing of cooperative trial study is essential for survival improvement. In addition to use more advanced methods and equipments of radiotherapy and chemotherapeutic drugs, we should seriously consider development of better surgical techniques to increase the rate of complete resection of malignant CNS tumors.

Central nervous system vasculitis in children

To review the current literature of childhood primary and secondary central nervous system (CNS) vasculitis and to evaluate the growing differential diagnosis of inflammatory and noninflammatory brain diseases. Primary angiitis of the central nervous system in children (cPACNS) is a reversible cause of severe neurological deficits and/or psychiatric symptoms. This disease is classified into subtypes based on distinct clinical and radiological features, treatment strategies, and disease trajectories. Also, the increased diagnostic yield from elective brain biopsies in children has improved our ability to diagnose angiography-negative cPACNS. Over the past few years, the differential diagnosis for cPACNS has rapidly expanded due to the characterization of novel inflammatory and noninflammatory brain diseases. Specifically, vasoconstrictive disorders and neuronal antibody-associated conditions have now been described in children and have overlapping clinical features with cPACNS. This review summarizes the recent data on diagnosis, treatment, and prognosis of cPACNS. It also addresses the evolving differential diagnosis for CNS vasculitis. Our improved understanding of these disorders allows a tailored diagnostic approach leading to rapid diagnosis and initiation of therapy in these potentially reversible conditions.

Clinical epidemiology for childhood primary central nervous system tumors

This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0-19 years) of newly diagnosed and histologically confirmed PCNST (during the years 2004-2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST.

Update on new treatments and developments in childhood brain tumors

Childhood primary central nervous system tumors remain a therapeutic conundrum. As the second most common pediatric cancer, brain tumors lead to significantly worse survival and long-term effects compared with those seen with hematologic malignancies and other solid tumors. This review discusses current management strategies in three pediatric brain tumors, the long-term effects of therapy, as well as novel laboratory findings that may alter future treatment strategies. The current literature focuses on tactics to predict those at risk of treatment failure and long-term effects. By analyzing tumors at a molecular genetics level rather than traditional histology, new data have begun to emerge on methods to begin to consider targeted therapies, tailored to the individual child. Furthermore, as survivorship has improved with current radiation and chemotherapy regimens, long-term effects have been identified and merit clinical attention. Even though long-term survival for children with a brain tumor approaches 70%, the need for improved treatment regimens is striking. Secondary malignancies, neurocognitive deficits and treatment failure continue to afflict these children and young adults. The current review will inform clinicians of the challenges faced by basic scientists and clinicians when treating brain tumors, and point to future research directions.

The value of tandem CSF/MRI evaluation for predicting disseminated disease in childhood central nervous system neoplasms

Leptomeningeal spread of childhood primary central nervous system (CNS) neoplasms, also known as leptomeningeal disease (LMD), significantly affects prognosis and treatment. Lumbar cerebrospinal fluid (CSF) cytology and spinal magnetic resonance imaging (MRI) are considered critical for diagnosis of LMD. It has been suggested that either CSF cytology or spinal MRI alone would miss LMD in up to 18% of children with CNS neoplasms. To determine the rate of LMD and the concordance of these two tests at our institution, we analyzed the results of concurrent CSF cytology and spinal MRI (tandem CSF/MRI) performed at the UCSF Pediatric Neuro-oncology Division. We identified all patients who underwent tandem CSF and MRI analysis during their treatment between 1990 and 2005. There were 127 tandem analyses from 78 patients, of which 115 were concordant. Among the remaining 12 discordant tandem analyses, spinal MRI was positive and CSF was negative for tumor in 8 patients, while CSF was positive and spinal MRI was normal in four others. In all discordant cases, positive spinal MRI was often associated with aggressive disease. Positive CSF cytology correlated with aggressive disease only in one patient who had evidence of disseminated intracranial tumor on MRI. In the absence of intracranial tumor spread or LMD on MRI, a positive CSF cytology did not correlate with aggressive disease or recurrence. Even though the number of cases is limited, our findings suggest that a positive CSF cytology with no other corroborating evidence of tumor spread or recurrence should be interpreted with caution.

一側性感音難聴が初発症状の橋部に発生した髄芽腫例

Medulloblastoma is the most common childhood primary central nervous system tumor. In adults, most medulloblastomas occur in patients younger than 40. Common symptoms are cerebellar dysfunction and signs of CSF flow obstruction.This report describes the case of a 25-year-old female who presented with progressive unilateral sensorineural hearing loss (SNHL) as the first symptom of a medulloblastoma in the right inferior cerebellar peduncle and pons. She was referred to an ENT outpatient clinic, and diagnosed with right low tone-dominant SNHL. Her right SNHL progressed with an additional symptom, left moderate facial palsy, 7 months later, and she consequently visited the clinic again. She was introduced to our clinic for further examination. At that time, magnetic resonance imaging (MRI) revealed a right Brainstem lesion. The ipsilateral stapedial reflex was normal in the right ear but absent in the left. Bekesy audiometry was type III. Electronystagmography showed a spontaneous nystagmus to the left and saccade pursuit. The auditory brainstem response was absent in the right ear.The presented case showed that unilateral SNHL can be the first symptom of a brainstem tumor lesion. Progressive SNHL cases should be checked by MRI, in order to exclude brainstem lesions just like cerebello-pontine angle lesions.

A case series of pediatric primary central nervous system lymphoma: Favorable outcome without cranial irradiation

To describe the outcome of childhood primary central nervous system lymphoma (PCNSL) treated with chemotherapy alone or with chemotherapy plus cranial radiotherapy (CRT). Retrospective chart review of children with PCNSL at six tertiary care pediatric centers. Eight immunocompetent and four immunocompromised children were included. Ten children received chemotherapy alone without CRT, with most receiving high-dose methotrexate and high-dose cytarabine. Five year event-free survival (EFS) in this group was 70.0 +/- 14.5%. Two children received chemotherapy plus CRT; one relapsed and died while the other is alive in remission. Three children died, including two from relapsed disease. The other child with human immunodeficiency virus infection died of an opportunistic infection while in remission following chemotherapy alone. Most children with PCNSL can achieve long-term remissions with chemotherapy alone without CRT. Multi-center prospective studies are needed to confirm or refute these results in a larger number of patients.

The role of radiation for pediatric low-grade gliomas

Purpose/Objective: Low-grade gliomas (LGGs) are the most common pediatric brain tumor, comprising 35% of childhood primary central nervous system malignancies. However, many aspects of treatment remain controversial, particularly with respect to non-pilocytic, World Health Organization (WHO) grade II lesions. One such controversy is whether to administer radiation to children with WHO II tumors, given questionable effectiveness of radiation and potential long-term toxicities. We sought to assess whether radiation therapy improves progression-free survival (PFS) or overall survival (OS) for pediatric patients with WHO grade II low-grade gliomas.

Diagnosis, treatment, and outcome of primary central nervous system tumors of childhood.

Significant work has been published over the past year on the management of childhood primary central nervous system tumors. Chemotherapy is taking on an increased role in the treatment of children with medulloblastoma and low-grade gliomas and infants with malignant tumors. Although survival remains poor for children with brain stem gliomas, even after treatment with high-dose radiotherapy regimens, subsets of patients have been identified who have a more favorable prognosis. Neurocognitive dysfunction remains a significant treatment outcome in children surviving brain tumors.

Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa

Chemotherapy has only marginal efficacy in adult malignant brain tumors. In contrast, drug therapy is considerably more effective in medulloblastoma/primitive neuroectodermal tumors (MB/PNET) of the posterior fossa, the most common childhood primary central nervous system tumor. At the time of disease recurrence, a variety of different single agents and drug combinations result in tumor shrinkage and increased survival. The addition of chemotherapy to standard radiotherapy improves the rate and length of disease-free survival for those children with MB/PNET who have the most extensive tumors at diagnosis. It remains to be determined which drug or drug combinations are the most effective in MB/PNET, and which patients are most likely to benefit from chemotherapy. Chemotherapy may be useful to reduce or, in selected cases, obviate the need for radiotherapy and reduce treatment-related sequelae.