Nervous System Tumors In Children Research Articles

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.

Diagnostic delay and morbidity of central nervous system tumors in children and young adults: a pediatric hospital experience.

For children with central nervous system (CNS) tumors, survival rates remain significantly lower than other childhood malignancies with a substantial increase in disability of survivors. Given this, it is imperative that these children are identified at the earliest sign of symptom onset. Our institution aimed to identify diagnostic delays, morbidity and mortality, and specific barriers that may exist within our specific healthcare system that result in diagnostic delay. A retrospective chart review was performed of newly diagnosed CNS tumors between January 1, 2008 and December 31, 2017. 235 patient cases were reviewed, 34 (14.5%) of which had an associated tumor predisposition syndrome. Median age at the time of diagnosis was 9years (range 1day to 25years), with median number of days from symptom onset to definitive diagnosis of 42days (interquartile range 14-120days). Delays longer than 60days occurred in 95 (47.5%) patients. The 10year relative survival rate for all tumors was 86.8%. Our institution had a shorter interval from symptom onset to diagnosis than currently reported in the literature, as well as a decrease in associated morbidity. In addition, for those with longer delays, we were able to characterize the etiology and barriers leading to these delays. With these identified, we are able to utilize this knowledge to further improve education and awareness in community members and healthcare professionals to continue to improve the time to diagnosis in the future.

Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma

Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.

BRAF V600E Inhibitor (Vemurafenib) for BRAF V600E Mutated Low Grade Gliomas.

Low-grade gliomas (LGG) are the most common central nervous system tumors in children. Prognosis depends on complete surgical resection. For patients not amenable of gross total resection (GTR) new approaches are needed. The BRAF mutation V600E is critical for the pathogenesis of pediatric gliomas and specific inhibitors of the mutated protein, such as Vemurafenib, are available. We investigated the safety and efficacy of Vemurafenib as single agent in pediatric patients with V600E+ LGG. From November 2013 to May 2018, 7 patients have been treated in our Institution; treatment was well-tolerated, the main concern being dermatological toxicity. The best responses to treatment were: 1 complete response, 3 partial responses, 1 stable disease, only one patient progressed; in one patient, the follow-up is too short to establish the clinical response. Two patients discontinued treatment, and, in both cases, immediate progression of the disease was observed. In one case the treatment was discontinued due to toxicity, in the other one the previously assessed BRAF V600E mutation was not confirmed by further investigation. Two patients, after obtaining a response, progressed during treatment, suggesting the occurrence of resistance mechanisms. Clinical response, with improvement of the neurologic function, was observed in all patients a few weeks after the therapy was started. Despite the limitations inherent to a small and heterogeneous cohort, this experience, suggests that Vemurafenib represents a treatment option in pediatric patients affected by LGG and carrying BRAF mutation V600E.

402P - Adult medulloblastoma: An oncology radiation therapy department experience with 22 cases

Background: Medulloblastoma is the most common central nervous system tumor in children. However, the occurrence in adults is rare and accounts for about 1% - 2%. The objective of this study is to define the clinical characteristic of this entity and therapeutic results. Methods: We retrospectively evaluated the treatment data of 22 adult patients (≥18 years) treated for medulloblatoma from 1993 to 2013 in our department. Median follow up was 161.5 months [58; 296 months]. Results: Male female ratio was 2.14 :1. Median age was 25 years [18 ; 57]. Eight patients (36%) had cerebellar hemispheric tumors, nine cases (41%) occur in the vermis and five patients (23%) had an hemispheric-vermian localisation. Twenty one patients (95%) underwent macroscopically total exicision. Sixteen patients (73%) had classic form; five patients had desmoplastic (23%) type and one patient had extensive nodularity type. Patients were stratified into standard and high risk in 14 and 5 cases respectively. The risk couldn’t be identified for 3 patients. Among patients in the high-risk group, four received a cisplatin/etoposide chemotherapy before radiation. All patients had craniospinal radiotherapy. The mean interval between surgery and the begining of radiation therapy was 107 days. Craniospinal dose range between 30Gy and 36Gy. The dose in the posterior fossa was respectively 54Gy and 64Gy in 18 (82%) and 4 (18%) cases. The 5 year overall survival was 63%. Conclusions: There are differences between pediatric and adult patients with medulloblastoma in terms of clinical and pathological characteristic. Ultimately, prospective trials including adult patient with medulloblastoma are needed to optimize the management of this rare and complex disease. Legal entity responsible for the study: Kallel Mouna. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

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.

Diffusion profiling of tumor volumes using a histogram approach can predict proliferation and further microarchitectural features in medulloblastoma.

Medulloblastomas are the most common central nervous system tumors in childhood. Treatment and prognosis strongly depend on histology and transcriptomic profiling. However, the proliferative potential also has prognostical value. Our study aimed to investigate correlations between histogram profiling of diffusion-weighted images and further microarchitectural features. Seven patients (age median 14.6years, minimum 2years, maximum 20years; 5 male, 2 female) were included in this retrospective study. Using a Matlab-based analysis tool, histogram analysis of whole apparent diffusion coefficient (ADC) volumes was performed. ADC entropy revealed a strong inverse correlation with the expression of the proliferation marker Ki67 (r = - 0.962, p = 0.009) and with total nuclear area (r = - 0.888, p = 0.044). Furthermore, ADC percentiles, most of all ADCp90, showed significant correlations with Ki67 expression (r = 0.902, p = 0.036). Diffusion histogram profiling of medulloblastomas provides valuable in vivo information which potentially can be used for risk stratification and prognostication. First of all, entropy revealed to be the most promising imaging biomarker. However, further studies are warranted.

Atypical Teratoid Rhabdoid Tumour : From Tumours to Therapies.

Atypical teratoid rhabdoid tumours (ATRTs) are the most common malignant central nervous system tumours in children ≤1 year of age and represent approximately 1–2% of all pediatric brain tumours. ATRT is a primarily monogenic disease characterized by the bi-allelic loss of the SMARCB1 gene, which encodes the hSNF5 subunit of the SWI/SNF chromatin remodeling complex. Though conventional dose chemotherapy is not effective in most ATRT patients, high dose chemotherapy with autologous stem cell transplant, radiotherapy and/or intrathecal chemotherapy all show significant potential to improve patient survival. Recent epigenetic and transcriptional studies highlight three subgroups of ATRT, each with distinct clinical and molecular characteristics with corresponding therapeutic sensitivities, including epigenetic targeting, and inhibition of tyrosine kinases or growth/lineage specific pathways.

Proton therapy for central nervous system tumors in children.

Proton therapy is a form of particle therapy with physical properties that provide a superior dose distribution compared to photons. The ability to spare healthy, developing tissues from low dose radiation with proton therapy is well known. The capability to decrease radiation exposure for children has been lauded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. In this review, we summarize the current literature for proton therapy for pediatric CNS malignancies, with a focus on clinical outcomes to date.

Chapter 19 - 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.

Natural history of optic pathway gliomas in a cohort of unselected patients affected by Neurofibromatosis 1.

Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion,OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.

A phase I study of convection enhanced delivery (CED) of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma (DIPG).

2010 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm3. The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.

Risk factors for central nervous system tumors in children: New findings from a case-control study.

BackgroundCentral nervous system tumors (CNS) are the most frequent solid tumor in children. Causes of CNS tumors are mainly unknown and only 5% of the cases can be explained by genetic predisposition. We studied the effects of environmental exposure on the incidence of CNS tumors in children by subtype, according to exposure to industrial and/or urban environment, exposure to crops and according to socio-economic status of the child.MethodsWe carried out a population-based case-control study of CNS tumors in Spain, covering 714 incident cases collected from the Spanish Registry of Childhood Tumors (period 1996–2011) and 4284 controls, individually matched by year of birth, sex, and autonomous region of residence. We built a covariate to approximate the exposure to industrial and/or urban environment and a covariate for the exposure to crops (GCI) using the coordinates of the home addresses of the children. We used the 2001 Census to obtain information about socio-economic status (SES). We fitted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs).ResultsThe results for all CNS tumors showed an excess risk (OR = 1.37; 95%CI = 1.09–1.73) for SES, i.e., children living in the least deprived areas had 37% more risk of CNS tumor than children living in the most deprived areas. For GCI, an increase of 10% in crop surface in the 1-km buffer around the residence implied an increase of 22% in the OR (OR = 1.22; 95%CI = 1.15–1.29). Children living in the intersection of industrial and urban areas could have a greater risk of CNS tumors than children who live outside these areas (OR = 1.20; 95%CI = 0.82–1.77). Living in urban areas (OR = 0.90; 95%CI = 0.65–1.24) or industrial areas (OR = 0.96; 95%CI = 0.81–1.77) did not seem to increase the risk for all CNS tumors together. By subtype, Astrocytomas, Intracranial and intraspinal embryonal tumors, and other gliomas showed similar results.ConclusionOur results suggest that higher socioeconomic status and exposure to crops could increase the risk of CNS tumors in children.

Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents

Leptomeningeal dissemination in paediatric central nervous system (CNS) tumours is associated with a poor outcome, and new therapeutic strategies are desperately needed. One of the main difficulties in the treatment of CNS tumours is blood brain barrier penetration. Intrathecal therapy has shown to be effective in several paediatric tumours. The aim of this article is to review the data available on the use of liposomal cytarabine for paediatric patients with leptomeningeal dissemination of CNS tumours, including the pharmacology, administration route, safety and efficacy data.

Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies.

The aim of this study was to assess the risk of childhood central nervous system (CNS) tumors associated with parental occupational pesticide exposure. We pooled three population-based case-control studies from France, Germany, and the United Kingdom. Cases were children below 15 years of age with CNS tumors; controls were matched by gender and age. A general population job-exposure matrix assessed parental occupational pesticide exposure. Logistic regressions estimated odds ratios (ORs) and 95% confidence intervals (CIs). The study included 1361 cases and 5498 controls. Prevalence of maternal occupational pesticide exposure during pregnancy was low and no association with childhood CNS tumors was detected (OR 0.76, 95% CI: 0.41 to 1.41). Around conception, OR for childhood CNS tumors associated with paternal occupational pesticide exposure was 0.71 (95% CI: 0.53 to 0.95). Our results do not suggest a role of parental occupational pesticide exposure in the etiology of childhood CNS tumors.

Conventional chemotherapy and perspectives for molecular-based oncological treatment in pediatric hemispheric low-grade gliomas

Pediatric low-grade gliomas (PLGG) are the most common primary central nervous system tumor in children. Patients in whom gross total resection can be achieved have an excellent overall (OS) and event-free survival (EFS) and do not require adjuvant therapy. However, children with unresectable tumors often experience multiple progressions and require additional treatment. Radiotherapy results in long-term tumor control, but it is associated with significant toxicity, making chemotherapy the preferred therapeutic option. Several chemotherapy combinations have been found to be successful in PLGG, but 5-year EFS has been below 60% with most of them. Recent molecular advances have led to a better understanding of the molecular pathways involved in the biology of LGG, allowing the development of promising tumor-specific, molecularly targeted therapies.

Core deficits and quality of survival after childhood medulloblastoma: a review.

Medulloblastoma is the most common malignant central nervous system tumor in children. Treatment most often includes surgical resection, craniospinal irradiation, and adjuvant chemotherapy. Although survival has improved dramatically, the tumor and its treatments have devastating long-term side effects that negatively impact quality of survival (QoS). The objective was to review the literature on QoS following childhood medulloblastoma. This narrative review is based on a Medline database search and examination of the reference lists of papers selected. Frequent problems after medulloblastoma treatment include medical complications, such as long-term neurological and sensory (hearing loss) impairments; endocrine deficits, including growth problems; and secondary tumors. Neurocognitive impairment is repeatedly reported, with decreasing cognitive performances over time. Although all cognitive domains may be affected, low processing speed, attention difficulties, and working memory difficulties are described as the core cognitive deficits resulting from both cerebellar damage and the negative effect of radiation on white matter development. Long-term psychosocial limitations include low academic achievement, unemployment, and poor community integration with social isolation. Important negative prognostic factors include young age at diagnosis, conventional craniospinal radiotherapy, presence of postoperative cerebellar mutism, and perioperative complications. The influence of environmental factors, such as family background and interventions, remains understudied. Future studies should focus on the respective impact of radiation, cerebellar damage, genomic and molecular subgroup parameters, and environmental factors on cognitive and psychosocial outcomes. Long-term (probably lifelong) follow-up into adulthood is required in order to monitor development and implement timely, suitable, multi-disciplinary rehabilitation interventions and special education or support when necessary.

Environmental exposures and risk of central nervous system tumors in children: new findings from a case-control study in Spain

Environmental exposures and risk of central nervous system tumors in children: new findings from a case-control study in Spain

Extra-Axial Cerebello-Pontine Angle Medulloblastoma

Medulloblastoma is the most common central nervous system tumor in children. Extra-axial medulloblastomas, especially tumors with no connection to the brain stem or cerebellum are extremely rare. We report a case of a 3-year-old patient, who presented with a history of subacute headache and vomiting. After performing a head computed tomography scan, a mass was detected in the left cerebello-pontine angle, along with concomitant hydrocephalus. The treatment was total resection of the tumor. Despite the fact that extra-axial medulloblastomas are extremely rare, this differential diagnosis should be included in the management of pediatric patients who present with posterior fossa tumors.

Central nervous system tumours in children in Ibadan, Nigeria: a histopathologic study.

IntroductionContrary to some earlier teachings that central nervous system (CNS) tumours are uncommon in black children, these neoplasms are the fourth most common paediatric tumours in Ibadan. Our centre is the major referral centre for CNS tumours in Nigeria. The last major study of paediatric CNS neoplasms from Ibadan was in 1985. An update of the data on paediatric CNS neoplasms at our centre is presented.MethodsA retrospective review of all histologically diagnosed CNS tumours in children (0-14 years) from January 2001 to December 2010 from the database of the Department of Pathology, University College Hospital, Ibadan, Nigeria was done. The cases were classified using the 2007 WHO Classification of Tumours of the Central Nervous System and were also based on their supratentorial and infratentorial locations.ResultsSeventy-seven tumours, 44 in males, were included in the study. Astrocytic tumour comprised 20 cases, embryonal tumours 15, ependymal tumours 15, germ cell tumours 6, sellar tumours (all craniopharyngiomas) 9 and other histological types- 12 cases. Thirty-seven were WHO Grade 1, eleven Grade 2, ten Grade 3 and nineteen Grade 4 neoplasms. Thirty-six cases were supratentorial and thirty-eight were infratentorial in location. The most common tumours in this series were pilocytic astrocytomas, medulloblastomas, craniopharyngiomas and ependymomas in that order.ConclusionChildhood CNS tumours are being increasingly diagnosed in our centre. This is largely explained by the recent expansion of the available neurosurgical services.