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Childhood Brain Tumours

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Coca HA, Cebula H, Benmekhbi M, et al.
Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note.
Neurochirurgie. 2016; 62(6):327-331 [PubMed] Related Publications
INTRODUCTION: Diffuse intrinsic pontine gliomas (DIPG) constitute 10-15% of all brain tumors in the pediatric population; currently prognosis remains poor, with an overall survival of 7-14 months. Recently the indication of DIPG biopsy has been enlarged due to the development of molecular biology and various ongoing clinical and therapeutic trials. Classically a biopsy is performed using a stereotactic frame assisted procedure but the workflow may sometimes be heavy and more complex especially in children. In this study the authors present their experience with frameless robotic-guided biopsy of DIPG in a pediatric population.
PATIENTS AND METHODS: Retrospective study on a series of five consecutive pediatric patients harboring DIPG treated over a 4-year period. All patients underwent frameless robotic-guided biopsy via a transcerebellar approach.
RESULTS: Among the 5 patients studied 3 were male and 2 female with a median age of 8.6 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy in all patients. MRI imaging of the lesion showed typical DIPG features (3 of them located in the pons) with hypo-intensity on T1 and hyper-intensity signal on T2 sequences and diffuse gadolinium enhancement. The mean procedure time was 56minutes (range 45 to 67minutes). No new postoperative neurological deficits were recorded. Histological diagnosis was achieved in all cases as follows: two anaplastic astrocytomas (grade III), two glioblastomas, and one diffuse astrocytoma (grade III).
CONCLUSION: Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis.

Zhu X, McDowell MM, Newman WC, et al.
Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report.
J Neurosurg Pediatr. 2017; 19(2):249-253 [PubMed] Related Publications
Nivolumab is an immune checkpoint inhibitor (ICI) currently undergoing Phase III clinical trials for the treatment of glioblastoma. The authors present the case of a 10-year-old girl with glioblastoma treated with nivolumab under compassionate-use guidelines. After the first dose of nivolumab the patient developed hemiparesis, cerebral edema, and significant midline shift due to severe tumor necrosis. She was managed using intravenous dexamethasone and discharged on a dexamethasone taper. The patient's condition rapidly deteriorated after the second dose of nivolumab, demonstrating hemiplegia, seizures, and eventually unresponsiveness with a fixed and dilated left pupil. Computed tomography of her brain revealed malignant cerebral edema requiring emergency decompressive hemicraniectomy. Repeat imaging demonstrated increased size of the lesion, reflecting immune-mediated inflammation and tumor necrosis. The patient remained densely hemiplegic, but became progressively more interactive and was ultimately extubated. She resumed nivolumab several weeks later, but again her condition deteriorated with headache, vomiting, swelling at the craniectomy site, and limited right-sided facial movement following the sixth dose. MRI demonstrated severe midline shift and uncal herniation despite her craniectomy. Her condition gradually declined, and she died several days later under "do not resuscitate/do not intubate" orders. To the authors' knowledge, this represents the first case of malignant cerebral edema requiring operative intervention following nivolumab treatment for glioblastoma in a pediatric patient.

Related: Monoclonal Antibodies Childhood Brain Tumours Childhood Brain Tumors

Konar SK, Bir SC, Maiti TK, Nanda A
A systematic review of overall survival in pediatric primary glioblastoma multiforme of the spinal cord.
J Neurosurg Pediatr. 2017; 19(2):239-248 [PubMed] Related Publications
OBJECTIVE The incidence of primary spinal cord glioblastoma multiforme (GBM) in the pediatric age group is very rare. Only a few case series and case reports have been published in the literature; therefore, overall survival (OS) outcome and the as-yet poorly defined management options are not discussed in detail. The authors performed a cumulative survival analysis of all reported cases of pediatric spinal cord GBM to identify the predictive factors related to final survival outcome. METHODS A comprehensive search for relevant articles was performed on PubMed's electronic database MEDLINE for the period from 1950 to 2015 using the search words "malignant spinal cord tumor" and "spinal glioblastoma multiforme." This study was limited to patients younger than 18 years of age. Survival rates for children with various tumor locations and treatments were collected from the published articles and analyzed. RESULTS After an extensive literature search, 29 articles met the study inclusion criteria. From the detailed information in these articles, the authors found 53 children eligible for the survival analysis. The majority (45%) of the children were more than 12 years old. Thirty-four percent of the cases were between 7 and 12 years of age, and 21% were younger than 7 years. In the Kaplan-Meier survival analysis, children younger than 7 years of age had better survival (13 months) than the children older than 7 years (7-12 years: 10 months, > 12 years: 9 months; p = 0.01, log-rank test). Fifty-five percent of the children were female and 45% were male. A cervical tumor location (32%) was the most common, followed by thoracic (28.3%). Cervicothoracic (18.9%) and conus (18.8%) tumor locations shared the same percentage of cases. Cervical tumors had a worse outcome than tumors in other locations (p = 0.003, log-rank test). The most common presenting symptom was limb weakness (53%), followed by sensory disturbances (25%). Median OS was 10 months. The addition of adjuvant therapy (radiotherapy [RT] and/or chemotherapy [CT]) after surgery significantly improved OS (p = 0.01, log-rank test). Children who underwent gross-total resection and RT had better outcomes than those who underwent subtotal resection and RT (p = 0.04, log-rank test). Cerebrospinal fluid spread, hydrocephalus, brain metastasis, and spinal metastasis were not correlated with OS in primary spinal GBM. CONCLUSIONS Adjuvant therapy after surgery had a beneficial effect on overall outcome of spinal GBM in the pediatric age group. Gross-total resection followed by RT produced a better outcome than subtotal resection with RT. Further large-scale prospective study is required to establish the genetic and molecular factors related to OS in primary GBM of the spinal cord in pediatric patients.

Tuntapakul S, Kitkhuandee A, Kanpittaya J, et al.
Pineal calcification is associated with pediatric primary brain tumor.
Asia Pac J Clin Oncol. 2016; 12(4):e405-e410 [PubMed] Related Publications
AIM: Melatonin has been associated with various tumors, including brain tumor, and shown to inhibit growth of neuroblastoma cells and gliomas in animal models. Likewise, patients with glioblastoma receiving melatonin reported better survival than controls. Pineal calcification may lead to a decreased production of melatonin by calcified glands. This study assessed association between pineal calcification and primary brain tumor in pediatric/adolescent patients.
METHODS: Medical chart review was conducted in 181 patients <15 years old who had undergone brain computed tomography (CT) during 2008-2012. Pineal calcification was identified using brain CT scan by an experienced neurosurgeon. Primary brain tumor was confirmed by CT scan and histology, and association with pineal calcification was estimated using multiple logistic regression, adjusted for age and gender.
RESULTS: Primary brain tumor was detected in 51 patients (mean age 9.0, standard deviation 4.0 years), with medulloblastoma being the most common (11 patients). Pineal calcification was detected in 12 patients (23.5%) with primary brain tumor, while only 11 patients (8.5%) without tumor had pineal calcification. Adjusted for patients' ages and genders, pineal calcification was associated with an increase in primary brain tumor of 2.82-fold (odds ratio 2.82; 95% confidence interval 1.12-7.08, P = 0.027).
CONCLUSION: Pineal calcification appears to be associated with primary brain tumor. Further studies to explore this link are discussed and warranted.

Related: Childhood Brain Tumours Childhood Brain Tumors

Emelifeonwu JA, Sokol D, Gallo P, et al.
Long-tunnelled external ventricular drain as a long-term treatment option for hydrocephalus in a child with an unresectable low-grade supratentorial tumor: case report.
J Neurosurg Pediatr. 2016; 18(4):430-433 [PubMed] Related Publications
The authors report a case of a child with hypothalamic-origin pilocytic astrocytoma and hydrocephalus, which was refractory to treatment with a ventriculoperitoneal shunt due to high CSF protein content. With parental education, the child's hydrocephalus was managed long-term in the community with a long-tunnelled external ventricular drain, which was maintained by his parents. To the authors' knowledge this is the first report of this management option as a long-term measure. No harm has come to the patient. The authors propose long-term, long-tunnelled external ventricular drain as a viable treatment option for such patients.

Cacchione A, Mastronuzzi A, Cefalo MG, et al.
Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival.
Chin J Cancer. 2016; 35:44 [PubMed] Free Access to Full Article Related Publications
High-grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated with severe disability and poor prognosis. We report a case of a 4-year-old child diagnosed with an isolated glioblastoma multiforme of the conus medullaris. The patient underwent subtotal surgical excision, followed by adjuvant radiotherapy and oral chemotherapy. He is alive with mild neurologic deficits at 52 months after diagnosis. We describe the peculiar characteristics of this rare condition in pediatric oncology. We also provide an overview of current multidisciplinary therapeutic approaches and prognostic factors for this disease.

Ehrstedt C, Kristiansen I, Ahlsten G, et al.
Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours.
Eur J Paediatr Neurol. 2016; 20(4):580-7 [PubMed] Related Publications
AIM: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glioneuronal tumours.
METHODS: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of ≥5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed.
RESULTS: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived ≥5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school.
CONCLUSION: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.

Related: Brain and Spinal Cord Tumours Brain Stem Glioma - Childhood Childhood Medulloblastoma / PNET Medulloblastoma Germ Cell Tumors Germ Cell Tumours in Children and Young Adults Germ Cell Tumors (Pediatric)

Kleinschmidt-DeMasters BK, Donson AM, Richmond AM, et al.
SOX10 Distinguishes Pilocytic and Pilomyxoid Astrocytomas From Ependymomas but Shows No Differences in Expression Level in Ependymomas From Infants Versus Older Children or Among Molecular Subgroups.
J Neuropathol Exp Neurol. 2016; 75(4):295-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
SOX10 is important in nonneoplastic oligodendroglial development, but mRNA transcripts and protein expression are identified in a wider variety of CNS glial neoplasms than oligodendrogliomas. We previously demonstrated high levels of SOX10 mRNA and protein in pilocytic astrocytomas (PAs) but not ependymomas (EPNs). We now extend these studies to investigate subsets of these 2 tumors that affect infants, pilomyxoid astrocytomas (PMAs) and infant (<1 year) ependymomas (iEPNs). By gene expression microarray analysis, we found that iEPNs and all EPNs in older children showed very low SOX10 expression levels, on average 7.1-fold below normal control tissues. EPN groups showed no significant difference in SOX10 expression between iEPN and EPN. PAs/PMAs had 24.1/29.4-fold higher transcript levels, respectively, than those in normal tissues. Using immunohistochemical analysis of adult, pediatric, and infantile EPNs and of PAs/PMAs, we found that EPNs from multiple anatomical locations and both age groups (n = 228) never showed 3+ diffuse nuclear immunostaining for SOX10; the majority were scored at 0 or 1+. Conversely, almost all pediatric and adult PAs and PMAs (n = 47) were scored as 3+. These results suggest that in select settings, SOX10 immunohistochemistry can supplement the diagnosis of PMA and PA and aid in distinguishing them from EPNs.

Related: Brain and Spinal Cord Tumours Childhood Ependymoma SOX10

Roth JJ, Fierst TM, Waanders AJ, et al.
Whole Chromosome 7 Gain Predicts Higher Risk of Recurrence in Pediatric Pilocytic Astrocytomas Independently From KIAA1549-BRAF Fusion Status.
J Neuropathol Exp Neurol. 2016; 75(4):306-15 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The most frequent genetic alteration identified in pediatric pilocytic astrocytomas and pilomyxoid variant is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. Less frequent abnormalities include fusion genes,BRAF, FGFR, KRAS, and NF1 point mutations, and whole chromosome gains. To correlate genetic alterations with clinical course data, we retrospectively analyzed the tumors with pilocytic and pilomyxoid histology of a cohort of 116 pediatric patients, aged 5 months to 23 years. Gross total resection was associated with a decreased risk of recurrence (p = 0.001), supporting previous findings that complete tumor excision correlates with long-term and disease-free survival. We found no significant association between recurrence rate and the presence of the KIAA1549-BRAF fusion or BRAF mutation (p = 0.167). Interestingly, gain of whole chromosome 7 (WC7) was associated with a 4.7-fold increased risk of tumor recurrence, even after adjusting for surgical status (p = 0.025), and other genetic alterations. Using fluorescence in situ hybridization, we demonstrated that when WC7 gain accompanies the KIAA1549-BRAF fusion, the fusion likely arises first. This study highlights the utility of genetic studies for risk assessment of pilocytic and pilomyxoid astrocytomas, which may impact treatment selections.

Related: Brain and Spinal Cord Tumours Chromosome 7 BRAF

Rosenfeld A, Etzl M, Lee D, et al.
A Case Series Characterizing Pilomyxoid Astrocytomas in Childhood.
J Pediatr Hematol Oncol. 2016; 38(2):e63-6 [PubMed] Related Publications
BACKGROUND: The term pilomyxoid astrocytoma (PMA) was added to the World Health Organization Classification of Tumours of the central nervous system in 2007. Pilomyxoid tumors are grade II tumors, considered to be variants of pilocytic astrocytomas. We attempted to determine if positron emission tomography (PET), proliferative index (PI), and BRAF V600E mutation help better define PMAs.
OBSERVATIONS: We report 5 patients' clinical and neuroimaging findings, pathology (PI), and outcome. Four of the 5 patients had PET scans. Three patients showed [18F]fluoro-deoxyglucose hypermetabolism. The PI was elevated in all 5 cases and the BRAF V600E mutation was found in 3 of the 3 patients tested.
CONCLUSION: Our data suggest that PMAs are hypermetabolic on PET, have elevated PIs and BRAF V600E mutations, and behave aggressively.

Related: Childhood Brain Tumours Childhood Brain Tumors BRAF

Braoudaki M, Lambrou GI, Giannikou K, et al.
miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas.
Tumour Biol. 2016; 37(7):9887-97 [PubMed] Related Publications
In the current setting, we attempted to verify and validate miRNA candidates relevant to pediatric primary brain tumor progression and outcome, in order to provide data regarding the identification of novel prognostic biomarkers. Overall, 26 resected brain tumors were studied from children diagnosed with pilocytic astrocytomas (PAs) (n = 19) and ependymomas (EPs) (n = 7). As controls, deceased children who underwent autopsy and were not present with any brain malignancy were used. The experimental approach included microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression profiles of miR-15a and miR-24-1. The multiparameter analyses were performed with MATLAB. Matching differentially expressed miRNAs were detected in both PAs and EPs, following distinct comparisons with the control cohort; however, in several cases, they exhibited tissue-specific expression profiles. On correlations between miRNA expression and EP progression or outcome, miR-15a and miR-24-1 were found upregulated in EP relapsed and EP deceased cases when compared to EP clinical remission cases and EP survivors, respectively. Taken together, following several distinct associations between miRNA expression and diverse clinical parameters, the current study repeatedly highlighted miR-15a and miR-24-1 as candidate oncogenic molecules associated with inferior prognosis in children diagnosed with ependymoma.

Related: Childhood Ependymoma MicroRNAs

Adams H, Adams HH, Jackson C, et al.
Evaluating extent of resection in pediatric glioblastoma: a multiple propensity score-adjusted population-based analysis.
Childs Nerv Syst. 2016; 32(3):493-503 [PubMed] Related Publications
PURPOSE: The benefit of radical resections for glioblastoma patients remains a source of contention in the literature. Few studies have been conducted in pediatric patients, and it is becoming increasingly evident that data regarding adult glioblastoma (GB) patients cannot be generalized to pediatric patients affected by this neoplasm. A comparative effectiveness study is performed for different extent of resection (EOR) groups in the largest cohort of pediatric GB (pGB) patients.
METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify pGB patients from 1988 through 2009. Multivariate- and multiple propensity score (mPS)-adjusted analyses were used to determine the effect of gross total resection (GTR), partial resection (PR), and biopsy (Bx) on overall survival. Survival prospects were summarized using direct adjusted survival curves.
RESULTS: A total of 342 pGB patients were identified, and 35.4 % of patients received a GTR, 28.8 % PR, 17.3 % Bx, and 17.0 % did not undergo surgery. In our cohort, a median overall survival of 12 months was observed with 1-, 2-, and 5-year survival rates of 51.7, 28.3, and 15.7 %, respectively. EOR was a predictor of survival in both the multivariate- (P < 0.001) and mPS-adjusted model (P < 0.001). Compared to the GTR group, a higher mortality rate was observed in patients who underwent a PR (HR 1.50; 95 % CI, 1.02-2.21) or Bx (HR 1.87; 95 % CI, 1.18-2.98). There were no significant differences in (adjusted) mortality risk between the PR and Bx groups.
CONCLUSION: Our study suggests that GTR is independently associated with improved survival for pediatric patients with glioblastoma.

Related: Childhood Brain Tumours Childhood Brain Tumors

de Blank PM, Fisher MJ, Lu L, et al.
Impact of vision loss among survivors of childhood central nervous system astroglial tumors.
Cancer. 2016; 122(5):730-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The impact of impaired vision on cognitive and psychosocial outcomes among long-term survivors of childhood low-grade gliomas has not been investigated previously but could inform therapeutic decision making.
METHODS: Data from the Childhood Cancer Survivor Study were used to investigate psychological outcomes (measures of cognitive/emotional function) and socioeconomic outcomes (education, income, employment, marital status, and independent living) among astroglial tumor survivors grouped by 1) vision without impairment, 2) vision with impairment (including unilateral blindness, visual field deficits, and amblyopia), or 3) bilateral blindness. The effect of vision status on outcomes was examined with multivariate logistic regression with adjustments for age, sex, cranial radiation therapy, and medical comorbidities.
RESULTS: Among 1233 survivors of childhood astroglial tumors 5 or more years after their diagnosis, 277 (22.5%) had visual impairment. In a multivariate analysis, survivors with bilateral blindness were more likely to be unmarried (adjusted odds ratio (OR), 4.7; 95% confidence interval [CI], 1.5-15.0), live with a caregiver (adjusted OR, 3.1; 95% CI, 1.3-7.5), and be unemployed (adjusted OR, 2.2; 95% CI, 1.1-4.5) in comparison with those without visual impairment. Bilateral blindness had no measurable effect on cognitive or emotional outcomes, and vision with impairment was not significantly associated with any psychological or socioeconomic outcomes.
CONCLUSIONS: Adult survivors of childhood astroglial tumors with bilateral blindness were more likely to live unmarried and dependently and to be unemployed. Survivors with visual impairment but some remaining vision did not differ significantly with respect to psychological function and socioeconomic status from those without visual impairment. Cancer 2016;122:730-739. © 2016 American Cancer Society.

Related: Brain and Spinal Cord Tumours

Dodgshun AJ, Maixner WJ, Hansford JR, Sullivan MJ
Low rates of recurrence and slow progression of pediatric pilocytic astrocytoma after gross-total resection: justification for reducing surveillance imaging.
J Neurosurg Pediatr. 2016; 17(5):569-72 [PubMed] Related Publications
OBJECTIVE Pilocytic astrocytomas (PAs) are common brain tumors in children. Optimal management of PA is gross-total resection (GTR), after which event-free survival (EFS) is excellent. The tempo of recurrences, when they do occur, is relatively sparsely reported, and there is no agreed upon surveillance recommendation for patients in this category. It has been suggested that surveillance MRI is performed too frequently and could be safely reduced in both frequency and duration. The authors conducted a retrospective review of pediatric patients with PA who underwent GTR at a single institution over an 18-year period and who had documented recurrences. METHODS All patients under 18 years of age who had undergone GTR of a PA between 1996 and 2013 were included in the study. Clinical, radiological, and tumor characteristics were recorded. RESULTS Sixty-seven patients met the criteria for GTR over the period studied. The 5-year EFS rate was 95% (95% CI 89%-100%) and overall survival was 100%. Recurrences showed a nonsignificant trend of occurring more commonly in patients with persistent nonenhancing FLAIR abnormalities after surgery, but there was no difference with regard to tumor location. All recurrences occurred before 3 years postresection, all were asymptomatic, and all patients were observed for at least one additional scan after the initial detection during routine surveillance MRI before further therapy was undertaken. CONCLUSIONS EFS and overall survival are excellent after GTR in this population with PAs. Progression after recurrence occurs slowly and is asymptomatic. A less intensive schedule of MRI surveillance in this group of patients would result in time and cost savings, without compromising safety. The authors suggest a schedule of 6 MRI scans to be obtained postoperatively, at 3-6 months, then at 1, 2, 3.5, and 5 years.

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Wilson MP, Johnson ES, Hawkins C, et al.
Hemorrhagic presentations of cerebellar pilocytic astrocytomas in children resulting in death: report of 2 cases.
J Neurosurg Pediatr. 2016; 17(4):446-52 [PubMed] Related Publications
Acute hemorrhagic presentation in pilocytic astrocytomas (PAs) has become increasingly recognized. This type of presentation poses a clinically emergent situation in those hemorrhages arising in PAs of the cerebellum, the most frequent site, because of the limited capacity of the posterior fossa to compensate for mass effect, predisposing to rapid neurological deterioration. As examples, we describe two cases of fatal hemorrhagic cerebellar PAs: one of a child with a slowly growing stereotypical WHO Grade I PA with a 1-year period of symptomatology that preceded a rapid clinical deterioration, and another of an asymptomatic child having a PA variant, presenting with progressive obtundation following a presumed Valsalva event. These two scenarios parallel previous reports in the literature of either a setting of progressive expression of cerebellar dysfunction and transient episodes of raised intracranial pressure (ICP), or abrupt onset of features of increased ICP in a previously well child. The literature is further reviewed for a current understanding of the factors that predispose, initiate and propagate bleeding, with specific reference to the role of vascular endothelial growth factor and other angiogenic agents in the genesis and stability of the vasculature in PAs. In this context, we propose that obliterative vascular mural hyalinization with associated altered flow dynamics and microaneurysm formation was the pathogenesis of the hemorrhage in our first case. In the second case, large tumor size, increased growth rate, looseness of the background myxoid matrix, and thinness of the tumor blood vessels with calcospherite deposition predisposed to vascular leakage and bleeding concurrent with sudden increases in intravascular hydrostatic pressure. In that cerebellar PAs are common, this report underscores the importance of considering in the differential diagnosis the possibility of a spontaneous hemorrhage in a posterior fossa PA in a child presenting with a sudden neurological ictus and raised ICP.

Jones TA, Jeyapalan JN, Forshew T, et al.
Molecular analysis of pediatric brain tumors identifies microRNAs in pilocytic astrocytomas that target the MAPK and NF-κB pathways.
Acta Neuropathol Commun. 2015; 3:86 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Pilocytic astrocytomas are slow-growing tumors that usually occur in the cerebellum or in the midline along the hypothalamic/optic pathways. The most common genetic alterations in pilocytic astrocytomas activate the ERK/MAPK signal transduction pathway, which is a major driver of proliferation but is also believed to induce senescence in these tumors. Here, we have conducted a detailed investigation of microRNA and gene expression, together with pathway analysis, to improve our understanding of the regulatory mechanisms in pilocytic astrocytomas.
RESULTS: Pilocytic astrocytomas were found to have distinctive microRNA and gene expression profiles compared to normal brain tissue and a selection of other pediatric brain tumors. Several microRNAs found to be up-regulated in pilocytic astrocytomas are predicted to target the ERK/MAPK and NF-κB signaling pathways as well as genes involved in senescence-associated inflammation and cell cycle control. Furthermore, IGFBP7 and CEBPB, which are transcriptional inducers of the senescence-associated secretory phenotype (SASP), were also up-regulated together with the markers of senescence and inflammation, CDKN1A (p21), CDKN2A (p16) and IL1B.
CONCLUSION: These findings provide further evidence of a senescent phenotype in pilocytic astrocytomas. In addition, they suggest that the ERK/MAPK pathway, which is considered the major driver of these tumors, is regulated not only by genetic aberrations but also by microRNAs.

Related: Childhood Brain Tumours Childhood Brain Tumors MicroRNAs Signal Transduction

Yazici G, Zorlu F, Cengiz M, et al.
High-grade glioma in children and adolescents: a single-center experience.
Childs Nerv Syst. 2016; 32(2):291-7 [PubMed] Related Publications
PURPOSE: The aim of this study was to report the outcome in children with high-grade astrocytoma outside the brain stem and spinal cord that were treated at a single center.
MATERIALS AND METHODS: The study included 26 patients with anaplastic astrocytoma and 37 patients with glioblastoma; all patients were aged ≤18 years. At initial diagnosis, 18 of the patients with glioblastoma received only temozolomide (TMZ), 14 received other chemotherapies, and 5 did not receive any chemotherapy. Among the patients with anaplastic astrocytoma, 9 received TMZ, 9 received other chemotherapy regimens, and 8 patients did not receive any chemotherapy. The median radiotherapy dose in all patients was 60 Gy.
RESULTS: Median age of the patients was 12.5 years. Median overall survival was 20 months and mean progression-free survival was 4.7-11.3 months (median: 8 months) in all patients. Patients with a Karnofsky performance score (KPS) ≥70 had median overall survival of 32 months, versus 7 months in those with a KPS < 70. Patients aged <15 years had median survival of 38 months, versus 16 months in those aged 15-18 years. Patients with anaplastic astrocytoma that received TMZ, other chemotherapy regimens, and no chemotherapy had median survival of 21 months, 132 months, and 11 months, respectively. Patients with glioblastoma that received TMZ, other chemotherapy regimens, and no chemotherapy had median survival of 32 months, 12 months, and 8 months, respectively.
CONCLUSION: In the present study, patients with anaplastic astrocytoma treated with chemotherapy protocols other than TMZ had the longest OS; however, in the glioblastoma group, OS was 32 months in those treated with standard TMZ and 12 months in those treated with other protocols (P = 0.493). Although TMZ is less toxic than PCV, it was not shown to be superior.

Related: Childhood Brain Tumours Childhood Brain Tumors Dacarbazine Lomustine Procarbazine Vincristine Temozolomide

Samadian M, Bakhtevari MH, Haddadian K, et al.
Spontaneous complete regression of hypothalamic pilocytic astrocytoma after partial resection in a child, complicated with Stevens-Johnson syndrome: a case report and literature review.
Neurosurg Rev. 2016; 39(2):335-40; discussion 340 [PubMed] Related Publications
Pilocytic astrocytoma (PA) is the most common pediatric central nervous system glial neoplasm and the most common pediatric cerebellar tumor. The spontaneous regression that occurs after partial/subtotal resection is multifactorial, depending on multiple factors, as for the case of humoral and cell-mediated immune responses of the host to the implanted tumor. A 7-year-old boy was referred to a neurosurgery clinic with headache. Further imaging workup revealed hypothalamic PA. Partial resection of the lesions was performed with right-side pterional approach. The patient developed a severe panmucositis [Stevens-Johnson syndrome (SJS)] and respiratory failure plus conjunctivitis, due to phenytoin allergy. During the patient's 6-month follow-up, postoperative magnetic resonance imaging (MRI) revealed a residual tumor, and about 9 months later (at 15 months postoperatively), the MRI showed total regression of the tumor. Clinically, symptomatic PA may undergo spontaneous regression after partial resection. We report a well-documented case of spontaneous regression hypothalamic PA after partial resection that complicated with SJS. Immune system reaction in SJS may have a role in tumor behavior and spontaneous regression. Multiple studies confirmed spontaneous regression in PA after partial/subtotal resection. This phenomenon occurs due to humoral and cell-mediated host immune responses to the implanted tumor. The immune system reaction in SJS may have a role in tumor behavior and spontaneous regression.

Georgiu C, MihuŢ E, Raus I, et al.
Pediatric glioblastoma with giant cells and "supratentorial" primitive neuroectodermal component - case report and review of the literature.
Rom J Morphol Embryol. 2015; 56(3):1165-71 [PubMed] Related Publications
INTRODUCTION: The glial differentiation in pediatric "supratentorial primitive neuroectodermal tumors" (sPNET) is occasionally revealed by immunohistochemistry with GFAP (glial fibrillary acidic protein) as isolated positive cells among undifferentiated cells, indicative of divergent cellular phenotypes. Large malignant glial tumors in sPNETs are extremely rare and challenge the neuropathologist by raising the possibility of glioblastomas with sPNET-like features (GB sPNET). The distinction between them is important because of their different treatment and prognostic.
CASE PRESENTATION: A large parieto-occipital tumor with minimal ventricular invasion, in an 11-year-old girl, with a five-month clinical history, was proven to be a highly malignant biphasic tumor, consisting in a glioblastoma with giant cells, representing 75% of the tumor, and sPNET nodules, with one larger dominant nodule. The immunohistochemistry confirmed positivity for synaptophysin, neurofilament, neuron-specific enolase and CD56 in the sPNET compartment and for GFAP, CD56 and vimentin in the glioblastoma. In some parts of the tumor, the two components were well delineated from each other as in a "collision" tumor, but in others, the two different tumors were intermingled. It was histologically diagnosed as sPNET with double differentiation (glial and neural) or glioblastoma with sPNET-like features.
CONCLUSIONS: These cases are very rare, few reported, especially in the pediatric population, and with high difficulties in histological differential diagnosis, subsequently reflected in the therapeutic decisions.

Related: Childhood Brain Tumours Childhood Brain Tumors

Steinbok P, Gopalakrishnan CV, Hengel AR, et al.
Pediatric thalamic tumors in the MRI era: a Canadian perspective.
Childs Nerv Syst. 2016; 32(2):269-80 [PubMed] Related Publications
BACKGROUND: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system.
METHODS: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed.
RESULTS: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53% of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13% for unithalamic tumors compared to 37 ± 32% for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive.
CONCLUSION: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors.

Related: Childhood Brain Tumours Childhood Brain Tumors Canada Childhood Ependymoma Brain Stem Glioma - Childhood

Ho CY, Cardinal JS, Kamer AP, et al.
Contrast Leakage Patterns from Dynamic Susceptibility Contrast Perfusion MRI in the Grading of Primary Pediatric Brain Tumors.
AJNR Am J Neuroradiol. 2016; 37(3):544-51 [PubMed] Related Publications
BACKGROUND AND PURPOSE: The pattern of contrast leakage from DSC tissue signal intensity time curves have shown utility in distinguishing adult brain neoplasms, but has limited description in the literature for pediatric brain tumors. The purpose of this study is to evaluate the utility of grading pediatric brain tumors with this technique.
MATERIALS AND METHODS: A retrospective review of tissue signal-intensity time curves from 63 pediatric brain tumors with preoperative DSC perfusion MR imaging was performed independently by 2 neuroradiologists. Tissue signal-intensity time curves were generated from ROIs placed in the highest perceived tumor relative CBV. The postbolus portion of the curve was independently classified as returning to baseline, continuing above baseline (T1-dominant contrast leakage), or failing to return to baseline (T2*-dominant contrast leakage). Interobserver agreement of curve classification was evaluated by using the Cohen κ. A consensus classification of curve type was obtained in discrepant cases, and the consensus classification was compared with tumor histology and World Health Organization grade.
RESULTS: Tissue signal-intensity time curve classification concordance was 0.69 (95% CI, 0.54-0.84) overall and 0.79 (95% CI, 0.59-0.91) for a T1-dominant contrast leakage pattern. Twenty-five of 25 tumors with consensus T1-dominant contrast leakage were low-grade (positive predictive value, 1.0; 95% CI, 0.83-1.00). By comparison, tumors with consensus T2*-dominant contrast leakage or return to baseline were predominantly high-grade (10/15 and 15/23, respectively) with a high negative predictive value (1.0; 95% CI, 0.83-1.0). For pilomyxoid or pilocytic astrocytomas, a T1-dominant leak demonstrated high sensitivity (0.91; 95% CI, 0.70-0.98) and specificity (0.90, 95% CI, 0.75-0.97).
CONCLUSIONS: There was good interobserver agreement in the classification of DSC perfusion tissue signal-intensity time curves for pediatric brain tumors, particularly for T1-dominant leakage. Among patients with pediatric brain tumors, a T1-dominant leakage pattern is highly specific for a low-grade tumor and demonstrates high sensitivity and specificity for pilocytic or pilomyxoid astrocytomas.

Related: Childhood Brain Tumours Childhood Brain Tumors

Nikitović M, Stanić D, Pekmezović T, et al.
Pediatric glioblastoma: a single institution experience.
Childs Nerv Syst. 2016; 32(1):97-103 [PubMed] Related Publications
PURPOSE: The aim of this study was to evaluate characteristics of childhood glioblastoma multiforme, effectiveness of treatment modalities, and detect factors related to outcome.
METHODS: A detailed analysis was performed on a series of 15 patients treated between 2000 and 2013, based on their clinical, radiologic, pathologic, treatment, and follow-up data.
RESULTS: Median survival time of children with glioblastoma was 13.5 months. One- and 2-year overall survival probabilities were 66.7 and 20 %, respectively. There were no significant differences in survival based on patients' gender, age, disease presentation with or without epileptic seizures, signs/symptoms of increased intracranial pressure, or tumor location. The presence of neurological deficit initially, as well as prior to radiotherapy, which was quantified by neurologic function score (NFS), had an impact on overall survival. Children with NFS 0 lived longer compared to others (p = 0.001). Survival of children that underwent gross total resection was longer than that of children that underwent subtotal resection (p = 0.030). Mean survival time of children with gross total resection was 73.5 months, compared to 13 months in children with subtotal resection. There was no significant correlation between outcome and type of radiotherapy. In four patients with gigantocellular glioblastoma, we found no evidence of a better prognosis. Two long-term survivors were recorded. Both of them underwent gross total resection and were assigned a NFS 0.
CONCLUSIONS: Gross total resection is essential for longer overall survival among pediatric patients with glioblastoma and offers a possibility for long-term survival. Severity of neurologic symptoms quantified by NFS can be considered as a potential predictor of outcome.

Related: Childhood Brain Tumours Childhood Brain Tumors

Narayan A, Jallo G, Huisman TA
Extracranial, peritoneal seeding of primary malignant brain tumors through ventriculo-peritoneal shunts in children: Case report and review of the literature.
Neuroradiol J. 2015; 28(5):536-9 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Ventriculoperitoneal shunts (VPS) have been implicated as a source of the extraneural spread of a wide variety of central nervous system tumors. The purpose is to review the literature on peritoneal seeding of central nervous system tumors from VPS in the context of a case report.
METHODS: Medline was searched using the phrase 'peritoneal seeding ventriculoperitoneal shunt'. Inclusion criteria included patients (<18 years) with evidence of peritoneal seeding from VPS.
RESULTS: Search of the literature revealed a final total of 22 articles and a total of 28 patients.
CASE REPORT: A 7-year-old boy presented with intermittent vomiting, headaches, photophobia; a 4.4 cm left thalamic mass (glioblastoma multiforme) was found. Occipital VPS catheters were placed for increasing hydrocephalus and the patient developed increased abdominal distention and pain. Computed tomography revealed diffuse ascites with carcinomatosis and the patient was diagnosed clinically with peritoneal metastases.
DISCUSSION: Our case report and literature review revealed 28 cases of central nervous system tumors demonstrating evidence of extraneural spread associated with VPS in children in a wide variety of tumors. Larger studies are required to evaluate VPS as potential risk factors for peritoneal seeding and familiarity with potential VPS-related peritoneal seeding is important for diagnostic consideration.

Related: Childhood Brain Tumours Childhood Brain Tumors

Chornenkyy Y, Agnihotri S, Yu M, et al.
Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma.
Mol Cancer Ther. 2015; 14(11):2560-8 [PubMed] Related Publications
Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 μmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG.

Related: Brain Stem Glioma - Childhood PARP1

Bonfield CM, Steinbok P
Pediatric cerebellar astrocytoma: a review.
Childs Nerv Syst. 2015; 31(10):1677-85 [PubMed] Related Publications
INTRODUCTION: Cerebellar astrocytomas (CA) are one of the most common posterior fossa tumors in children. The vast majority is low grade, and prognosis for long-term survival is excellent.
METHODS: Recent literature about CA was reviewed to provide an up to date overview of the epidemiology, pathology, molecular and cell biology, diagnosis, presentation, management, and long-term outcomes.
RESULTS: Surgical resection remains the first-line treatment with complete removal of the tumor the goal. However, even when only subtotal resection has been achieved, there is a significant chance that the tumor will remain stable or will regress spontaneously. Adjuvant chemotherapy is reserved for those tumors that progress despite surgery, and more personalized chemotherapy is being pursued with better understanding of the molecular genetics of this tumor. Radiotherapy has generally not been recommended, but stereotactic radiotherapy and conformal proton beam radiotherapy may be reasonable options in the setting of relapse or progression. In the long term, permanent neurologic deficits, mainly cerebellar dysfunction, are common, but quality of life and cognitive function are generally good.
CONCLUSIONS: Low-grade CA remains primarily a surgical disease, with excellent survival rates. Care must be taken with surgery and adjuvant treatments to preserve neurologic function to allow for optimal outcomes in the long term.

Wakefield A, Pignata A, Ghazi A, et al.
Is CMV a target in pediatric glioblastoma? Expression of CMV proteins, pp65 and IE1-72 and CMV nucleic acids in a cohort of pediatric glioblastoma patients.
J Neurooncol. 2015; 125(2):307-15 [PubMed] Free Access to Full Article Related Publications
While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor. Understanding the mechanisms of tumorigenesis and tumor propagation can identify therapeutic targets to improve these outcomes. Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM. Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics. Furthermore, CMV appears to contribute to GBM's malignant phenotype, although its role in tumorigenesis is less certain. In this cohort of 25 serially diagnosed pediatric GBMs, the largest described cohort to date, we used immunohistochemical staining and in situ hybridization to show the presence of CMV antigens pp65 and IE1-72 as well as CMV nucleic acids, respectively. Our cohort indicated either CMV antigen pp65 or IE1-72 was present in approximately 67 % of pediatric GBM samples. The majority of samples stained positive for either CMV antigen showing a cytoplasmic pattern in 25-50 % of cells within the sample at a moderate intensity, while a few samples showed nuclear staining and higher grade/intensity. Of 16 samples where in situ hybridization was performed, 13 (81 %) showed specific staining using a CMV genome specific probe cocktail. ISH positive samples showed high concordance with being pp65 or IE1-72 positive. These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death. Also, the expression of these antigens in a majority of tumor tissues should be considered for immunotherapeutic targets in cases of pediatric GBM.

Related: Childhood Brain Tumours Childhood Brain Tumors

Kun Y, Duan Z, Mei X, et al.
A rare case of malignant pediatric ectomesenchymoma arising from the cerebrum.
Int J Clin Exp Pathol. 2015; 8(7):8545-50 [PubMed] Free Access to Full Article Related Publications
Malignant ectomesenchymoma is a rare tumor that contains both ectodermal and mesenchymal elements. So far, only 7 patients with a manifestation in the cerebrum (with confirmed clinicopathological data) have been reported. A 4-year-old girl was present at our hospital with a 3-week history of intermittent sudden dizzy with no apparent cause. MRI showed an irregular enhanced lesion in the left frontal-parietal lobe and lateral ventricle with peripheral gadolinium-enhancement with a significant surrounding edema. Total removal of the tumor was performed. Histological examination of the resected tumor revealed a mixed astrocytoma and anaplastic ependymoma component with undifferentiated mesenchymal spindle cell component. Generally speaking, the main malignant part in most cases of malignant ectomesenchymoma (MEM) is the mesenchymal component. In the present case, the malignant component was both in the mesenchymal and ectodermal part. In particular, the mesenchymal part was mainly composed of spindle cells, and the ectodermal part primarily consisted of gliomatous component and anaplastic ependymoma component. The patient was then treated with chemotherapy and as regard to the prognosis, there was no evidence of tumor recurrence at the 5 months' follow-up. The long term follow-up is still in progress.

Ryu HH, Jung TY, Lee GJ, et al.
Differences in the clinical courses of pediatric and adult pilocytic astrocytomas with progression: a single-institution study.
Childs Nerv Syst. 2015; 31(11):2063-9 [PubMed] Related Publications
PURPOSE: Pilocytic astrocytoma (PA) is a World Health Organization grade I neoplasm that generally follows a benign course. However, in some patients, PA exhibits an aggressive clinical course. Here, we examined the clinical course of pediatric and adult PAs with progression at a single institution.
METHODS: Between 1995 and 2013, 39 patients with PA were treated. Nineteen were pediatric patients (mean age, 12 years; range, 1-17 years) with a male-to-female patient ratio of 10:9, while 20 were adults (mean age, 36.4 years; range, 19-65 years) with a male-to-female ratio of 9:11. We analyzed and compared tumor location, extent of tumor resection, adjuvant treatment, and clinical course in all patients.
RESULTS: In the 19 pediatric patients, tumors were located in the cerebellar vermis, cerebellar hemisphere, optic pathways plus hypothalamus, hypothalamus, brainstem, and the temporal lobe in 6 (31.6%), 5 (26.3%), 3 (15.8%), 2 (10.5%), and 2 (10.5%) patients and 1 (5.3%) patient, respectively. The mass was totally, subtotally, or partially resected in 11 (57.9%), 2 (10.5%), and 4 (21.1%) patients, respectively; biopsies were performed in 2 (10.5%) patients. Immediate postoperative adjuvant treatment was carried out in 6 patients. Tumor progression was detected in 3 patients at 3.0, 4.6, and 5.2 years after treatment, respectively, without significant symptoms. In the 20 adult patients, tumors were located in the cerebellar hemisphere, cerebellar vermis, hypothalamus, brainstem, cerebral hemisphere, and lateral ventricle in 5 (25%), 4 (20%), 3 (15%), 3 (15%), 3 (15%), and 2 (10%) patients, respectively. The mass was totally, subtotally, or partially resected in 11 (55%) and 6 (30%) patients and 1 (5%) patient, respectively; biopsies were performed in 2 patients. Immediate adjuvant treatment was carried out in 2 patients. Progression was detected in 3 patients at 0.3, 0.9, and 2.5 years after treatment, respectively, with progressive neurologic symptoms. There was one case of disease-related mortality during follow-up among the adult patients.
CONCLUSION: Most of the PA cases evaluated in this study were benign. However, tumor progression in adult PAs followed a more aggressive clinical course than those in pediatric PAs.

Related: Childhood Brain Tumours Childhood Brain Tumors

Amayiri N, Al-Hussaini M, Swaidan M, et al.
Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.
Childs Nerv Syst. 2016; 32(3):553-7 [PubMed] Related Publications
Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m(2)/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome.

Related: Colorectal (Bowel) Cancer Childhood Medulloblastoma / PNET Medulloblastoma TP53 MLH1

Coutinho de Souza P, Mallory S, Smith N, et al.
Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts.
PLoS One. 2015; 10(8):e0134276 [PubMed] Free Access to Full Article Related Publications
Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients.

Related: Childhood Brain Tumours Childhood Brain Tumors PDGFRA Signal Transduction

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