Fourth ventricle tumors in children: complications and influence of surgical approach.

OBJECTIVES: The goal of this study was to characterize the complications and morbidity related to the surgical management of pediatric fourth ventricle tumors. METHODS: All patients referred to the authors' institution with posterior fossa tumors from 2002 to 2018 inclusive were screened to include only true fourth ventricle tumors. Preoperative imaging and clinical notes were reviewed to extract data on presenting symptoms; surgical episodes, techniques, and adjuncts; tumor histology; and postoperative complications. RESULTS: Three hundred fifty-four children with posterior fossa tumors were treated during the study period; of these, 185 tumors were in the fourth ventricle, and 167 fourth ventricle tumors with full data sets were included in this analysis. One hundred patients were male (mean age ± SD, 5.98 ± 4.12 years). The most common presenting symptom was vomiting (63.5%). The most common tumor types, in order, were medulloblastoma (94 cases) > pilocytic astrocytoma (30 cases) > ependymoma (30 cases) > choroid plexus neoplasms (5 cases) > atypical teratoid/rhabdoid tumor (4 cases), with 4 miscellaneous lesions. Of the 67.1% of patients who presented with hydrocephalus, 45.5% had an external ventricular drain inserted (66.7% of these prior to tumor surgery, 56.9% frontal); these patients were more likely to undergo ventriculoperitoneal shunt (VPS) placement at a later date (p = 0.00673). Twenty-two had an endoscopic third ventriculostomy, of whom 8 later underwent VPS placement. Overall, 19.7% of patients had a VPS sited during treatment.Across the whole series, the transvermian approach was more frequent than the telovelar approach (64.1% vs 33.0%); however, the telovelar approach was significantly more common in the latter half of the series (p < 0.001). Gross-total resection was achieved in 70.7%. The most common postoperative deficit was cerebellar mutism syndrome (CMS; 28.7%), followed by new weakness (24.0%), cranial neuropathy (18.0%), and new gait abnormality/ataxia (12.6%). Use of intraoperative ultrasonography significantly reduced the incidence of CMS (p = 0.0365). There was no significant difference in the rate of CMS between telovelar or transvermian approaches (p = 0.745), and multivariate logistic regression modeling did not reveal any statistically significant relationships between CMS and surgical approach. CONCLUSIONS: Surgical management of pediatric fourth ventricle tumors continues to evolve, and resection is increasingly performed through the telovelar route. CMS is enduringly the major postoperative complication in this patient population.

Molecular analysis of pediatric brain tumors identifies microRNAs in pilocytic astrocytomas that target the MAPK and NF-κB pathways.

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.

Challenges for the functional diffusion map in pediatric brain tumors.

BACKGROUND: The functional diffusion map (fDM) has been suggested as a tool for early detection of tumor treatment efficacy. We aim to study 3 factors that could act as potential confounders in the fDM: areas of necrosis, tumor grade, and change in tumor size. METHODS: Thirty-four pediatric patients with brain tumors were enrolled in a retrospective study, approved by the local ethics committee, to examine the fDM. Tumors were selected to encompass a range of types and grades. A qualitative analysis was carried out to compare how fDM findings may be affected by each of the 3 confounders by comparing fDM findings to clinical image reports. RESULTS: Results show that the fDM in areas of necrosis do not discriminate between treatment response and tumor progression. Furthermore, tumor grade alters the behavior of the fDM: a decrease in apparent diffusion coefficient (ADC) is a sign of tumor progression in high-grade tumors and treatment response in low-grade tumors. Our results also suggest using only tumor area overlap between the 2 time points analyzed for the fDM in tumors of varying size. CONCLUSIONS: Interpretation of fDM results needs to take into account the underlying biology of both tumor and healthy tissue. Careful interpretation of the results is required with due consideration to areas of necrosis, tumor grade, and change in tumor size.

Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma.

Promoter hypermethylation and transcriptional silencing is a common epigenetic mechanism of gene inactivation in cancer. To identify targets of epigenetic silencing in paediatric intracranial ependymoma, we used a pharmacological unmasking approach through treatment of 3 ependymoma short-term cell cultures with the demethylating agent 5-Aza-2'-deoxycytidine followed by global expression microarray analysis. We identified 55 candidate epigenetically silenced genes, which are involved in the regulation of apoptosis, Wnt signalling, p53 and cell differentiation. The methylation status of 26 of these genes was further determined by combined bisulfite restriction analysis (COBRA) and genomic sequencing in a cohort of 40 ependymoma samples. The most frequently methylated genes were BEX1 (27/40 cases), BAI2 (20/40), CCND2 (18/40), and CDKN2A (14/40). A high correlation between promoter hypermethylation and decreased gene expression levels was established by real-time quantitative PCR, suggesting the involvement of these genes in ependymoma tumourigenesis. Furthermore, ectopic expression of brain-expressed X-linked 1 (BEX1) in paediatric ependymoma short-term cell cultures significantly suppressed cell proliferation and colony formation. These data suggest that promoter hypermethylation contributes to silencing of target genes in paediatric intracranial ependymoma. Epigenetic inactivation of BEX1 supports its role as a candidate tumour suppressor gene in intracranial ependymoma, and a potential target for novel therapies for ependymoma in children.

A two-stage model for in vivo assessment of brain tumor perfusion and abnormal vascular structure using arterial spin labeling.

The ability to assess brain tumor perfusion and abnormalities in the vascular structure in vivo could provide significant benefits in terms of lesion diagnosis and assessment of treatment response. Arterial spin labeling (ASL) has emerged as an increasingly viable methodology for non-invasive assessment of perfusion. Although kinetic models have been developed to describe perfusion in healthy tissue, the dynamic behaviour of the ASL signal in the brain tumor environment has not been extensively studied. We show here that dynamic ASL data acquired in brain tumors displays an increased level of 'biphasic' behaviour, compared to that seen in healthy tissue. A new two-stage model is presented which more accurately describes this behaviour, and provides measurements of perfusion, pre-capillary blood volume fraction and transit time, and capillary bolus arrival time. These biomarkers offer a novel contrast in the tumor and surrounding tissue, and provide a means for measuring tumor perfusion and vascular structural abnormalities in a fully non-invasive manner.

Survival analysis for apparent diffusion coefficient measures in children with embryonal brain tumours.

Embryonal brain tumors constitute a large and important subgroup of pediatric brain tumors. Apparent diffusion coefficient (ADC) measures have been previously used in the analysis of these tumors. We investigated a newly described ADC-derived parameter, the apparent transient coefficient in tumor (ATCT), a measure of the gradient change of ADC from the peri-tumoral edema into the tumor core, to study whether ATCT correlates with survival outcome. Sixty-one patients with histologically proven embryonal brain tumors and who had diffusion-weighted imaging (DWI) as part of their clinical imaging were enrolled in a retrospective study correlating ADC measures with survival. Kaplan-Meier survival curves were constructed for extent of surgical resection, age <3 years at diagnosis, tumor type, and metastasis at presentation. A multivariate survival analysis was performed that took into consideration ATCT and variables found to be significant in the Kaplan-Meier analysis as covariates. Results from the multivariate analysis showed that ATCT was the only significant covariate (P < .001). Survival analysis using Kaplan-Meier curves, dividing the patients into 4 groups of increasing values of ATCT, showed that more negative values of ATCT were significantly associated with a poorer prognosis (P < .001). A statistically significant difference was observed for survival data with respect to the change in ADC from edema into the tumor volume. Results show that more negative ATCT values are significantly associated with a poorer survival among children with embryonal brain tumors, irrespective of tumor type, extent of resection, age <3 years at diagnosis, and metastasis at presentation.

Cytogenetic analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in-situ hybridisation.

Little is known about the cytogenetic and molecular genetic events that lead to the formation of paediatric astrocytoma. We have analysed 57 paediatric astrocytoma (WHO grades I-IV) using comparative genomic hybridisation in order to identify common regions of abnormality. Large regions of copy number alterations were infrequent with 71% of tumours demonstrating no genomic imbalance. Furthermore, the most frequent aberrations (including gain of 6q, 2q, and 7q, and loss of 16 and 12q) occurred in only a subset of cases. High-copy number amplification was seen in five tumours at 12 different regions. The presence of copy number alterations was significantly associated with increasing grade of malignancy, and gain of 12q and the presence of high-copy number amplification were associated with a poor outcome in patients with malignant astrocytoma (P = 0.0039 and 0.0085, respectively). FISH analysis confirmed loss of 1p36 identified by CGH. There was no evidence of amplification of EGFR, CDK4, MET, CDK6, c-myc, or MDM2.

Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma.

The molecular pathogenesis of pediatric pilocytic astrocytoma (PA) is not well defined. Previous cytogenetic and molecular studies have not identified nonrandom genetic aberrations. To correlate differential gene expression and genomic copy number aberrations (CNAs) in PA, we have used Affymetrix GeneChip HG_U133A to generate gene expression profiles of 19 pediatric patients and the SpectralChip 2600 to investigate CNAs in 11 of these tumors. Hierarchical clustering according to expression profile similarity grouped tumors and controls separately. We identified 1844 genes that showed significant differential expression between tumor and normal controls, with a large number clearly influencing phosphatidylinositol and mitogen-activated protein kinase signaling in PA. Most CNAs identified in this study were single-clone alterations. However, a small region of loss involving up to seven adjacent clones at 7q11.23 was observed in seven tumors and correlated with the underexpression of BCL7B. Loss of four individual clones was also associated with reduced gene expression including SH3GL2 at 9p21.2-p23, BCL7A (which shares 90% sequence homology with BCL7B) at 12q24.33, DRD1IP at 10q26.3, and TUBG2 and CNTNAP1 at 17q21.31. Moreover, the down-regulation of FOXG1B at 14q12 correlated with loss within the gene promoter region in most tumors. This is the first study to correlate differential gene expression with CNAs in PA.

Real-time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12-q13.

Loss of chromosome 22 and gain of 1q are the most frequent genomic aberrations in ependymomas, indicating that genes mapping to these regions are critical in their pathogenesis. Using real-time quantitative PCR, we measured relative copy numbers of 10 genes mapping to 22q12.3-q13.33 and 10 genes at 1q21-32 in a series of 47 pediatric intracranial ependymomas. Loss of one or more of the genes on 22 was detected in 81% of cases, with RAC2 and C22ORF2 at 22q12-q13.1 being deleted most frequently in 38% and 32% of ependymoma samples, respectively. Combined analysis of quantitative-PCR with methylation-specific PCR and bisulphite sequencing revealed a high rate (>60% ependymoma) of transcriptional inactivation of C22ORF2, indicating its potential importance in the development of pediatric ependymomas. Increase of relative copy numbers of at least one gene on 1q were detected in 61% of cases, with TPR at 1q25 displaying relative copy number gains in 38% of cases. Patient age was identified as a significant adverse prognostic factor, as a significantly shorter overall survival time (P = 0.0056) was observed in patients <2 years of age compared with patients who were >2 years of age. Loss of RAC2 at 22q13 or amplification of TPR at 1q25 was significantly associated with shorter overall survival in these younger patients (P = 0.0492 and P = < 0.0001, respectively). This study identifies candidate target genes within 1q and 22q that are potentially important in the pathogenesis of intracranial pediatric ependymomas.

Surveillance imaging strategies following surgery and/or radiotherapy for childhood cerebellar low-grade astrocytoma.

OBJECT: The authors sought to evaluate surveillance strategies for the detection and monitoring of residual and recurrent disease in children with cerebellar low-grade astrocytomas (CLGAs) treated surgically or with radiotherapy. Patients were divided into three groups: (1) those in whom a "complete" resection was achieved; (2) those with residual disease with no immediate adjuvant therapy; and (3) those who received radiotherapy for residual/recurrent disease. METHODS: Magnetic resonance (MR) imaging studies and clinical data obtained in children with CLGA who presented between January 1988 and September 1998 were reviewed. Eighty-four children were followed for a mean period of 73 months (range 2-159 months). One child died. Of the 70 children in whom a complete resection was achieved, nine (13%) developed a recurrence detected by surveillance imaging at 6, 8, 9, 9, 13, 27, 39, 44, and 47 months, respectively. Following an incomplete resection, radiologically detected tumor progression leading to further treatment was detected at 7, 9, 12, 13, and 20 months, respectively, and an additional six tumors regressed or stablized. In 11 of 12 children treated with radiotherapy, stabilization/regression occurred radiologically at a mean of 14.9 months. CONCLUSIONS: The authors recommend surveillance MR imaging in children treated for CLGA at 6 months and 1, 2, 3.5, and 5 years following a complete resection and after radiotherapy performed either initially or following recurrence. For follow up of residual tumor, 6-month interval imaging for at least 3 years, yearly images for another 2 years, and subsequent 2-year imaging is recommended.

Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children.

BACKGROUND: Cerebellar low-grade astrocytomas (CLGAs) of childhood are benign tumours and are usually curable by surgical resection alone or combined with adjuvant radiotherapy. OBJECTIVE: To undertake a retrospective study of our children with CLGA to determine the optimum schedule for surveillance imaging following initial surgery. In this report we describe the phenomenon of spontaneous regression of residual tumour and discuss its prognostic significance regarding future imaging. MATERIALS AND METHODS: A retrospective review was conducted of children treated for histologically proven CLGA at Great Ormond Street Hospital from 1988 to 1998. RESULTS: Of 83 children with CLGA identified, 13 (15.7%) had incomplete resections. Two children with large residual tumours associated with persistent symptoms underwent additional treatment. Eleven children were followed by surveillance imaging alone for a mean of 6.83 years (range 2-13.25 years). Spontaneous tumour regression was seen in 5 (45.5%) of the 11 children. There were no differences in age, gender, symptomatology, histological grade or Ki-67 fractions between those with spontaneous tumour regression and those with progression. There was a non-significant trend that larger volume residual tumours progressed. CONCLUSIONS: Residual tumour followed by surveillance imaging may either regress or progress. For children with residual disease we recommend surveillance imaging every 6 months for the first 2 years, every year for years 3, 4 and 5, then every second year if residual tumour is still present 5 years after initial surgery. This would detect not only progressive or recurrent disease, but also spontaneous regression which can occur later than disease progression.

Surveillance neuroimaging of intracranial medulloblastoma in children: how effective, how often, and for how long?

OBJECT: The goal of this paper was to review brain and spine images obtained in children with medulloblastomas to determine the risk factors for tumor recurrence and to assess the impact of surveillance imaging on patient outcomes among patients who remain alive 1 month postsurgery. METHODS: Imaging studies and clinical data obtained in children with medulloblastomas, who presented between January 1987 and August 1998, were retrospectively reviewed. Images were termed surveillance if they were follow-up studies and symptom prompted if they were obtained to investigate new symptoms. One hundred seven patients (mean age 6 years and 3 months, range 2 months-15 years and 6 months) were entered into the study. Fifty-three children experienced tumor recurrence; 41 had one recurrence, nine had two, and three had three recurrences. Surveillance imaging revealed 10 of the first 53 recurrences and 15 of all 68 recurrences. When the first recurrence was identified by the emergence of symptoms (42 patients), the children tended to survive for a shorter time (hazard ratio 3.72, 95% confidence interval 1.42-9.76, p = 0.008) than children in whom the first recurrence was detected before symptoms occurred (10 patients). The median survival time following symptomatic tumor recurrence was 4 months and that after surveillance-detected tumor recurrence was 17 months. The median increased survival time among patients whose recurrence was asymptomatic and identified by imaging studies was 13 months, more than half the mean time between surveillance imaging sessions. Incomplete tumor resection was associated with a significantly reduced time to recurrence (p = 0.048) and to death (p = 0.002). The number of recurrences that were experienced was associated with a reduced time to death (p < 0.001). CONCLUSIONS: Surveillance imaging is associated with an increase in survival in children with medulloblastomas. More frequent surveillance imaging in children with incomplete tumor excision and recurrent disease may further improve the length of survival.