Background

Dysembryoplastic neuroepithelial tumors (DNETs) are benign glioneuronal tumors that occur in children. These tumors are characterized by seizures, lack of neurologic deficits, and a seemingly benign course after resection.

Methods

We conducted a retrospective review of data relating to 11 children diagnosed with DNET between January 1988 and December 2007 at St. Jude Children's Research Hospital. This report documents the clinical features, neurocognitive function, and treatment outcomes in our institutional series.

Results

Our patient cohort included 8 boys and 3 girls (median age at diagnosis, 10 years); all patients presented with seizures: 4 complex partial, 3 generalized tonic clonic, 2 absence, 1 partial simple, and 1 not classified. Of the 11 patients, 1 died of cardiac fibrosis, and tumors recurred or progressed in 4 (36%). Seizure control was achieved in all patients but 1. Of the 9 patients who completed neuropsychologic testing, only 3 (23%) functioned at or above the expected level of same-age peers.

Conclusion

The high recurrence and progression rates of DNETs and the high rate of abnormal neurocognitive test results in this study highlight the need for regular follow-up and appropriate academic counseling of children with these tumors.

Object

Thalamopeduncular tumors arise at the junction of the inferior thalamus and cerebral peduncle and present with a common clinical syndrome of progressive spastic hemiparesis. Pathologically, these lesions are usually juvenile pilocytic astrocytomas and are best treated with resection with the intent to cure. The goals of this study are to define a common clinical syndrome produced by thalamopeduncular tumors and to discuss imaging characteristics as well as surgical adjuncts, intraoperative nuances, and postoperative complications relating to the resection of these neoplasms.

Methods

The authors present a retrospective review of their experience with 10 children presenting between 3 and 15 years of age with a thalamopeduncular syndrome. Formal preoperative MR imaging was obtained in all patients, and diffusion tensor (DT) imaging was performed in 9 patients. Postoperative MR imaging was obtained to evaluate the extent of tumor resection. A prospective analysis of clinical outcomes was then conducted by the senior author.

Results

Pilocytic astrocytoma was the pathological diagnosis in 9 cases, and the other was fibrillary astrocytoma. Seven of 9 pilocytic astrocytomas were completely resected. Radical surgery was avoided in 1 child after DT imaging revealed that the corticospinal tract (CST) coursed through the center of the tumor, consistent with the infiltrative nature of fibrillary astrocytoma as identified by stereotactic biopsy. In 8 patients, tractography served as an important adjunct for designing a surgical approach that spared the CST. In 6 cases the CSTs were pushed anterolaterally, making a transsylvian approach a poor choice, as was evidenced by the first patient in the series, who underwent operation prior to the advent of tractography, and who awoke with a dense contralateral hemiparesis. Thus, subsequent patients with this deviation pattern underwent a transcortical approach via the middle temporal gyrus. One patient exhibited medial deviation of the tracts and another had lateral deviation, facilitating a transtemporal and a transfrontal approach, respectively.

Conclusions

The thalamopeduncular syndrome of progressive spastic hemiparesis presenting in children with or without symptoms of headache should alert the examiner to the possibility of a tumoral involvement of CSTs. Preoperative tractography is a useful adjunct to surgical planning in tumors that displace motor pathways. Gross-total resection of pilocytic astrocytomas usually results in cure, and therefore should be entertained when developing a treatment strategy for thalamopeduncular tumors of childhood.

Little is known about brain tumors in early infancy. We reviewed the records of 27 patients (12 boys and 15 girls) diagnosed within 120 days of birth. The median age was 66 days (range, 0–110 days) at diagnosis. All patients underwent surgery; 18 received adjuvant chemotherapy, and 3 received adjuvant chemotherapy and radiation therapy. The median follow-up was 2.1 years (range, 0.2–21.6 years). At last encounter, 15 patients were alive, and 11 had no evidence of disease. Ten patients died of progressive disease, and 2 died of treatment-related complications. All survivors experienced late effects, including endocrine, neurologic, and cognitive deficits. Of the 13 patients who completed neurocognitive assessments, 7 had an IQ score less than 70. Children in whom brain tumors arise during early infancy can be cured with conventional therapy; however, contemporary approaches can adversely affect long-term function, and families need to be aware when making therapeutic decisions.

Background

Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype.

Methods

Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.

Results

Tissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17).

Conclusions

Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).

Please see related article: http://www.biomedcentral.com/1741-7015/10/36

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor1–4. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype)3–8. The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype)1,3,4, arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.

Background

Infratentorial ependymoma is a common central nervous system tumor of childhood and in patients > 1 year of age is treated with maximally feasible surgical resection and radiotherapy. Because of this tumor typically arises within the 4th ventricle and can invade the brainstem, patients are at risk for significant neurological impairment.

Purpose

To characterize the incidence, evolution, and persistence of neurologic impairment in children with infratentorial ependymoma following maximal safe surgery and conformal or intensity-modulated radiation therapy (CRT/IMRT).

Patients and Methods

After surgical resection, 96 children with non-metastatic infratentorial ependymoma were enrolled on a phase II study of image-guided radiation therapy and were prospectively followed with interval comprehensive neurological examinations. Late adverse neurological severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Results

The most common deficits detected at baseline examination were limb dysmetria, cranial nerve VI/VII palsy, limb paresis, dysphagia, and truncal ataxia/hypotonia. When present, gait dysfunction and dysphagia were often severe. Oculomotor dysfunction, facial paresis, dysphagia, and gait impairment improved over time. With the exception of hearing loss, in the survivor cohort, very few severe late effects (CTCAE Grade 3/4/5) were present at 60 month survival.

Conclusion

In general, neurological deficits were maximal in the post-operative period and either remained stable or improved during radiation and the post-treatment evaluation period. With the exception of hearing, the majority of chronic residual neurological deficits in this at-risk population are mild and only minimally intrude upon daily life.

Purpose

The use of radiotherapy in pediatric low-grade glioma (LGG) is controversial, especially for young patients. We conducted a phase II trial of conformal radiation therapy (CRT) to estimate disease control by using a 10-mm clinical target volume (CTV) margin.

Materials and Methods

Between August 1997 and August 2006, 78 pediatric patients with LGG and a median age of 8.9 years (range, 2.2 to 19.8 years) received 54 Gy CRT by using a 10-mm CTV and by targeting with systematic magnetic resonance imaging (MRI) registration. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Sixty-seven patients had documented or presumed WHO grade 1 tumors, 25 patients had prior chemotherapy, and 13 patients had neurofibromatosis type 1.

Results

During a median follow-up of 89 months, 13 patients experienced disease progression. One patient experienced marginal treatment failure, eight experienced local failures, and four experienced metastatic failure. The mean and standard error 5- and 10-year event-free (87.4% ± 4.4% and 74.3% ± 15.4%, respectively) and overall (98.5% ± 1.6% and 95.9% ± 5.8%, respectively) survival rates were determined. The mean and standard error cumulative incidences of local failure at 5 and 10 years were 8.7% ± 3.5% and 16.4% ± 5.4%, respectively. The mean and standard error cumulative incidence of vasculopathy was 4.79% ± 2.73% at 6 years, and it was higher for those younger than 5 years of age (P = .0105) at the time of CRT.

Conclusion

This large, prospective series of irradiated children with LGG demonstrates that CRT with a 10-mm CTV does not compromise disease control. The results suggest that CRT should be delayed in young patients to reduce the risk of vasculopathy.

We undertook this study to estimate the event-free survival (EFS) of patients with newly diagnosed supratentorial primitive neuroectodermal tumor (SPNET) treated with risk-adapted craniospinal irradiation (CSI) with additional radiation to the primary tumor site and subsequent high-dose chemotherapy supported by stem cell rescue. Between 1996 and 2003, 16 patients with SPNET were enrolled. High-risk (HR) disease was differentiated from average-risk (AR) disease by the presence of residual tumor (M0 and tumor size > 1.5 cm2) or disseminated disease in the neuraxis (M1–M3). Patients received risk-adapted CSI: those with AR disease received 23.4 Gy; those with HR disease, 36–39.6 Gy. The tumor bed received a total of 55.8 Gy. Subsequently, all patients received four cycles of high-dose cyclophosphamide, cisplatin, and vincristine with stem cell support. The median age at diagnosis was 7.9 years; eight patients were female. Seven patients had pineal PNET. Twelve patients are alive at a median follow-up of 5.4 years. The 5-year EFS and overall survival (OS) estimates for all patients were 68% ± 14% and 73% ± 13%. The 5-year EFS and OS estimates were 75% ± 17% and 88% ± 13%, respectively, for the eight patients with AR disease and 60% ± 19% and 58% ± 19%, respectively, for the eight with HR disease. No deaths were due to toxicity. High-dose cyclophosphamide-based chemotherapy with stem cell support after risk-adapted CSI results in excellent EFS estimates for patients with newly diagnosed AR SPNET. Further, this chemotherapy allows for a reduction in the dose of CSI used to treat AR SPNET without compromising EFS.

Background

The prognosis for children with M1 medulloblastoma (positive CSF cytology) has not been well-defined.

Methods

We retrospectively reviewed the records of 285 newly diagnosed medulloblastoma patients treated between 1984 and 2006. Older children received post-operative craniospinal and tumor bed irradiation; radiotherapy for younger children depended on treatment era and physician/family preference.

Results

55 patients were <3 years old and 230 patients were = 3 years old at diagnosis. We detected significant (p<0.0001) associations between M1 disease and EFS for the entire cohort and for both younger and older patients. Among younger children, M1 patients had lower EFS than M0 (p=0.0044).

Conclusions

Children <3 years old with M1 medulloblastoma fared poorly in our small series. Survival for older children with M1 disease treated with higher-dose CSI was better than that of M2/M3 patients, but still less than optimal; our findings do not support reduction in therapy for either cohort.