Embryonal tumors in Canadian children less than 36 months of age: results from the Canadian Pediatric Brain Tumor Consortium (CPBTC).

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.

Genetic regulation of vertebrate eye development.

Eye development is a complex and highly regulated process that consists of several overlapping stages: (i) specification then splitting of the eye field from the developing forebrain; (ii) genesis and patterning of the optic vesicle; (iii) regionalization of the optic cup into neural retina and retina pigment epithelium; and (iv) specification and differentiation of all seven retinal cell types that develop from a pool of retinal progenitor cells in a precise temporal and spatial manner: retinal ganglion cells, horizontal cells, cone photoreceptors, amacrine cells, bipolar cells, rod photoreceptors and Müller glia. Genetic regulation of the stages of eye development includes both extrinsic (such as morphogens, growth factors) and intrinsic factors (primarily transcription factors of the homeobox and basic helix-loop helix families). In the following review, we will provide an overview of the stages of eye development highlighting the role of several important transcription factors in both normal developmental processes and in inherited human eye diseases.

BNIP3 acts as transcriptional repressor of death receptor-5 expression and prevents TRAIL-induced cell death in gliomas.

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor, and current treatment modalities such as surgical resection, adjuvant radiotherapy and temozolomide (TMZ) chemotherapy are ineffective. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel cancer therapeutic agent for GBM because of its capability of inducing apoptosis in glioma cells. Unfortunately, the majority of glioma cells are resistant to TRAIL-induced apoptosis. The Bcl-2 nineteen kilodalton interacting protein (BNIP3) is a pro-cell death BH3-only member of the Bcl-2 family that is one of the highest expressed genes in hypoxic regions of GBM tumors. We previously found that BNIP3 is localized to the nucleus in GBM tumors and suppresses cell death in glioma cells. Herein, we have discovered when BNIP3 nuclear expression is knockdown in glioma cell lines and in normal mouse astrocytes, TRAIL and its death receptor, death receptor-5 (DR5) expression is increased. In addition, when nuclear BNIP3 expression is increased, the amount of TRAIL-induced apoptosis is reduced. Using a streptavidin pull-down assay, we found that BNIP3 binds to the DR5 promoter and nuclear BNIP3 binds to the DR5 promoter. Furthermore, nuclear BNIP3 expression in GBM tumors correlates with decreased DR5 expression. Taken together, we have discovered a novel transcriptional repression function for BNIP3 conferring a TRAIL resistance in glioma cells.

Extended adjuvant temozolomide with cis-retinoic acid for adult glioblastoma.

OBJECTIVE: To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (tmz) with cis-retinoic acid (cra) for patients with glioblastoma. METHODS: This retrospective population-based review considered the charts of all patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002-2008. Consecutive patients came from a population-based referral centre and provincial cancer registry. All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and tmz 75 mg/m(2) daily, followed by tmz 150-200 mg/m(2) for days 1-5, repeated every 28 days for up to 24 cycles, and cra 50 mg/m(2) twice daily for days 1-21, repeated every 28 days. The main outcome measures were safety, tolerability, and effectiveness of long-term tmz and cra. RESULTS: Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant tmz. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of tmz and 3 cycles of cra. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years. CONCLUSIONS: Extended adjuvant tmz and cra is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant tmz. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.

Brn-3b inhibits generation of amacrine cells by binding to and negatively regulating DLX1/2 in developing retina.

During retinogenesis, the basic helix-loop-helix proneural gene math5 (atoh7) initiates the generation of the first-born neurons, retinal ganglion cells (RGCs), by activating a network of RGC transcription factors, including Brn-3b (POU4F2). Herein, we show that the expression of DLX1 and DLX2 is significantly down-regulated in math5-null retina but is markedly increased in Brn-3b-null retina. Interestingly, Brn-3b interacts with DLX1 through its homeodomain, and this interaction represses DLX1 activity. Retrovirus-mediated mis-expression of DLX1 or DLX2 dramatically increases the number of amacrine/bipolar cells and concurrently reduces rod photoreceptors. Conversely, combined ectopic expression of Brn-3b with DLX1 or DLX2 promotes the production of RGCs and inhibits amacrine cell differentiation. Thus, DLX1/2 play an essential role in cell fate selection between amacrine and RGCs. Brn-3b suppresses the role of DLX1/2 through physical interaction and biases the competent precursors toward RGC fates.

Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme.

Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re-irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.

Homeobox genes in vertebrate forebrain development and disease.

Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators of developmental processes such as regional specification, patterning, migration and differentiation. In both mouse and humans, the developing forebrain is marked by distinct boundaries of homeobox gene expression at different developmental time points. These genes regulate the patterning of the forebrain along the dorsal/ventral and rostral/caudal axes and are also essential for the differentiation of specific neuronal subtypes. Inhibitory interneurons that arise from the ganglionic eminences and migrate tangentially to the neocortex and hippocampus are dramatically affected by mutations in several homeobox genes. In this review, we discuss the identification, expression patterns, loss- and/or gain-of-function models, and confirmed transcriptional targets for a set of homeobox genes required for the correct development of the forebrain in the mouse. In humans, mutations of homeobox genes expressed in the forebrain have been shown to result in mental retardation, epilepsy or movement disorders. The number of homeobox genes currently linked to human nervous system disease is surprisingly low, perhaps reflecting the essential functions of these genes throughout embryogenesis or the degree of functional redundancy during central nervous system development.

DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation.

The homeobox genes in the Dlx family are required for differentiation of basal forebrain neurons and craniofacial morphogenesis. Herein, we studied the expression of Dlx-1, Dlx-2, and Dlx-5 RNA and protein in the mouse forebrain from embryonic day 10.5 (E10.5) to E12.5. We provide evidence that Dlx-2 is expressed before Dlx-1, which is expressed before Dlx-5. We also demonstrate that these genes are expressed in the same cells, which may explain why single mutants of the Dlx genes have mild phenotypes. The DLX proteins are localized primarily to the nucleus, although DLX-5 also can be found in the cytoplasm. During development, the fraction of Dlx-positive cells increases in the ventricular zone. Analysis of the distribution of DLX-1 and DLX-2 in M-phase cells suggests that these proteins are distributed symmetrically to daughter cells during mitosis. We propose that DLX-negative cells in the ventricular zone are specified progressively to become DLX-2-expressing cells during neurogenesis; as these cells differentiate, they go on to express DLX-1, DLX-5, and DLX-6. This process appears to be largely the same in all regions of the forebrain that express the Dlx genes. In the basal telencephalon, these DLX-positive cells differentiate into projection neurons of the striatum and pallidum as well as interneurons, some of which migrate to the cerebral cortex and the olfactory bulb.

Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes.

Although previous analyses indicate that neocortical neurons originate from the cortical proliferative zone, evidence suggests that a subpopulation of neocortical interneurons originates within the subcortical telencephalon. For example, gamma-aminobutyric acid (GABA)-expressing cells migrate in vitro from the subcortical telencephalon into the neocortex. The number of GABA-expressing cells in neocortical slices is reduced by separating the neocortex from the subcortical telencephalon. Finally, mice lacking the homeodomain proteins DLX-1 and DLX-2 show no detectable cell migration from the subcortical telencephalon to the neocortex and also have few GABA-expressing cells in the neocortex.

Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons.

The striatum has a central role in many neurobiological processes, yet little is known about the molecular control of its development. Inroads to this subject have been made, due to the discovery of transcription factors, such as the Dlx genes, whose expression patterns suggest that they have a role in striatal development. We report that mice lacking both Dlx-1 and Dlx-2 have a time-dependent block in striatal differentiation. In these mutants, early born neurons migrate into a striatum-like region, which is enriched for markers of the striosome (patch) compartment. However, later born neurons accumulate within the proliferative zone. Several lines of evidence suggest that mutations in Dlx-1 and Dlx-2 produce abnormalities in the development of the striatal subventricular zone and in the differentiation of striatal matrix neurons.

Dlx-2 homeobox gene controls neuronal differentiation in primary cultures of developing basal ganglia.

Homeodomain-containing genes of the Dlx family are expressed in the developing basal ganglia. To investigate the role of Dlx genes during development, we studied their cellular localization in primary cultures of embryonic basal telencephalon, and examined the changes in cellular phenotypes resulting from blockade of Dlx-2 expression. Cells containing Dlx-1, Dlx-2, and Dlx-5 mRNAs are immature cells of the neuronal lineage expressing the microtubule-associated proteins (MAPs) MAP1B and MAP2, but not glial fibrillary acidic protein (GFAP). Treatment of these cells with antisense oligonucleotides targeted to Dlx-2 caused a specific decrease of Dlx-2 mRNA and protein. This decrease in the Dlx-2 gene product was associated with a decrease in the expression of MAP2, a protein localized in neuronal dendrites, along with a smaller decrease in the 200-kDa neurofilament subunit (NF-H). Proteins expressed preferentially in axons were unchanged. This reduction in MAP2 expression was associated with a decrease in dendrite outgrowth and an increased level of cell proliferation. None of these changes were elicited by antisense oligonucleotides targeted to Dlx-1. We suggest that the Dlx-2 gene product regulates two interrelated aspects of neuronal differentiation: the exit from the mitotic cycle and the capability to grow MAP2-positive dendrites. As such, this gene product may be important for the establishment of neuronal polarity, setting the stage for afferent synaptic connectivity.

Acute cytomegalovirus infection in a child with Ménétrier's disease.

The cause of Ménétrier's disease is unknown, although allergic, autoimmune, and infectious, particularly viral, causes have been postulated. This case report describes a 3-year-old child with Ménétrier's disease in whom evidence of acute cytomegalovirus (CMV) infection was found. To our knowledge, this is the first case with evidence of acute infection, indicated by the presence of CMV-specific immunoglobulin M antibody in the acute serum as well as a seroconversion to CMV. CMV was also found in a gastric mucosal biopsy specimen using monoclonal antibodies to the early antigen of CMV.

Amantadine neurotoxicity in a pediatric patient with renal insufficiency.

Amantadine hydrochloride, a dopamine agonist with antiviral and antiparkinsonism properties, is used for the prevention and treatment of influenza A respiratory infections in high-risk populations. The occurrence of amantadine-induced hallucinations and tremors is described in a young, renal transplant patient with declining renal function. Following discontinuation of amantadine, plasma amantadine concentrations were correlated with central nervous system toxicity. In view of the usage of amantadine in renal transplant recipients and the elderly, clinicians must be alert to the possibility of amantadine-induced neurotoxicity in patients with changing renal function.

Chiari malformation in adults: a review of 40 cases.

Forty adult patients (average age 40 years), with the clinical and radiological features of the Chiari malformations, were seen at the Toronto Western Hospital between 1967 and 1984. Surgical confirmation of the diagnosis was obtained in 32 cases; of these, 23 were classified as Chiari I malformation while 9 fulfilled the anatomic criteria of Chiari II. The patient population consisted of 22 males and 18 females. Common presenting symptoms included head and neck pain (60%), sensory complaints (60%), upper extremity weakness (42%), and gait disturbance (40%). Neurological findings included signs of central cord dysfunction (73%), long-tract motor and/or sensory findings (58%), brainstem signs (38%), cerebellar dysfunction (18%), and increased intracranial pressure (15%). The majority of patients underwent myelography with or without computed tomography of the cervical-medullary junction. Two recent patients had 0.15T MRI scans which helped demonstrate an intramedullary syrinx. Thirty-three patients underwent 47 operative procedures (discounting spinal fusion and CSF shunt revisions). Open surgical management was performed in 32 patients, with CSF shunting along in one patient. Five patients (15%) incurred surgical complications within a six week postoperative period. Follow-up to date, ranges from one month to 11 years. In the 33 surgically treated patients, 18 are improved (55%), 10 are neurologically stable (30%), and five have worsened clinically (15%), including one death. Based on this study it appears that the Chiari II malformation may be more common in adults than previously recognized. Surgical intervention has a favourable outcome in the majority of patients but a significant proportion continue to deteriorate.