Drug Repurposing in Medulloblastoma: Challenges and Recommendations.

OPINION STATEMENT: Medulloblastoma is the most frequently diagnosed primary malignant brain tumor among children. Currently available therapeutic strategies are based on surgical resection, chemotherapy, and/or radiotherapy. However, majority of patients quickly develop therapeutic resistance and are often left with long-term therapy-related side effects and sequelae. Therefore, there remains a dire need to develop more effective therapeutics to overcome the acquired resistance to currently available therapies. Unfortunately, the process of developing novel anti-neoplastic drugs from bench to bedside is highly time-consuming and very expensive. A wide range of drugs that are already in clinical use for treating non-cancerous diseases might commonly target tumor-associated signaling pathways as well and hence be of interest in treating different cancers. This is referred to as drug repurposing or repositioning. In medulloblastoma, drug repurposing has recently gained a remarkable interest as an alternative therapy to overcome therapy resistance, wherein existing non-tumor drugs are being tested for their potential anti-neoplastic effects outside the scope of their original use.

Neurogenic stunned myocardium after acute hydrocephalus.

Neurogenic stunned myocardium (NSM) is a syndrome of cardiac stunning after a neurological insult. It is commonly observed after aneurysmal subarachnoid hemorrhage but is increasingly being reported after other neurological events. The underlying mechanism of NSM is believed to be a hypothalamic-mediated sympathetic surge causing weakened cardiac contractility and even direct cardiac myocyte damage. The authors report 2 cases of NSM in pediatric patients after acute hydrocephalus. Both patients experienced severe cardiac dysfunction in the acute phase but ultimately had a good neurological outcome and a full cardiac recovery. The identification, treatment, and outcome in 2 rare pediatric cases of NSM are discussed, and the history of the brain-cardiac connection is reviewed.

Pilocytic astrocytoma of the optic pathway: a tumour deriving from radial glia cells with a specific gene signature.

Pilocytic astrocytomas are WHO grade I gliomas that occur predominantly in childhood. They share features of both astroglial and oligodendroglial lineages. These tumours affect preferentially the cerebellum (benign clinical course) and the optic pathway, especially the hypothalamo-chiasmatic region (poor prognosis). Understanding the molecular basis responsible for the aggressive behaviour of hypothalamo-chiasmatic pilocytic astrocytomas is a prerequisite to setting up new molecular targeted therapies. We used the microarray technique to compare the transcriptional profiles of five hypothalamo-chiasmatic and six cerebellar pilocytic astrocytomas. Validation of the microarray results and comparison of the tumours with normal developing tissue was done by quantitative real-time PCR and immunohistochemistry. Results demonstrate that cerebellar and hypothalamo-chiasmatic pilocytic astrocytomas are two genetically distinct and topography-dependent entities. Numerous genes upregulated in hypothalamo-chiasmatic pilocytic astrocytomas also increased in the developing chiasm, suggesting that developmental genes mirror the cell of origin whereas migrative, adhesive and proliferative genes reflect infiltrative properties of these tumours. Of particular interest, NOTCH2, a gene expressed in radial glia and involved in gliomagenesis, was upregulated in hypothalamo-chiasmatic pilocytic astrocytomas. In order to find progenitor cells that could give rise to hypothalamo-chiasmatic pilocytic astrocytomas, we performed a morphological study of the hypothalamo-chiasmatic region and identified, in the floor of the third ventricle, a unique population of vimentin- and glial fibrillary acidic protein-positive cells highly suggestive of radial glia cells. Therefore, pilocytic astrocytomas of the hypothalamo-chiasmatic region should be considered as a distinct entity which probably originates from a unique population of cells with radial glia phenotype.

Very late frontal relapse of medulloblastoma mimicking a meningioma in an adult: usefulness of 1H magnetic resonance spectroscopy and diffusion-perfusion magnetic resonance imaging for preoperative diagnosis: case report.

OBJECTIVE AND IMPORTANCE: We present a rare case of very long-term medulloblastoma relapse in an adult patient and discuss the pattern of recurrence and metabolic imaging of the tumor. CLINICAL PRESENTATION: A 45-year-old man was referred for evaluation of a frontobasal midline tumor 21 years after treatment of a cerebellar medulloblastoma by surgery followed by chemotherapy and craniospinal radiotherapy. Magnetic resonance images were suggestive of a meningioma. Several hypotheses were discussed, such as other radio-induced tumors, sarcomas, high-grade gliomas, or lymphomas (previous chemotherapy) and even recurrence of medulloblastoma. Preoperative exploration included H magnetic resonance single-voxel spectroscopy (35 and 135 ms echo time), diffusion imaging, and perfusion magnetic resonance imaging. INTERVENTION: On magnetic resonance spectroscopy, N-acetyl-aspartate and an elevated choline/creatine ratio were retrieved, with a huge unidentified peak at 1.27 parts per million (ppm). Myoinositol signal was present at both echo times. On diffusion imaging, the tumor appeared hyperintense, with a low apparent diffusion coefficient value of 0.689. In the perfusion study, the maximal relative cerebral blood volume was 2. Metabolic imaging favored the diagnosis of medulloblastoma over the initially suspected diagnosis of meningioma. The patient underwent complete removal of the tumor that was confirmed to be a metastasis of his primary medulloblastoma. The postoperative course was uneventful, and complementary courses of radiotherapy and chemotherapy were planned. CONCLUSION: Late relapse should be considered, even after several decades, on occurrence of a second intracranial tumor in this context. Our observation validates the clinical interest of preoperative metabolic imaging for brain tumors with distinctive pattern.

Neurofibromatosis type 1: diffusion weighted imaging findings of brain.

PURPOSE: The purposes of this study were to evaluate the differences in apparent diffusion coefficient (ADC) values between infra and supratentorial unidentified bright objects (UBOs), between UBOs and normal appearing side (NAS, contralateral regions of the UBOs and/or normal appearing region without UBOs) in the neurofibromatosis type 1 patients (NF1) and control group and also to investigate correlation between age and ADC values. METHODS: A total of 30 patients and 26 healthy controls were included. The MRI examination consisted of routine imaging and diffusion weighted imaging (DWI). Seven distinct locations (frontal, parieto-occipital and cerebellar white matter, globus pallidum, thalamus, hippocampus, and midbrain) were selected for the analysis. The ADC values were calculated directly from these automatically generated ADC maps with ROI. RESULTS: The ADC values of UBOs were significantly increased in cerebellar white matter, hippocampus, globus pallidum, midbrain, and thalamus when compared with NAS and control group. There were statistically significant differences between NAS and control group in the ADC values obtained from hippocampus and thalamus. There were statistically significant differences between supra and infratentorial UBOs in ADC values. There was a negative correlation between age and the ADC values obtained from normal appearing midbrain, hippocampus, thalamus, and globus pallidum. CONCLUSION: ADC values both in UBOs and in the normal appearing locations as hippocampus and thalamus were detected to be higher in the patients with NF1. The detection of lesions might be independent of MRI appearance in NF1, i.e. although the brain is affected, MRI appearance may be normal. Therefore, DWI and ADC values should also be utilized in the delineation of brain involvement of NF1 patients.

Diagnostic difficulties in childhood bilateral thalamic astrocytomas.

We report on two children with bilateral thalamic astrocytomas. The first patient developed psychomotor regression at the age of 20 months followed by rapidly progressive ataxia, intention tremor, slurred speech, and bouts of drowsiness. Magnetic resonance imaging (MRI) of the brain showed swelling and high signal intensity in both thalami accompanied by supratentorial hydrocephalus. The second patient presented with progressive cerebellar ataxia, headache, and vomiting at the age of 11 years. MRI of the brain revealed symmetrical, hyperintense and sharply delineated swelling of both thalami. Additional lesions were seen in the cerebellum and the right temporal lobe. In both cases proton magnetic resonance spectroscopy (MRS) of the lesions showed a striking decrease of the neuronal marker N-acetylaspartate, an increase of choline-containing compounds, and a minimal lactate peak. Stereotactic biopsies from the thalamus of the first patient and from a cerebellar lesion of the second patient finally revealed glial tumors, namely a diffuse astrocytoma of World Health Organization (WHO) grade II in the first patient and an anaplastic astrocytoma of WHO grade III in the second patient. We conclude that the clinical manifestations and MRI patterns of bilateral thalamic astrocytomas are very similar to those of encephalitis and neurometabolic disorders and should therefore be included in the differential diagnosis of these encephalopathies.

[Click-evoked myogenic potential as a new diagnostic tool for the vestibular disorders].

In accordance with Colebatch's method, click-evoked myogenic potential(VEMP: vestibular evoked myogenic potential) was studied to evaluate 11 healthy subjects and 24 patients with peripheral and central vestibular disorders such as sensorineural hearing loss, peripheral vestibular disorder, endolymphatic hydrops(Meniere disease), cerebellopontine (CP) angle tumor, and Wallenberg's syndrome. Surface electromyograms(EMG) were recorded from both sides of the sternocleidomastoid muscles, with a reference over the jugular notch. The EMG were averaged from 500 responses to 135 dB SPL, 3 c/s(0.1 ms) through one side of a headphone, with 115 dB masking noise in the other side. The average potentials were collected at 20 ms before the clicks to 80 ms afterwards. All healthy subjects showed typical biphasic complex responses(P 13-N 23-N 34-P 44) bilaterally by unilateral stimulation, predominantly on the ipsilateral side. The average latencies were as follows: P 13(13.3 ms +/- 2.1 SD); N 23(22.2 ms +/- 2.7 SD); N 34(32.2 ms +/- 3.1 SD); and P 44(43.6 ms +/- 3.1 SD). The average P 13-N 23 peak amplitude was 20.4 +/- 3.3 microV. In 5 cases of sensorineural hearing loss, in which pure tone audiograms showed thresholds higher than 80 dB, latencies of VEMP were within normal limits of the deaf side. In contrast, VEMP could not be evoked in the affected side in 4 patients with peripheral vestibular disorders or patients with 7 cerebello-pontine angle tumors. In 4 patients with endolymphatic hydrops, latencies of VEMP were within normal limits on the affected side. The P 13-N 23 peak amplitude, however, was remarkably enlarged after 500 ml of glycerol drip infusion(glycerol test). In 2 patients with Wallenberg's syndrome, the latency of P 13 was prolonged on the affected side. Thus, it is concluded that the present study would provide additional information about the vestibular function, especially the otolith function, and clinical usefulness of detecting both central and peripheral vestibular disorders.

Current therapy and new perspectives in the treatment of medulloblastoma.

Medulloblastoma, a malignant tumor arising from the medullary velum, is the most common malignant brain tumor of childhood. Local extension into the cerebellar hemisphere, infiltration of the floor of the fourth ventricle, and seeding into the subarachnoid space are common. Early diagnosis and improved treatment consisting of surgery followed by radiation and chemotherapy for selected high-risk patients has contributed to a dramatic change in survival. This article reviews current treatment strategies and describes new therapies that have the potential to improve the outlook of children with medulloblastoma.

MRI of inner ear and facial nerve pathology using 3D MP-RAGE and 3D CISS sequences.

The aim of this study was to evaluate 3D CISS, unenhanced 3D MP-RAGE and contrast enhanced 3D MP-RAGE for the diagnosis of neoplastic, vascular and inflammatory lesions of the cerebellopontine angle, the inner auditory canal, the labyrinth and the facial nerve 42 MR examinations were performed on a total of 38 patients (25 males, 13 females; aged 1-77 years, mean age 43 +/- 20 years) using a 1.5 T MR unit. A T2* weighted 3D CISS sequence (TR 14.65 ms, TE 21 ms, flip angle 65 degrees, voxel size 0.7 x 0.7 x 0.7 mm3) and a T1 weighted 3D MP-RAGE sequence (TR 12.5 ms, TE 5 ms, T1 300 ms, flip angle 15 degrees, voxel size 1.0 x 0.9 x 0.9 mm3) with and without contrast medium (gadolinium-DTPA, 0.1 mmol kg-1 body weight) were used. Results of contrast enhanced 3D MP-RAGE-pathological enhancement was found in the following lesions: schwannomas of the cerebellopontine angle (CPA) and the internal auditory canal (IAC), 4; schwannomas of the IAC, 7 and labyrinthine tumours, 3; posterior fossa lymphoma, 1; meatal meningioma, 1; acute labyrinthitis, 15 and neuritis of the seventh cranial nerve, 10. Results of 3D CISS-filling defects were found with the following lesions: schwannomas of the CPA, the IAC or labyrinth, 14; lymphoma, 1; meningioma, 1; labyrinthine fibrosis, 13 and scar in the IAC, 4. These results suggest that unenhanced and contrast enhanced 3D MP-RAGE and 3D CISS are complementary MR imaging modalities. T1 weighted 3D MP-RAGE is preferred to T1 weighted 2D (turbo) spin echo sequences because of the multiplanar reconstruction possibilities of 3D sequences, which are very useful in the case of the inner ear and facial nerve.

Posterior fossa tumors in children: a case study.

Brain tumors are the second most common malignancy to occur during childhood and the posterior fossa is the most common region of the brain affected. Diagnosis and treatment are complex and challenging. Once a child suffering from a posterior fossa tumor is identified, a multidisciplinary team must be assembled to provide comprehensive care through all phases of treatment. The nursing staff is vital to this team because they are often the individuals who coordinate services involved in the care of the child with a posterior fossa tumor. This case study illustrates the phases of diagnosis and treatment of a child with a medulloblastoma and highlights critical care nursing challenges. Following the case study presentation, a summary describes posterior fossa tumors including epidemiology, pathophysiology, clinical manifestations, and outcome. The case study is integrated throughout this review to highlight key issues for critical care nurses to explore.

Usefulness of auditory brainstem responses at high stimulus rates in the diagnosis of acoustic neuroma.

The effects of the stimulus rate on the auditory brainstem responses (ABRs) of acoustic neuroma (AN) patients were studied. Ninety-decibel click stimuli at a normal hearing level were delivered at stimulus rates of 9.5, 20, 40 and 90 Hz, and ABRs were recorded of 40 AN patients (40 ears) at each stimulus rate. Subjects with normal hearing (42 ears) and patients with sensorineural hearing loss (30 ears) were also studied to obtain normative data. The following two parameters were examined: the interpeak latency difference between wave I and wave V (IPL I-V) at each stimulus rate, and the increase in IPL I-V (delta IPL I-V) when the stimulus rate was increased from 9.5 Hz. AN patients showed significantly larger values for both parameters at all stimulus rates compared to those of the control groups. Among 6 AN patients with normal ABRs at 9.5 Hz, 5 showed abnormal IPL I-V or abnormal delta IPL I-V at 90 Hz, when the upper normal limits of both parameters were defined as the mean plus 2 SD of the group with normal hearing. These results suggest that recording ABR at high stimulus rates provides valuable information for detecting AN patients with normal ABRs.

Brainstem auditory evoked potentials and blink reflexes in patients with pontocerebellar angle tumors.

Brainstem auditory evoked potentials (BAEP) and blink reflexes (BR) were obtained from 13 patients with pontocerebellar angle (PCA) tumors whose pathological diagnosis was as follows: 7 acoustic neurinoma, 3 meningioma, 1 neurinoma, 1 brain stem epidermoid tumor, 1 arteriovenous malformation. The most prominent abnormality was noted in BAEP generated by stimulating the ear ipsilateral to the lesion and ipsilateral R1 reflexes obtained from ipsilateral stimulation of the supraorbital nerve.

Prolonged I-III interwave interval in cerebellar astrocytoma.

We are reporting the case of a 41-year-old female diagnosed with a cerebellar astrocytoma. The tumor was detected after the patient was referred for MRI scan because of an abnormal ABR. The ABR was unusual as the I-V interwave intervals (IWIs) were within normal limits bilaterally, but the I-III IWI was prolonged by .40 msec on the left ear in comparison to the right ear. This case report illustrates the importance of the I-III IWI in the detection of retrocochlear pathology and the nonsequential generation of the components of the ABR.

[An analysis of the level and bilateralness of disorders of the brain stem auditory evoked potential in tumors of the posterior cranial fossa with different locations]. / Analiz urovnia i bilateral'nosti narushenii stvolovogo slukhovogo vyzvannogo potentsiala pri opukholiakh zadnei cherepnoi iamki razlichnoi lokalizatsii.

The method of stem auditory evoked potential was used in the examination of 39 patients with tumors of the posterior cranial fossa of various localization. The time indices of the response were analysed: the peak latency of components I, III, and V and interpeak I-III, III-V, and I-V intervals. The most coarse disorders were revealed in patients with tumors of the cerebellopontile angle (100% of cases), which were clearly lateralized. Changes of stem auditory evoked potential in patients with cerebellar tumors were encountered somewhat less frequently (in up to 90%) and the response was asymmetric in most cases. As compared to the first group, however, a high percentage of disorders of component V to stimulation of the intact side was noted. Among patients with median localization of the tumor (vermis cerebelli, floor of fourth ventricle) changes were found in 62% of cases (component V). No authentic differences to stimulation of different sides were revealed. The authors discuss problems on the levels of occurrence of disorders of stem auditory evoked potential in patients with lesions of posterior cranial fossa structures.