Predictive value of Blink reflex and facial corticobulbar motor evoked potential in cerebellopontine angle tumor surgery.

OBJECTIVE: The current study examined the efficacy of the facial corticobulbar motor evoked potentials (FCoMEPs) and blink reflex (BR) on predicting postoperative facial nerve function during cerebellopontine angle (CPA) tumor surgery. METHODS: Data from 110 patients who underwent CPA tumor resection with intraoperative FCoMEPs and BR monitoring were retrospectively reviewed. The association between the amplitude reduction ratios of FCoMEPs and BR at the end of surgery and postoperative facial nerve function was determined. Subsequently, the optimal threshold of FCoMEPs and BR for predicting postoperative facial nerve dysfunction were determined by receiver operating characteristic curve analysis. RESULTS: Valid BR was record in 103 of 110 patients, whereas only 43 patients successfully recorded FCoMEP in orbicularis oculi muscle. A reduction over 50.3% in FCoMEP (O. oris) amplitude was identified as a predictor of postoperative facial nerve dysfunction (sensitivity, 77.1%; specificity, 83.6%). BR was another independent predictor of postoperative facial nerve deficit with excellent predictive performance, especially eyelid closure function. Its optimal cut-off value for predicting long-term postoperative eyelid closure dysfunction was was 51.0% (sensitivity, 94.4%; specificity, 94.4%). CONCLUSIONS: BR can compensate for the deficiencies of the FCoMEPs. The combination of BR and FCoMEPs can be used in CPA tumor surgery. SIGNIFICANCE: The study first proposed an optimal cut-off value of BR amplitude deterioration (50.0%) for predicting postoperative eyelid closure deficits in patients undergoing CPA tumor surgery.

Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning.

PURPOSE: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.

White matter hyperintensity volumes are related to processing speed in long-term survivors of childhood cerebellar tumors.

PURPOSE: Across several clinical populations, higher white matter hyperintensity (WMH) burden is consistently associated with decreases in cognitive performance, especially processing speed. Research of childhood cancer survivors has not utilized WMH quantification methodology to better understand the impact of WMH burden and its relationship with core cognitive skills. The present study aimed to quantify WMH volumes in a sample of long-term survivors of childhood cerebellar tumor and investigate the relationships with performance on a measure of oral processing speed. To further explore brain-behavior relationships, multivariate sparse canonical correlations was employed to identify WMH areas that predict processing speed performance. METHODS: Thirty-five survivors and 56 healthy controls underwent neuroimaging and completed a measure of oral processing speed. The survivor group was further divided based on treatment (i.e., chemoradiation therapy (n = 20) vs. surgery only (n = 15)) to better understand the impact of treatment. RESULTS: Survivors, and especially those treated with chemoradiation therapy, showed higher total WMH volumes and slower processing speed. Higher total WMH volumes were significantly associated with poorer processing speed (r = - 0.492, p = 0.003). Multivariate brain-behavior relationships revealed that periventricular WMHs were significantly associated with slower processing speed performance (p < 0.05). CONCLUSION: Results exemplify that long-term survivors treated with and without chemoradiation therapy are at increased risk of developing higher WMH volumes compared to healthy peers. In addition, processing speed was robustly shown to be related to periventricular WMHs using an automated neuroimaging pipeline. This methodology to monitor WMH burden has the potential to be implemented efficiently with routine clinical neuroimaging of cancer survivors.

Anesthesia Exposure during Therapy Predicts Neurocognitive Outcomes in Survivors of Childhood Medulloblastoma.

OBJECTIVE: To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3 years after tumor diagnosis. STUDY DESIGN: In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St Jude Children's Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. RESULTS: For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1 years, and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1 to 52 events (mean = 19.9); mean cumulative duration per patient was 21.1 hours (range 0.7-59.7). Compared with normative expectations (16%), the group had a significantly greater frequency of at-risk scores (<1 SD) on measures of intelligence (28.7%), attention (35.2%), working memory (26.6%), processing speed (46.7%), and reading (25.8%). Including anesthesia exposure duration to linear regression models accounting for age at diagnosis, treatment intensity, and baseline IQ significantly increased the predicted variance for intelligence (r2 = 0.59), attention (r2 = 0.29), working memory (r2 = 0.31), processing speed (r2 = 0.44), and reading (r2 = 0.25; all P values <.001). CONCLUSIONS: In survivors of childhood medulloblastoma, a neurodevelopmentally vulnerable population, greater exposure to anesthesia significantly and independently predicts deficits in neurocognitive and academic functioning. When feasible, anesthesia exposure during treatment should be reduced.

Double Dissociation of Auditory Attention Span and Visual Attention in Long-Term Survivors of Childhood Cerebellar Tumor: A Deterministic Tractography Study of the Cerebellar-Frontal and the Superior Longitudinal Fasciculus Pathways.

OBJECTIVE: Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation. METHODS: Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment. RESULTS: A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = -.50, p = .01) and was not associated with visual attention (FA: r = -.11, p = .59; RD: r = -.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = -.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = -.10, p = .62). CONCLUSIONS: The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

Infratentorial Multinodular and Vacuolating Neuronal Tumor or Multinodular and Vacuolating Posterior Fossa Lesions of Unknown Significance? Clinico-Radiologic Findings from 2 Cases.

BACKGROUND: Infratentorial multinodular lesions resembling multinodular and vacuolating neuronal tumor of the cerebrum (MVNT) have been indicated in literature with 2 different names reflecting alternative perspectives: multinodular and vacuolating posterior fossa lesions of unknown significance (MV-PLUS), suggesting that these lesions may belong to a new entity, and MVNT of the brain, assuming that they actually correspond to infratentorial MVNT. Because of the limited number of cases reported and the absence of histopathologic data, it is unclear which denomination should be used. CASES DESCRIPTION: Two patients, a 41-year-old man (case 1) suffering headache and a 44-year-old man (case 2) with vertigo, underwent magnetic resonance imaging (MRI) examination. MRI showed, in both cases, multinodular lesions involving the vermis, broadly extending to the superior part of the right cerebellar hemisphere in case 1, and involving the superior paravermian part of the left cerebellar hemisphere in case 2. The follow-up period was 3 years in case 1 and 14 years in case 2. CONCLUSIONS: Infratentorial lesions show nodules with cystic or cyst-like signal intensity on MRI, a feature infrequently reported in supratentorial MVNT, and may involve the cortex. No variations were noted during a prolonged follow-up supporting the benign behavior of these lesions.

Central nervous system hemangioblastomas in the elderly (over 65 years): Clinical characteristics and outcome analysis.

OBJECTIVES: Hemangioblastomas (HBs) in the elderly are very uncommon and have rarely been studied. This retrospective study aimed to identify clinical features, optimal treatment, surgical outcomes and long-term prognostic factors in these rare lesions. PATIENTS AND METHODS: We performed a retrospective analysis of HBs patients over 65 years old who underwent surgery from 2008 to 2018 at our department. Clinical data was retrospectively reviewed and statistically analyzed. RESULTS: Thirty-three elderly patients with a mean age of 68.76 years were included in this study. Cerebellum, brainstem, and spinal cord locations accounted for 72.7 %, 18.2 % and 9.1 %. Two patients (6.1 %) were diagnosed as von Hippel-Lindau (VHL) syndrome. After mean follow-up of 37.95 ± 22.12 months, clinical symptoms improved in 22 patients (67 %), unchanged in seven patients (21 %) and aggravated in 4 patients (12 %). Only 1(3 %) patient experienced local recurrence during follow-up. Univariate analysis showed tumor size (P = 0.044) and tumor characteristic (cystic or solid) (P = 0.034) were significantly related to long-term outcomes, while multiple logistic regression analysis depicted tumor characteristics were exclusively correlated with outcomes (P = 0.04). CONCLUSIONS: Our study suggests elderly hemangioblastomas may be different from their younger counterparts in that they often display solid configuration with large size and include more cerebellar tumors. HBs should be included in the differential diagnosis of elderly patients presenting with cerebellar mass. Despite many challenges involved, surgical removal of HBs in this age group is a safe procedure with acceptable risks. They may do not require as frequent follow-up as younger counterparts due to the low associations with VHL disease and tumor recurrence rate.

Audiovestibular findings in a 6 year old child with pilocytic astrocytoma - a case report.

Objective: Pilocytic astrocytoma commonly occurs in children and depending on the extension of the lesion may cause varied audiovestibular dysfunctions. However, audiovestibular findings are scarcely reported in the literature.Design: Audiovestibular testing was performed on a single subject on two occasions pre-surgically.Study sample: A 6 year old girl with pilocytic astrocytoma.Results: All audiological tests revealed normal findings except for the cervical vestibular evoked myogenic potential testing (cVEMP). The amplitude of cVEMP was higher in the lesion side indicating a hypersensitive vestibulocollic reflex pathway functioning.Conclusions: This case study reported a unique finding of hypersensitive cVEMP findings in the lesion side in a patient with pilocytic astrocytoma. The pathophysiological basis for this hypersensitivity is attributed to anatomical connections between the cerebellum and the vestibular nuclei through the inferior cerebellar peduncle.

Pain affect disrupted in children with posterior cerebellar tumor resection.

Objectives: Damage to the posterior cerebellum can cause affective deficits in patients. In adults, cerebellar infarcts result in thermal hyperalgesia and affect descending modulation of pain. This study evaluated the effect of resection of low-grade cerebellar tumors on pain processing in human children. Methods: Twelve pediatric patients treated with surgery only for low-grade gliomas (8 females, 4 males; mean age = 13.8 ± 5.6) and twelve matched controls (8 females, 4 males; mean age = 13.8 ± 5.7) were evaluated using quantitative sensory testing and fMRI. Five patients had tumors localized to posterior cerebellar hemispheres, henceforth identified as Crus Patients. Results: Crus Patients had significantly lower pain tolerance to a cold pressor test than controls. No significant differences were detected between subject groups for heat and cold detection thresholds (HDT, CDT), and heat and cold pain thresholds (HPT, CPT). Crus Patients also showed significantly decreased fMRI responses to painful heat in anterior insula, which has been associated with pain affect. Interpretation: Damage to posterior cerebellar hemispheres disrupted affective pain processing and endogenous pain modulation, resulting in decreased pain tolerance to suprathreshold noxious stimuli. This suggests that surgical resection of this region in children may increase the risk of developing pain disorders.

Neurocognitive dysfunction in adult cerebellar medulloblastoma.

OBJECTIVE: Impaired neurocognitive function (NCF) is a well-established consequence of pediatric medulloblastoma (MB) and its treatments. However, the frequency and features of neurocognitive dysfunction in adult-onset MB patients are largely unknown. METHODS: Adult patients (≥ 18 years) with MB who had received formal neurocognitive evaluation (N = 27) were identified. Demographic, medical, and treatment histories were extracted from the medical record. Lesion properties on MRI were analyzed and used to evaluate lesion-symptom mapping further. Demographically adjusted z-scores were calculated for each neurocognitive test and used to assess impairment frequency. Regression analyses were conducted to identify clinical and paraclinical factors associated with impaired NCF. RESULTS: Mean age of the patient sample was 33 years (SD = 11) at the time of MB diagnosis. Prior therapy included surgical resection (89%), radiation (70%), and chemotherapy (26%). A significant proportion of patients were impaired on tests of verbal learning and memory (32%), executive function (29%), and naming (18%). Age, education, lesion size, time from surgery, and number of chemotherapy cycles had the greatest contribution to test performance in random-forest regression models. CONCLUSION: This study identifies frequent impairment of NCF in adult patients with MB, particularly in the domains of learning and memory and executive function. Neurocognitive impairment is influenced by patients' demographic, disease, and treatment history. Further study is warranted to characterize the clinical impact of adult MB more fully.

Continuous and Dynamic Facial Nerve Mapping During Surgery of Cerebellopontine Angle Tumors: Clinical Pilot Series.

OBJECTIVE: To evaluate a new surgical tool combining suction and monopolar neurostimulation (stimulation sucker) for cerebellopontine angle (CPA) tumors. The usefulness for continuous (time) and dynamic (space) facial nerve mapping was studied. METHODS: Patients operated on with the stimulation sucker for a CPA tumor between April 2016 and May 2017 in a tertiary care center were identified. Clinical charts were retrospectively evaluated. The minimum follow-up time of patients was 12 months. RESULTS: The study population included 17 patients with tumor (6 women and 11 men). The age range was from 2 to 77 years (mean age, 45.7 years; standard error of the mean, 22.7 years). Most CPA tumors were large (Koos grade 4) vestibular schwannomas (n = 10); other pathologies included petrous meningioma (n = 1), metastasis (n = 1), medulloblastoma (n = 2), ependymoma (n = 2), and pilocytic astrocytoma (n = 1). One patient with trigeminal neuralgia served as the normal control subject. No complications because of the stimulation sucker were encountered. Clinical and radiologic outcomes compared favorably with institutional experience and literature. The stimulation sucker allowed for continuous (time) mapping of the facial nerve at the site of resection (space). This real-time feedback allowed early identification of the facial nerve. Handling and ergonomy were excellent and workflow improved. The shortcomings compared with a bayonet-shaped bipolar probe were decreased visibility of neurovascular structures and lower spatial discrimination. The new device did not simplify delicate at the brainstem and on the nerve. We think it should be considered as a complementary tool in the surgeon's armamentarium. CONCLUSIONS: Until now, nerve damage as assessed by neuromonitoring (e.g., facial nerve electromyography, motor evoked potential) served as surrogate for nerve function. This concept should be challenged. The studied stimulation sucker detected the facial nerve earlier than conventional techniques, preventing harm by surgical trauma. A larger, prospective study is warranted to better define its role in CPA surgery.

UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts.

BACKGROUND: Group 3 tumors account for approximately 25-30% of medulloblastomas and have the worst prognosis. UAB30 is a novel synthetic rexinoid shown to have limited toxicities in humans and significant efficacy in the pediatric neuroectodermal tumor, neuroblastoma. We hypothesized that treatment with UAB30 would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). METHODS: Three group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Cell viability, proliferation, migration and invasion assays were performed after treatment with UAB30 or 13-cis-retinoic acid (RA). Cell cycle analysis was completed using flow cytometry. A flank model, a cerebellar model, and a model of leptomeningeal metastasis using human medulloblastoma PDX cells was used to assess the in vivo effects of UAB30 and RA. RESULTS: UAB30 treatment led to cell differentiation and decreased medulloblastoma PDX cell viability, proliferation, migration and invasion and G1 cell cycle arrest in all three PDXs similar to RA. UAB30 and RA treatment of mice bearing medulloblastoma PDX tumors resulted in a significant decrease in tumor growth and metastasis compared to vehicle treated animals. CONCLUSIONS: UAB30 decreased viability, proliferation, and motility in group 3 medulloblastoma PDX cells and significantly decreased tumor growth in vivo in a fashion similar to RA, suggesting that further investigations into the potential therapeutic application of UAB30 for medulloblastoma are warranted.

Triptolide inhibits the proliferation and migration of medulloblastoma Daoy cells by upregulation of microRNA-138.

Medulloblastoma is a primitive neuroectodermal-derived brain tumor and the most common malignant brain tumor in children. Triptolide (TPL) is the major active component extracted from Tripterygium wilfordii Hook F. This study aimed to explore the effects of TPL on medulloblastoma cell proliferation, migration, and apoptosis, as well as the underlying possible molecular mechanism. Viability, proliferation, and apoptosis of Daoy cells were measured using cell counting kit-8 assay, 5-bromo-2'-deoxyuridine incorporation assay, and Guava Nexin assay, respectively. Cell migration was detected using two-chamber transwell assay and wound healing assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to determine the relative expression of microRNA-138 (miR-138) in Daoy cells. Cell transfection was used to change the expression of miR-138 in cells. Western blot analysis was used to analyze the expression of key factors involved in cell apoptosis, cell migration, the phosphatidylinositol 3-kinase (PI3K)/protein kinase 3 (AKT) pathway, and the Notch pathway in Daoy cells. We found that TPL significantly inhibited the viability, proliferation, and migration of Daoy cells but promoted Daoy cell apoptosis. The expression levels of matrix metalloproteinases (MMP)-2 and MMP-9 after TPL treatment were decreased. The expression of miR-138 in Daoy cells after TPL treatment was increased. Suppression of miR-138 obviously reversed the TPL-induced Daoy cell proliferation, migration inhibition, and cell apoptosis enhancement, as well as the inactivation of the PI3K/AKT and Notch pathways. Cyclin-dependent kinase 6 (CDK6) was a direct target gene of miR-138, which might be involved in the antitumor effects of TPL on Daoy cells. In conclusion, our study verified that TPL exerted anticancer effects on medulloblastoma cells possibly via upregulating miR-138 and inactivating the PI3K/AKT and Notch pathways.

Childhood Lhermitte-Duclos Disease Progressing to Medulloblastoma in Bilateral Cerebellar Hemispheres: Report of Unusual Case.

BACKGROUND: Lhermitte-Duclos disease is an extremely rare pathologic entity characterized by a cerebellar mass composed of enlarged cerebellar folia containing abnormal ganglion cells. This entity usually presents in young and middle-aged adults and rarely in children. There is no study in the literature analyzing the long-term clinical course of this disease to assess the behavior primarily because of its rarity. CASE DESCRIPTION: We present our experience with a 7-year-old patient of Lhermitte-Duclos disease who was followed up for 5 years and found to have progressed to bilateral World Health Organization grade IV medulloblastoma. This case denotes the malignant potential of this rare disorder. CONCLUSIONS: LDD is seen rarely and demands a high degree of suspicion in patients presenting with cerebellar mass and/or imaging characteristics. It is prudent to keep these patients in close follow-up for early detection of malignant transformation.

TAp73 is a marker of glutamine addiction in medulloblastoma.

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

Neuronal correlates of cognitive function in patients with childhood cerebellar tumor lesions.

While it has been shown that cerebellar tumor lesions have an impact on cognitive functions, the extent to which they shape distant neuronal pathways is still largely undescribed. Thus, the present neuroimaging study was designed to investigate different aspects of cognitive function and their neuronal correlates in patients after childhood cerebellar tumor surgery. An alertness task, a working memory task and an incompatibility task were performed by 11 patients after childhood cerebellar tumor surgery and 17 healthy controls. Neuronal correlates as reflected by alterations in functional networks during tasks were assessed using group independent component analysis. We were able to identify eight networks involved during task performance: default mode network, precuneus, anterior salience network, executive control network, visual network, auditory and sensorimotor network and a cerebellar network. For the most 'basic' cognitive tasks, a weaker task-modulation of default mode network, left executive control network and the cerebellar network was observed in patients compared to controls. Results for higher-order tasks are in line with a partial restoration of networks responsible for higher-order task execution. Our results provide tentative evidence that the synchronicity of brain activity in patients was at least partially restored in the course of neuroplastic reorganization, particularly for networks related to higher-order cognitive processes. The complex activation patterns underline the importance of testing several cognitive functions to assess the specificity of cognitive deficits and neuronal reorganization processes after brain lesions.

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa.

BACKGROUND: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. METHODS: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. DISCUSSION: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Restore the brake on tumor progression.

Sonic hedgehog (Shh) signaling plays a key role in regulation of normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts to finely tune Shh signaling, providing tight control of normal developmental processes. Hyperactivation of Shh signaling often leads to many human malignancies, including basal cell carcinoma and medulloblastoma (MB). However, how tumor cells sustain the aberrant activation of Shh signaling is still not completely understood. We recently revealed that during MB formation, tumor cells express Nestin, a type VI intermediate filament protein, which maintains uncontrolled Shh signaling by abolishing negative feedback by Gli3. Therefore, Nestin expression is a necessary step for MB formation. These findings highlight the novel function of Nestin in regulating Shh signaling, as well as the important role of a disrupted negative feedback mechanism in MB tumorigenesis. Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies.