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To increase our understanding of the molecular pathogenesis of medulloblastoma (MB), we utilized the technique of suppression subtractive hybridization (SSH) to identify genes that are dysregulated in MB when compared to cerebellum. SSH-enriched cDNA libraries from both human and Ptch+/- heterozygous murine MBs were generated by subtracting common cDNAs from corresponding non-neoplastic cerebellum. For the human classic MB library, total human cerebellar RNA was used as control tissue; for the Ptch+/- heterozygous MB, non-neoplastic cerebellum from an unaffected Ptch+/- littermate was used as the control. Through differential screening of these libraries, over 100 upregulated tumor cDNA fragments were isolated, sequenced and identified with the NCBI BLAST program. From these, we selected genes involved in cellular proliferation, antiapoptosis, and cerebellar differentiation for further analysis. Upregulated genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, Neuronatin (NNAT), the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be upregulated in the murine MB library included cyclin D2 (Ccnd2), thymopoietin (Tmpo), Musashi-1 (Msh1), protein phosphatase 2A inhibitor-2 (I-2pp2a), and Unc5h4(D). Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels for these genes were markedly higher in human MBs than in cerebellum. Western blot analysis was used to further confirm the overexpression of a subset of these genes at the protein level. Notch pathway overactivity was demonstrated in the TE671 MB cell line expressing high levels of MSH1 through HES1-Luciferase transfections. This study has revealed a panel of developmentally regulated genes that may be involved in the pathogenesis of MB.Oncogene (2004) 23, 3444-3453. doi:10.1038/sj.onc.1207475 Published online 5 April 2004 [ABSTRACT FROM AUTHOR]

Although medulloblastoma is usually sporadic, there are a number of uncommon predisposing germline mutation syndromes, including: Gorlin’s Syndrome, Turcot’s Syndrome and Li-Fraumeni Syndrome. Patients with Rubenstein-Taybi Syndrome secondary to mutation/deletion of the CBP gene on chromosome 16 are predisposed to a variety of developmental anomalies as well as cancer. We report a child with Rubenstein-Taybi syndrome who developed a cerebellar medulloblastoma and review the literature on Rubenstein-Taybi Syndrome and pediatric medulloblastoma. As the product of the CBP gene functions in a variety of signaling pathways, we discuss the molecular implications of findings a medulloblastoma in a child with Rubenstein-Taybi Syndrome.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of "sonicated" and "unsonicated" tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation. [ABSTRACT FROM AUTHOR]

Outcome after severe traumatic brain injury (TBI) differs substantially between hospitals. Explaining this variation begins with understanding the differences in structures and processes of care, particularly at intensive care units (ICUs) where acute TBI care takes place. We invited trauma medical directors (TMDs) from 187 centers participating in the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) to complete a survey. The survey domains included ICU model, type, availability of specialized units, staff, training programs, standard protocols and order sets, approach to withdrawal of life support, and perceived level of neurosurgeons' engagement in the ICU management of TBI. One hundred forty-two TMDs (76%) completed the survey. Severe TBI patients are admitted to dedicated neurocritical care units in 52 hospitals (37%), trauma ICUs in 44 hospitals (31%), general ICUs in 34 hospitals (24%), and surgical ICUs in 11 hospitals (8%). Fifty-seven percent are closed units. Board-certified intensivists directed 89% of ICUs, whereas 17% were led by neurointensivists. Sixty percent of ICU directors were general surgeons. Thirty-nine percent of hospitals had critical care fellowships and 11% had neurocritical care fellowships. Fifty-nine percent of ICUs had standard order sets and 61% had standard protocols specific for TBI, with the most common protocol relating to intracranial pressure management (53%). Only 43% of TMDs were satisfied with the current level of neurosurgeons' engagement in the ICU management of TBI; 46% believed that neurosurgeons should be more engaged; 11% believed they should be less engaged. In the largest survey of North American ICUs caring for TBI patients, there is substantial variation in the current approaches to ICU care for TBI, highlighting multiple opportunities for comparative effectiveness research. [ABSTRACT FROM AUTHOR]

Purpose: Limited data exist quantifying the risk of adverse radiation effect (ARE) specific to hypofractionated stereotactic radiosurgery (HSRS). We present our analyses of the risk of ARE after 5 daily fractions of HSRS to surgical cavities and intact metastases.Methods and Materials: One hundred and eighty-seven consecutively treated patients with 118 surgical cavities and 132 intact metastases were retrospectively reviewed. All patients were treated with 5 daily fractions with a 2 mm planning target volume applied. Clinical and dosimetric variables were assessed to identify predictors of ARE.Results: The median total prescribed dose was 30 Gy (range, 20-35 Gy) and median follow-up was 12 months. One hundred forty-four patients (77%) received treatment to a single target. Median planning target volumes for resection cavity and intact metastases were 24.9 cm3 and 7.7 cm3, respectively. ARE and symptomatic ARE were observed 21.2% and 10.8% of targets, respectively, and the median time to ARE was 8 months. Time to ARE was <6 months for 38%, 6 to 12 months for 43%, and >12 months for 19% of targets. Multivariable analysis identified intact metastases versus cavities (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.33-10) as a significant predictor of symptomatic ARE. Specific to cavity HSRS, prior whole brain radiation therapy (OR 7.73; 95% CI, 1.67-35.69) and prior stereotactic radiosurgery (OR 8.66; 95% CI, 1.14-65.7) were significant predictors of symptomatic ARE. For intact metastases, the total brain minus gross tumor volume (GTV) receiving 30 Gy (BMC30) was a significant predictor of symptomatic ARE (OR, 1.21; 95% CI, 1.02-1.43), and a volume-based BMC30 threshold of 10.5 cm3 was significant with an OR of 7.21 (95% CI, 1.31-39.45).Conclusions: The risk of ARE was greater for intact metastases compared with cavities after HSRS. For intact lesions, the BMC30 was predictive for symptomatic necrosis, and a threshold of 10.5 cm3 may guide treatment planning. [ABSTRACT FROM AUTHOR]

Background Context: Computer-assisted navigation (CAN) may guide spinal instrumentation, and requires alignment of patient anatomy to imaging. Iterative closest-point (ICP) algorithms register anatomical and imaging surface datasets, which may fail in the presence of geometric symmetry (congruence), leading to failed registration or inaccurate navigation. Here we computationally quantify geometric congruence in posterior spinal exposures, and identify predictors of potential navigation inaccuracy. Methods: Midline posterior exposures were performed from C1-S1 in four human cadavers. An optically-based CAN generated surface maps of the posterior elements at each level. Maps were reconstructed to include bilateral hemilamina, or unilateral hemilamina with/without the base of the spinous process. Maps were fitted to symmetrical geometries (cylindrical/spherical/planar) using computational modelling, and the degree of model fit quantified based on the ratio of model inliers to total points. Geometric congruence was subsequently assessed clinically in 11 patients undergoing midline exposures in the cervical/thoracic/lumbar spine for posterior instrumented fusion. Results: In cadaveric testing, increased cylindrical/spherical/planar symmetry was seen in the high-cervical and subaxial cervical spine relative to the thoracolumbar spine (p<0.001). Extension of unilateral exposures to include the ipsilateral base of the spinous process decreased symmetry independent of spinal level (p<0.001). In clinical testing, increased cylindrical/spherical/planar symmetry was seen in the subaxial cervical relative to the thoracolumbar spine (p<0.001), and in the thoracic relative to the lumbar spine (p<0.001). Symmetry in unilateral exposures was decreased by 20% with inclusion of the ipsilateral base of the spinous process. Conclusions: Geometric congruence is most evident at C1 and the subaxial cervical spine, warranting greater vigilance in navigation accuracy verification. At all levels, inclusion of the base of the spinous process in unilateral registration decreases the likelihood of geometric symmetry and navigation error. This work is important to allow the extension of line-of-sight based registration techniques to minimally-invasive unilateral approaches. [ABSTRACT FROM AUTHOR]

Computer-assisted three-dimensional navigation often guides spinal instrumentation. Optical topographic imaging (OTI) offers comparable accuracy and significantly faster registration relative to current navigation systems in open posterior thoracolumbar exposures. We validate the usefulness and accuracy of OTI in minimally invasive spinal approaches. Mini-open midline posterior exposures were performed in 4 human cadavers. Square exposures of 25, 30, 35, and 40 mm were registered to preoperative computed tomography imaging. Screw tracts were fashioned using a tracked awl and probe with instrumentation placed. Navigation data were compared with screw positions on postoperative computed tomography imaging, and absolute translational and angular deviations were computed. In vivo validation was performed in 8 patients, with mini-open thoracolumbar exposures and percutaneous placement of navigated instrumentation. Navigated instrumentation was performed in the previously described manner. For 37 cadaveric screws, absolute translational errors were (1.79 ± 1.43 mm) and (1.81 ± 1.51 mm) in the axial and sagittal planes, respectively. Absolute angular deviations were (3.81 ± 2.91°) and (3.45 ± 2.82°), respectively (mean ± standard deviation). The number of surface points registered by the navigation system, but not exposure size, correlated positively with the likelihood of successful registration (odds ratio, 1.02; 95% confidence interval, 1.009–1.024; P < 0.001). Fifty-five in vivo thoracolumbar pedicle screws were analyzed. Overall (mean ± standard deviation) axial and sagittal translational errors were (1.79 ± 1.41 mm) and (2.68 ± 2.26 mm), respectively. Axial and sagittal angular errors were (3.63° ± 2.92°) and (4.65° ± 3.36°), respectively. There were no radiographic breaches >2 mm or any neurovascular complications. OTI is a novel navigation technique previously validated for open posterior exposures and in this study has comparable accuracy for mini-open minimally invasive surgery exposures. The likelihood of successful registration is affected more by the geometry of the exposure than by its size. [ABSTRACT FROM AUTHOR]

Objective: To determine changes in post-surgical cavity volume for metastases based on time from surgery, pre-operative tumor dimensions and other predictors, in patients planned for postoperative stereotactic radiosurgery (SRS). Methods: Patients with resected brain metastases from a primary solid tumor, treated with postoperative surgical cavity SRS from 2008 to 2014 were identified from an institutional prospective database. The segmented three-dimensional (3D) volume of the pre-operative tumor and postoperative surgical cavity were determined based on MRI and percent volume change was calculated. Patients were grouped according to early (<21 days), intermediate (22-42 days), and late (>42 days) intervals based on the number of days between the date of surgery and the treatment planning MRI. Potential predictive factors including tumor size, location, age, dural involvement, and degree of surgical resection were also analyzed. Results: Sixty-one cavities in 59 patients were evaluated. Overall, a significant volume reduction (4cm3, p=0.03) was observed comparing tumor and cavity volumes. For larger tumors, an average volume reduction of 11.6% (p=0.01) was observed compared to an increase of 34.4% in smaller tumors (p=0.69). For both large and small tumors, cavities were larger in the early interval especially for smaller tumors. During the intermediate interval, a significant volume reduction was observed for larger tumors (28%, p=0.0007). Tumor size, dural involvement, age and time from surgery were significant predictors for volume change on univariate analysis. On multivariate analysis, tumor size, dural involvement and time from surgery were significant. Conclusion: Tumor size (>3cm), dural involvement and longer time from surgery were significant predictors of cavity volume reduction. Caution must be taken when treating cavities in the early (<21 days) interval after surgery as it may lead to irradiating more normal tissue especially in small tumors. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 49-year-old right-handed female who was presented with a solid and cystic pineal region mass of the brain. The result of the magnetic resonance imaging (MRI) is discussed, along with the pineal region tumor biopsy and ventriculostomy. Images are also offered depicting tumor cells of the brain.

A trans-agency workshop on the blood-brain interface (BBI), sponsored by the National Heart, Lung and Blood Institute, the National Cancer Institute and the Combat Casualty Care Research Program at the Department of Defense, was conducted in Bethesda MD on June 7-8, 2016. The workshop was structured into four sessions: (1) blood sciences; (2) exosome therapeutics; (3) next generation in vitro blood-brain barrier (BBB) models; and (4) BBB delivery and targeting. The first day of the workshop focused on the physiology of the blood and neuro-vascular unit, blood or biofluid-based molecular markers, extracellular vesicles associated with brain injury, and how these entities can be employed to better evaluate injury states and/or deliver therapeutics. The second day of the workshop focused on technical advances in in vitro models, BBB manipulations and nanoparticle-based drug carrier designs, with the goal of improving drug delivery to the central nervous system. The presentations and discussions underscored the role of the BBI in brain injury, as well as the role of the BBB as both a limiting factor and a potential conduit for drug delivery to the brain. At the conclusion of the meeting, the participants discussed challenges and opportunities confronting BBI translational researchers. In particular, the participants recommended using BBI translational research to stimulate advances in diagnostics, as well as targeted delivery approaches for detection and therapy of both brain injury and disease. [ABSTRACT FROM AUTHOR]

Background Context: Spinal intraoperative computer-assisted navigation (CAN) may guide pedicle screw placement. Computer-assisted navigation techniques have been reported to reduce pedicle screw breach rates across all spinal levels. However, definitions of screw breach vary widely across studies, if reported at all. The absolute quantitative error of spinal navigation systems is theoretically a more precise and generalizable metric of navigation accuracy. It has also been computed variably and reported in less than a quarter of clinical studies of CAN-guided pedicle screw accuracy.Purpose: This study aimed to characterize the correlation between clinical pedicle screw accuracy, based on postoperative imaging, and absolute quantitative navigation accuracy.Design/setting: This is a retrospective review of a prospectively collected cohort.Patient Sample: We recruited 30 patients undergoing first-time posterior cervical-thoracic-lumbar-sacral instrumented fusion±decompression, guided by intraoperative three-dimensional CAN.Outcome Measures: Clinical or radiographic screw accuracy (Heary and 2 mm classifications) and absolute quantitative navigation accuracy (translational and angular error in axial and sagittal planes).Methods: We reviewed a prospectively collected series of 209 pedicle screws placed with CAN guidance. Each screw was graded clinically by multiple independent raters using the Heary and 2 mm classifications. Clinical grades were dichotomized per convention. The absolute accuracy of each screw was quantified by the translational and angular error in each of the axial and sagittal planes.Results: Acceptable screw accuracy was achieved for significantly fewer screws based on 2 mm grade versus Heary grade (92.6% vs. 95.1%, p=.036), particularly in the lumbar spine. Inter-rater agreement was good for the Heary classification and moderate for the 2 mm grade, significantly greater among radiologists than surgeon raters. Mean absolute translational-angular accuracies were 1.75 mm-3.13° and 1.20 mm-3.64° in the axial and sagittal planes, respectively. There was no correlation between clinical and absolute navigation accuracy.Conclusions: Radiographic classifications of pedicle screw accuracy vary in sensitivity across spinal levels, as well as in inter-rater reliability. Correlation between clinical screw grade and absolute navigation accuracy is poor, as surgeons appear to compensate for navigation registration error. Future studies of navigation accuracy should report absolute translational and angular errors. Clinical screw grades based on postoperative imaging may be more reliable if performed in multiple by radiologist raters. [ABSTRACT FROM AUTHOR]

Early access to specialized care after acute traumatic spinal cord injury (SCI) is associated with improved outcomes. However, many SCI patients do not receive timely access to such care. To characterize and quantify patients' pathway to definitive care and surgery post SCI, and to identify factors that may delay expeditious care, a population based cohort study was performed in Ontario. Using provincial administrative health data, adult patients with acute traumatic SCI who underwent surgery between 2002 and 2011 were identified using SCI specific ICD-10 codes. The relationship between predictor variables and a) time to arrival at the site of definitive care and b) time to surgery was statistically evaluated. Of 1,111 patients meeting eligibility criteria, mean times to arrival at the site of definitive care and to surgery were 8.1 ± 25.5 and 49.4 ± 65.0 hours respectively, with 53.3% of patients having surgery prior to 24 hours. While most patients (88.4%) reached the site of definitive care within 6 hours, only 34.2% reached surgery within 12 hours of arrival. Older age (IRR = 1.01; 95% CI: 1.01, 1.02), increased number of stops at intermediate health care centers (IRR = 7.70; 95% CI: 7.54, 7.86), higher comorbidity index (IRR = 1.43; 95% CI: 1.14, 1.72) and fall related SCI etiology (IRR = 1.16; 95% CI: 1.02, 1.29) were associated with increased time to arrival at definitive care. For surgery, increased age (OR = 1.02; 95% CI: 1.01, 1.03) and stops at intermediate health centers (OR = 2.48; 95% CI: 1.35, 4.56) were associated with a greater odds of undergoing late surgery (>24hrs). These results can inform policy decisions and facilitate creation of a streamlined path to specialized care for patients with acute SCI. [ABSTRACT FROM AUTHOR]

Background Economic evaluations provide a unique opportunity to identify the optimal strategies for the diagnosis and management of traumatic brain injury (TBI), for which uncertainty is common and the economic burden is substantial. Objective The objective of this study was to systematically review and examine the quality of contemporary economic evaluations in the diagnosis and management of TBI. Methods Two reviewers independently searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, Health Technology Assessment Database, EconLit, and the Tufts CEA Registry for comparative economic evaluations published from 2000 onward (last updated on August 30, 2013). Data on methods, results, and quality were abstracted in duplicate. The results were summarized quantitatively and qualitatively. Results Of 3539 citations, 24 economic evaluations met our inclusion criteria. Nine were cost-utility, five were cost-effectiveness, three were cost-minimization, and seven were cost-consequences analyses. Only six studies were of high quality. Current evidence from high-quality studies suggests the economic attractiveness of the following strategies: a low medical threshold for computed tomography (CT) scanning of asymptomatic infants with possible inflicted TBI, selective CT scanning of adults with mild TBI as per the Canadian CT Head Rule, management of severe TBI according to the Brain Trauma Foundation guidelines, management of TBI in dedicated neurocritical care units, and early transfer of patients with TBI with nonsurgical lesions to neuroscience centers. Conclusions Threshold-guided CT scanning, adherence to Brain Trauma Foundation guidelines, and care for patients with TBI, including those with nonsurgical lesions, in specialized settings appear to be economically attractive strategies. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Decompressive craniectomy and barbiturate coma are often used as second-tier strategies when intracranial hypertension following severe traumatic brain injury is refractory to first-line treatments. Uncertainty surrounds the decision to choose either treatment option. We investigated which strategy is more economically attractive in this context. DESIGN: We performed a cost-utility analysis. A Markov Monte Carlo microsimulation model with a life-long time horizon was created to compare quality-adjusted survival and cost of the two treatment strategies, from the perspective of healthcare payer. Model parameters were estimated from the literature. Two-dimensional simulation was used to incorporate parameter uncertainty into the model. Value of information analysis was conducted to identify major drivers of decision uncertainty and focus future research. SETTING: Trauma centers in the United States. SUBJECTS: Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury. INTERVENTIONS: We compared two treatment strategies: decompressive craniectomy and barbiturate coma. MEASUREMENTS AND MAIN RESULTS: Decompressive craniectomy was associated with an average gain of 1.5 quality-adjusted life years relative to barbiturate coma, with an incremental cost-effectiveness ratio of $9,565/quality-adjusted life year gained. Decompressive craniectomy resulted in a greater quality-adjusted life expectancy 86% of the time and was more cost-effective than barbiturate coma in 78% of cases if our willingness-to-pay threshold is $50,000/quality-adjusted life year and 82% of cases at a threshold of $100,000/quality-adjusted life year. At older age, decompressive craniectomy continued to increase survival but at higher cost (incremental cost-effectiveness ratio = $197,906/quality-adjusted life year at mean age = 85 yr). CONCLUSIONS: Based on available evidence, decompressive craniectomy for the treatment of refractory intracranial hypertension following traumatic brain injury provides better value in terms of costs and health gains than barbiturate coma. However, decompressive craniectomy might be less economically attractive for older patients. Further research, particularly on natural history of severe traumatic brain injury patients, is needed to make more informed treatment decisions. [ABSTRACT FROM AUTHOR]

Objectives: Decompressive craniectomy and barbiturate coma are often used as second-tier strategies when intracranial hypertension following severe traumatic brain injury is refractory to firstline treatments. Uncertainty surrounds the decision to choose either treatment option. We investigated which strategy is more economically attractive in this context. Design: We performed a cost-utility analysis. A Markov Monte Carlo microsimulation model with a life-long time horizon was created to compare quality-adjusted survival and cost of the two treatment strategies, from the perspective of healthcare payer. Model parameters were estimated from the literature. Two-dimensional simulation was used to incorporate parameter uncertainty into the model. Value of information analysis was conducted to identify major drivers of decision uncertainty and focus future research. Setting: Trauma centers in the United States. Subjects: Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury. Interventions: We compared two treatment strategies: decompressive craniectomy and barbiturate coma. Measurements and Main Results: Decompressive craniectomy was associated with an average gain of 1.5 quality-adjusted life years relative to barbiturate coma, with an incremental costeffectiveness ratio of $9,565/quality-adjusted life year gained. Decompressive craniectomy resulted in a greater quality-adjusted life expectancy 86% of the time and was more cost-effective than barbiturate coma in 78% of cases if our willingness-to-pay threshold is $50,000/quality-adjusted life year and 82% of cases at a threshold of $100,000/quality-adjusted life year. At older age, decompressive craniectomy continued to increase survival but at higher cost (incremental cost-effectiveness ratio = $197,906/ quality-adjusted life year at mean age = 85 yr). Conclusions: Based on available evidence, decompressive craniectomy for the treatment of refractory intracranial hypertension following traumatic brain injury provides better value in terms of costs and health gains than barbiturate coma. However, decompressive craniectomy might be less economically attractive for older patients. Further research, particularly on natural history of severe traumatic brain injury patients, is needed to make more informed treatment decisions. [ABSTRACT FROM AUTHOR]

Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, ß-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind ß-catenin, export it from the nucleus, and thereby repress ß-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of ß-catenin, and cannot inhibit ß-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.Oncogene (2004) 23, 4577-4583. doi:10.1038/sj.onc.1207605 Published online 12 April 2004 [ABSTRACT FROM AUTHOR]

The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulIoblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism. [ABSTRACT FROM AUTHOR]

Presents a case of familial posterior brain tumors carrying a germlike splice-site mutation of the hSNF5 gene. Exclusion of exon 7 from the mature cDNA; Association of germlike mutations in hSNF5 with autosomal dominant syndrome; Predisposition of the brain tumors in infancy.