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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]

Somatosensory evoked potentials (SSEPs) are used for neuroprognosis after severe traumatic brain injury (TBI). However decompressive craniectomy (DC), involving removal of a portion of the skull to alleviate elevated intracranial pressure, is associated with an increase in SSEP amplitude. Accordingly, SSEPs are not available for neuroprognosis over the hemisphere with DC. We aim to determine the degree to which SSEP amplitudes are increased in the absence of cranial bone. This will serve as a precursor for translation to clinically prognostic ranges. Intra-operative SSEPs were performed before and after bone flap replacement in 22 patients with severe TBI. SSEP measurements were also performed in a comparison non-traumatic group undergoing craniotomy for tumor resection. N20/P25 amplitudes and central conduction time were measured with the bone flap in (BI) and out (BO). Linear regressions, adjusting for skull thickness and study arm, were performed to evaluate the contribution of bone presence to SSEP amplitudes. Latencies were not different between BO or BI trials in either group. Mean N20/P25 amplitudes recorded with BO were statistically different (p = 0.0001) from BI in both cohorts, showing an approximate doubling in BO amplitudes. For contralateral-ipsilateral montages r2 was 0.28 and for frontal pole montages r2 was 0.62. Cortical SSEP amplitudes are influenced by the presence of cortical bone as is particularly evident in frontal pole montages. Larger, longitudinal trials to assess feasibility of neuroprognosis over the hemisphere with DC in severe TBI patients are warranted. [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]

Abstract: Purpose: Noninvasive frameless systems are increasingly being utilized for head immobilization in stereotactic radiosurgery (SRS). Knowing the head positioning reproducibility of frameless systems and their respective ability to limit intrafractional head motion is important in order to safely perform SRS. The purpose of this study was to evaluate and compare the intrafractional head motion of an invasive frame and a series of frameless systems for single fraction SRS and fractionated/hypofractionated stereotactic radiotherapy (FSRT/HF‐SRT). Methods: The noninvasive PinPoint system was used on 15 HF‐SRT and 21 SRS patients. Intrafractional motion for these patients was compared to 15 SRS patients immobilized with Cosman‐Roberts‐Wells (CRW) frame, and a FSRT population that respectively included 23, 32, and 15 patients immobilized using Gill‐Thomas‐Cosman (GTC) frame, Uniframe, and Orfit. All HF‐SRT and FSRT patients were treated using intensity‐modulated radiation therapy on a linear accelerator equipped with cone‐beam CT (CBCT) and a robotic couch. SRS patients were treated using gantry‐mounted stereotactic cones. The CBCT image‐guidance protocol included initial setup, pretreatment and post‐treatment verification images. The residual error determined from the post‐treatment CBCT was used as a surrogate for intrafractional head motion during treatment. Results: The mean intrafractional motion over all fractions with PinPoint was 0.62 ± 0.33 mm and 0.45 ± 0.33 mm, respectively, for the HF‐SRT and SRS cohort of patients (P‐value = 0.266). For CRW, GTC, Orfit, and Uniframe, the mean intrafractional motions were 0.30 ± 0.21 mm, 0.54 ± 0.76 mm, 0.73 ± 0.49 mm, and 0.76 ± 0.51 mm, respectively. For CRW, PinPoint, GTC, Orfit, and Uniframe, intrafractional motion exceeded 1.5 mm in 0%, 0%, 5%, 6%, and 8% of all fractions treated, respectively. Conclusions: The noninvasive PinPoint system and the invasive CRW frame stringently limit cranial intrafractional motion, while the latter provides superior immobilization. Based on the results of this study, our clinical practice for malignant tumors has evolved to apply an invasive CRW frame only for metastases in eloquent locations to minimize normal tissue exposure. [ABSTRACT FROM AUTHOR]

Opinion Statement: Newly diagnosed elderly patients (age > 65-70 years) with glioblastoma should be treated with a patient-centred approach by a multi-disciplinary team. Chronological age alone should not be considered as a contraindication to treatment with maximal safe surgical resection. A 3-week course of adjuvant radiation and chemotherapy is appropriate in selected elderly patients with favourable Karnofsky performance status (KPS) who cannot tolerate a longer 6-week course of fractionated radiotherapy. The presence or absence of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation can be used to guide clinical decision-making as both prognostic and predictive biomarkers. This review provides an update and summary of the available evidence for treating newly diagnosed elderly patients with glioblastoma. [ABSTRACT FROM AUTHOR]

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: The revolution in molecular biology that has taken place over the past 2 decades has provided researchers with new and powerful tools for detailed study of the molecular mechanisms giving rise to the spectrum of pediatric brain tumors. Application of these tools has greatly advanced our understanding of the molecular pathogenesis of these lesions. Review: After familiarizing readers with some promising new techniques in the field of oncogenomics, this review will present the current state of knowledge as it pertains to the molecular biology of pediatric brain neoplasms. Along the way, we hope to highlight specific instances where the detailed mechanistic knowledge acquired thus far may be exploited for therapeutic advantage. [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]

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]

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]

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]

A large variety of mass lesions have been reported in the region of the pineal gland. Pineal parenchymal tumors and germ cell tumors (GCTs) are especially characteristic of this region. Despite their rarity, a number of excellent studies on the cytogenetics and molecular genetics of pineal parenchymal tumors and pineal region GCTs have been published. These studies draw attention to a number of distinct genomic regions recurrently involved in the various subtypes of malignancies of the pineal gland. Outcomes for tumors in this location vary widely between patients and among differing histologies. Development of novel therapies for patients with poor prognoses will depend on the acquisition of a more detailed understanding of the molecular basis associated with the etiopathogenesis of these neoplasms. We review the literature on cytogenetics, familial syndromes, animal models and molecular genetics of pineal region neoplasms. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) of the central nervous system (CNS) is enriched in hyaluronate (HA). Ubiquitous receptors for HA are CD44 and the Receptor for HA- Mediated Motility known as RHAMM. In the present study, we have investigated the potential role of CD44 and RHAMM in the migration and proliferation of human astrocytoma cells. HA-receptor expression in brain tumor cell lines and surgical specimens was determined by immunocytochemistry and western blot analyses. The ability of RHAMM to bind ligand was determined through cetylpyridinium chloride (CPC) precipitations of brain tumor lysates in HA-binding assays. The effects of HA, CD44 blocking antibodies, and RHAMM soluble peptide on astrocytoma cell growth and migration was determined using MTT and migration assays. Our results show that the expression of the HA-receptors, CD44, and RHAMM, is virtually ubiquitous amongst glioma cell lines, and glioma tumor specimens. There was a gradient of expression amongst gliomas with high grade gliomas expressing more RHAMM and CD44 than did lower grade lesions or did normal human astrocytes or non-neoplastic specimens of human brain. Specific RHAMM variants of 85- and 58-kDa size were shown to bind avidly to HA following CPC precipitations. RHAMM soluble peptide inhibited glioma cell line proliferation in a dose-dependent fashion. Finally, while anti-CD44 antibodies did not inhibit the migration of human glioma cells, soluble peptides directed at the HA-binding domain of RHAMM inhibited glioma migration both on and off an HA-based ECM. These data support the notion that HA-receptors contribute to brain tumor adhesion, proliferation, and migration, biological features which must be better understood before more effective treatment strategies for these tumors can be found. [ABSTRACT FROM AUTHOR]

The cell cycle is a precisely controlled cellular program that ensures normal cellular proliferation and development. The cyclin-dependant kinases (CDK) are molecules central to the continued progression through the cell-cycle checkpoints and as such are regulated by various mechanisms including cyclin levels, phosphorylation/dephosphorylation and cyclin-dependant kinase inhibitors (CKI). The CKIs are grouped into two families based on their structure and function, four Ink4 CKIs and three Cip/Kip CKIs. Abnormalities in these proteins can give rise to developmental defects and cancer. In this review, we will discuss the biochemistry and cell biology of the each of the Cip/Kip CKIs, their role in development as evidenced by targeted mutations in mice, and their role as possible tumor suppressor genes. [ABSTRACT FROM AUTHOR]

The new millennium beckons for novel advances in the diagnosis and treatment of pediatric neurosurgical conditions. Almost every aspect of pediatric neurosurgery has changed over the last decade. Undoubtedly with the application of knowledge in molecular biology to human disease many aspects of neurosurgery, especially neuro-oncology and the field of neuro-developmental anomalies, will change appreciably over the next decade. Overall, the trend in surgery in general and neurosurgery in particular is toward less invasive procedures and possibly non-surgical interventions. This review will briefly cover many of the important areas of pediatric neurosurgery. We will describe the state-of-the-art of our subspecialty and discuss possible future directions. [ABSTRACT FROM AUTHOR]

MR-guided focused ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS. MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients. [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]

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.