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Purpose: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG., Methods: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review., Results: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred., Conclusion: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and most common brain cancer in adults. Not only is there an urgent need to identify efficacious therapeutics, but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations. We built patient drug response models by integrating patient tumor transcriptome data with high-throughput cell line drug screening data as well as Bayesian networks to infer relationships between patient gene expression and drug response. Through these discovery pipelines, we identified agents of interest for GBM to be effective across five independent patient cohorts and in a mouse avatar model: among them are a number of MEK inhibitors (MEKis). We also predicted phosphoglycerate dehydrogenase enzyme (PHGDH) gene expression levels to be causally associated with MEKi efficacy, where knockdown of this gene increased tumor sensitivity to MEKi and overexpression led to MEKi resistance. Overall, our work demonstrated the power of integrating computational approaches. In doing so, we quickly nominated several drugs with varying known mechanisms of action that can efficaciously target GBM. By simultaneously identifying biomarkers with these drugs, we also provide tools to select the right patient populations for subsequent evaluation.

Direct electrolysis of pH-neutral seawater to generate hydrogen is an attractive approach for storing renewable energy. However, due to the anodic competition between the chlorine evolution and the oxygen evolution reaction (OER), direct seawater splitting suffers from a low current density and limited operating stability. Exploration of catalysts enabling an OER overpotential below the hypochlorite formation overpotential (≈490 mV) is critical to suppress the chloride evolution and facilitate seawater splitting. Here, a proton-adsorption-promoting strategy to increase the OER rate is reported, resulting in a promoted and more stable neutral seawater splitting. The best catalysts herein are strong-proton-adsorption (SPA) materials such as palladium-doped cobalt oxide (Co 3- x Pd x O 4 ) catalysts. These achieve an OER overpotential of 370 mV at 10 mA cm -2 in pH-neutral simulated seawater, outperforming Co 3 O 4 by a margin of 70 mV. Co 3- x Pd x O 4 catalysts provide stable catalytic performance for 450 h at 200 mA cm -2 and 20 h at 1 A cm -2 in neutral seawater. Experimental studies and theoretical calculations suggest that the incorporation of SPA cations accelerates the rate-determining water dissociation step in neutral OER pathway, and control studies rule out the provision of additional OER sites as a main factor herein., (© 2023 Wiley-VCH GmbH.)

Background: Treatment of recurrent glioblastoma (GBM) remains problematic with survival after additional therapy typically less than 12 months. We prospectively evaluated whether outcomes might be improved with resection plus permanent implantation of a novel radiation device utilizing the gamma-emitting isotope Cs-131 embedded within bioresorbable collagen tiles., Methods: Recurrent histologic GBM were treated in a single-arm trial. Following radiation, the surgical bed was lined with the tiles. Subsequent treatments were at the treating physician's discretion., Results: 28 patients were treated (20 at first recurrence, range 1-3). Median age was 58 years, KPS was 80, female:male ratio was 10:18. Methylguanine methyltransferase (MGMT) was methylated in 11%, unmethylated in 18%, and unknown in 71%. Post implant, 17 patients (61%) received ≥1 course of systemic therapy. For all patients, Kaplan-Meier estimates of median time to local failure were 12.1 months, post-implant survival was 10.7 months for all patients and 15.1 months for patients who received systemic therapy; for all patients, median overall survival from diagnosis was 25.0 months (range 9.1-143.1). Sex, age, and number of prior progressions were not statistically significant. Local control was continuously maintained in 46% of patients. Two deaths within 30 days occurred, one from intracranial hemorrhage and one after persistent coma. Three symptomatic adverse events occurred: one wound infection requiring surgery and two late radiation brain injury, resolved non-surgically., Conclusion: This pre-commercial trial demonstrated acceptable safety and favorable post-treatment local control and survival. The device has received FDA clearance for use in newly diagnosed malignant and all recurrent intracranial neoplasms., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma., Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers., Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc., Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Radiomics seeks to apply classical methods of image processing to obtain quantitative parameters from imaging. Derived features are subsequently fed into algorithmic models to aid clinical decision making. The application of radiomics and machine learning techniques to clinical medicine remains in its infancy. The great potential of radiomics lies in its objective, granular approach to investigating clinical imaging. In neuro-oncology, advanced machine learning techniques, particularly deep learning, are at the forefront of new discoveries in the field. However, despite the great promise of machine learning aided radiomic approaches, the current use remains confined to scholarly research, without real-world deployment in neuro-oncology. The paucity of data, inconsistencies in preprocessing, radiomic feature instability, and the rarity of the events of interest are critical barriers to clinical translation. In this article, we will outline the major steps in the process of radiomics, as well as review advances and challenges in the field as they pertain to neuro-oncology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Long-term implant durability is a key concern when considering total hip arthroplasty (THA) in young patients. The ideal bearing surface used in these patients remains unknown. The purpose of this study was to analyze trends in THA bearing surface use from 2006 to 2016 using a large, pediatric national database., Methods: This was a retrospective review from January 1, 2006, to December 31, 2016, using the Kids' Inpatient Database. International Classification of Diseases, 9 th revision and 10 th revision codes were used to identify patients who underwent THA and create cohorts based on bearing surfaces: metal-on-metal, metal-on-polyethylene, ceramic-on-polyethylene (CoP), and ceramic-on-ceramic (CoC). Annual utilization of each bearing surface and associated patient and hospital demographics were analyzed., Results: A total of 1004 THAs were identified during the 11-year study period. The annual number of THAs performed increased by 169% from 2006 to 2016. The mean patient age was 17.1 years. The most prevalent bearing surface used in 2006 was CoC (37.3%), metal-on-metal (31.8%) in 2009, and CoP in 2012 and 2016 (50.6% and 64.8%, respectively). From 2006 to 2016, utilization of CoP increased from 5.0% to 64.8%, representing a 1196% increase over the study period., Conclusions: The number of THAs performed in pediatric patients is increasing significantly. Although CoC was previously the most commonly used bearing surface in this patient population, CoP is currently the most common. Further investigation is needed to determine whether bearing longevity and clinical outcomes with CoP are superior to other bearing surfaces., (© 2021 The Authors.)

Purpose: GammaTile cesium-131 ( 131 Cs) permanent brain implant has received Food and Drug Administration (FDA) clearance as a promising treatment for certain brain tumors. Our center was the first institution in the United States after FDA clearance to offer the clinical use of GammaTile brachytherapy outside of a clinical trial. The purpose of this work is to aid the medical physicist and radiation oncologist in implementing this collagen carrier tile brachytherapy (CTBT) program in their practice., Methods: A total of 23 patients have been treated with GammaTile to date at our center. Treatment planning system (TPS) commissioning was performed by configuring the parameters for the 131 Cs (IsoRay Model CS-1, Rev2) source, and doses were validated with the consensus data from the American Association of Physicists in Medicine TG-43U1S2. Implant procedures, dosimetry, postimplant planning, and target delineations were established based on our clinical experience. Radiation safety aspects were evaluated based on exposure rate measurements of implanted patients, as well as body and ring badge measurements., Results: An estimated timeframe of the GammaTile clinical responsibilities for the medical physicist, radiation oncologist, and neurosurgeon is presented. TPS doses were validated with published dose to water for 131 Cs. Clinical aspects, including estimation of the number of tiles, treatment planning, dosimetry, and radiation safety considerations, are presented., Conclusion: The implementation of the GammaTile program requires collaboration from multiple specialties, including medical physics, radiation oncology, and neurosurgery. This manuscript provides a roadmap for the implementation of this therapy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Laser Interstitial Thermotherapy (LITT; also known as Stereotactic Laser Ablation or SLA), is a minimally invasive treatment modality that has recently gained prominence in the treatment of malignant primary and metastatic brain tumors and radiation necrosis and studies for treatment of spinal metastasis has recently been reported., Methods: Here we provide a brief literature review of the various contemporary uses for LITT and their reported outcomes., Results: Historically, the primary indication for LITT has been for the treatment of recurrent glioblastoma (GBM). However, indications have continued to expand and now include gliomas of different grades, brain metastasis (BM), radiation necrosis (RN), other types of brain tumors as well as spine metastasis. LITT is emerging as a safe, reliable, minimally invasive clinical approach, particularly for deep seated, focal malignant brain tumors and radiation necrosis. The role of LITT for treatment of other types of tumors of the brain and for spine tumors appears to be evolving at a small number of centers. While the technology appears to be safe and increasingly utilized, there have been few prospective clinical trials and most published studies combine different pathologies in the same report., Conclusion: Well-designed prospective trials will be required to firmly establish the role of LITT in the treatment of lesions of the brain and spine.

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo . Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies. SIGNIFICANCE: Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas. This article is highlighted in the In This Issue feature, p. 1611 ., (©2020 American Association for Cancer Research.)

Background: Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN) is an ongoing multicenter prospective NeuroBlate (Monteris Medical) LITT (laser interstitial thermal therapy) registry collecting real-world outcomes and quality-of-life (QoL) data., Objective: To compare 12-mo outcomes from all subjects undergoing LITT for intracranial tumors/neoplasms., Methods: Demographics, intraprocedural data, adverse events, QoL, hospitalizations, health economics, and survival data are collected; standard data management and monitoring occur., Results: A total of 14 centers enrolled 223 subjects; the median follow-up was 223 d. There were 119 (53.4%) females and 104 (46.6%) males. The median age was 54.3 yr (range 3-86) and 72.6% had at least 1 baseline comorbidity. The median baseline Karnofsky Performance Score (KPS) was 90. Of the ablated tumors, 131 were primary and 92 were metastatic. Most patients with primary tumors had high-grade gliomas (80.9%). Patients with metastatic cancer had recurrence (50.6%) or radiation necrosis (40%). The median postprocedure hospital stay was 33.4 h (12.7-733.4). The 1-yr estimated survival rate was 73%, and this was not impacted by disease etiology. Patient-reported QoL as assessed by the Functional Assessment of Cancer Therapy-Brain was stabilized postprocedure. KPS declined by an average of 5.7 to 10.5 points postprocedure; however, 50.5% had stabilized/improved KPS at 6 mo. There were no significant differences in KPS or QoL between patients with metastatic vs primary tumors., Conclusion: Results from the ongoing LAANTERN registry demonstrate that LITT stabilizes and improves QoL from baseline levels in a malignant brain tumor patient population with high rates of comorbidities. Overall survival was better than anticipated for a real-world registry and comparative to published literature., (© Congress of Neurological Surgeons 2020.)

Background: This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs., Objectives: To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection., Search Methods: Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update., Selection Criteria: We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS)., Data Collection and Analysis: Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting., Main Results: We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively)., Authors' Conclusions: Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Cell classification based on phenotypical, spatial, and genetic information greatly advances our understanding of the physiology and pathology of biological systems. Technologies derived from next generation sequencing and fluorescent activated cell sorting are cornerstones for cell- and genomic-based assays supporting cell classification and mapping. However, there exists a deficiency in technology space to rapidly isolate cells based on high content image information. Fluorescence-activated cell sorting can only resolve cell-to-cell variation in fluorescence and optical scattering. Utilizing microfluidics, photonics, computation microscopy, real-time image processing and machine learning, we demonstrate an image-guided cell sorting and classification system possessing the high throughput of flow cytometer and high information content of microscopy. We demonstrate the utility of this technology in cell sorting based on (1) nuclear localization of glucocorticoid receptors, (2) particle binding to the cell membrane, and (3) DNA damage induced γ-H2AX foci. © 2019 International Society for Advancement of Cytometry., (© 2019 International Society for Advancement of Cytometry.)

Understanding biological heterogeneity at the single cell level is required for advancing insights into the complexity of human physiology and diseases. While advances in technological and analytical methods have afforded unprecedented glimpses of this heterogeneity, the information captured to date largely represents one-time "snap" shots of single cell physiology. To address the limits of existing methods and to accelerate discoveries from single cell studies, we developed a single-cell translocation and secretion assay (TransSeA) that supports time lapse analysis, enables molecular cargo analysis of secretions such as extracellular vesicles (EVs) from single cells, allows massively parallel single cell transfer according to user-defined cell selection criteria, and supports tracking of phenotypes between parental and progeny cells derived from single cells. To demonstrate the unique capabilities and efficiencies of the assay, we present unprecedented single cell studies related to cell secretions, EV cargos and cell intrinsic properties. Although used as examples to demonstrate the feasibility and versatility of the technology, the studies already provided insights into key unanswered questions such as the microRNAs carried by EVs, the relationships between EV secretion rates and gene expressions, and the spontaneous, trans-generational phenotypic changes in EV secretion between parental and progeny cells.

Exosomes can mediate a dynamic method of communication between malignancies, including those sequestered in the central nervous system and the immune system. We sought to determine whether exosomes from glioblastoma (GBM)-derived stem cells (GSCs) can induce immunosuppression. We report that GSC-derived exosomes (GDEs) have a predilection for monocytes, the precursor to macrophages. The GDEs traverse the monocyte cytoplasm, cause a reorganization of the actin cytoskeleton, and skew monocytes toward the immune suppresive M2 phenotype, including programmed death-ligand 1 (PD-L1) expression. Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch. Western blot analysis revealed that upregulation of PD-L1 in GSC exosome-treated monocytes and GBM-patient-infiltrating CD14 + cells predominantly correlates with increased phosphorylation of STAT3, and in some cases, with phosphorylated p70S6 kinase and Erk1/2. Cumulatively, these data indicate that GDEs are secreted GBM-released factors that are potent modulators of the GBM-associated immunosuppressive microenvironment.

Treating scaphoid nonunions presents difficulties particularly when there is bone loss, significant humpback deformity or avascular necrosis. We describe a new type of fixation with a volar scaphoid plate that adds to the methods of internal fixation that are available for the treatment of recalcitrant scaphoid nonunions. We will also discuss 'lessons learned' from a cases series. The case series includes 20 consecutive patients treated with volar buttress plating and a pedicled vascularized bone graft from the ipsilateral volar distal radius. There was clinical and radiographic evidence of union in 18 of 20 patients, 13 of which were verified by computed tomographic scan. The range of motion was improved in all patients post-operatively. Four patients with radiographic union experienced intermittent clicking with maximal wrist flexion, believed to be due to the impingement of the plate on the volar aspect of the radioscaphoid articulation and underwent removal at approximately 1 year after the index procedure. Volar scaphoid plating is a useful alternative to headless scaphoid screw fixation in the treatment of unstable scaphoid waist fractures and nonunions., Level of Evidence: IV.

Background: RNAs within extracellular vesicles (EVs) have potential as diagnostic biomarkers for patients with cancer and are identified in a variety of biofluids. Glioblastomas (GBMs) release EVs containing RNA into cerebrospinal fluid (CSF). Here we describe a multi-institutional study of RNA extracted from CSF-derived EVs of GBM patients to detect the presence of tumor-associated amplifications and mutations in epidermal growth factor receptor (EGFR)., Methods: CSF and matching tumor tissue were obtained from patients undergoing resection of GBMs. We determined wild-type (wt)EGFR DNA copy number amplification, as well as wtEGFR and EGFR variant (v)III RNA expression in tumor samples. We also characterized wtEGFR and EGFRvIII RNA expression in CSF-derived EVs., Results: EGFRvIII-positive tumors had significantly greater wtEGFR DNA amplification (P = 0.02) and RNA expression (P = 0.03), and EGFRvIII-positive CSF-derived EVs had significantly more wtEGFR RNA expression (P = 0.004). EGFRvIII was detected in CSF-derived EVs for 14 of the 23 EGFRvIII tissue-positive GBM patients. Conversely, only one of the 48 EGFRvIII tissue-negative patients had the EGFRvIII mutation detected in their CSF-derived EVs. These results yield a sensitivity of 61% and a specificity of 98% for the utility of CSF-derived EVs to detect an EGFRvIII-positive GBM., Conclusion: Our results demonstrate CSF-derived EVs contain RNA signatures reflective of the underlying molecular genetic status of GBMs in terms of wtEGFR expression and EGFRvIII status. The high specificity of the CSF-derived EV diagnostic test gives us an accurate determination of positive EGFRvIII tumor status and is essentially a less invasive "liquid biopsy" that might direct mutation-specific therapies for GBMs., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

The technique of cryosurgery has been used to control local recurrence in a variety of benign and malignant bone tumors. Early studies revealed significant complication rates (25%) that included fracture, infection, and soft tissue injury. Our method of cryosurgery has yielded excellent tumor control with improved complication rates. The objective of this study is to determine the characteristics of postoperative complications after pouring liquid nitrogen into curettaged bone defects, and to review our current indications and surgical technique in bone tumor management. We reviewed charts in over 200 patients who received cryoablation for bone tumors from 1994 to 2015. Imaging studies were evaluated in all patients diagnosed with a complication. All patients receiving cryotherapy had soft tissue management intraoperatively that included warm saline directed to the structures. Liquid nitrogen was poured into the bone defect and in some cases, additional spraying with a cryogun into the defect was performed. The majority of cryotherapy was used in cases of active or aggressive benign tumors. Our low complication rate of 2.34% included 1 post-operative fracture, 3 infection, and 1 paraesthesia. Bone graft or cementation was used in the majority of patients, all of which fully incorporated. Cryoablation is an excellent from of adjuvant therapy for active and aggressive benign tumors and may be used in malignant tumors as well. Soft tissue protection is critical to avoid skin necrosis and wound breakdown. We recommend the use of cryotherapy in active and aggressive bone tumors as an adjuvant treatment prior to bone grafting or cementation.

The levels of expression of O6-methylguanine-DNA methyltransferase (MGMT) are relevant in predicting the response to the alkylating chemotherapy in patients affected by glioblastoma. MGMT promoter methylation and the published MGMT regulating microRNAs (miRNAs) do not completely explain the expression pattern of MGMT in clinical glioblastoma specimens. Here we used a genome-wide microarray-based approach to identify MGMT regulating miRNAs. Our screen unveiled three novel MGMT regulating miRNAs, miR-127-3p, miR-409-3p, and miR-124-3p, in addition to the previously identified miR-181d-5p. Transfection of these three novel miRNAs into the T98G glioblastoma cell line suppressed MGMT mRNA and protein expression. However, their MGMT- suppressive effects are 30-50% relative that seen with miR-181d-5p transfection. In silico analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) revealed that miR-181d-5p is the only miRNA that consistently exhibited inverse correlation with MGMT mRNA expression. However, statistical models incorporating both miR-181d-5p and miR-409-3p expression better predict MGMT expression relative to models involving either miRNA alone. Our results confirmed miR-181d-5p as the key MGMT-regulating miRNA. Other MGMT regulating miRNAs, including the miR-409-3p identified in this report, modify the effect of miR-181d-5p on MGMT expression. MGMT expression is, thus, regulated by cooperative interaction between key MGMT-regulating miRNAs., Competing Interests: None for all authors.

Background: Radiotherapy is of critical importance in the treatment of breast cancer. However, not all patients derive therapeutic benefit and some breast cancers are resistant to the treatment, and are thus evidenced with prospective distant metastatic spread and local recurrence. In this study, we investigated the potential therapeutic effects of all-trans retinoic acid (ATRA) on radiation-resistant breast cancer cells and the associated invasiveness., Methods: The MCF7/C6 cells with gained radiation resistance after a long term treatment with fractionated ionizing radiation were derived from human breast cancer MCF7 cell line, and are enriched with cells expressing putative breast cancer stem cell biomarker CD44(+)/CD24(-/low)/ALDH(+). The enhanced invasiveness and the acquired resistances to chemotherapeutic treatments of MCF7/C6 cells were measured, and potential effects of all-trans retinoic acid (ATRA) on the induction of differentiation, invasion and migration, and on the sensitivities to chemotherapies in MCF7/C6 cells were investigated., Results: MCF7/C6 cells are with enrichment of cancer stem-cell like cells with positive staining of CD44(+)/CD24(-/low), OCT3/4 and NANOG. MCF7/C6 cells showed an increased tumoregensis potential and enhanced aggressiveness of invasion and migration. Treatment with ATRA induces the differentiation in MCF7/C6 cells, resulting in reduced invasiveness and migration, and increased sensitivity to Epirubincin treatment., Conclusion: Our study suggests a potential clinic impact for ATRA as a chemotherapeutic agent for treatment of therapy-resistant breast cancer especially for the metastatic lesions. The study also provides a rationale for ATRA as a sensitizer of Epirubincin, a first-line treatment option for breast cancer patients.

Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM inhibitor KU-60019 was specifically toxic to PTEN mutant cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors., (©2015 American Association for Cancer Research.)

Background: Patients afflicted with low-grade glioma (LGG) frequently suffer from seizures. The mechanisms of seizure initiation in these patients remain poorly understood. Tumor location has been correlated with seizure initiation. However, these correlative studies relied on dichotomized data analysis based on arbitrary lobe assignments. As a result, the lesion-symptom correlation may be incorrectly interpreted. Here, we present the first study that used a voxel-wise quantitative lesion analysis to investigate the spatial correlation between tumor location and seizure susceptibility., Methods: We collected the medical records and magnetic resonance images of 410 LGG patients. The dataset was divided into a discovery set and a validation set. A voxel-based lesion-symptom correlative analysis was performed to determine whether tumor location was associated with seizure risk and could be related to the specific type of seizure., Results: For all seizure types, increased seizure risks were identified for LGGs that involved the left premotor area. The LGGs that involved the posterior portion of the left inferior and middle frontal gyrus were associated with increased risk of simple partial seizures. LGGs that involved the right temporal-insular region were associated with an increased risk of complex partial seizures. LGGs that involved the left premotor area were more likely to be associated with seizures that generalize. These correlations were consistently observed in both the discovery and the validation datasets., Conclusions: Our quantitative neuroimaging analyses support the concept that the anatomic location of an LGG is a contributing factor in tumor-related seizure., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hydrocephalus is characterized by ventricular dilatation because of progressive accumulation of cerebrospinal fluid. Normal pressure hydrocephalus (NPH) affects a subset of patients representing a reversible clinical triad of gait disturbance, urinary incontinence, and dementia with normal cerebrospinal fluid pressure and composition. Various shunting procedures have been used for treatment, but techniques and outcomes remain under debate. The objective of this study was to evaluate the clinical outcomes of 232 patients with and without NPH after the first-time Ventriculoperitoneal shunt placement and assessed patterns of failure between December 2004 and December 2012., Results: Mean age was 54.7 y in non-NPH and 71.9 y in NPH patients. We used open technique in 34.3% and laparoscopic technique in 65.7% of NPH patients and 32.7% and 67.3% of the non-NPH patients, respectively. A total of 36 of 232 patients displayed shunt failure, 16.4% in NPH and 15.2% in non-NPH patients. Twenty-three of 155 patients failed after laparoscopic and 13 of 77 failed after open placement. Proximal shunt failure was more frequent in the non-NPH cohort. Distal failures accounted for 13 of 232 cases, and the difference between laparoscopic (six of 155) and open failures (seven of 77) was profound, but not between NPH- and non-NPH patients., Conclusions: Shunt failures are related to the placement method. Non-NPH patients showed more proximal failures. NPH patients showed fewer proximal failures. Less distal failures were observed after laparoscopic ventriculoperitoneal shunt placement without significant differences between NPH and non-NPH patients. Beyond this, laparoscopic surgery carries distinct advantages such as shorter operating room times and hospital stays, which should translate into less use of pain medications, earlier mobilization, and a lower incidence of ileus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Object: Hospital readmission within 30 days of discharge is a major contributor to the high cost of health care in the US and is also a major indicator of patient care quality. The purpose of this study was to investigate the incidence, causes, and predictors of 30-day readmission following craniotomy for malignant supratentorial tumor resection., Methods: The longitudinal California Office of Statewide Health Planning & Development inpatient-discharge administrative database is a data set that consists of 100% of all inpatient hospitalizations within the state of California and allows each patient to be followed throughout multiple inpatient hospital stays, across multiple institutions, and over multiple years (from 1995 to 2010). This database was used to identify patients who underwent a craniotomy for resection of primary malignant brain tumors. Causes for unplanned 30-day readmission were identified by principle ICD-9 diagnosis code and multivariate analysis was used to determine the independent effect of various patient factors on 30-day readmissions., Results: A total of 18,506 patients received a craniotomy for the treatment of primary malignant brain tumors within the state of California between 1995 and 2010. Four hundred ten patients (2.2%) died during the index surgical admission, 13,586 patients (73.4%) were discharged home, and 4510 patients (24.4%) were transferred to another facility. Among patients discharged home, 1790 patients (13.2%) were readmitted at least once within 30 days of discharge, with 27% of readmissions occurring at a different hospital than the initial surgical institution. The most common reasons for readmission were new onset seizure and convulsive disorder (20.9%), surgical infection of the CNS (14.5%), and new onset of a motor deficit (12.8%). Medi-Cal beneficiaries were at increased odds for readmission relative to privately insured patients (OR 1.52, 95% CI 1.20-1.93). Patients with a history of prior myocardial infarction were at an increased risk of readmission (OR 1.64, 95% CI 1.06-2.54) as were patients who developed hydrocephalus (OR 1.58, 95% CI 1.20-2.07) or venous complications during index surgical admission (OR 3.88, 95% CI 1.84-8.18)., Conclusions: Using administrative data, this study demonstrates a baseline glioma surgery 30-day readmission rate of 13.2% in California for patients who are initially discharged home. This paper highlights the medical histories, perioperative complications, and patient demographic groups that are at an increased risk for readmission within 30 days of home discharge. An analysis of conditions present on readmission that were not present at the index surgical admission, such as infection and seizures, suggests that some readmissions may be preventable. Discharge planning strategies aimed at reducing readmission rates in neurosurgical practice should focus on patient groups at high risk for readmission and comprehensive discharge planning protocols should be implemented to specifically target the mitigation of potentially preventable conditions that are highly associated with readmission.

Development of biofluid-based molecular diagnostic tests for cancer is an important step towards tumor characterization and real-time monitoring in a minimally invasive fashion. Extracellular vesicles (EVs) are released from tumor cells into body fluids and can provide a powerful platform for tumor biomarkers because they carry tumor proteins and nucleic acids. Detecting rare point mutations in the background of wild-type sequences in biofluids such as blood and cerebrospinal fluid (CSF) remains a major challenge. Techniques such as BEAMing (beads, emulsion, amplification, magnetics) PCR and droplet digital PCR (ddPCR) are substantially more sensitive than many other assays for mutant sequence detection. Here, we describe a novel approach that combines biofluid EV RNA and BEAMing RT-PCR (EV-BEAMing), as well droplet digital PCR to interrogate mutations from glioma tumors. EVs from CSF of patients with glioma were shown to contain mutant IDH1 transcripts, and we were able to reliably detect and quantify mutant and wild-type IDH1 RNA transcripts in CSF of patients with gliomas. EV-BEAMing and EV-ddPCR represent a valuable new strategy for cancer diagnostics, which can be applied to a variety of biofluids and neoplasms.Molecular Therapy-Nucleic Acids (2013) 2, e109; doi:10.1038/mtna.2013.28; published online 23 July 2013.

Background: Kawasaki disease is an acute, self-limited vasculitis of childhood that can result in structural damage to the coronary arteries. Previous studies have implicated the TGF-β pathway in disease pathogenesis and generation of myofibroblasts in the arterial wall. microRNAs are small non-coding RNAs that modulate gene expression at the post-transcriptional level and can be transported between cells in extracellular vesicles. To understand the role that microRNAs play in modifying gene expression in Kawasaki disease, we studied microRNAs from whole blood during the acute and convalescent stages of the illness., Methodology/principal Findings: RNA isolated from the matched whole blood of 12 patients with acute and convalescent Kawasaki disease were analyzed by sequencing of small RNA. This analysis revealed six microRNAs (miRs-143, -199b-5p, -618, -223, -145 and -145* (complementary strand)) whose levels were significantly elevated during the acute phase of Kawasaki disease. The result was validated using targeted qRT-PCR using an independent cohort (n = 16). miR-145, which plays a critical role in the differentiation of neutrophils and vascular smooth muscle cells, was expressed at high levels in blood samples from acute Kawasaki disease but not adenovirus-infected control patients (p = 0.005). miR-145 was also detected in small extracellular vesicles isolated from acute Kawasaki disease plasma samples. Pathway analysis of the predicted targets of the 6 differentially expressed microRNAs identified the TGF-β pathway as the top pathway regulated by microRNAs in Kawasaki disease., Conclusion: Sequencing of small RNA species allowed discovery of microRNAs that may participate in Kawasaki disease pathogenesis. miR-145 may participate, along with other differentially expressed microRNAs, in regulating expression of genes in the TGF-β pathway during the acute illness. If the predicted target genes are confirmed, our findings suggest a model of Kawasaki disease pathogenesis whereby miR-145 modulates TGF-β signaling in the arterial wall.

Background: Frameless stereotactic radiosurgery is commonly used to treat intracranial metastases, but mask-based immobilization can be uncomfortable for patients., Objective: To describe the clinical outcomes using a novel real-time, frameless, surface imaging--guided radiosurgery (SIG-RS) technique to treat brain metastases., Methods: Data were prospectively gathered for 44 consecutive patients totaling 115 intracranial metastases treated with SIG-RS in a median of 1 fraction (range, 1-5) to a median dose of 20 Gy (range, 15-30 Gy). Local control, regional control, and overall survival were estimated by the Kaplan-Meier method., Results: Median follow-up for all patients was 6.0 months (range, 0.3-21.6 months), with 31 of 44 (70%) deceased at the time of analysis. The 35 patients (80%) with follow-up imaging totaled 88 lesions evaluable for local control. Actuarial 6- and 12-month local control was 90% (95% confidence interval, 82-98) and 76% (95% confidence interval, 60-91), respectively. Regional failure was observed in 16 patients (46%). The median actuarial overall survival was 7.7 months (95% confidence interval, 5.7-9.7). Analysis of the subset of 22 patients (55 lesions) who received SIG-RS alone (no prior treatment) in a single fraction yielded comparable clinical outcomes. Grade 3 or greater toxicity occurred in 4 patients (9%). The median treatment time from beam on to beam off was 15 minutes (range, 3-36 minutes)., Conclusion: SIG-RS for treating intracranial metastases can produce clinical outcomes comparable to those with conventional frame-based and frameless stereotactic radiosurgery techniques while providing greater patient comfort with an open-faced mask and fast treatment times.

Background: Hemicraniectomy is an established neurosurgical procedure. However, before cranial vault reconstruction, it is imperative that sufficient scalp soft tissue is available for coverage of the reconstructed skull., Objective: To present 2 complex cases of posttraumatic patients requiring soft tissue expansion of the scalp before definite cranioplasty with use of a synthetic polyethylene graft., Methods: Two patients underwent decompressive hemicraniectomy for trauma and required delayed cranioplasty. Both patients had developed significant scalp contraction and presented with a paucity of soft tissue. These patients underwent a staged cranioplasty in which we first achieved scalp-tissue expansion adjacent to the craniectomy site over a prolonged interval. In a second stage, the patient underwent definite reconstructive surgery in which the subgaleal expanders were removed and polyethylene allograft cranioplasty was performed., Results: Cutaneous coverage of the underlying defect could be achieved in this setting without causing tension on the incision line secondary to the now available excess scalp tissue., Conclusion: Repair of a cranial defect requires detailed attention to the available scalp and its size relationship to the skull defect to achieve a successful outcome with an aesthetically pleasing, reliable, and lasting result. Preoperative scalp tissue expansion is a valuable step in taking care of patients presenting with scalp soft tissue defect. This technique reduces the morbidity associated with conventional rotational and free-flap techniques.

Objective: Surgical resection of skull base tumors can be associated with significant morbidity. In cases where the risks outweigh the benefits, radiation therapy can offer an alternative means to effectively control tumor growth. However, the optimal dose regime for radiation therapy remains controversial. The objective of this study was to assess the neurological outcome, local control rate and morbidity associated with a 5-fraction regime of hypofractionated stereotactic radiotherapy (HSRT) for benign skull base tumors., Methods: Twenty-six patients presenting with two of the most prevalent benign skull base tumors were included in the study. The tumors comprised 16 meningiomas and 10 acoustic neuromas. All patients exhibited preserved cranial nerve function prior to treatment, and a detailed audiological assessment was performed pre- and post-treatment for those patients with acoustic neuroma. Stereotactic radiosurgery was administered with the frameless CyberKnife Robotic Radiosurgery System. In each case, a 5-fraction HSRT regime was used: a dose of 5 Gy × 5 = 25 Gy to 6 Gy × 5 = 30 Gy was prescribed for skull base meningiomas, and 5 Gy × 5 = 25 Gy was prescribed for acoustic neuromas., Results: The clinical and radiographic median follow-up was 22 months (range: 6-54 months). Radiological assessment showed local control in all 26 tumors (100%), and in 5/26 patients (20%) the tumor showed a decrease in size. Cranial nerve function was preserved in all cases thus far studied; however, 28% of patients had transient Grade II side effects, including fatigue, headaches, unsteadiness and transient subjective worsening of hearing. In two of these patients, the period of transient worsening of hearing was associated with a temporary increase in the size of the tumor on control T2 MR images, consistent with radiation-induced edema. One patient had transient decrease in visual acuity from treatment-related edema. At the last follow-up, 3/16 patients with meningiomas (19%) and 2/10 with acoustic neuromas (20%) showed a decrease in tumor volume and improvement in hearing., Conclusion: A 5-fraction stereotactic radiotherapy regime, as used in this study, seems to be effective for local control of benign skull base tumors in this early follow-up evaluation. Neurological function preservation is excellent with this short regime in the early post-treatment period, but long-term follow-up is crucial for validation.

Background: Penetrating brain injuries caused by explosions are survived in extremely rare cases only. However, potential casualties of such cases may be encountered by regular physicians even outside a war zone, e.g., due to an assault or terror blast. There is very limited literature to this end; therefore, we report the successful neurosurgical management of a penetrating head injury due to a pipe bomb explosion., Case Description: A 19-year-old man was brought to the ER with a swollen, bleeding right orbit, and a severely injured left hand after having sustained an unwitnessed explosion from a self-made pipe bomb. He presented with a GCS (Glasgow Coma Scale) of 15 at time of admission, work-up revealed an intracranial retained metal fragment measuring 5 × 1 × 0.2 cm lodged retro-orbitally and in the skull base. The patient underwent emergent right temporal craniotomy and temporal lobectomy and simultaneous right enucleation before the petrous bone and sphenoid wing lodged metal fragment was successfully removed., Conclusion: This case underscores the importance of having a high suspicion for the presence of an intracranial injury and a retained foreign body in the setting of a penetrating head injury. Aggressive and timely workup as well as expeditious surgical management are crucial in these settings and can generate exceptionally good outcomes despite a major trauma.

The most important acute phase complication of massive cerebral infarction is cerebral herniation secondary to brain edema. In the past decade, there has been heightened interest in surgical treatment of this problem with the use of the techniques of hemicraniectomy and dural augmentation. In this article, we review the theoretical and clinical data supporting the use of hemicraniectomy in malignant cerebral infarction and the range of outcomes expected in patients who undergo this procedure.