Search

Objective: Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that allows cytoreduction of brain tumors and can be considered as an alternative to craniotomy. The authors surveyed 27 patients who underwent both craniotomy and LITT during distinct stages of their oncology journey to assess patient-reported outcomes comparing both procedures., Methods: A 9-question survey was developed and validated to assess patient-reported postoperative recovery, pain level, narcotic use, and procedure preference. The survey was administered to patients with WHO grade II-IV gliomas who underwent both craniotomy and LITT., Results: The survey was reviewed by independent surgeons, patient advocates, and patients for face validity and showed > 90% intrarater agreement over time. The cohort had a mean age of 57 ± 12 years, and 78% had glioblastoma. There was no significant difference in symptomatic improvement postcraniotomy or post-LITT (30% vs 4%, p = 0.17). Similarly, no significance was detected in patient-reported recovery time from craniotomy (time required to return to preoperative state: mean 4.3 ± 9.1 weeks, median 2 weeks) or LITT (mean 2 ± 2.3 weeks, median 1 week; p = 0.21). Notably, postsurgical pain (0-10 on the visual analog scale) and need for narcotic use in the first week (yes/no) after the procedure were significantly lower post-LITT (average visual analog scale score 1.7 vs 5 points, narcotic use 4% vs 81%; p < 0.0001 for both comparisons). When asked which procedure they would choose-having experienced both craniotomy and LITT-surveyed patients overwhelmingly chose LITT over craniotomy (89% vs 11%, p < 0.0001). Of note, the patients who preferred craniotomy experienced improved neurological function postcraniotomy or suffered new deficits post-LITT., Conclusions: In this pilot study, patients reported less pain and narcotic use post-LITT relative to craniotomy and generally preferred the former procedure if given the choice. Validation of these results in future studies can help inform decision-making in clinical scenarios where there is equipoise between LITT and craniotomy.

Objective: How maximal safe resection of glioblastoma (GBM) is implemented in the clinical setting remains understudied. Here, we utilized a survey-based approach to understand physician perspectives on this matter., Methods: Scenarios involving GBMs were presented to physicians who were asked to select from planned subtotal resection, gross total resection (GTR), medical therapy only, or palliative care. Demographic, experience, and Likert scales of value assessment were collected., Results: In the scenario involving a corpus callosum GBM, 2.33% opted for GTR. For a right frontal GBM, 91.7% opted for GTR. In contrast, only 30.8% chose GTR of a right motor strip GBM (P < 0.001). When presented with a left motor strip GBM, fewer respondents (12.7%, P < 0.001) opted for GTR. Physicians who placed a high value on preserving physical independence were more likely to forgo GTR for right motor GBMs (hazard ratio = 0.068, 95% confidence interval: 0.47-0.97, P = 0.035), and physicians who placed a high value on their faith were more likely to opt for surgical treatments that differ from the general consensus, for instance opting for GTR of the corpus callosum GBM (hazard ratio = 4.18, 95% confidence interval: 1.63-10.74, P = 0.003). No other associations were found between the choice for GTR and other variables collected., Conclusions: Our results suggest that while maximal safe resection remains a guiding principle for GBM resection, physician preference in terms of the extent of resection varies significantly as a function of tumor location and personal values., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The efficacy and safety of laser interstitial thermal therapy followed by consolidation radiosurgery (LITT-cSRS) was previously studied in brain metastasis that recurs locally after initial radiosurgery (BMRS). Here, we characterize the clinical outcome of LITT-cSRS in patients with newly diagnosed brain metastasis., Methods: Between 2017 and 2023, ten consecutive cancer patients with newly diagnosed brain mass of unclear etiology who underwent stereotactic needle biopsy (SNB) and LITT in the same setting followed by consolidation SRS (cSRS) with > 6 months follow-up were identified retrospectively. Clinical and imaging outcomes were collected., Results: The histology of the BM were: breast cancer (n = 3), melanoma (n = 3), non-cell cell lung cancer (n = 3), colon (n = 1). There were no wound or procedural complications. All patients were discharged home, with a median one-day hospital stay (range: 1-2 days). All patients were off corticosteroid therapy by the one-month follow-up. cSRS were carried out 12-27 days (median of 19 days) after SNB + LITT. There were no subsequent emergency room presentation, 30-day or 90-day re-admission. The Karnofsky Performance Score (KPS) remains stable or improved at the 3 months-follow-up. With a median follow-up of 416 days (13.8 mo; range: 199-1,096 days), there was one local recurrence at 384 days (12.8 mo) post-LITT-cSRS. With exception of this patient with local recurrence, all patients showed decreased FLAIR volume surrounding the LITT-cSRS treated BMRS by the six-month follow-up., Conclusions: To our awareness, this case series represent the first to describe LITT-cSRS in the setting of newly diagnosed BM. The results presented here provide pilot data to support the safety and efficacy of LITT-cSRS and lay the foundation for future studies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: GammaTile® (GT) is a brachytherapy platform that received Federal Drug Administration (FDA) approval as brain tumor therapy in late 2018. Here, we reviewed our institutional experience with GT as treatment for recurrent glioblastomas and characterized dosimetric parameter and associated clinical outcome., Methods and Materials: A total of 20 consecutive patients with 21 (n = 21) diagnosis of recurrent glioblastoma underwent resection followed by intraoperative GT implant between 01/2019 and 12/2020. Data on gross tumor volume (GTV), number of GT units implanted, dose coverage for the high-risk clinical target volume (HR-CTV), measured by D 90 or dose received by 90% of the HR-CTV, dose to organs at risk, and six months local control were collected., Results: The median D 90 to HR-CTV was 56.0 Gy (31.7-98.7 Gy). The brainstem, optic chiasm, ipsilateral optic nerve, and ipsilateral hippocampus median D max were 11.2, 5.4, 6.4, and 10.0 Gy, respectively. None of the patients in this study cohort suffered from radiation necrosis or adverse events attributable to the GT. Correlation was found between pre-op GTV, the volume of the resection cavity, and the number of GT units implanted. Of the resection cavities, 7/21 (33%) of the cavity experienced shrinkage, 3/21 (14%) remained stable, and 11/21 (52%) of the cavities expanded on the 3-months post-resection/GT implant MRIs. D 90 to HR-CTV was found to be associated with local recurrence at 6-month post GT implant, suggesting a dose response relationship (p = 0.026). The median local recurrence-free survival was 366.5 days (64-1,098 days), and a trend towards improved local recurrence-free survival was seen in patients with D 90 to HR-CTV ≥ 56 Gy (p = 0.048)., Conclusions: Our pilot, institutional experience provides clinical outcome, dosimetric considerations, and offer technical guidance in the clinical implementation of GT brachytherapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Background: With continued evolution in stereotactic techniques and an expanding armamentarium of surgical therapeutic options, non-craniotomy stereotactic procedures in neuro-oncology are becoming increasingly complex, often requiring multi-trajectory approaches. Here we demonstrate that the ClearPoint SmartFrame Array (Solana Beach, California, USA), a second-generation magnetic resonance imaging-compatible stereotactic frame, supports such non-craniotomy, multi-trajectory (NCMT) stereotactic procedures., Methods: We previously published case reports demonstrating the feasibility of NCMT through the ClearPoint SmartFrame Array. Here we prospectively followed the next 10 consecutive patients who underwent such multi-trajectory procedures to further establish procedural safety and clinical utility., Results: Ten patients underwent complex, multi-trajectory stereotactic procedures, including combinations of needle biopsy ± cyst drainage and laser interstitial thermal therapy targeting geographically distinct regions of neoplastic lesions under the same anesthetic event. The median maximal radial error of stereotaxis was 1.0 mm. In all cases, definitive diagnosis was achieved, and >90% of the intended targets were ablated. The average stereotaxis time for the multi-trajectory procedure was 119 ± 22.2 minutes, comparing favorably to our previously published results of single-trajectory procedures (80 ± 9.59 minutes, P = 0.125). There were no procedural complications. Post-procedure, the neurologic condition of 1 patient improved, while the remaining 9 patients remained stable. All patients were discharged home, with a median hospital stay of 1 day (range: 1-12 days). With a median follow-up of 376 days (range: 155-1438 days), there were no 30-day readmissions or wound complications., Conclusions: Geographically distinct regions of brain cancer can be safely and accurately accessed through the ClearPoint Array frame in NCMT stereotactic procedures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Radiation plays a central role in glioblastoma treatment. Logistics related to coordinating clinic visits, radiation planning, and surgical recovery necessitate delay in radiation delivery from the time of diagnosis. Unimpeded tumor growth occurs during this period, and is associated with poor clinical outcome. Here we provide a pilot experience of GammaTile ® (GT), a collagen tile-embedded Cesium-131 ( 131 Cs) brachytherapy platform for such aggressive tumors., Methods: We prospectively followed seven consecutive patients (2019-2023) with newly diagnosed (n = 3) or recurrent (n = 4) isocitrate dehydrogenase wild-type glioblastoma that grew > 100% in volume during the 30 days between the time of initial diagnosis/surgery and the radiation planning MRI. These patients underwent re-resection followed by GT placement., Results: There were no surgical complications. One patient developed right hemiparesis prior to re-resection/GT placement and was discharged to rehabilitation, all others were discharged home-with a median hospital stay of 2 days (range: 1-5 days). There was no 30-day mortality and one 30-day readmission (hydrocephalus, requiring ventriculoperitoneal shunting (14%)). With a median follow-up of 347 days (11.6 months), median progression free survival of ≥ 320 days (10.6 months) was achieved for both newly and recurrent glioblastoma patients. The median overall survival (mOS) was 304 and 347 days (10 and 11.5 mo) for recurrent and newly diagnosed glioblastoma patients, respectively., Conclusion: Our pilot experience suggests that GT offers favorable local control and safety profile for patients afflicted with rapidly proliferating glioblastomas and lay the foundation for future clinical trial design., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: While postoperative resection cavity radiosurgery (post-SRS) is an accepted treatment paradigm for brain metastasis (BM) patients who undergo surgical resection, there is emerging interest in preoperative radiosurgery (pre-SRS) followed by surgical resection as an alternative treatment paradigm. Here, we performed a meta-analysis of the available literature on this matter., Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of all studies evaluating pre-SRS and post-SRS was completed. Local recurrence (LR), overall survival (OS), radiation necrosis (RN), and leptomeningeal disease (LMD) were evaluated from the available data. Moderator analysis and pooled effect sizes were performed using a proportional meta-analysis with R using the metafor package. Statistics are presented as mean [95% confidence interval]., Results: We identified 6 pre-SRS and 33 post-SRS studies with comparable tumor volume (4.5-17.6 cm 3 ). There were significant differences in the pooled estimates of LR and LMD, favoring pre-SRS over post-SRS. Pooled aggregate for LR was 11.0% [4.9-13.7] and 17.5% [15.1-19.9] for pre- and post-SRS studies (P = 0.014). Similarly, pooled estimates of LMD favored pre-SRS, 4.4% [2.6-6.2], relative to post-SRS, 12.3% [8.9-15.7] (P = 0.019). In contrast, no significant differences were found in terms of RN and OS. Pooled estimates for RN were 6.4% [3.1-9.6] and 8.9% [6.3-11.6] for pre- and post-SRS studies (P = 0.393), respectively. Pooled estimates for OS were 60.2% [55.8-64.6] and 60.5% [56.9-64.0] for pre- and post-SRS studies (P = 0.974)., Conclusions: This meta-analysis supports further exploration of pre-SRS as a strategy for the treatment of BM., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic radiosurgery (SRS) to the resection cavity is essential in the treatment of brain metastasis (BM) amenable to surgical resection. The two most common platforms for SRS delivery include Gamma Knife (GK) and LINAC. Here we collated the available peer-reviewed literature and performed a meta-analysis on clinical outcomes after GK or LINAC resection cavity SRS., Methods: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include all studies evaluating each post-operative SRS modality. Local control, overall survival, radiation necrosis, and leptomeningeal disease were evaluated from the available data. A proportional meta-analysis was performed via R using the metafor package to pool the outcomes of studies and a moderator effect to assess the significance between groups., Results: We identified 21 GK studies (n = 2009) and 28 LINAC studies (n = 2219). The radiosurgery doses employed were comparable between GK and LINAC studies. The pooled estimate of 1-year local control, 1-year overall survival, and risk of leptomeningeal disease were statistically comparable between GK and LINAC (81.7 v 85.8%; 61.4 v 62.7%; 10.6 v 12.5%, respectively). However, the risk of radiation necrosis (RN) was higher for LINAC resection cavity SRS (5.4% vs. 10%, p = 0.036). The volume of the resection cavity was a significant modifying factor for RN in both modalities (p = 0.007) with a 0.5% and 0.7% increase in RN risk with every 1 cm 3 increase in tumor volume for GK and LINAC, respectively., Conclusions: Our meta-analysis suggests that GK and LINAC SRS of resection cavity achieve comparable 1-year local control and survival. However, resection cavity treated with GK SRS was associated with lowered RN risk relative to those treated with LINAC SRS., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Although tractography-guided surgery is used by many surgeons, there is controversy in the published literature as it relates to its clinical utility. Here we adopted a survey-based approach with the goal of attaining a broader view of how tractography influence preoperative planning in a sampling of practicing neurosurgeons., Methods: Three cases were prepared where the presence of a tumor distorted the optic radiation (case 1), arcuate fasciculus (case 2), and corticospinal tract (case 3). This survey was administered at the Medtronic Cranial Consortium attended by 20 practicing neurosurgeons. To avoid commercial bias, we used both the Brainlab and Medtronic platform to compute tractography. Each participant is asked to vote on a surgical trajectory before and after seeing the tractography images, as well as whether tractography added value in validating their surgical approach., Results: In the 3 cases surveyed, 16%-44% of the surgeons changed the surgical corridor selected after seeing the tractography images. The most common finding associated with a change in surgical corridor involved intersection of the surgical corridor with visualized tracts. Consistently, >80% of the surgeons surveyed felt that tractography added value in their surgical planning., Conclusions: The clinical utility of tractography in preoperative planning varies as a function of surgeon and the tumor anatomy, with >80% of the participating surgeons believing that tractography added value in preoperative surgical planning., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Cerebral atrophy with leukoencephalopathy is a known morbidity after whole brain radiation therapy (WBRT), resulting in ex-vacuo ventriculomegaly with leukoencephalopathy (EVL). Here we studied the correlation between WBRT, stereotactic radiosurgery (SRS), and risk for EVL in brain metastases patients., Methods: In a retrospective study, we identified 195 patients (with 1,018 BM) who underwent SRS for BM (2007-2017) and had > 3 months of MRI follow-up. All patients who underwent ventriculoperitoneal shunting were excluded. Cerebral atrophy was measured by ex-vacuo-ventriculomegaly, defined based on Evans' criteria. Demographic and clinical variables were analyzed using logistic regression models., Results: Ex-vacuo ventriculomegaly was observed on pre-radiosurgery imaging in 29.7% (58/195) of the study cohort. On multivariate analysis, older age was the only variable associated with pre-radiosurgery ventriculomegaly. Of the 137 patients with normal ventricular size before radiosurgery, 27 (19.7 %) developed ex-vacuo ventriculomegaly and leukoencephalopathy (EVL) post-SRS. In univariate analysis, previous whole brain radiation therapy was the main factor associated with increased risk for developing EVL (OR = 5.08, p < 0.001). In bivariate models that included prior receipt of WBRT, both the number of SRS treatments (OR = 1.499, p = 0.025) and WBRT (OR = 11.321, p = 0.003 were independently associated with increased EVL risk., Conclusions: While repeat radiosurgery contributes to the risk of EVL in BM patients, this risk is ∼20-fold lower than that associated with WBRT., 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 © 2023 Elsevier Ltd. All rights reserved.)

In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

Objective and Methods: We conducted a retrospective review of the first 30 patients treated with stereotactic laser ablation (SLA) at our institution since the introduction of the technique in September 2019. We aimed to analyze our initial results and potential learning curve by investigating precision and lesion coverage and assessing the frequency and nature of adverse events according to the Landriel-Ibanez classification for neurosurgical complications., Results: Indications were de novo gliomas (23%), recurrent gliomas (57%), and epileptogenic foci (20%). There was a trend toward improvement of lesion coverage and target deviation, and a statistically significant improvement in entry point deviation, over time. Four patients (13.3%) experienced a new neurological deficit, where three patients had transient and one patient had permanent deficits, respectively. Our results show a learning curve on precision measures over the first 30 cases. Based on our results the technique can safely be implemented at centers with experience in stereotaxy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Tissue diagnosis through stereotactic needle biopsy (SNB) is often needed prior to laser interstitial thermal therapy (LITT). Whether these procedures should be performed in the same surgery or in separate settings remain unclear. As a first step to address this question, we assess safety profile of procedures involving LITT alone versus SNB + LITT., Methods: Using International Classification of Disease (ICD) codes, we queried the National Readmissions Database (NRD, 2010-2018) for malignant brain tumor patients who underwent either (1) LITT alone or (2) elective LITT in combination with SNB (SNB + LITT). Survey regression methods were utilized. Additionally, the procedural outcome of LITT or SNB + LITT performed by the senior surgeon (2014-2022) were reviewed., Results: During the study period, an estimated 678 malignant brain tumor patients underwent LITT alone versus 373 patients that underwent SNB + LITT. Patients undergoing LITT and SNB + LITT exhibited statistically comparable median lengths of hospital stay (IQR; LITT = 2 day [1, 3]; SNB + LITT = 1 day [1, 3]; p = 0.405) and likelihood of routine discharge (LITT = 73.5%; SNB + LITT = 81.1%; p = 0.068). The odds of 30-day medical or neurological readmissions were comparable between LITT and SNB + LITT treated patients (all p ≥ 0.793). In the single surgeon experience of 218 procedures performed over an eight year period (2014-2022), the complications (LITT = 3.9%; SNB + LITT = 2.6%, p = 0.709), discharge within 48 h (LITT = 84.5%; SNB + LITT = 87.8%; p = 0.556), routine discharge (LITT = 91.3%; SNB + LITT = 93.9%; p = 0.604), and unplanned 30-day readmission (LITT = 3.9%; SNB + LITT = 1.7%; p = 0.423) were similarly comparable between LITT and SNB + LITT., Conclusion: The length of hospital stay, the likelihood of routine discharge, and 30-day readmission for malignant brain tumor patients who underwent LITT and SNB + LITT were comparable., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Among children and adolescents in the United States (0 to 19 years old), brain and other central nervous system tumors are the second most common types of cancers, surpassed in incidence only by leukemias. Despite significant progress in the diagnosis and treatment modalities, brain cancer remains the leading cause of death in the pediatric population. There is an obvious unfulfilled need to streamline the therapeutic strategies and improve survival for these patients. For that purpose, preclinical models play a pivotal role. Numerous models are currently used in pediatric brain tumor research, including genetically engineered mouse models, patient-derived xenografts and cell lines, and newer models that utilize novel technologies such as genome engineering and organoids. Furthermore, extensive studies by the Children's Brain Tumor Network (CBTN) researchers and others have revealed multiomic landscapes of variable pediatric brain tumors. Combined with such integrative data, these novel technologies have enabled numerous applicable models. Genome engineering, including CRISPR/Cas9, expanded the flexibility of modeling. Models generated through genome engineering enabled studying particular genetic alterations in clean isogenic backgrounds, facilitating the dissection of functional mechanisms of those mutations in tumor biology. Organoids have been applied to study tumor-to-tumor-microenvironment interactions and to address developmental aspects of tumorigenesis, which is essential in some pediatric brain tumors. Other modalities, such as humanized mouse models, could potentially be applied to pediatric brain tumors. In addition to current valuable models, such novel models are anticipated to expedite functional tumor biology study and establish effective therapeutics for pediatric brain tumors., Competing Interests: Declaration of Competing Interests 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 © 2022. Published by Elsevier Inc.)

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: Intraoperative magnetic resonance imaging (iMRI) is a useful adjunct for resection of primary malignant brain tumors (MBTs). The aim of our study is to investigate the impact of iMRI on health care utilization in patients who underwent craniotomy for resection of MBTs., Materials and Methods: MarketScan database were queried using the ICD-9/10 and CPT 4th edition, from 2008 to 2020. We included patients ≥ 18 years of age who underwent a craniotomy with at-least one year follow-up. Outcomes were length of stay (LOS), discharge disposition, hospital/emergency room (ER) re-admissions, outpatient services, medication refills and corresponding payments., Results: Of 6,640 patients who underwent craniotomy for MBTs, 465 patients (7%) had iMRI used during the procedure with 0.7% per year increase in iMRI use during the study period. Patients without iMRI use had higher complications at index hospitalization compared to those with iMRI use (19% vs. 14%, p = 0.04). There was no difference in the ER admission rates among the patients who underwent surgery with and without iMRI use at 6-months and 1-year after the index procedure. In terms of post-discharge payments, no significant differences were noted among the patients without and with iMRI use at 6-months ($81,107 vs. $ 81,458, p = 0.26) and 1-year ($132,657 vs. $ 118,113, p = 0.12)., Conclusion: iMRI use during craniotomy for MBT gradually increased during the study period. iMRI did not result in higher payments at index hospitalization, 6-months, and 1-year after the index procedure., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Pediatric posterior fossa tumors often present with hydrocephalus; postoperatively, up to 25% of patients develop cerebellar mutism syndrome. Arterial spin-labeling is a noninvasive means of quantifying CBF and bolus arrival time. The aim of this study was to investigate how changes in perfusion metrics in children with posterior fossa tumors are modulated by cerebellar mutism syndrome and hydrocephalus requiring pre-resection CSF diversion., Materials and Methods: Forty-four patients were prospectively scanned at 3 time points (preoperatively, postoperatively, and at 3-month follow-up) with single- and multi-inflow time arterial spin-labeling sequences. Regional analyses of CBF and bolus arrival time were conducted using coregistered anatomic parcellations. ANOVA and multivariable, linear mixed-effects modeling analysis approaches were used. The study was registered at clinicaltrials.gov (NCT03471026)., Results: CBF increased after tumor resection and at follow-up scanning ( P = .045). Bolus arrival time decreased after tumor resection and at follow-up scanning ( P = .018). Bolus arrival time was prolonged ( P = .058) following the midline approach, compared with cerebellar hemispheric surgical approaches to posterior fossa tumors. Multivariable linear mixed-effects modeling showed that regional perfusion changes were more pronounced in the 6 children who presented with symptomatic obstructive hydrocephalus requiring pre-resection CSF diversion, with hydrocephalus lowering the baseline mean CBF by 20.5 (standard error, 6.27) mL/100g/min. Children diagnosed with cerebellar mutism syndrome (8/44, 18.2%) had significantly higher CBF at follow-up imaging than those who were not ( P = .040), but no differences in pre- or postoperative perfusion parameters were seen., Conclusions: Multi-inflow time arterial spin-labeling shows promise as a noninvasive tool to evaluate cerebral perfusion in the setting of pediatric obstructive hydrocephalus and demonstrates increased CBF following resolution of cerebellar mutism syndrome., (© 2022 by American Journal of Neuroradiology.)

Purpose: Despite procedural similarities between laser interstitial thermal therapy (LITT) and stereotactic needle biopsy (SNB), LITT induces delayed, pro-inflammatory responses not associated with SNB that may increase the risk of readmission within 30- or 90- days. Here, we explore this hypothesis., Methods: We queried the National Readmissions Database (NRD, 2010-18) for malignant brain tumor patients who underwent elective LITT or SNB using International Classification of Diseases codes. Readmissions were defined as non-elective inpatient hospitalizations. Survey regression methods and a weighted analysis were utilized to adjust for demographic and clinical differences between LITT and SNB cohorts., Results: During the study period, an estimated 685 malignant brain patients underwent elective LITT and 15,177 underwent elective SNB. Patients undergoing LITT and SNB exhibited comparable median lengths of hospital stay [IQR; LITT = 2 (1, 3); SNB = 1 (1, 2); p = 0.820]. Likelihood of routine discharge was not significantly different between the two procedures (p = 0.263). No significant differences were observed in the odds of 30- or 90-day unplanned readmission between the LITT and SNB cohorts after multivariable adjustment (all p ≥ 0.177). The covariate balancing weighted analysis confirmed comparable 30 or 90-day readmission risk between LITT and SNB treated patients (all p ≥ 0.201)., Conclusion: The likelihood of 30- and 90-day readmission for malignant brain tumor patients who underwent LITT or SNB are comparable, supporting the safety profile of LITT as therapy for malignant brain cancers., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastoma multiforme (GBM) is among the most aggressive, treatment-resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8 + T cells expressing tissue-resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific memory T cells through intratumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to antineoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific memory T cells are a significant part of the glioblastoma immune microenvironment and may be leveraged to promote anti-tumoral immunity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glioblastoma is the most common malignant brain cancer with dismal survival and prognosis. Temozolomide (TMZ) is a first-line chemotherapeutic agent for glioblastoma, but the emergence of drug resistance limits its anti-tumor activity. We previously discovered that the interferon inducible guanylate binding protein 3 (GBP3) is highly elevated and promotes tumorigenicity of glioblastoma. Here, we show that TMZ treatment significantly upregulates the expression of GBP3 and stimulator of interferon genes (STING), both of which increase TMZ-induced DNA damage repair and reduce cell apoptosis of glioblastoma cells. Mechanistically, relying on its N-terminal GTPase domain, GBP3 physically interacts with STING to stabilize STING protein levels, which in turn induces expression of p62 (Sequestosome 1), nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and O6-methlyguanine-DNA-methyltransferase (MGMT), leading to the resistance to TMZ treatment. Reducing GBP3 levels by RNA interference in glioblastoma cells markedly increases the sensitivity to TMZ treatment in vitro and in murine glioblastoma models. Clinically, GBP3 expression is high and positively correlated with STING, NRF2, p62, and MGMT expression in human glioblastoma tumors, and is associated with poor outcomes. These findings provide novel insight into TMZ resistance and suggest that GBP3 may represent a novel potential target for the treatment of glioblastoma., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The ClearPoint SmartFrame Array (ClearPoint Neuro, Inc., Solana Beach, CA) system consists of a magnetic resonance imaging compatible frame supported by a customized neuro navigation software. This system received U.S. Food and Drug Administrationclearance for clinical use in January 2021. Our objective was to report initial safety data and user experience of SmartFrame Array-supported stereotactic procedures., Methods: We prospectively followed the first 10 consecutive patients who underwent stereotactic procedures supported by SmartFrame Array. Clinical and procedural data were recorded and compared to data obtained from prior cases with SmartFrame XG., Results: Ten patients underwent stereotactic needle biopsy, stereotactic laser ablation (SLA), or combined biopsy/SLA procedures. For needle biopsies (n = 9), the average maximal diameter of the contrast-enhancing target lesion was 9.9 ± 2.8 mm. The radial error of stereotaxis was less than 2 mm. Definitive diagnosis was achieved in all cases. For procedures involving SLA (n = 5), 100% of the contrast-enhancing lesion was ablated. All patients were discharged home by postoperative day 2. There were no 30-day readmissions, morbidity, or mortality. The average stereotaxis time for the SmartFrame Array-aided single trajectory procedure was 80 ± 9.5 minutes, which compared favorably to that required for the earlier generation SmartFrame XG frame (111.5 ± 16.5 minutes; P < 0.01). The unique Array design supported stereotactic procedures that cannot be easily achieved with the previous SmartFrame XG frame., Conclusions: The SmartFrame Array system offers a more rigid and compact build to enhance procedural efficiency while maintaining accuracy and safety. The design supports multi-trajectory stereotaxis, allowing novel clinical applications., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The optimal treatment paradigm for brain metastasis that recurs locally after initial radiosurgery remains an area of active investigation. Here, we report outcomes for patients with BMRS treated with stereotactic laser ablation (SLA, also known as laser interstitial thermal therapy, LITT) followed by consolidation radiosurgery., Methods: Clinical outcomes of 20 patients with 21 histologically confirmed BMRS treated with SLA followed by consolidation SRS and > 6 months follow-up were collected retrospectively across three participating institutions., Results: Consolidation SRS (5 Gy × 5 or 6 Gy × 5) was carried out 16-73 days (median of 26 days) post-SLA in patients with BMRS. There were no new neurological deficits after SLA/cSRS. While 3/21 (14.3%) patients suffered temporary Karnofsky Performance Score (KPS) decline after SLA, no KPS decline was observed after cSRS. There were no 30-day mortalities or wound complications. Two patients required re-admission within 30 days of cSRS (severe headache that resolved with steroid therapy (n = 1) and new onset seizure (n = 1)). With a median follow-up of 228 days (range: 178-1367 days), the local control rate at 6 and 12 months (LC 6 , LC 12 ) was 100%. All showed diminished FLAIR volume surrounding the SLA/cSRS treated BMRS at the six-month follow-up; none of the patients required steroid for symptoms attributable to these BMRS. These results compare favorably to the available literature for repeat SRS or SLA-only treatment of BMRS., Conclusions: This multi-institutional experience supports further investigations of SLA/cSRS as a treatment strategy for BMRS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Stereotactic needle biopsy remains the cornerstone for tissue diagnosis for tumors located in regions of the brain that are difficult to access through open surgery., Objective: We perform a meta-analysis of the literature to examine the relation between number of samples taken during biopsy and diagnostic yield, morbidity and mortality., Methods: We identified 2416 patients from 28 cohorts in studies published in PubMed database that studied stereotactic needle biopsies for tumor indications. Meta-analysis by proportions and meta-regression analyses were performed., Results: On meta-analysis, the morbidity profile of the published needle biopsy studies clustered into three groups: studies that performed < 3 samples (n = 8), 3-6 samples (n = 13), and > 6 samples during biopsy (n = 7). Pooled estimates for biopsy related morbidity were 4.3%, 16.3%, and 17% for studies reporting < 3, 3-6, and > 6 biopsy samples, respectively. While these morbidity estimates significantly differed (p < 0.001), the diagnostic yields reported for studies performing < 3 biopsies, 3-6 samples, and > 6 samples were comparable. Pooled estimates of diagnostic yield for these three groups were 90.4%, 93.8%, and 88.1%, respectively. Mortality did not significantly differ between studies reporting differing number of samples taken during biopsy., Conclusions: Our meta-analysis suggests that morbidity risk in needle biopsy is non-linearly associated with the number of samples taken. There was no association between the number of biopsies taken, and diagnostic yield or mortality., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The rarity of Isocitrate Dehydrogenase mutated (mIDH) glioblastomas relative to wild-type IDH glioblastomas, as well as their distinct tumor physiology, effectively render them "outliers". Specialized tools are needed to identify these outliers., Objective: To carefully craft and apply anomaly detection methods to identify mIDH glioblastoma based on radiomic features derived from magnetic resonance imaging., Methods: T1-post gadolinium images for 188 patients and 138 patients were downloaded from The Cancer Imaging Archive's (TCIA) The Cancer Genome Atlas (TCGA) glioblastoma collection, and from the University of Minnesota Medical Center (UMMC), respectively. Anomaly detection methods were tested on glioblastoma image features for the precision of mIDH detection and compared to standard classification methods., Results: Using anomaly detection training methods, we were able to detect IDH mutations from features in noncontrast-enhancing regions in glioblastoma with an average precision of 75.0%, 69.9%, and 69.8% using three different models. Anomaly detection methods consistently outperformed traditional two-class classification methods from 2 unique learning models (67.9%, 67.6%). The disparity in performances could not be overcome through newer, popular models such as neural networks (67.4%)., Conclusion: We employed an anomaly detection strategy in the detection of IDH mutation in glioblastoma using preoperative T1 postcontrast imaging. We show these methods outperform traditional two-class classification in the setting of dataset imbalances inherent to IDH mutation prevalence in glioblastoma. We validate our results using an external dataset and highlight new possible avenues for radiogenomic rare event prediction in glioblastoma and beyond., (© Congress of Neurological Surgeons 2021.)

Radiomics is an emerging discipline that aims to make intelligent predictions and derive medical insights based on quantitative features extracted from medical images as a means to improve clinical diagnosis or outcome. Pertaining to glioblastoma, radiomics has provided powerful, noninvasive tools for gaining insights into pathogenesis and therapeutic responses. Radiomic studies have yielded meaningful biological understandings of imaging features that are often taken for granted in clinical medicine, including contrast enhancement on glioblastoma magnetic resonance imaging, the distance of a tumor from the subventricular zone, and the extent of mass effect. They have also laid the groundwork for noninvasive detection of mutations and epigenetic events that influence clinical outcomes such as isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT). In this article, we review advances in the field of glioblastoma radiomics as they pertain to prediction of IDH mutation status and MGMT promoter methylation status, as well as the development of novel, higher order radiomic parameters., (© Congress of Neurological Surgeons 2021.)

Glioblastoma multiforme (GBM) is a primary brain tumor with a high mortality rate and a median survival time of ~14 months from the initial diagnosis. Although progress has been made in the currently available therapies, the treatment of GBM remains palliative. GBM contains subsets of GBM stem cells (GSCs) that share numerous neural stem/progenitor cell characteristics, such as expression of stem cell markers, self‑renewal and multi‑lineage differentiation capacity, thus contributing to the heterogeneity and complexity of these tumors. GSCs are potentially associated with tumor initiation and they are considered as the driving force behind tumor formation, as they possess tumor‑propagating potential and exhibit preferential resistance to radiotherapy and chemotherapy. Targeting self‑renewal signaling pathways in cancer stem cells may effectively reduce tumor recurrence and significantly improve prognosis. The aim of the present review was to summarize the current knowledge on the self‑renewal signaling pathways of GSCs and discuss potential future targeting strategies for the design of differentiation therapies.

Purpose: Understanding factors that influence technology diffusion is central to clinical translation of novel therapies. We characterized the pattern of adoption for laser interstitial thermal therapy (LITT), also known as stereotactic laser ablation (SLA), in neuro-oncology using the National Inpatient Sample (NIS) database., Methods: We identified patients age ≥ 18 in the NIS (2012-2018) with a diagnosis of primary or metastatic brain tumor that underwent LITT or craniotomy. We compared characteristics and outcomes for patients that underwent these procedures., Results: LITT utilization increased ~ 400% relative to craniotomy during the study period. Despite this increase, the total number of LITT procedures performed for brain tumor was < 1% of craniotomy. After adjusting for this time trend, LITT patients were less likely to have > 2 comorbidities (OR 0.64, CI 95 0.51-0.79) or to be older (OR 0.92, CI 95 0.86-0.99) and more likely to be female (OR 1.35, CI 95 1.08-1.69), Caucasian compared to Black (OR 1.94, CI 95 1.12-3.36), and covered by private insurance compared to Medicare or Medicaid (OR 1.38, CI 95 1.09-1.74). LITT hospital stays were 50% shorter than craniotomy (IRR 0.52, CI 95 0.45-0.61). However, charges related to the procedures were comparable between LITT and craniotomy ($1397 greater for LITT, CI 95 $-5790 to $8584)., Conclusion: For neuro-oncology indications, LITT utilization increased ~ 400% relative to craniotomy. Relative to craniotomy-treated patients, LITT-treated patients were likelier to be young, female, non-Black race, covered by private insurance, or with < 2 comorbidities. While the total hospital charges were comparable, LITT was associated with a shorter hospitalization relative to craniotomy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.

Background: There are ongoing clinical trials exploring the efficacy of dopamine receptor D2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy., Methods: The Cancer Genome Atlas glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and epidermal growth factor receptor (EGFR) expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient-derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201., Results: Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD2 mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, variant (v)III, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (0.037)., Conclusions: High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs., (© The Author(s) 2020. 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.)

Guanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P < 0.001). A cut off value for mean ADC between Ependymomas and Medulloblastomas was found to be of 0.984 × 10 -3 mm 2  s -1 with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.

Background: Balloon test occlusion is a widely used method for predicting tolerance of vessel occlusion in the treatment of aneurysms, fistulae, and head and neck neoplasms. However, the false-negative rate is variably reported due in part to the diversity of perfusion monitoring methods., Objective: To evaluate the rate of symptomatic ischemic events after a negative balloon test occlusion and determine whether perfusion monitoring methods contribute to differences in these rates., Methods: PubMed was systematically searched for studies between 1990 and 2020 that reported rates of ischemic outcomes of parental vessel occlusion in patients who passed balloon test occlusion. A generalized linear mixed model meta-analysis was performed. Results were expressed as the rate of symptomatic ischemic events after parental vessel occlusion without vessel bypass in patients who passed balloon test occlusion., Results: Thirty-two studies met the inclusion criteria. The overall pooled rate of ischemic events after passing balloon test occlusion was 3.7% (95% confidence interval [CI]: 1.7-7.8). This rate was 3.8% (95% CI: 1.1-12.8) when monitored with angiography, 2.2% (95% CI: 0.4-10.2) when monitored by a form of computed tomography, and 5.3% (95% CI: 1.2-20.4) when monitored by 2 or more methods of perfusion assessment. The complication rate of balloon test occlusion was 0.8% (95% CI: 0.2-2.7)., Conclusions: Balloon test occlusion results in a low rate of subsequent ischemic events, without conclusive evidence of variation between methods of perfusion assessment. The choice of method should focus on reduction of complication risk, experience of the interventional team, and avoidance of prolonged test occlusion times., (Copyright © 2020 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.

Symptomatic epilepsy is frequently encountered in patients with brain metastases (BM), affecting up to 25% of them. However, it generally remains unknown whether the risk of seizures in such cases is affected by stereotactic radiosurgery (SRS), which involves highly conformal delivery of high-dose irradiation to the tumor with a minimal effect on adjacent brain tissue. Thus, the role of prophylactic administration of antiepileptic drugs (AED) after SRS remains controversial. A comprehensive review and analysis of the available literature reveals that according to prospective studies, the incidence of seizures after SRS for BM varies from 8% to 22%, and there is no evidence that SRS increases the incidence of symptomatic epilepsy. Therefore, routine prophylactic administration of AED prior to, during, or after SRS in the absence of a seizure history is not recommended. Nevertheless, short-course administration of an AED may be judiciously considered (on the basis of class III evidence) for selected high-risk individuals.

The four-and-a-half LIM domain protein 1 (FHL1) plays a key role in multiple cancers. Here, we characterized its role in glioblastoma (GBM), the most common and incurable form of brain cancer. Overexpression of FHL1 promotes growth, migration, and invasion of GBM cells in vivo and in vitro. In contrast, FHL1 silencing by RNAi exhibits the opposite effects. FHL1 interacts with the transcription factor SP1 to upregulate epidermal growth factor receptor (EGFR) expression and activate the downstream signaling cascades, including Src, Akt, Erk1/2, and Stat3, leading to GBM malignancy. FHL1 is highly expressed and positively correlated with EGFR levels in human GBM, particularly those of the classical subtype. Our results suggest that the FHL1-SP1-EGFR axis plays a tumor-promoting role, and highlight the translational potential of inhibiting FHL1 for GBM treatment., (© 2020 Federation of European Biochemical Societies.)

Approximately 25-35% of all cancer patients suffer from brain metastases (BM), and many of them-in particular, those with a limited number of intracranial tumors-are treated with stereotactic radiosurgery (SRS). Accurate prediction of survival remains a key clinical challenge in this population. Several prognostic scales have been developed to facilitate this prognostication, including the Recursive Partitioning Analysis (RPA) classification, the modified Recursive Partitioning Analysis (mRPA) subclassifications, the Basic Score for Brain Metastases (BS-BM), the Score Index for Radiosurgery (SIR), the Graded Prognostic Assessment (GPA), and the diagnosis-specific Graded Prognostic Assessment (dsGPA). However, none of these scales include consideration of the cumulative intracranial tumor volume (CITV), which is defined as the sum of all intracranial tumor volumes. Since there is mounting evidence that the CITV carries significant prognostic value in SRS-treated patients with BM, this variable should be considered during survival prognostication, along with other pertinent clinical, pathological, and molecular characteristics.

Importance: New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma., Objective: To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC)., Design, Setting, and Participants: A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma., Interventions: Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab., Main Outcomes and Measures: The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS., Results: All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group., Conclusions and Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points., Trial Registration: ClinicalTrials.gov Identifier: NCT02414165.

Glioblastoma is the most common primary malignant neoplasm of the central nervous system in adults. Standard of care is resection followed by chemo-radiation therapy. Despite this aggressive approach, >80% of glioblastomas recur in proximity to the resection cavity. Brachytherapy is an attractive strategy for improving local control. GammaTile ® is a newly US FDA-cleared device which incorporates 131 Cs radiation emitting seeds in a resorbable collagen-based carrier tile for surgically targeted radiation therapy to achieve highly conformal radiation at the time of surgery. Embedding encapsulated 131 Cs radiation emitter seeds in collagen-based tiles significantly lowers the technical barriers associated with traditional brachytherapy. In this review, we highlight the potential of surgically targeted radiation therapy and the currently available data for this novel approach.

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.)

Genome engineering using programmable nucleases such as transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeat-associated protein nine facilitated the introduction of genetic alterations at specific genomic sites in various cell types. These tools have been applied to cancer modeling to understand the pathogenic effects of the growing catalog of mutations found in human cancers. Pertaining to brain tumors, neural progenitor cells derived from human induced pluripotent stem cells (iPSCs) engineered with different combinations of genetic driver mutations observed in distinct molecular subtypes of glioblastomas, the most common form of primary brain cancer in adults, give rise to brain tumors when engrafted orthotopically in mice. These glioblastoma models recapitulate the transcriptomic signature of each molecular subtype and authentically resemble pathobiology of glioblastoma, including inter- and intra-tumor heterogeneity, chromosomal aberrations, and extrachromosomal DNA amplifications. Similar engineering with genetic mutations found in medulloblastoma and atypical teratoid rhabdoid tumors in iPSCs have led to genetically trackable models that bear clinical relevance to these pediatric brain tumors. These models have contributed to improved comprehension of the genetic causation of tumorigenesis and offered a novel platform for therapeutic discovery. Studied in the context of three-dimensional cerebral organoids, these models have aided in the study of tumor invasion as well as therapeutic responses. In summary, modeling brain tumors through genome engineering enables not only the establishment of authentic tumor avatars driven by bona fide genetic mutations observed in patient samples but also facilitates functional investigations of particular genetic alterations in an otherwise isogenic background.

Background: Stereotactic laser ablation(SLA) or laser interstitial thermal therapy (LITT) has been increasingly adopted as a treatment for primary and metastatic brain cancers. Here, we examined the published economic assessments of SLA, and review the current state of knowledge., Methods: The PubMed database was queried for articles investigating the cost-effectiveness of LITT. 3068 articles were screened. Two studies that met the inclusion criteria were included in this review., Results: Cost-effectiveness analysis(CEA) favored SLA( n  = 8) relative to craniotomy ( n  = 92) for brain metastases (Mean difference [MD]=-US$6522; 95% confidence interval (CI) -$11,911 to -$1133; p  = 0.02). SLA ( n  = 19) was found to be cost equivalent to craniotomy ( n  = 248) (MD=-US$1669; 95%(CI) -$8192 to $4854, p  = 0.62) for primary brain tumors in general. CEA favored SLA for a subset of primary brain cancers. SLA was found to be cost-effective for difficult to access high-grade gliomas(HGG). When compared to 'other' existing treatments, the cost per life-years gained (LYG) through SLA was ∼$29,340, a threshold below that set for new technology adaptation in the U.S. Factors contributing to these cost-effectiveness were: (1) SLA of HGGs was associated with three-months prolongation in survival; (2) SLA of brain metastasis was associated with (i) shorter average length of stay (SLA: 2.3 days; craniotomy: 4.7 days), (ii) decreased discharge to inpatient rehabilitation facility (IRF), skilled nursing facility (SNF), or home healthcare (SLA: 14.8%; craniotomy: 52%), (iii) lowered 30-day readmission (SLA: 0%; craniotomy: 14.1%)., Conclusion: There is limited data on the cost-effectiveness of SLA. In the available literature, SLA compared favorably to craniotomy in terms of cost-effectiveness as a treatment for primary and metastatic brain cancers.

Introduction: Conflicting results have been reported in the association between glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) glioblastoma subjects., Methods: Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival., Results: Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that glioblastoma stem cells exhibit increased DNA repair capacity, glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that glioblastoma stem cells are more aggressive and refractory to therapy, patients with glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P < 0.01)., Conclusion: An unbiased analysis of TCIA suggests that glioblastomas located in proximity to the SVZ exhibited mRNA expression profiles associated with stem cell properties, increased DNA repair capacity, and is associated with poor clinical survival.

Guanylate-binding protein 2 (GBP2) is an interferon-inducible large GTPase which is crucial to the protective immunity against microorganisms. However, its biological function in cancer remains largely unknown. Glioblastoma multiforme (GBM) is the most common and deadly brain tumor in adults. Here we show that GBP2 expression is highly elevated in GBM tumor and cell lines, particularly in those of the mesenchymal subtype. High GBP2 expression is associated with poor prognosis. GBP2 overexpression significantly promotes GBM cell migration and invasion in vitro, and GBP2 silencing by RNA interference exhibits opposite effects. We further show that fibronectin (FN1) is dramatically induced by GBP2 expression at both mRNA and protein levels, and FN1 is essential for GBP2-promoted GBM invasiveness. Inhibition of Stat3 pathway prevents GBP2-promoted FN1 induction and cell invasion. Consistently, GBP2 dramatically promotes GBM tumor growth and invasion in mice and significantly reduces the survival time of the mice with tumor. Taken together, these findings establish the role of GBP2/Stat3/FN1 signaling cascade in GBM invasion and suggest GBP2 may serve as a potential therapeutic target for inhibiting GBM invasion.

Objective: To investigate outcomes after surgery for rare brain tumors using the Swedish Brain Tumor Registry (SBTR)., Methods: This is a nationwide study of patient in the SBTR, validated in the Surveillance, Epidemiology, and End Results (SEER) registries. We included all adults diagnosed 2009-2015 with a rare brain tumor entity (n = 216), defined as ependymoma (EP, n = 64), subependymoma (SUBEP, n = 21), ganglioglioma (GGL, n = 54), pilocytic astrocytoma (PA, n = 56) and primitive neuroectodermal tumor (PNET, n = 21). We analyzed symptomatology, tumor characteristics and outcomes., Results: Mean age was 38.3 ± 17.2 years in GGL, 36.2 ± 16.9 in PA, 37.0 ± 19.1 in PNET, 51.7 ± 16.3 in EP and 49.8 ± 14.3 in SUBEP. The most common symptom was focal deficit (39.6-71.4%), and this symptom was most common in GGL patients with 64.2% of GGL presenting with seizures. Most patients had no or little restriction in activity before surgery (Performance Status 0-1), although up to 15.0% of PNET patients had a performance status of 4. Gross total resection was achieved in most (> 50%) tumor categories. Incidence of new deficits was 11.1-34.4%. In terms of postoperative complications, 0-4.8% had a hematoma of any kind, 1.9-15.6% an infection, 0-7.8% a venous thromboembolism and 3.7-10.9% experienced a complication requiring reoperation. There were 3 deaths within 30-days of surgery, and a 1-year mortality of 0-14.3%., Conclusion: We have provided benchmarks for the current symptomatology, tumor characteristics and outcomes after surgery for rare brain tumors as collected by the SBTR and validated our results in an independent registry. These results may aid in clinical decision making and advising patients.

Background: Recurrence after radiation therapy is nearly universal for glioblastomas, the most common form of adult brain cancer. The study aims to define clinically pertinent mechanisms underlying this recurrence., Methods: microRNA (miRNA) profiling was performed using matched pre- and post-radiation treatment glioblastoma specimens from the same patients. All specimens harbored unmethylated O 6 -methylguanine-DNA methyltransferase promoters (umMGMT) and wild-type isocitrate dehydrogenase (wtIDH). The most altered miRNA, miR-603, was characterized., Findings: While nearly all miRNAs remained unchanged after treatment, decreased levels of few, select miRNAs in the post-treatment specimens were observed, the most notable of which involved miR-603. Unbiased profiling of miR-603 targets revealed insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R). Ionizing radiation (IR) induced cellular export of miR-603 through extracellular vesicle (EV) release, thereby de-repressing IGF1 and IGF1R. This de-repression, in turn, promoted cancer stem-cell (CSC) state and acquired radiation resistance in glioblastomas. Export of miR-603 additionally de-repressed MGMT, a DNA repair protein responsible for detoxifying DNA alkylating agents, to promote cross-resistance to these agents. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and DNA alkylating agents., Interpretation: Profiling of matched pre- and post-treatment glioblastoma specimens revealed altered homeostasis of select miRNAs in response to radiation. Radiation-induced EV export of miR-603 simultaneously promoted the CSC state and up-regulated DNA repair to promote acquired resistance. These effects were abolished by exogenous miR-603 expression, suggesting potential for clinical translation., Funding: NIH 1R01NS097649-01, 9R44GM128223-02, 1R01CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (C.C.C)., Competing Interests: Declaration of Competing Interest B.S.C. and C.C.C. received personal fees from Tocagen Co. Other authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: More than half of pediatric tumors of central nervous system (CNS) primarily originate in the posterior fossa and are conventionally treated with radiation therapy (RT)., Objectives: The objective of this study was to establish whether corpus callosum volumes (CCV) and whole brain volumes (WBV) are correlated and to determine the impact of whole-brain lowvs high-dose RT on brain parenchymal volume loss as assessed using each technique., Material and Methods: Of the 30 identified children (6-12 years) with newly diagnosed posterior fossa tumors treated with cranial RT, including focal and whole-brain RT, suitable imaging was obtained for 23. Radiotherapy regimens were the following: no whole-brain RT (Group 1, n = 7), low-dose whole-brain RT (<30 Gy, Group 2, n = 9) and high-dose whole-brain RT (>30 Gy, Group 3, n = 7) in addition to focal boost. Magnetic resonance images (MRIs) were analyzed at baseline and follow-up (median 14 months). The CCVs were manually segmented on midline sagittal slice (n = 23), while WBVs were segmented semi-automatically using Freesurfer (n = 15). This was done twice (6-month interval) for all baseline CCV measurements and 5 randomly selected WBV measurements to establish measurement reproducibility. Correlations between CCV and WBV were investigated and percentage of children demonstrating reduction in CCV or WBV noted., Results: Correlation between baseline CCV and WBV was not significant (p = 0.37). Measurement reproducibility was from 6% to -9% for CCV and from 4.8% to -1.2% for WBV. Among the children studied, 30.4% (7/23) had >9% reduction in CCV at follow-up, while 33.3% (5/15) had >1.2% reduction in WBV. Five of 7 patients with CCV loss were not picked up by WBV measurements. Similarly, 3 of 5 patients with WBV loss were not picked up by CCV measurements., Conclusions: The CCV and the WBV are unrelated and may indicate different brain parenchymal losses following RT. Up to a third of posterior fossa tumors treated with RT have measurable CCV or WBV loss; incidence was equivalent in lowvs high-dose whole-brain RT.

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.)