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Stereotactic frameless needle brain biopsy is a common neurosurgical procedure performed via twist drill or open burr hole approaches. We aim to compare diagnostic yields and surgical outcomes to delineate the safety and efficacy of both approaches. A retrospective database of all stereotactic needle biopsy procedures performed at a single institution over 30 months was conglomerated. Demographics, medical comorbidities, operative details/complications, immediate post-operative imaging, and pathology were abstracted. Two hundred and twenty-five needle biopsies were identified, of which 165 (73.3%) were open, and 60 (26.7%) were twist drill. Diagnostic pathology yield rates between open (84.8%) and twist drill (93.3%) approaches were similar (p = 0.15), with a median of 4 cores taken in each (p = 0.30). Diagnostic tissue yields with an intra-operative pause for pathology confirmation was 90.4% compared to 79.1% without pause (p = 0.036, OR 2.49). Median operative times for open versus twist drill procedures were 68.0 min (IQR 49–83) versus 35.5 min (IQR 26–54), respectively (Wilcoxon p < 0.001), which remained significant after controlling for awaiting intraoperative pathology using bivariable linear modeling (p < 0.001). Intraoperative bleeding through the needle cannula was noted in 22 patients (9.8%), including eight twist drill (13.3%) and 14 open needles (8.5%). Of 197 cases (87.6%) with post-operative cranial imaging (CT/MRI), 90 (45.7%) demonstrated some degree of post-operative hemorrhage characterized as superficial (n = 10, 11.1%), deep/intralesional (n = 64, 71.1%) bleeding, or both (n = 16, 17.9%). Bleeding rates between open (46.7%) and twist drill (43.3%) approaches were similar (p = 0.78). Post-operative clinical decline or neurological change was noted in 9 patients (4.0%), including one twist drill (1.7%) and eight open needles (4.8%), among which 7 (78%) had deep blood products identified on post-operative imaging. Stereotactic needle biopsy via twist drill approach has similar diagnostic yield rates, asymptomatic bleeding rates, and post-operative complications with significantly shorter operative time and smaller incision size than conventional open burr hole needle biopsy. Using intra-operative frozen histopathology for presumed sufficient diagnostic tissue may improve final pathologic diagnostic rates regardless of approach technique. [ABSTRACT FROM AUTHOR]

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = −0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization. Oncolytic measles virus (MV) vaccine strains have shown preclinical antitumor activity against glioblastoma (GBM). Here the authors report the results of a phase 1 trial of intratumoral administration of a MV strain engineered to express the carcinoembryonic antigen in patients with recurrent GBM including assessment of viral replication and proinflammatory remodeling of the treated tumors. [ABSTRACT FROM AUTHOR]

High-grade gliomas are primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to tumor recurrence. Moreover, senescent tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of senolytic agents to ablate latent, senescent-like cells that could contribute to tumor recurrence. We also discuss how senescent cell clearance can decrease the SASP within the tumor microenvironment thereby reducing tumor aggressiveness at recurrence. Finally, senolytics could improve the long-term sequelae of prior therapy on cognition and bone marrow function. We critically review the senolytic drugs currently under preclinical and clinical investigation and the potential challenges that may be associated with deploying senolytics against latent glioma. In conclusion, senescence in glioma and the microenvironment are critical and potential targets for delaying or preventing tumor recurrence and improving patient functional outcomes through senotherapeutics. [ABSTRACT FROM AUTHOR]

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence. Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence. [ABSTRACT FROM AUTHOR]

Object: Hemangioblastoma is a relatively rare neoplasm occurring mostly in the cerebellum that may arise sporadically or in the context of von Hippel–Lindau (VHL) syndrome. Presentation, imaging, natural history, surgical patterns of care, and outcomes are incompletely defined for this uncommon lesion. We reviewed our large institutional series to help clarify these issues. Methods: Retrospective analysis of consecutive, neurosurgically managed CNS hemangioblastomas at Mayo Clinic, 1988–2018. Results: Two hundred and eighty five hemangioblastomas were treated in 184 unique patients (115 sporadic, 69 VHL). Compared to sporadic patients, VHL patients were younger (36.7 vs 51.7 years; p < 0.0001), were treated while asymptomatic more commonly (47.3 vs 4.2%; p < 0.0001), had smaller lesions (6.6 vs 13.9 mL; p < 0.0001), and harbored lesions with associated cysts less frequently (51.0 vs 75.0%; p = 0.0002). Macrocystic tumor architecture was associated with larger lesion size and greater symptom severity. Solid lesions later formed cysts at a median 130 months. Growth in both total volume and solid component accelerated after cyst formation (10.6 and 6.0 times median rate prior to cyst emergence). VHL patients died at a younger age (47.9 vs 74.5, p = 0.0017) and were more likely to die of direct disease sequelae. Though treatment-free survival time was significantly longer in sporadic cases, a substantial fraction (> 40%) developed tumor recurrence/progression requiring additional treatment. Conclusions: Hemangioblastoma presentation varies with etiology and clinical course is more complicated in VHL cases. Nodular lesions often develop cysts over time which is associated with accelerated tumor growth. Sporadic cases have a previously unappreciated but substantial risk of late recurrence/progression requiring treatment. [ABSTRACT FROM AUTHOR]

Purpose: To clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM). Methods: A retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. Results: Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months. Eighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7–18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n = 7). Prior EBRT was associated with reduced PFS (HR 5.92, P < 0.01), reduced DSS (HR 5.84, P < 0.01), and an increased risk of ARE (HR 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR 3.17, P = 0.01) or late salvage treatment (HR 4.39, P < 0.01). Conclusion: PFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS. [ABSTRACT FROM AUTHOR]

Introduction: WHO grades II (atypical) and III (malignant) meningiomas are associated with significant morbidity and mortality. The role of adjuvant radiotherapy (RT) in management remains controversial. The goal of this study was to evaluate the impact of adjuvant RT on 5-year survival in patients with atypical and malignant meningiomas. We secondarily aimed to assess contemporary practice patterns and the impact of sociodemographic factors on outcome. Methods: We queried the National Cancer Database for patients ≥ 18 years of age with cranial atypical or malignant meningiomas from 2010 through 2015 who underwent surgical resection with or without adjuvant radiotherapy. Subjects with unknown WHO grade or radiation status and those not receiving any surgical procedure were excluded from analysis. Results: The study includes 7486 patients, 6788 with atypical and 698 with malignant meningiomas. Overall 5-year survival was 76.9% (95% CI 75.5–78.3%) and 43.3% (95% CI 38.8–48.2%) among patients with WHO grades II and III meningiomas, respectively. Adjuvant RT correlated with improved survival in a multivariable model in patients with grade II tumors (HR 0.78; p = 0.029) regardless of the extent of resection. Age (HR 2.33; p < 0.001), male sex (HR 1.27; p < 0.001), Black race (HR 1.27; p = 0.011) and Charlson-Deyo Score ≥ 2 (1.35; p = 0.001) correlated with poorer survival whereas private insurance (HR 0.71; p < 0.001) correlated with improved survival. Adjuvant RT was also associated with improved 5-year survival among those with grade III tumors on univariate analysis (log-rank p = 0.006) but was underpowered for multivariable modeling. Utilization of adjuvant radiotherapy was only 28.4% and correlated with private insurance status. Academic institutions (25.3%) and comprehensive community cancer programs (21.4%) had lower radiotherapy utilization rates compared with integrated network cancer programs (30.5%) and community cancer programs (29.7%). Conclusions: Adjuvant RT may correlate with improved overall survival in patients with grades II and III intracranial meningiomas regardless of the extent of resection. There is poor utilization of adjuvant RT for patients with grades II and III meningiomas likely due to a paucity of quality data on the subject. These findings will be strengthened with prospective data evaluating the role of adjuvant RT. [ABSTRACT FROM AUTHOR]

Brain metastases are the most common malignant tumors of the brain. Leptomeningeal dissemination is a late-stage complication of intracranial metastasis and portends an extremely poor prognosis. An increased risk of leptomeningeal disease (LMD) from metastatic breast cancer compared to other cancer types after stereotactic radiosurgery (SRS) has been reported. Validation of this observation has significant public health ramifications. The aim of this study was to determine the consistency of this association in the available literature via formal meta-analysis and systematic review of the literature. Searches of seven electronic databases from inception to August 2019 were conducted following PRISMA guidelines and appropriate selection criteria. Prognostic hazard ratios (HRs) for LMD in breast cancer brain metastases derived from multivariate regression analysis were analyzed using meta-analysis of proportions. Our search strategy identified 8 studies meeting inclusion criteria which provided data on 2555 unique brain metastases patients treated with SRS. The risk of LMD in the setting of breast cancer brain metastasis was significantly greater compared to other histologic cancer types (pooled HR = 2.22; 95% CI 1.69–2.93; P < 0.001). Statistical assessment of small studies bias and heterogeneity were negative. Outcome certainty was low. Breast cancer brain metastases are associated with an increased risk of LMD compared to other cancer types after SRS. The certainty of this outcome will be improved with future prospective studies. Providers should factor this increased susceptibility for LMD in breast cancer brain metastasis to allow for appropriate risk stratification and the development of appropriate surveillance paradigms. [ABSTRACT FROM AUTHOR]

Introduction: Surgical resection of high-grade brainstem gliomas is challenging and treatment mostly involves radiation and chemotherapy. In this study, we utilized registry data to determine prognostic features and impact of chemotherapy and radiation on overall survival. Methods: The National Cancer Database was queried from 2006 to 2015 for adult cases with histologically confirmed high-grade brainstem glioma. Covariates including patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Multivariable Cox proportional hazards regression was performed to identify predictors of survival. Results: A total of 422 patients were analyzed. Most patients (66.6%) underwent postoperative radiation with chemotherapy, 9.2% underwent radiation alone, while the remaining had no postoperative treatment (24.2%). Overall median survival was 9.8 months (95% CI 8.8–12). Survival was longer (p < 0.001) in the radiation + chemotherapy group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no postoperative treatment (median: 1.8 months, 95% CI 1.4–4) groups. In multivariable analysis, increasing age was associated with worse survival (HR: 1.87, 95% CI 1.47–2.37, p < 0.001), whereas radiation + chemotherapy was associated with lower mortality compared to radiation alone (HR: 0.67, 95% CI 0.46–0.98, p = 0.038). In subgroup analysis, postoperative chemotherapy with radiation was associated with significant survival benefit compared to radiation alone for grade IV (HR: 0.46, 95% CI 0.28–0.76, p = 0.003), but not for grade III tumors (HR: 0.87, 95% CI 0.48–1.58, p = 0.65). Conclusion: Analysis from a national registry illustrated the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should identify specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy. [ABSTRACT FROM AUTHOR]

Background: There is no clear consensus regarding the optimal treatment for glioblastoma (GBM) in the elderly. Hypofractionated radiation therapy (hRT) has emerged as a viable and comparable radiation regime compared to standard radiation therapy (sRT), however the survival effect of temozolomide (TMZ) with hRT is uncertain. The aim of this meta-analysis was to evaluate survival outcomes of hRT + TMZ vs sRT + TMZ in this specific demographic. Methods: Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The progression free survival (PFS) and overall survival (OS) metrics were then extracted and pooled by meta-analysis evaluating mean difference (MD). Results: A total of 7 individual comparative studies describing hRT + TMZ vs sRT + TMZ (n = 917) respectively satisfied inclusion criteria. Meta-analysis by random-effects modelling indicated that compared to sRT + TMZ, hRT + TMZ resulted in comparable PFS (MD 0.3 months; 95% CI − 2.4 to 2.9; I2 = 91.7%; P-effect = 0.85) and significantly shorter OS (MD − 3.5 months; 95% CI − 6.3 to − 0.6; I2 = 98.9%; P-effect = 0.02). Subgroup analysis between age definitions of elderly of > 65 vs > 70 years old both demonstrated the same significant trend with no statistical difference between the groups. Conclusion: The combination of hRT + TMZ is feasible in well-selected elderly GBM cases, and appears to confer a statistically comparable PFS compared to sRT + TMZ. However, expectations that the OS with hRT + TMZ is comparable to that of sRT + TMZ in all elderly GBM presentations should be tempered. It is likely a specific subgroup of elderly GBM patients will benefit greatly from the addition of TMZ to hRT, and greater investigation is needed to identify their characteristics. [ABSTRACT FROM AUTHOR]