Pre-operative vs. post-operative stereotactic radiosurgery for operative metastatic brain tumors: study protocol for a phase III clinical trial.

BACKGROUND AND OBJECTIVES: Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS. METHODS: This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS. EXPECTED OUTCOMES: If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline. DISCUSSION: Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease. TRIAL REGISTRATION NUMBER: NCT03750227 (Registration date: 21/11/2018).

Clinical presentation, role of surgery and prognosis in spinal astrocytoma: Cohort study.

Spinal astrocytoma is a rare neoplasm with discouraging prognosis, which accounts for 6-8 % of total intramedullary spinal tumors. As this is a rare entity, details of the clinical and molecular features have not been fully unraveled. We evaluated the radiologic findings, perioperative clinical presentation, histopathological features and treatment response in a single institution series of 37 consecutive cases of spinal astrocytomas (WHO grades 1 to 4). We identified 8, 16, 8, and 5 patients with grade 1, 2, 3, and 4 lesions, respectively, from 1988 to 2017. Peak ages were youngest in grade 1, followed in order by grades 4, 3 and 2. Whereas all cases of grade 1 and 4 enhanced with contrast, less than half of the cases of grade 2 tumors enhanced (44 %). Grade 3 tumors had a higher rate of multiplicity at presentation (50 %). A concomitant brain lesion at presentation was present in 14 % and 43 % of grade 2 and 3 lesions, respectively. Progression-free and overall survival were worse in grades 3 and 4 compared to grade 2 lesions but no significant difference was observed between grade 3 and 4. Many patients (16-of-36) experienced new neurological deficits postoperatively regardless of grade. Most patients (88 %) required postoperative rehabilitation, and 61 % were not discharged to home. Discharge destination closely correlated with age (p = 0.002). These clinical findings may be useful in understanding the clinical phenotype and improving the management of this rare disease.

Methodological and analytical considerations for intra-operative microdialysis.

BACKGROUND: Microdialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known as gliomas. Gliomas are mainly accessible at the time of surgery, but have rarely been analyzed via interstitial fluid collected via microdialysis. To that end, we obtained an investigational device exemption for high molecular weight catheters (HMW, 100 kDa) and a variable flow rate pump to perform microdialysis at flow rates amenable to an intra-operative setting. We herein report on the lessons and insights obtained during our intra-operative HMW microdialysis trial, both in regard to methodological and analytical considerations. METHODS: Intra-operative HMW microdialysis was performed during 15 clinically indicated glioma resections in fourteen patients, across three radiographically diverse regions in each patient. Microdialysates were analyzed via targeted and untargeted metabolomics via ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: Use of albumin and lactate-containing perfusates impacted subsets of metabolites evaluated via global metabolomics. Additionally, focal delivery of lactate via a lactate-containing perfusate, induced local metabolic changes, suggesting the potential for intra-operative pharmacodynamic studies via reverse microdialysis of candidate drugs. Multiple peri-operatively administered drugs, including levetiracetam, cefazolin, caffeine, mannitol and acetaminophen, could be detected from one microdialysate aliquot representing 10 min worth of intra-operative sampling. Moreover, clinical, radiographic, and methodological considerations for performing intra-operative microdialysis are discussed. CONCLUSIONS: Intra-operative HMW microdialysis can feasibly be utilized to sample the live human CNS microenvironment, including both metabolites and drugs, within one surgery. Certain variables, such as perfusate type, must be considered during and after analysis. Trial registration NCT04047264.

A case of disseminated spinal astroblastoma harboring a MAMLD1::BEND2 fusion.

Astroblastoma, MN1-altered, is a rare neoplasm of the central nervous system (CNS). This malignancy shares similar histopathological features with other CNS tumors, including ependymomas, making it challenging to diagnose. DNA methylation profiling is a new and robust technique that may be used to overcome this diagnostic hurdle. We report the case of a now 25-year-old female diagnosed with what was initially called an ependymoma located in the cervical spine at the age of 2 years old. After initial resection, the tumor recurred multiple times and within 2 years of diagnosis had disseminated disease throughout the brain and spinal cord. She has now undergone over two decades of treatment, including multiple surgical resections, radiation therapy, and administration of numerous chemotherapeutic agents. In 2021, the patient presented to our institution with lumbosacral radicular symptoms due to enlarging lesions within the lumbosacral spine. Reexamination of formalin-fixed, paraffin-embedded material from the patient's tumor using genomic DNA methylation profiling resulted in a diagnostic change from grade III anaplastic ependymoma to astroblastoma, MN1-altered. This work describes another confirmed case of astroblastoma, MN1-altered, to the growing body of literature.

FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres.

Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun-PTEN-AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy.

An untapped window of opportunity for glioma: targeting therapy-induced senescence prior to recurrence.

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.

Clinical protocol: Feasibility of evaluating abemaciclib neuropharmacokinetics of diffuse midline glioma using intratumoral microdialysis.

Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.

The role of the dura mater in cerebral metastases.

OBJECTIVE: The objective of this review was to describe the immunological changes that take place in the dura mater in response to metastatic disease that seeds the CNS. The authors hypothesized that the dura's anatomy and resident immune cell population play a role in enabling metastasis to the brain and leptomeninges. METHODS: An extensive literature search was conducted to identify evidence that supports the dura's participation in metastasis to the CNS. The authors' hypothesis was informed by a recent upsurge in studies that have investigated the dura's role in metastatic development, CNS infections, and autoimmunity. They reviewed this literature as well as the use of immunotherapy in treating brain metastases and how these therapies change the meningeal immune landscape to overcome and reverse tumor-promoting immunosuppression. RESULTS: Evidence suggests that the unique architecture and immune cell profile of the dura, compared with other immune compartments within the CNS, facilitate entry of metastatic tumor cells into the brain. Once these tumor cells penetrate the dural barrier, they propagate an immunosuppressive tumor microenvironment. Therefore, immunotherapy may serve to overcome this immunosuppressive environment and liberate proinflammatory immune cells in an effort to combat metastatic disease. CONCLUSIONS: Within the next few years, the authors expect the addition of several more scientific studies into the literature that further underscore the dura as a chief participant and neuroanatomical barrier in neuro-oncology.

Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.

Objective assessment of patients with idiopathic normal pressure hydrocephalus following ventriculoperitoneal shunt placement using activity-monitoring data: pilot study.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) results in significant morbidity in the elderly with symptoms of dementia, gait instability, and urinary incontinence. In well-selected patients, ventriculoperitoneal shunt (VPS) placement often results in clinical improvement. Most postshunt assessments of patients rely on subjective scales. The goal of this study was to assess the utility of remote activity monitoring to provide objective evidence of gait improvement following VPS placement for iNPH. METHODS: Patients with iNPH were prospectively enrolled and fitted with 5 activity monitors (on the hip and bilateral thighs and ankles) that they wore for 4 days preoperatively within 30 days of surgery and for 4 days within 30 days postoperatively. Monitors collected continuous data for number of steps, cadence, body position (upright, prone, supine, and lateral decubitus), gait entropy, and the proportion of each day spent active or static. Data were retrieved from the devices and a comparison of pre- and postoperative movement assessment was performed. The gait data were also correlated with formal clinical gait assessments before and after lumbar puncture and with motion analysis laboratory testing at baseline and 1 month and 1 year after VPS placement. RESULTS: Twenty patients fulfilled the inclusion and exclusion criteria (median age 76 years). The baseline median number of daily steps was 1929, the median percentage of the day spent inactive was 70%, the median percentage of the day with a static posture was 95%, the median gait velocity was 0.49 m/sec, and the median number of steps required to turn was 8. There was objective improvement in median entropy from pre- to postoperatively, increasing from 0.6 to 0.8 (p = 0.002). There were no statistically significant differences for any of the remaining variables measured by the activity monitors when comparing the preoperative to the 1-month postoperative time point. All variables from motion analysis testing showed statistically significant differences or a trend toward significance at 1 year after VPS placement. Among the significantly correlated variables at baseline, cadence was inversely correlated with percentage of gait cycle spent in the support phase (contact with ground vs swing phase). CONCLUSIONS: This pilot study suggests that activity monitoring provides an early objective measure of improvement in gait entropy after VPS placement among patients with iNPH, although a more significant improvement was noted on the detailed clinical gait assessments. Further long-term studies are needed to determine the utility of remote monitoring for assessing gait improvement following VPS placement.

VertebralArtery Injury with Anterior Cervical Spine Operations: A Systematic Review of Risk Factors, Clinical Outcomes, and Management Strategies.

OBJECTIVE: Anterior cervical spine operations are commonly performed on cervical spine pathologies and to a large extent are safe and successful. However, these surgical procedures expose the vertebral artery, posing a risk of harm to it. METHODS: A systematic review was conducted using PubMed, Google Scholar, and Web of Science electronic databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to critically assess primary articles discussing treatment strategies "vertebral artery injury" AND "anterior cervical spine" and develop a management strategy based on our experience and meta-analysis of the literature. In addition, we present an illustrative case of iatrogenic vertebral artery injury presenting with 6 to 7 months' history of progressive dysphagia was transferred to our care from an outside institution. RESULTS: Included and analyzed were 43 articles that detailed 75 cases involving vertebral artery injury (VAI) in anterior cervical spine operations. Preoperatively, frequent clinical findings reported were sensory deficit (26 patients [63.41%]), motor deficit (20 patients [48.78%]), and pain (17 patients [41.46%]). In total, 32 patients (50.00%) endured injury of their left VA, and 30 patients had a right VAI. The 2 common causes of VAI were drilling (24 patients [40.00%]) and instrumentation (8 patients [13.33%]). CONCLUSIONS: Altogether, our review recommends repair or tamponade packing with a hemostatic agent for primary management. Should tamponade packing with a hemostatic agent be used for primary management, secondary management should entail either repair, stenting occlusion, embolization, anticoagulants, or ligation. Further examination of this treatment strategy based on a larger cohort is necessary.

A Review on the Surgical Management of Insular Gliomas.

The surgical treatment of insular gliomas requires specialized knowledge. Over the last three decades, increased momentum in surgical resection of insular gliomas shifted the focus from one of expectant management to maximal safe resection to establish a diagnosis, characterize tumor genetics, treat preoperative symptoms (i.e., seizures), and delay malignant transformation through tumor cytoreduction. A comprehensive review of the literature was performed regarding insular glioma classification/genetics, insular anatomy, surgical approaches, and patient outcomes. Modern large, published series of insular resections have reported a median 80% resection, 80% improvement in preoperative seizures, and postsurgical permanent neurologic deficits of less than 10%. Major complication avoidance includes recognition and preservation of eloquent cortex for language and respecting the lateral lenticulostriate arteries.

Glioblastoma may evade immune surveillance through primary cilia-dependent signaling in an IL-6 dependent manner.

Glioblastoma is the most common, malignant primary brain tumor in adults and remains universally fatal. While immunotherapy has vastly improved the treatment of several solid cancers, efficacy in glioblastoma is limited. These challenges are due in part to the propensity of glioblastoma to recruit tumor-suppressive immune cells, which act in conjunction with tumor cells to create a pro-tumor immune microenvironment through secretion of several soluble factors. Glioblastoma-derived EVs induce myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs) from myeloid precursors leading to systemic and local immunosuppression. This process is mediated by IL-6 which contributes to the recruitment of tumor-associated macrophages of the M2 immunosuppressive subtype, which in turn, upregulates anti-inflammatory cytokines including IL-10 and TGF-ß. Primary cilia are highly conserved organelles involved in signal transduction and play critical roles in glioblastoma proliferation, invasion, angiogenesis, and chemoradiation resistance. In this perspectives article, we provide preliminary evidence that primary cilia regulate intracellular release of IL-6. This ties primary cilia mechanistically to tumor-mediated immunosuppression in glioblastomas and potentially, in additional neoplasms which have a shared mechanism for cancer-mediated immunosuppression. We propose potentially testable hypotheses of the cellular mechanisms behind this finding.

Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1.

Background: Glioblastoma (GBM), the most common primary brain tumor, has a median survival of 15-16 months. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. GBMs express the interferon-gamma (IFN-γ)-responsive immunosuppressive molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1). Extracellular vesicles (EVs) have also been implicated in GBM-mediated immunosuppression, in part through PD-L1. We therefore sought to determine if GBM IFN-γ exposure increased GBM EV-mediated immunosuppression and mechanisms underlying this. Methods: Human GBM-derived cells were cultured in the presence/absence of IFN-γ. EVs were harvested. PD-L1, IDO1, and EV-associated protein expression was assessed. GBM EVs (+/-IFN-γ) were cultured with healthy donor monocytes. Immunosuppressive myeloid-derived suppressor cell (MDSC) and nonclassical monocyte (NCM) frequency was determined. Impact of GBM (+/-IFN-γ) EV-treated monocytes on CD3/CD28-mediated T cell proliferation was assessed. The impact of PD-L1 and IDO1 knockdown in GBM EVs in this system was evaluated. Results: IFN-γ exposure increased PD-L1 and IDO1 expression in GBM cells and EVs without altering EV size or frequency. IFN-γ-exposed GBM EVs induced more MDSC and NCM differentiation in monocytes and these monocytes caused more T cell inhibition than IFN-γ-naive GBM EVs. PD-L1 and/or IDO1 knockdown in GBM cells abrogated the immunosuppressive effects of IFN-γ-exposed GBM EVs on monocytes. Conclusions: IFN-γ exposure such as might occur during an antitumor immune response results in superinduction of GBM EVs' baseline immunosuppressive effects on monocytes. These effects are mediated by increased PD-L1 and IDO1 expression in GBM EVs. These data highlight mechanisms of GBM EV-mediated immunosuppression and identify therapeutic targets (PD-L1, IDO1) to reverse these effects.

Presentation, imaging, patterns of care, growth, and outcome in sporadic and von Hippel-Lindau-associated central nervous system hemangioblastomas.

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.

Syngeneic murine glioblastoma models: reactionary immune changes and immunotherapy intervention outcomes.

Glioblastoma is the most common primary malignant brain neoplasm with dismal 10-year survival rates of < 1%. Despite promising preliminary results from several novel therapeutic agents, clinical responses have been modest due to several factors, including tumor heterogeneity, immunosuppressive tumor microenvironment, and treatment resistance. Novel immunotherapeutics have been developed to reverse tumor-induced immunosuppression in patients with glioblastomas. In order to recapitulate the tumor microenvironment, reliable in vivo syngeneic murine models are critical for the development of new targeted agents as these models demonstrate rapid tumor induction and reliable tumor growth over multiple generations. Despite the clear advantages of murine models, choosing an appropriate model from an immunological perspective can be difficult and have significant ramifications on the translatability of the results from murine to human trials. Herein, the authors reviewed the 4 most commonly used immunocompetent syngeneic murine glioma models (GL261 [C57BL/6], SB28 [C57BL/6], CT-2A [C57BL/6], and SMA-560 [VM/Dk]) and compared their strengths and weaknesses from an immunological standpoint.

Clinical utility of brain biopsy for presumed CNS relapse of systemic lymphoma.

OBJECTIVE: The objective of this study was to determine the frequency with which brain biopsy for presumed CNS relapse of systemic hematological malignancies yields new, actionable diagnostic information. Hematological malignancies represent a disparate group of genetic and histopathological disorders. Proclivity for brain involvement is dependent on the unique entity and may occur synchronously or metasynchronously with the systemic lesion. Diffuse large B-cell lymphomas (DLBCLs) have a high propensity for brain involvement. Patients in remission from systemic DLBCL may present with a lesion suspicious for brain relapse. These patients often undergo brain biopsy. The authors' a priori hypothesis was that brain biopsy in patients with a history of systemic DLBCL and a new brain MRI lesion would have lower diagnostic utility compared with patients with non-DLBCL systemic malignancies. METHODS: The authors performed a retrospective review of patients who underwent brain biopsy between 2000 and 2019. Inclusion criteria were patients ≥ 18 years of age with a prior systemic hematological malignancy in remission presenting with a new brain MRI lesion concerning for CNS relapse. Patients with a history of any CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. The main outcome was the proportion of patients with a distinct histopathological brain diagnosis compared with the systemic malignancy. The authors secondarily assessed overall survival, procedure-related morbidity, and 30-day mortality. RESULTS: Sixty patients met inclusion criteria (40 males and 20 females); the median age at brain biopsy was 67 years (range 23-88 years). The median follow-up was 8.5 months (range 0.1-231 months). Thirty-nine (65.0%) patients had DLBCL and 21 (35%) had non-DLBCL malignancies. Thirty-five of 36 (97.2%) patients with prior systemic DLBCL and a diagnostic biopsy had histopathological confirmation of the original systemic disease versus 0 of 21 patients with non-DLBCL systemic malignancies (p < 0.001). Morbidity and 30-day mortality were 8.3% and 10.0%, respectively; 2 of 6 30-day mortalities were directly attributable to the biopsy. The median overall survival following brain biopsy was 10.8 months. CONCLUSIONS: Patients with a history of systemic DLBCL and presumed CNS relapse gained minimal clinical benefit from brain biopsy but were at high risk of morbidity and mortality. In patients with a history of non-DLBCL systemic malignancies, brain biopsy remained critical given the high likelihood for discovery of distinct diagnostic entities. It was determined that patients with a prior systemic DLBCL and presumed brain relapse should likely receive empirical therapy obviating treatment delay and the risks of brain biopsy.

Disparities in access to surgery for glioblastoma multiforme at high-volume Commission on Cancer-accredited hospitals in the United States.

OBJECTIVE: Although it has been shown that surgery for glioblastoma (GBM) at high-volume facilities (HVFs) may be associated with better postoperative outcomes, the use of such hospitals may not be equally distributed. The authors aimed to evaluate racial and socioeconomic differences in access to surgery for GBM at high-volume Commission on Cancer (CoC)-accredited hospitals. METHODS: The National Cancer Database was queried for patients with GBM that was newly diagnosed between 2004 and 2015. Patients who received no surgical intervention or those who received surgical intervention at a site other than the reporting facility were excluded. Annual surgical case volume was calculated for each hospital, with volume ≥ 90th percentile defined as an HVF. Multivariable logistic regression was performed to identify patient-level predictors for undergoing surgery at an HVF. Furthermore, multiple subgroup analyses were performed to determine the adjusted odds ratio of the likelihood of undergoing surgery at an HVF in 2016 as compared to 2004 for each patient subpopulation (by age, race, sex, educational group, etc.). RESULTS: A total of 51,859 patients were included, with 10.7% (n = 5562) undergoing surgery at an HVF. On multivariable analysis, Hispanic White patients (OR 0.58, 95% CI 0.49-0.69, p < 0.001) were found to have significantly lower odds of undergoing surgery at an HVF (reference = non-Hispanic White). In addition, patients from a rural residential location (OR 0.55, 95% CI 0.41-0.72, p < 0.001; reference = metropolitan); patients with nonprivate insurance status (Medicare [OR 0.78, 95% CI 0.71-0.86, p < 0.001], Medicaid [OR 0.68, 95% CI 0.60-0.78, p < 0001], other government insurance [OR 0.68, 95% CI 0.52-0.86, p = 0.002], or who were uninsured [OR 0.61, 95% CI 0.51-0.72, p < 0.001]); and lower-income patients ($50,354-$63,332 [OR 0.68, 95% CI 0.63-0.74, p < 0.001], $40,227-$50,353 [OR 0.84, 95% CI 0.76-0.92, p < 0.001]; reference = ≥ $63,333) were also found to be significantly associated with a lower likelihood of surgery at an HVF. Subgroup analyses revealed that elderly patients (age ≥ 65 years), both male and female patients and non-Hispanic White patients, and those with private insurance, Medicare, metropolitan residential location, median zip code-level household income in the first and second quartiles, and educational attainment in the first and third quartiles had increased odds of undergoing surgery at an HVF in 2016 compared to 2004 (all p ≤ 0.05). On the other hand, patients with other governmental insurance, patients with a rural residence, and those from a non-White racial category did not show a significant difference in odds of surgery at an HVF over time (all p > 0.05). CONCLUSIONS: The present analysis from the National Cancer Database revealed significant disparities in access to surgery at an HVF for GBM within the United States. Furthermore, there was evidence that these racial and socioeconomic disparities may have widened between 2004 and 2016. The findings should assist health policy makers in the development of strategies for improving access to HVFs for racially and socioeconomically disadvantaged populations.

Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications.

Glioblastoma (GBM) is the most common primary brain tumor in adults an carries and carries a terrible prognosis. The current regiment of surgical resection, radiation, and chemotherapy has remained largely unchanged in recent years as new therapeutic approaches have struggled to demonstrate benefit. One of the most challenging hurdles to overcome in developing novel treatments is the profound immune suppression found in many GBM patients. This limits the utility of all manner of immunotherapeutic agents, which have revolutionized the treatment of a number of cancers in recent years, but have failed to show similar benefit in GBM therapy. Understanding the mechanisms of tumor-mediated immune suppression in GBM is critical to the development of effective novel therapies, and reversal of this effect may prove key to effective immunotherapy for GBM. In this review, we discuss the current understanding of tumor-mediated immune suppression in GBM in both the local tumor microenvironment and systemically. We also discuss the effects of current GBM therapy on the immune system. We specifically explore some of the downstream effectors of tumor-driven immune suppression, particularly myeloid-derived suppressor cells (MDSCs) and other immunosuppressive monocytes, and the manner by which GBM induces their formation, with particular attention to the role of GBM-derived extracellular vesicles (EVs). Lastly, we briefly review the current state of immunotherapy for GBM and discuss additional hurdles to overcome identification and implementation of effective therapeutic strategies.

Laser Interstitial Thermal Therapy for Recurrent Glioblastoma: Pooled Analyses of Available Literature.

OBJECTIVE/BACKGROUND: The efficacy of laser interstitial thermal therapy (LITT) in recurrent glioblastoma (rGBM) is unknown. The goal of this study was to conduct a systematic review and pooled analysis of the literature for outcomes on patients with rGBM undergoing LITT. METHODS: A literature search was performed to retrieve all studies investigating overall survival, postprocedure survival, and progression-free survival outcomes of patients with rGBM undergoing LITT. Statistics were pooled together by meta-analysis of mean using a weighted random-effects or fixed-effect model. RESULTS: Eleven studies were included in the final cohort, representing a total of 134 patients with rGBM. The pooled mean age of the cohort at the time of recurrence was 56.7 ± 4.56 years; 41% of the cohort were female. For delivery of LITT, 2 studies used neodymium-yttrium aluminum-garnet laser (Nd:YAG laser), 3 studies used the Visualase system, 5 studies used the NeuroBlate system, and 1 study used both the NeuroBlate and the Visualase system. A total of 8 studies with 107 patients had available data for overall median survival. The pooled overall survival was found to be 18.6 months (95% confidence interval [CI] 16.2-21.1). A total of 6 studies with 93 patients had available data for post-LITT survival. The pooled post-LITT survival was found to be 10.1 months (95% CI 8.8-11.6). A total of 8 studies with 119 patients had available data for progression-free survival. Pooled progression free survival was found to be 6 months (95% CI 5.3-6.7). CONCLUSIONS: LITT is a novel minimally invasive procedure which, when used with optimal adjuvant therapy, may confer survival benefit for patients with rGBM.