Response of treatment-naive brain metastases to stereotactic radiosurgery.

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm.

Ventriculoperitoneal shunting with an on-off valve for patients with leptomeningeal metastases and intracranial hypertension.

Background: We report our experience with using a ventriculoperitoneal shunt (VPS) with an on-off valve and in-line Ommaya reservoir for the treatment of hydrocephalus or intracranial hypertension in patients with leptomeningeal disease (LMD). Our goal was to determine whether control of intracranial pressure elevation combined with intrathecal (IT) chemotherapy would extend patient survival. Methods: In this IRB-approved retrospective study, we reviewed 58 cases of adult patients with LMD from solid cancers who received a VPS with a reservoir and an on-off valve at M D Anderson Cancer Center from November 1996 through December 2021. Primary tumors were most often melanoma (n = 19) or breast carcinoma (n = 20). Hydrocephalus was diagnosed by clinical symptoms and findings on magnetic resonance imaging (MRI), and LMD by MRI or cerebrospinal fluid analysis. Differences in overall survival (OS) were assessed with standard statistical techniques. Results: Patients who received a VPS and more than 3 IT chemotherapy sessions survived longer (n = 26; OS time from implantation 11.7 ± 3.6 months) than those who received an occludable shunt but no IT chemotherapy (n = 24; OS time from implantation 2.8 ± 0.7 months, P < .018). Peritoneal seeding appeared after shunt insertion in only two patients (3%). Conclusions: This is the largest series reported to date of patients with LMD who had had shunts with on-off valves placed to relieve symptoms of intracranial hypertension. Use of IT chemotherapy and control of hydrocephalus via such shunts was associated with improved survival.

A phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases.

Stereotactic radiation therapy yields high rates of local control for brain metastases, but patients in rural or suburban areas face geographic and socioeconomic barriers to its access. We conducted a phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases in an integrated academic satellite network for patients 18 years of age or older with 4 or fewer brain metastases. Dose was based on gross tumor volume: less than 3.0 cm, 27 Gy in 3 fractions and 3.0 to 3.9 cm, 30 Gy in 5 fractions. Median follow-up was 10 months for 73 evaluable patients, with a median age of 68 years. Median intracranial progression-free survival was 7.1 months (95% confidence interval = 5.3 to not reached), and median survival was 7.2 months (95% confidence interval = 5.4 to not reached); there were no serious adverse events. Outcomes of this trial compare favorably with contemporary trials, and this treatment strategy provides opportunities to expand stereotactic radiation therapy access to underserved populations.

Subependymomas of the fourth ventricle: To operate or not to operate?

BACKGROUND: There is a paucity of literature regarding the clinical characteristics and management of subependymomas of the fourth ventricle due to their rarity. Here, we describe the operative and non-operative management and outcomes of patients with such tumors. METHODS: This retrospective single-institution case series was gathered after Institutional Review Board (IRB) approval. Patients diagnosed with a subependymoma of the fourth ventricle between 1993 and 2021 were identified. Clinical, radiology and pathology reports along with magnetic resonance imaging (MRI) images were reviewed. RESULTS: Patients identified (n = 20), showed a male predominance (n = 14). They underwent surgery (n = 9) with resection and histopathological confirmation of subependymoma or were followed with imaging surveillance (n = 11). The median age at diagnosis was 51.5 years. Median tumor volume for the operative cohort was 8.64 cm3 and median length of follow-up was 65.8 months. Median tumor volume for the non-operative cohort was 0.96 cm3 and median length of follow-up was 78 months. No tumor recurrence post-resection was noted in the operative group, and no tumor growth from baseline was noted in the non-operative group. Most patients (89 %) in the operative group had symptoms at diagnosis, all of which improved post-resection. No patients were symptomatic in the non-operative group. CONCLUSIONS: Surgical resection is safe and is associated with alleviation of presenting symptoms in patients with large tumors. Observation and routine surveillance are warranted for smaller, asymptomatic tumors.

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .

Changes in outcomes and factors associated with survival in melanoma patients with brain metastases.

BACKGROUND: Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients. METHODS: Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA). RESULTS: A total of 791 MBM patients (PE, n = 332; CE, n = 459) were included in analysis. Median OS from MBM diagnosis was 10.3 months (95% CI, 8.9-12.4) and improved in the CE vs PE (14.4 vs 10.3 months, P < .001). Elevated serum lactate dehydrogenase (LDH) was the only factor associated with worse OS in both PE and CE patients. Factors associated with survival in CE MBM patients included patient age, primary tumor Breslow thickness, prior immunotherapy, leptomeningeal disease, symptomatic MBMs, and whole brain radiation therapy. Several factors associated with OS in the PE were not significant in the CE. RPA demonstrated that elevated serum LDH and prior immunotherapy treatment are the most important determinants of survival in CE MBM patients. CONCLUSIONS: OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations.

Automated Brain Metastases Segmentation With a Deep Dive Into False-positive Detection.

Purpose: The clinical management of brain metastases after stereotactic radiosurgery (SRS) is difficult, because a physician must review follow-up magnetic resonance imaging (MRI) scans to determine treatment outcome, which is often labor intensive. The purpose of this study was to develop an automated framework to contour brain metastases in MRI to help treatment planning for SRS and understand its limitations. Methods and Materials: Two self-adaptive nnU-Net models trained on postcontrast 3-dimensional T1-weighted MRI scans from patients who underwent SRS were analyzed. Performance was evaluated by computing positive predictive value (PPV), sensitivity, and Dice similarity coefficient (DSC). The training and testing sets included 3482 metastases on 845 patient MRI scans and 930 metastases on 206 patient MRI scans, respectively. Results: In the per-patient analysis, PPV was 90.1% ± 17.7%, sensitivity 88.4% ± 18.0%, DSC 82.2% ± 9.5%, and false positive (FP) 0.4 ± 1.0. For large metastases (≥6 mm), the per-patient PPV was 95.6% ± 17.5%, sensitivity 94.5% ± 18.1%, DSC 86.8% ± 7.5%, and FP 0.1 ± 0.4. The quality of autosegmented true-positive (TP) contours was also assessed by 2 physicians using a 5-point scale for clinical acceptability. Seventy-five percent of contours were assigned scores of 4 or 5, which shows that contours could be used as-is in clinical application, and the remaining 25% were assigned a score of 3, which means they needed minor editing only. Notably, a deep dive into FPs indicated that 9% were TP metastases not identified on the original radiology review, but identified on subsequent follow-up imaging (early detection). Fifty-four percent were real metastases (TP) that were identified but purposefully not contoured for target treatment, mainly because the patient underwent whole-brain radiation therapy before/after SRS treatment. Conclusions: These findings show that our tool can help radiologists and radiation oncologists detect and contour tumors from MRI, make precise decisions about suspicious lesions, and potentially find lesions at early stages.

Surgical Management of Brain Metastasis: Challenges and Nuances.

Brain metastasis is the most common type of intracranial tumor. The contemporary management of brain metastasis is a challenging issue and traditionally has carried a poor prognosis as these lesions typically occur in the setting of advanced cancer. However, improvement in systemic therapy, advances in radiation techniques and multimodal therapy tailored to the individual patient, has given hope to this patient population. Surgical resection has a well-established role in the management of brain metastasis. Here we discuss the evolving role of surgery in the treatment of this diverse patient population.

Cerebrovascular Reactivity Mapping Using Resting-State Functional MRI in Patients With Gliomas.

BACKGROUND: Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the CO2 inhalation-based method in health subjects and patients with neurovascular diseases. PURPOSE: To investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas. STUDY TYPE: Retrospective. POPULATION: Twenty-five patients (12 males, 13 females; mean age ± SD, 48 ± 13 years) with gliomas. FIELD STRENGTH/SEQUENCE: Dynamic T2*-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T scanner. ASSESSMENT: rs-CVR with various frequency ranges and resting-state fluctuation amplitude (RSFA) were assessed. The agreement between each rs-based CVR measurement and bh-CVR was determined by voxel-wise correlation and Dice coefficient in the whole brain, gray matter, and the lesion region of interest (ROI). STATISTICAL TESTS: Voxel-wise Pearson correlation, Dice coefficient, Fisher Z-transformation, repeated-measure analysis of variance and post hoc test with Bonferroni correction, and nonparametric repeated-measure Friedman test and post hoc test with Bonferroni correction were used. Significance was set at P < 0.05. RESULTS: Compared with bh-CVR, the highest correlations were found at the frequency bands of 0.04-0.08 Hz and 0.02-0.04 Hz for rs-CVR in both whole brain and the lesion ROI. RSFA had significantly lower correlations than did rs-CVR of 0.02-0.04 Hz and a wider frequency range (0-0.1164 Hz). Significantly higher correlations and Dice coefficient were found in normal tissues than in the lesion ROI for all three methods. DATA CONCLUSION: The optimal frequency ranges for rs-CVR are determined by comparing with bh-CVR in patients with gliomas. The rs-CVR method outperformed the RSFA. Significantly higher correlation and Dice coefficient between rs- and bh-CVR were found in normal tissue than in the lesion. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression.

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68+ cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures.CONCLUSIONOur results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.FUNDINGThis study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry & Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics & Data Science Training Grant (T32GM141746).

Advances in Diagnosis and Treatment for Leptomeningeal Disease in Melanoma.

PURPOSE OF REVIEW: Melanoma has one of the highest incidences of causing leptomeningeal disease (LMD) among solid tumors. LMD patients have very poor prognosis with a dismal survival despite aggressive management. In this article, we review the current approaches in the management of patients with LMD secondary to melanoma, including updates in diagnosis, treatment, up-to-date clinical studies, and future directions. RECENT FINDINGS: Cerebrospinal fluid (CSF) cytology remains the gold standard for diagnosis, and alternatively, MRI based on clinical presentation can be used. Other approaches such as "liquid biopsies" that detect circulating tumor cells and cell-free DNA have the potential to considerably enhance the diagnosis of LMD from melanoma. As for treatment options, several systemic therapies, involving systemic targeted and immunotherapies have evolved that showed to have possible benefit in LMD patients. Intrathecal chemotherapy, cellular therapy, and immunotherapy are currently under evaluation in Phase I/II clinical trials. In addition, new radiation therapy approaches such as proton cranial-spinal irradiation (CSI) are currently under investigation. LMD management still remains challenging. Future studies are critical to elucidate the pathophysiology of LMD in order to develop new urgently needed diagnostic tools and therapies. Clinical trials ought to be expanded to include patients with LMD. Future clinical studies should also integrate tissue interrogation, scientifically designed therapies, and aggressive, early intervention in patients with suspected LMD.

Circumferential sulcus-guided resection technique for improved outcomes of low-grade gliomas.

OBJECTIVE: Many neurosurgeons resect nonenhancing low-grade gliomas (LGGs) by using an inside-out piecemeal resection (PMR) technique. At the authors' institution they have increasingly used a circumferential, perilesional, sulcus-guided resection (SGR) technique. This technique has not been well described and there are limited data on its effectiveness. The authors describe the SGR technique and assess the extent to which SGR correlates with extent of resection and neurological outcome. METHODS: The authors identified all patients with newly diagnosed LGGs who underwent resection at their institution over a 22-year period. Demographics, presenting symptoms, intraoperative data, method of resection (SGR or PMR), volumetric imaging data, and postoperative outcomes were obtained. Univariate analyses used ANOVA and Fisher's exact test. Multivariate analyses were performed using multivariate logistic regression. RESULTS: Newly diagnosed LGGs were resected in 519 patients, 208 (40%) using an SGR technique and 311 (60%) using a PMR technique. The median extent of resection in the SGR group was 84%, compared with 77% in the PMR group (p = 0.019). In multivariate analysis, SGR was independently associated with a higher rate of complete (100%) resection (27% vs 18%) (OR 1.7, 95% CI 1.1-2.6; p = 0.03). SGR was also associated with a statistical trend toward lower rates of postoperative neurological complications (11% vs 16%, p = 0.09). A subset analysis of tumors located specifically in eloquent brain demonstrated SGR to be as safe as PMR. CONCLUSIONS: The authors describe the SGR technique used to resect LGGs and show that SGR is independently associated with statistically significantly higher rates of complete resection, without an increase in neurological complications, than with PMR. SGR technique should be considered when resecting LGGs.

Long term outcomes following surgery for pineal region tumors.

PURPOSE: Pineal region tumors are surgically demanding tumors to resect. Long term neuro-oncologic outcomes following surgical excision of tumors from this region have been underreported. We sought to define the long term outcomes of patients undergoing resection of pineal region tumors. METHODS: A retrospective analysis of a prospectively maintained database was performed on patients who underwent intended surgical excision of pineal region tumors. Overall survival (OS) and progression free survival (PFS) were the primary endpoints of this study. Factors associated with OS, PFS and the degree of resection were analyzed, along with 30-day complication rates and dependence on CSF diversion. RESULTS: Sixty-eight patients with a mean age of 30.9 ± 15.3 years were analyzed. The median clinical and radiographic follow-up was 95.7 and 48.2 months, respectively. The supracerebellar infratentorial and the occipital transtentorial corridors were utilized in the majority of cases (80.9%). The gross total resection (GTR) rate was 52.9% (n=36). The 5-year OS and PFS rates were 70.2% and 58.5%, respectively. Achieving GTR was associated with improved OS (HR 0.39, p = 0.03) and PFS (HR 0.4, p = 0.006). The 30-day mortality rate was 5.9%. The need for CSF diversion was high with 77.9% of patients requiring a shunt or ETV by last follow-up. CONCLUSIONS: This is the first modern surgical series providing long term follow-up for patients undergoing surgical resection of pineal region tumors. Obtaining a GTR of these challenging tumors is beneficial with regards to PFS/OS. Higher grade tumors have diminished PFS/OS and are treated with adjuvant chemotherapy and/or radiotherapy.

CD11c+CD163+ Cells and Signal Transducer and Activator of Transcription 3 (STAT3) Expression Are Common in Melanoma Leptomeningeal Disease.

Leptomeningeal disease (LMD) in melanoma patients is associated with significant neurological sequela and has a dismal outcome, with survival measured typically in weeks. Despite the therapeutic benefit of targeted therapies and immunotherapies for Stage IV melanoma, patients with LMD do not typically benefit. A deeper understanding of the tumor microenvironment (TME) of LMD may provide more appropriate therapeutic selection. A retrospective analysis of subjects who underwent surgical resection with LMD (n=8) were profiled with seven color multiplex staining to evaluate the expression of the global immune suppressive hub - the signal transducer and activator of transcription 3 (STAT3) and for the presence of CD3+ T cells, CD68+ monocyte-derived cells, CD163+ immune suppressive macrophages, and CD11c+ cells [potential dendritic cells (DCs)] in association with the melanoma tumor marker S100B and DAPI for cellular nuclear identification. High-resolution cellular imaging and quantification was conducted using the Akoya Vectra Polaris. CD11c+ cells predominate in the TME (10% of total cells), along with immunosuppressive macrophages (2%). Another potential subset of DCs co-expressing CD11c+ and the CD163+ immunosuppressive marker is frequently present (8/8 of specimens, 8%). Occasional CD3+ T cells are identified, especially in the stroma of the tumor (p=0.039). pSTAT3 nuclear expression is heterogeneous in the various immune cell populations. Occasional immune cluster interactions can be seen in the stroma and on the edge. In conclusion, the TME of LMD is largely devoid of CD3+ T cells but is enriched in immune suppression and innate immunity.

A validated integrated clinical and molecular glioblastoma long-term survival-predictive nomogram.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors. METHODS: A retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas. RESULTS: Univariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden (P = .0055) and PTEN mutations (P = .0235) negatively impacted survival, whereas IDH1 mutations positively impacted survival (P < .0001). Clinical factors significantly associated with GBM survival included age (P < .0001), preoperative Karnofsky Performance Scale score (P = .0001), sex (P = .0164), and clinical trial participation (P < .0001). Higher preoperative T1-enhancing volume (P = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival (P = .0022). CONCLUSIONS: Our newly devised long-term survival-predictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials.

Challenges and Advances in Diagnosis and Treatment of Leptomeningeal Disease (LMD).

Leptomeningeal disease (LMD) is a devastating category of CNS metastasis with a very poor prognosis and limited treatment options. With maximal aggressive therapy, survival times remain short and, without treatment, prognosis is measured in weeks. Both LMD diagnosis and treatment are challenging topics within neuro-oncology. In this review, we discuss the advances in LMD diagnosis with a focus on the role of circulating tumor DNA (ctDNA) and discuss the role of targeted and immunotherapy in LMD treatment.

Alterations in Functional Connectomics Associated With Neurocognitive Changes Following Glioma Resection.

BACKGROUND: Decline in neurocognitive functioning (NCF) often occurs following brain tumor resection. Functional connectomics have shown how neurologic insults disrupt cerebral networks underlying NCF, though studies involving patients with brain tumors are lacking. OBJECTIVE: To investigate the impact of brain tumor resection upon the connectome and relationships with NCF outcome in the early postoperative period. METHODS: A total of 15 right-handed adults with left perisylvian glioma underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment before and after awake tumor resection. Graph theoretical analysis was applied to rs-fMRI connectivity matrices to calculate network properties. Network properties and NCF measures were compared across the pre- to postoperative periods with matched pairs Wilcoxon signed-rank tests. Associations between pre- to postoperative change in network and NCF measures were determined with Spearman rank-order correlations (ρ). RESULTS: A majority of the sample showed postoperative decline on 1 or more NCF measures. Significant postoperative NCF decline was found across measures of verbal memory, processing speed, executive functioning, receptive language, and a composite index. Regarding connectomic properties, betweenness centrality and assortativity were significantly smaller postoperatively, and reductions in these measures were associated with better NCF outcomes. Significant inverse associations (ρ = -.51 to -.78, all P < .05) were observed between change in language, executive functioning, and learning and memory, and alterations in segregation, centrality, and resilience network properties. CONCLUSION: Decline in NCF was common shortly following resection of glioma involving eloquent brain regions, most frequently in verbal learning/memory and executive functioning. Better postoperative outcomes accompanied reductions in centrality and resilience connectomic measures.

Targeting the Tumor Microenvironment in Brain Metastasis.

Dynamic interplay between cancer cells and the surrounding microenvironment is a feature of the metastatic process. Successful metastatic brain colonization requires complex mechanisms that ultimately allow tumor cells to adapt to the unique microenvironment of the central nervous system, evade immune destruction, survive, and grow. Accumulating evidence suggests that components of the brain tumor microenvironment (TME) play a vital role in the metastatic cascade. In this review, the authors summarize the contribution of the TME to the development and progression of brain metastasis. They also highlight opportunities for TME-directed targeted therapy.