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Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis., Competing Interests: Declaration of interests N.S.M. has consulted for AstraZeneca. D.P. is on the scientific advisory board of Insitro. J.M. holds company stock of Scholar Rock, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS)., Objective: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort., Design, Setting, and Participants: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021., Intervention: SRS for RCC BMs., Outcome Measurements and Statistical Analysis: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death., Results and Limitations: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041)., Conclusions: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting., Patient Summary: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT., Observations: A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease., Lessons: Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

BACKGROUND. Brain tumors induce language reorganization, which may influence the extent of resection in surgical planning. Direct cortical stimulation (DCS) allows definitive language mapping during awake surgery by locating areas of speech arrest (SA) surrounding the tumor. Although functional MRI (fMRI) combined with graph theory analysis can illustrate whole-brain network reorganization, few studies have corroborated these findings with DCS intraoperative mapping and clinical language performance. OBJECTIVE. We evaluated whether patients with low-grade gliomas (LGGs) without SA during DCS show increased right-hemispheric connections and better speech performance compared with patients with SA. METHODS. We retrospectively recruited 44 consecutive patients with left perisylvian LGG, preoperative language task-based fMRI, speech performance evaluation, and awake surgery with DCS. We generated language networks from ROIs corresponding to known language areas (i.e., language core) on fMRI using optimal percolation. Language core connectivity in the left and right hemispheres was quantified as fMRI laterality index (LI) and connectivity LI on the basis of fMRI activation maps and connectivity matrices. We compared fMRI LI and connectivity LI between patients with SA and without SA and used multivariable logistic regression ( p < .05) to assess associations between DCS and connectivity LI, fMRI LI, tumor location, Broca area and Wernicke area involvement, prior treatments, age, handedness, sex, tumor size, and speech deficit before surgery, within 1 week after surgery, and 3-6 months after surgery. RESULTS. Patients with SA showed left-dominant connectivity; patients without SA lateralized more to the right hemisphere ( p < .001). Between patients with SA and those without, fMRI LI was not significantly different. Patients without SA showed right-greater-than-left connectivity of Broca area and premotor area compared with patients with SA. Regression analysis showed significant association between no SA and right-lateralized connectivity LI ( p < .001) and fewer speech deficits before ( p < .001) and 1 week after ( p = .02) surgery. CONCLUSION. Patients without SA had increased right-hemispheric connections and right translocation of the language core, suggesting language reorganization. Lack of interoperative SA was associated with fewer speech deficits both before and immediately after surgery. CLINICAL IMPACT. These findings support tumor-induced language plasticity as a compensatory mechanism, which may lead to fewer postsurgical deficits and allow extended resection.

Introduction: Patients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear., Methods: Patients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology., Results: There were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28-1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression., Conclusions: Intracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients., (© 2023 The Authors.)

The HER2-directed antibody-drug conjugate trastuzumab deruxtecan is active against lower levels of HER2 expression than prior-generation therapies. The rate of HER2 expression in brain metastases among patients with initially HER2-null breast cancer is undefined, and receptor discordance in advanced breast cancer with brain metastases may underestimate CNS response potential in the absence of brain metastasis sampling. In this cohort study including 136 patients with 401 samples scored according to ASCO/CAP guidelines, 15/28 patients (54%) with HER2-null primary breast cancer have detectable HER2 expression in subsequently resected brain metastases, a significant discordant population., (© 2023. Springer Nature Limited.)

Importance: Adjuvant stereotactic radiosurgery (SRS) enhances the local control of resected brain metastases (BrM). However, the risks of local failure (LF) and potential for posttreatment adverse radiation effects (PTRE) after early postoperative adjuvant SRS have not yet been established., Objective: To evaluate whether adjuvant SRS delivered within a median of 14 days after surgery is associated with improved LF without a concomitant increase in PTRE., Design, Setting, and Participants: This prospective cohort study examines a clinical workflow (RapidRT) that was implemented from 2019 to 2022 to deliver SRS to surgical patients within a median of 14 days, ensuring all patients were treated within 30 days postoperatively. This prospective cohort was compared with a historical cohort (StanRT) of patients with BrM resected between 2013 and 2019 to assess the association of the RapidRT workflow with LF and PTRE. The 2 cohorts were combined to identify optimal SRS timing, with a median follow-up of 3.3 years for survivors., Exposure: Timing of adjuvant SRS (14, 21, and 30 days postoperatively)., Main Outcomes and Measures: LF and PTRE, according to modified Response Assessment in Neuro-Oncology Brain Metastases criteria., Results: There were 438 patients (265 [60.5%] female patients; 23 [5.3%] Asian, 27 [6.2%] Black, and 364 [83.1%] White patients) with a mean (SD) age of 62 (13) years; 377 were in the StanRT cohort and 61 in the RapidRT cohort. LF and PTRE rates at 1 year were not significantly different between RapidRT and StanRT cohorts. Timing of SRS was associated with radiographic PTRE. Patients receiving radiation within 14 days had the highest 1-year PTRE rate (18.08%; 95% CI, 8.31%-30.86%), and patients receiving radiation between 22 and 30 days had the lowest 1-year PTRE rate (4.10%; 95% CI, 1.52%-8.73%; P = .03). LF rates were highest for patients receiving radiation more than 30 days from surgery (10.65%; 95% CI, 6.90%-15.32%) but comparable for patients receiving radiation within 14 days, between 15 and 21 days, and between 22 and 30 days (≤14 days: 5.12%; 95% CI, 0.86%-15.60%; 15 to ≤21 days: 3.21%; 95% CI, 0.59%-9.99%; 22 to ≤30 days: 6.58%; 95% CI, 3.06%-11.94%; P = .20)., Conclusions and Relevance: In this cohort study of adjuvant SRS timing following surgical resection of BrM, the optimal timing for adjuvant SRS appears to be within 22 to 30 days following surgery. The findings of this study suggest that this timing allows for a balanced approach that minimizes the risks associated with LF and PTRE.

Objectives: While fully supervised learning can yield high-performing segmentation models, the effort required to manually segment large training sets limits practical utility. We investigate whether data mined line annotations can facilitate brain MRI tumor segmentation model development without requiring manually segmented training data., Methods: In this retrospective study, a tumor detection model trained using clinical line annotations mined from PACS was leveraged with unsupervised segmentation to generate pseudo-masks of enhancing tumors on T1-weighted post-contrast images (9911 image slices; 3449 adult patients). Baseline segmentation models were trained and employed within a semi-supervised learning (SSL) framework to refine the pseudo-masks. Following each self-refinement cycle, a new model was trained and tested on a held-out set of 319 manually segmented image slices (93 adult patients), with the SSL cycles continuing until Dice score coefficient (DSC) peaked. DSCs were compared using bootstrap resampling. Utilizing the best-performing models, two inference methods were compared: (1) conventional full-image segmentation, and (2) a hybrid method augmenting full-image segmentation with detection plus image patch segmentation., Results: Baseline segmentation models achieved DSC of 0.768 (U-Net), 0.831 (Mask R-CNN), and 0.838 (HRNet), improving with self-refinement to 0.798, 0.871, and 0.873 (each p < 0.001), respectively. Hybrid inference outperformed full image segmentation alone: DSC 0.884 (Mask R-CNN) vs. 0.873 (HRNet), p < 0.001., Conclusions: Line annotations mined from PACS can be harnessed within an automated pipeline to produce accurate brain MRI tumor segmentation models without manually segmented training data, providing a mechanism to rapidly establish tumor segmentation capabilities across radiology modalities., Key Points: • A brain MRI tumor detection model trained using clinical line measurement annotations mined from PACS was leveraged to automatically generate tumor segmentation pseudo-masks. • An iterative self-refinement process automatically improved pseudo-mask quality, with the best-performing segmentation pipeline achieving a Dice score of 0.884 on a held-out test set. • Tumor line measurement annotations generated in routine clinical radiology practice can be harnessed to develop high-performing segmentation models without manually segmented training data, providing a mechanism to rapidly establish tumor segmentation capabilities across radiology modalities., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression., (© 2023. Springer Nature Limited.)

Purpose: The purpose of this study was to evaluate the safety and efficacy of middle meningeal artery embolization (MMAE) performed under cone-beam computed tomography (CBCT) augmented guidance in patients with cancer., Materials and Methods: Eleven patients with cancer (seven women, four men; median age, 75 years; age range: 42-87 years) who underwent 17 MMAEs under CBCT with a combination of particles and coils for chronic subdural hematoma (SDH) (n = 6), postoperative SDH (n = 3), or preoperative embolization of meningeal tumor (n = 2) from 2022 to 2023 were included. Technical success, fluoroscopy time (FT), reference dose (RD), kerma area product (KAP) were analyzed. Adverse events and outcomes were recorded., Results: The technical success rate was 100% (17/17). Median MMAE procedure duration was 82 min (interquartile range [IQR]: 70, 95; range: 63-108 min). The median FT was 24 min (IQR: 15, 48; range: 21.5-37.5 min); the median RD was 364 mGy (IQR: 37, 684; range: 131.5-444.5 mGy); and the median KAP was 46.4 Gy.cm 2 (9.6, 104.5; range: 30.2-56.6 Gy.cm 2 ). No further interventions were needed. The adverse event rate was 9% (1/11), with one pseudoaneurysm at the puncture site in a patient with thrombocytopenia, which was treated by stenting. The median follow-up was 48 days (IQR; 14, 251; range: 18.5-91 days]. SDH reduced in 11 of 15 SDHs (73%) as evidenced by follow-up imaging, with a size reduction greater than 50% in 10/15 SDHs (67%) ., Conclusion: MMAE under CBCT is a highly effective treatment option, but appropriate patient selection and careful consideration of potential risks and benefits is important for optimal patient outcomes., (Copyright © 2023 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Brain metastases are rare in patients with prostate cancer and portend poor outcome. Prostate-specific membrane antigen positron emission tomography (PSMA PET)/CT scans including the brain have identified incidental tumors. We sought to identify the incidental brain tumor detection rate of PSMA PET/CT performed at initial diagnosis or in the setting of biochemical recurrence., Methods: An institutional database was queried for patients who underwent 68 Ga-PSMA-11 or 18 F-DCFPyL ( 18 F-piflufolastat) PET/CT imaging at an NCI-designated Comprehensive Cancer Center from 1/2018 to 12/2022. Imaging reports and clinical courses were reviewed to identify brain lesions and describe clinical and pathologic features., Results: Two-thousand seven hundred and sixty-three patients underwent 3363 PSMA PET/CT scans in the absence of neurologic symptoms. Forty-four brain lesions were identified, including 33 PSMA-avid lesions: 10 intraparenchymal metastases (30%), 4 dural-based metastases (12%), 16 meningiomas (48%), 2 pituitary macroadenomas (6%), and 1 epidermal inclusion cyst (3%) (incidences of 0.36, 0.14, 0.58, 0.07, and 0.04%). The mean parenchymal metastasis diameter and mean SUVmax were 1.99 cm (95%CI:1.25-2.73) and 4.49 (95%CI:2.41-6.57), respectively. At the time of parenchymal brain metastasis detection, 57% of patients had no concurrent extracranial disease, 14% had localized prostate disease only, and 29% had extracranial metastases. Seven of 8 patients with parenchymal brain metastases remain alive at a median 8.8 months follow-up., Conclusion: Prostate cancer brain metastases are rare, especially in the absence of widespread metastatic disease. Nevertheless, incidentally detected brain foci of PSMA uptake may represent previously unknown prostate cancer metastases, even in small lesions and in the absence of systemic disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Highly effective brain-penetrant ALK-targeted tyrosine kinase inhibitors (TKIs) have been developed for the management of NSCLC patients with brain metastases (BM). Local therapy (LT) such as SRS or therapeutic craniotomy is increasingly being deferred for such patients. Herein we report detailed patient- and lesion-level intracranial outcomes and co-mutational genomic profiles from a cohort of NSCLC patients with BM treated with alectinib, with or without LT., Methods: We retrospectively reviewed ALK fusion-positive NSCLC patients with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. Outcome variables included intracranial progression-free survival (iPFS), overall survival (OS), duration of TKI therapy, and CNS response rates. Genomic characteristics from tumor specimens were assessed with MSK-IMPACT, a next-generation sequencing (NGS)-based genomic profiling assay., Results: A total of 38 patients with 114 CNS lesions were included. Twelve of these patients also received contemporaneous LT (SRS, WBRT, or surgical resection). Maximal BM diameter in the TKI + LT group was greater (p < 0.003) but despite this difference, iPFS (TKI only, HR 1.21, 95 % CI 0.51-2.89; p = 0.66) and OS (TKI only, HR 5.99, 95 % CI 0.77-46.6; p = 0.052) were similar between groups and trended towards more favorable outcomes with the addition of LT. SMARCA4 co-alterations were associated with inferior OS (HR 8.76, 1.74-44.2; p = 0.009)., Conclusions: Our study demonstrated that patients with ALK fusion-positive NSCLC treated with TKI + LT had larger BM and higher likelihood of pre-treatment neurologic symptoms. Despite these differences, iPFS was similar between groups. Results should be interpreted with caution as our study was limited by an underpowered sample size. SMARCA4 co-alterations were associated with inferior OS and these findings warrant further investigation., 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 B.V. All rights reserved.)

Aim: Immune checkpoint inhibitor (ICI) efficacy is undefined for melanoma brain metastases (MBM) with concurrent corticosteroid exposure. Materials & methods: We retrospectively evaluated patients with untreated MBM who received corticosteroids (≥1.5 mg dexamethasone equivalent) within 30 days of ICI. mRECIST criteria and Kaplan-Meier methods defined intracranial progression-free survival (iPFS). The lesion size-response association was evaluated with repeated measures modeling. Results: A total of 109 MBM were evaluated. The patient level intracranial response rate was 41%. Median iPFS was 2.3 months and overall survival was 13.4 months. Larger lesions were more likely to progress, with diameter >2.05 cm most predictive of progression (OR: 18.9; 95% CI: 2.6-139.5; p = 0.004). There was no difference in iPFS with steroid exposure pre- versus post-ICI initiation. Conclusion: In the largest reported ICI+corticosteroid cohort, we identify size dependent MBM response.

A 65-year-old woman with a known right-sided, dural-based lesion and metastatic pancreatic neuroendocrine tumor presented with multiple days of progressive lethargy and left-sided weakness culminating with obtundation and dilated pupils. Computed tomography demonstrated an acute right convexity subdural hematoma and a frontotemporal intraparenchymal hemorrhage with 1.3 cm of midline shift, uncal herniation, and an increase in size of now a hemorrhagic dural-based lesion. She underwent emergency hemicraniectomy for evacuation of subdural hematoma and resection of hemorrhagic meningioma with excellent postoperative result including improvement in midline shift and gross total resection of lesion. Pathology was consistent with a World Health Organization grade II meningioma with a chordoid component. She underwent adjuvant stereotactic radiosurgery and cranioplasty and made a full neurologic recovery. Identification of hemorrhagic meningioma as the underlying pathology causing multicompartmental hemorrhage is crucial. We recommend single-stage decompression with extraaxial clot evacuation and resection of the meningioma when feasible., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cystic postradiation degeneration has previously been described in the literature as a rare but potentially severe complication after central nervous system (CNS) irradiation for vascular malformations. Limited cases have been reported in the setting of brain metastases., Observations: Thirty-six total cases, including three reported here, of cystic postradiation degeneration are identified. Of 35 cases with complete clinical information, 34 (97.25%) of 35 were symptomatic from cystic changes at diagnosis. The average time between initial radiation dose and cyst development was 7.61 years (range 2-31 years). Although most patients were initially treated conservatively with medication, including steroids, 32 (88.9%) of 36 ultimately required surgical intervention. The most common interventions were craniotomy for cyst fenestration or resection (25 of 36; 69.4%) and Ommaya placement (8 of 36). After intervention, clinical improvement was seen in 10 (67%) of 15 cases, with persistent or worsening deficit or death seen in 5 (33%) of 15. Cysts were decompressed or obliterated on postoperative imaging in 20 (83.3%) of 24 cases, and recurrence was seen in 4 (16.7%) of 24., Lessons: Cystic degeneration is a rare and delayed sequela after radiation for brain metastases. This entity has the potential to cause significant and permanent neurological deficit if not properly recognized and addressed. Durable control can be achieved with a variety of surgical treatments, including cyst fenestration and Ommaya placement.

Objective: The ability of functional MRI (fMRI) to localize patient-specific eloquent areas has proved worthwhile in efforts to maximize resection while minimizing risk of iatrogenic damage in patients with brain tumors. Although cortical reorganization has been described, the frequency of its occurrence and the factors that influence incidence are not well understood. The authors investigated changes in language laterality between 2 fMRI studies in patients with brain tumors to elucidate factors contributing to cortical reorganization., Methods: The authors analyzed 33 patients with brain tumors involving eloquent language areas who underwent 2 separate presurgical, language task-based fMRI examinations (fMRI1 and fMRI2). Pathology consisted of low-grade glioma (LGG) in 15, and high-grade glioma (HGG) in 18. The mean time interval between scans was 35 ± 38 months (mean ± SD). Regions of interest were drawn for Broca's area (BA) and the contralateral BA homolog. The laterality index (LI) was calculated and categorized as follows: > 0.2, left dominance; 0.2 to -0.2, codominance; and < -0.2, right dominance. Translocation of language function was defined as a shift across one of these thresholds between the 2 scans. Comparisons between the 2 groups, translocation of language function (reorganized group) versus no translocation (constant group), were performed using the Mann-Whitney U-test., Results: Nine (27%) of 33 patients demonstrated translocation of language function. Eight of 9 patients with translocation had tumor involvement of BA, compared to 5/24 patients without translocation (p < 0.0001). There was no difference in LI between the 2 groups at fMRI1. However, the reorganized group showed a decreased LI at fMRI2 compared to the constant group (-0.1 vs 0.53, p < 0.01). The reorganized cohort showed a significant difference between LI1 and LI2 (0.50 vs -0.1, p < 0.0001) whereas the constant cohort did not. A longer time interval was found in the reorganized group between fMRI1 and fMRI2 for patients with LGG (34 vs 107 months, p < 0.002). Additionally, the reorganized cohort had a greater proportion of local tumor invasion into eloquent areas at fMRI2 than the constant group. Aphasia was present following fMRI2 in 13/24 (54%) patients who did not exhibit translocation, compared to 2/9 (22%) patients who showed translocation., Conclusions: Translocation of language function in patients with brain tumor is associated with tumor involvement of BA, longer time intervals between scans, and is seen in both LGG and HGG. The reduced incidence of aphasia in the reorganized group raises the possibility that reorganization supports the conservation of language function. Therefore, longitudinal fMRI is useful because it may point to reorganization and could affect therapeutic planning for patients.

Purpose: Timely surgical cavity stereotactic radiosurgery (SRS) is an important adjuvant to brain metastasis resection, with earlier treatment associated with less frequent recurrence. The logistical complexity of treatment organization, however, has resulted in suboptimal start times postsurgically. We implemented a process improvement approach to reduce the time from surgery to adjuvant irradiation of resected brain metastases., Methods: A multidisciplinary working group used process mapping to identify opportunities to reduce visits and shorten treatment times. The care delivery process was modified to streamline perioperative SRS preparation with (1) early patient identification, (2) preoperative intrateam communication, and (3) consolidation of required steps. Plan-Do-Study-Act cycles were used for process improvement. The surgery-to-SRS initiation time interval was the primary outcome. Secondary outcomes included the number of associated patient encounters., Results: After implementation, the median (interquartile range) interval from surgery to SRS was reduced 48% from 27 (21-34) to 14 days (13-17; P < .001). The rate of surgical cavity SRS within 30 days increased from 64% (n = 63 of 98) to 97% (n = 60 of 62; P < .001). The median (interquartile range) number of CNS-associated encounters between resection and SRS decreased from 5 (4-6) to 4 (3-5; P < .001). The proportion of patients who had > 1 magnetic resonance imaging/computed tomography between surgery and SRS decreased from 45% (44 of 98) to 13% (8 of 62; P < .001). The time from surgery to systemic therapy resumption/initiation among patients treated within 90 days postoperatively decreased from 35 (24-48) to 32 days (23-40; P = .074). There were no wound complications in either group., Conclusion: Adjuvant SRS latency and treatment-associated encounters were significantly reduced after care-coordination implementation. This approach reduces patient and health care system burden and can be applied to other scenarios where early postoperative SRS administration is critical., Competing Interests: Nelson S. MossConsulting or Advisory Role: AstraZenecaResearch Funding: GT Medical Technologies (Inst) Samantha BrownResearch Funding: AACR (Inst) Justin ChenStock and Other Ownership Interests: MindMed, Moderna Therapeutics, Tonix Pharmaceuticals, Ocugen, Ocuphire Pharma, Innerscope Hearing Technologies, Heat Biologics Brandon S. ImberHonoraria: GT Medical Technologies Luke PikeStock and Other Ownership Interests: Clovis Oncology, Schrodinger, NovavaxConsulting or Advisory Role: Blackstone, Deerfield Management, Third Rock Ventures, Aviko, Monograph Capital, Roivant, Galera Therapeutics, Dynamo Therapeutics, Myst Therapeutics, Turnstone Bio, Best Doctors Inc Katherine S. PanageasStock and Other Ownership Interests: AstraZeneca, Pfizer, Sunesis Pharmaceuticals Cameron BrennanStock and Other Ownership Interests: AVEOPatents, Royalties, Other Intellectual Property: Co-inventor on patents licensed through Memorial Sloan Kettering to Elucida Oncology Viviane TabarStock and Other Ownership Interests: BlueRock Therapeutics (I)Honoraria: BlueRock Therapeutics (I)Consulting or Advisory Role: BlueRock Therapeutics (I)Research Funding: BlueRock Therapeutics (I)Patents, Royalties, Other Intellectual Property: BlueRock Therapeutics (I)Travel, Accommodations, Expenses: BlueRock Therapeutics (I) Kathryn BealStock and Other Ownership Interests: MMT (I)No other potential conflicts of interest were reported.

Objective: Cesium-131 brachytherapy is an adjunct for brain tumor treatment, offering potential clinical and radiation protection advantages over other isotopes including iodine-125. We present evidence-based radiation safety recommendations from an initial experience with Cs-131 brachytherapy in the resection cavities of recurrent, previously irradiated brain metastases., Methods: Twenty-two recurrent brain metastases in 18 patients were resected and treated with permanent Cs-131 brachytherapy implantation using commercially procured seed-impregnated collagen tiles (GammaTile, GT Medical Technologies). Exposure to intraoperative staff was monitored with NVLAP-accredited ring dosimeters. For patient release considerations, NCRP guidelines were used to develop an algorithm for modeling lifetime exposure to family and ancillary staff caring for patients based on measured dose rates., Results: A median of 16 Cs-131 seeds were implanted (range 6-46) with median cumulative strength of 58.72U (20.64-150.42). Resulting dose rates were 1.19 mSv/h (0.28-3.3) on contact, 0.08 mSv/h (0.01-0.35) at 30 cm, and 0.01 mSv/h (0.001-0.03) at 100 cm from the patient. Modeled total caregiver exposure was 0.91 mSv (0.16-3.26), and occupational exposure was 0.06 mSv (0.02-0.23) accounting for patient self-shielding via skull and soft tissue attenuation. Real-time dose rate measurements were grouped into brackets to provide close contact precautions for caregivers ranging from 1-3 weeks for adults and longer for pregnant women and children, including cases with multiple implantations., Conclusions: Radiological protection precautions were developed based on patient-specific emissions and accounted for multiple implantations of Cs-131, to maintain exposure to staff and the public in accordance with relevant regulatory dose constraints., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Salvage of recurrent previously irradiated brain metastases (rBrM) is a significant challenge. Resection without adjuvant re-irradiation is associated with a high local failure rate, while reirradiation only partially reduces failure but is associated with greater radiation necrosis risk. Salvage resection plus Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced normal brain dose versus re-irradiation, however data are limited., Methods: A prospective registry of consecutive patients with post-stereotactic radiosurgery (SRS) rBrM undergoing resection plus implantation of collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60 Gy at 5 mm from the cavity was analyzed., Results: Twenty patients underwent 24 operations with Cs131 implantation in 25 tumor cavities. Median maximum preoperative diameter was 3.0 cm (range 1.1-6.3). Gross- or near-total resection was achieved in 80% of lesions. A median of 16 Cs131 seeds (range 6-30), with a median air-kerma strength of 3.5 U/seed were implanted. There was one postoperative wound dehiscence. With median follow-up of 1.6 years for survivors, two tumors recurred (one in-field, one marginal) resulting in 8.4% 1-year progression incidence (95%CI = 0.0-19.9). Radiographic seed settling was identified in 7/25 cavities (28%) 1.9-11.7 months post-implantation, with 1 case of distant migration (4%), without clinical sequelae. There were 8 cases of radiation necrosis, of which 4 were symptomatic., Conclusions: With > 1.5 years of follow-up, intraoperative brachytherapy with commercially available Cs131 implants was associated with favorable local control and toxicity profiles. Weak correlation between preoperative tumor geometry and implanted tiles highlights a need to optimize planning criteria., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Antibody-drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to poor macromolecule penetration across the blood-brain tumor barrier. Trastuzumab deruxtecan (T-DXd), a high-payload antibody-drug conjugate, was recently found to improve progression-free survival in HER2+ breast cancer patients versus prior-generation trastuzumab emtansine, prompting us to evaluate CNS activity in a woman with brain-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent, previously-irradiated lesions were biopsy-proven to represent treatment effect. Subsequent recurrence occurred upon treatment holiday; partial response was observed with rechallenge. This case suggests T-DXd is active in HER2+ breast cancer brain metastases and supports further prospective evaluation.

Importance: Brain metastasis (BrM) in gastroesophageal adenocarcinoma (GEA) is a rare and poorly understood phenomenon associated with poor prognosis., Objectives: To examine the clinical and genomic features of patients with BrM from GEA and evaluate factors associated with survival., Design, Setting, and Participants: In this single-institution retrospective cohort study, 68 patients with BrM from GEA diagnosed between January 1, 2008, and December 31, 2020, were identified via review of billing codes and imaging reports from the electronic medical record with follow-up through November 3, 2021. Genomic data were derived from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical sequencing platform., Exposures: Treatment with BrM resection and/or radiotherapy., Main Outcomes and Measures: Overall survival after BrM diagnosis., Results: Sixty-eight patients (median age at diagnosis, 57.4 years [IQR, 49.8-66.4 years]; 59 [86.8%] male; 55 [85.9%] White) participated in the study. A total of 57 (83.8%) had primary tumors in the distal esophagus or gastroesophageal junction. Median time from initial diagnosis to BrM diagnosis was 16.9 months (IQR, 8.5-27.7 months). Median survival from BrM diagnosis was 8.7 months (95% CI, 5.5-11.5 months). Overall survival was 35% (95% CI, 25%-48%) at 1 year and 24% (95% CI, 16%-37%) at 2 years. In a multivariable analysis, an Eastern Cooperative Oncology Group performance status of 2 or greater (hazard ratio [HR], 4.66; 95% CI, 1.47-14.70; P = .009) and lack of surgical or radiotherapeutic intervention (HR, 7.71; 95% CI, 2.01-29.60; P = .003) were associated with increased risk of all-cause mortality, whereas 3 or more extracranial sites of disease (HR, 1.85; 95% CI, 0.64-5.29; P = .25) and 4 or more BrMs (HR, 2.15; 95% CI, 0.93-4.98; P = .07) were not statistically significant. A total of 31 patients (45.6%) had ERBB2 (formerly HER2 or HER2/neu)-positive tumors, and alterations in ERBB2 were enriched in BrM relative to primary tumors (8 [47.1%] vs 7 [20.6%], P = .05), as were alterations in PTPRT (7 [41.2%] vs 4 [11.8%], P = .03)., Conclusions and Relevance: This study suggests that that a notable proportion of patients with BrM from GEA achieve survival exceeding 1 and 2 years from BrM diagnosis, a more favorable prognosis than previously reported. Good performance status and treatment with combination surgery and radiotherapy were associated with the best outcomes. ERBB2 positivity and amplification as well as PTPRT alterations were enriched in BrM tissue compared with primary tumors; therefore, further study should be pursued to identify whether these variables represent genomic risk factors for BrM development.

Purpose: Pseudoprogression mimicking recurrent glioblastoma remains a diagnostic challenge that may adversely confound or delay appropriate treatment or clinical trial enrollment. We sought to build a radiomic classifier to predict pseudoprogression in patients with primary isocitrate dehydrogenase wild type glioblastoma., Methods and Materials: We retrospectively examined a training cohort of 74 patients with isocitrate dehydrogenase wild type glioblastomas with brain magnetic resonance imaging including dynamic contrast enhanced T1 perfusion before resection of an enhancing lesion indeterminate for recurrent tumor or pseudoprogression. A recursive feature elimination random forest classifier was built using nested cross-validation without and with O 6 -methylguanine-DNA methyltransferase status to predict pseudoprogression., Results: A classifier constructed with cross-validation on the training cohort achieved an area under the receiver operating curve of 81% for predicting pseudoprogression. This was further improved to 89% with the addition of O 6 -methylguanine-DNA methyltransferase status into the classifier., Conclusions: Our results suggest that radiomic analysis of contrast T1-weighted images and magnetic resonance imaging perfusion images can assist the prompt diagnosis of pseudoprogression. Validation on external and independent data sets is necessary to verify these advanced analyses, which can be performed on routinely acquired clinical images and may help inform clinical treatment decisions., (© 2022 The Authors.)

During July 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.617.2 variant infections, including vaccine breakthrough infections, occurred after large public gatherings in Provincetown, Massachusetts, USA, prompting a multistate investigation. Public health departments identified primary and secondary cases by using coronavirus disease surveillance data, case investigations, and contact tracing. A primary case was defined as SARS-CoV-2 detected <14 days after travel to or residence in Provincetown during July 3-17. A secondary case was defined as SARS-CoV-2 detected <14 days after close contact with a person who had a primary case but without travel to or residence in Provincetown during July 3-August 10. We identified 1,098 primary cases and 30 secondary cases associated with 26 primary cases among fully and non-fully vaccinated persons. Large gatherings can have widespread effects on SARS-CoV-2 transmission, and fully vaccinated persons should take precautions, such as masking, to prevent SARS-CoV-2 transmission, particularly during substantial or high transmission.

Brain metastases (BrM) are treated with multimodality therapy, however the optimal combination and timing of modalities in the setting of recurrent tumours that have failed prior treatments remain poorly defined. We present a case of a patient with biopsy-confirmed renal cell carcinoma BrM with good performance status initially treated with laser interstitial thermal ablation therapy (LITT) followed by stereotactic radiosurgery and dual checkpoint inhibitor immunotherapy. He subsequently developed rapid in-field recurrence which was treated with salvage surgical resection and implantation of intracavitary cesium-131 brachytherapy. The patient's disease remained stable through 18 months postoperatively. This case illustrates the range of options available and provides a combination salvage therapy strategy in a select group of locally recurrent patients who have exhausted conventional treatment options., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Thalamic gliomas are rare neoplasms that pose significant surgical challenges. The literature is limited to single-institution retrospective case series. We systematically review the literature and describe the clinical characteristics, treatment strategies, and survival outcomes of adult thalamic gliomas., Methods: Relevant articles were identified on PubMed, Scopus, and Cochrane databases. Papers containing cases of adult thalamic gliomas with clinical outcome data were included. A comprehensive review of clinical characteristics and survival analysis was conducted., Results: We included 25 studies comprising 617 patients. The median age was 45 years (male = 58.6%). Glioblastoma was the most frequent histological type (47.2%), and 82 tumors were H3 K27M-mutant. Motor deficit was the most common presenting symptom (51.8%). Surgical resection was performed in 69.1% of cases while adjuvant chemotherapy and radiotherapy were administered in 56.3% and 72.6%, respectively. Other treatments included laser interstitial thermal therapy, which was performed in 15 patients (2.4%). The lesion laterality (P = 0.754) and the surgical approach (P = 0.111) did not correlate with overall survival. The median progression-free survival was 9 months, and the overall two-year survival rate was 19.7%. The two-year survival rates of low-grade and high-grade thalamic gliomas were 31.0% and 16.5%, respectively. H3 K27M-mutant gliomas showed worse overall survival (P = 0.017)., Conclusion: Adult thalamic gliomas are associated with poor survival. Complete surgical resection is associated with improved survival rates but is not always feasible. H3 K27M mutation is associated with worse survival and a more aggressive approach should be considered for mutant neoplasms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The efficacy of salvage resection (SR) of recurrent brain metastases (rBrM) following stereotactic radiosurgery (SRS) is undefined. We sought to describe local recurrence (LR) and radiation necrosis (RN) rates in patients undergoing SR, with or without adjuvant post-salvage radiation therapy (PSRT)., Methods: A retrospective cohort study evaluated patients undergoing SR of post-SRS rBrM between 3/2003-2/2020 at an NCI-designated cancer center. Cases with histologically-viable malignancy were stratified by receipt of adjuvant PSRT within 60 days of SR. Clinical outcomes were described using cumulative incidences in the clustered competing-risks setting, competing risks regression, and Kaplan-Meier methodology., Results: One-hundred fifty-five rBrM in 135 patients were evaluated. The overall rate of LR was 40.2% (95% CI 34.3-47.2%) at 12 months. Thirty-nine (25.2%) rBrM treated with SR + PSRT trended towards lower 12-month LR versus SR alone [28.8% (95% CI 17.0-48.8%) versus 43.9% (95% CI 36.2-53.4%), p = .07 by multivariate analysis]. SR as re-operation (p = .03) and subtotal resection (p = .01) were independently associated with higher rates of LR. On univariate analysis, tumor size (p = .48), primary malignancy (p = .35), and PSRT technique (p = .43) bore no influence on LR. SR + PSRT was associated with an increased risk of radiographic RN at 12 months versus SR alone [13.4% (95% CI 5.5-32.7%) versus 3.5% (95% CI 1.5-8.0%), p = .02], though the percentage with symptomatic RN remained low (5.1% versus 0.9%, respectively). Median overall survival from SR was 13.4 months (95% CI 10.5-17.7)., Conclusion: In this largest-known series evaluating SR outcomes in histopathologically-confirmed rBrM, we identify a significant LR risk that may be reduced with adjuvant PSRT and with minimal symptomatic RN. Prospective analysis is warranted., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Stereotactic biopsy is increasingly performed on brain metastases (BrMs) as improving cancer outcomes drive aggressive multimodality treatment, including laser interstitial thermal therapy (LITT). However, the tract recurrence (TR) risk is poorly defined in an era defined by focused-irradiation paradigms. As such, the authors aimed to define indications and adjuvant therapies for this procedure and evaluate the BrM-biopsy TR rate., Methods: In a single-center retrospective review, the authors identified stereotactic BrM biopsies performed from 2002 to 2020. Surgical indications, radiographic characteristics, stereotactic planning, dosimetry, pre- and postoperative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria., Results: In total, 499 patients underwent stereotactic intracranial biopsy for any diagnosis, of whom 25 patients (5.0%) underwent biopsy for pathologically confirmed viable BrM, a proportion that increased over the time period studied. Twelve of the 25 BrM patients had ≥ 3 months of radiographic follow-up, of whom 6 patients (50%) developed new metastatic growth along the tract at a median of 5.0 months post-biopsy (range 2.3-17.1 months). All of the TR cases had undergone pre- or early post-biopsy stereotactic radiosurgery (SRS), and 3 had also undergone LITT at the time of initial biopsy. TRs were treated with resection, reirradiation, or observation/systemic therapy., Conclusions: In this study the authors identified a nontrivial, higher than previously described rate of BrM-biopsy tract recurrence, which often required additional surgery or radiation and justified close radiographic surveillance. As BrMs are commonly treated with SRS limited to enhancing tumor margins, consideration should be made, in cases lacking CNS-active systemic treatments, to include biopsy tracts in adjuvant radiation plans where feasible.

Background: Leptomeningeal metastasis (LM) occurs in 3-5% of patients with solid metastatic tumors and often portends a severe prognosis including symptomatic hydrocephalus and intracranial hypertension. Cerebrospinal fluid (CSF) shunting can provide symptomatic relief in this patient subset; however, few studies have examined the role of shunting in the palliation, prognosis and overall oncologic care of these patients., Objective: To identify and evaluate risk factors associated with prognosis after CSF diversion and assess surgical, symptomatic and oncologic outcomes in this population., Methods: A retrospective study was conducted on patients with solid-malignancy LM treated with a shunt at a NCI-designated Comprehensive Cancer Center between 2010 and 2019., Results: One hundred and ninety patients with metastatic LM underwent CSF diversion. Overall survival was 4.14 months from LM diagnosis (95% CI: 3.29-4.70) and 2.43 months (95% CI: 2.01-3.09) from shunting. Karnofsky performance status (KPS) at time of shunting and brain metastases (BrM) number at LM diagnosis demonstrated significant associations with survival (HR = 0.66; 95% CI [0.51-0.86], p = 0.002; HR = 1.40; 95% CI [1.01-1.93] per 10 BrM, p = 0.04, respectively). Eighty-three percent of patients experienced symptomatic relief, and 79% were discharged home or to rehabilitation facilities post-shunting. Post-shunt, 56% of patients received additional systemic therapy or started or completed WBRT. Complications included infection (5%), symptomatic subdural hygroma/hematoma (6.3%), and shunt externalization/removal/repair (8%). Abdominal seeding was not identified., Conclusions: CSF diversion for LM with hydrocephalus and intracranial hypertension secondary to metastasis can achieve symptomatic relief, hospital discharge, and return to further oncologic therapy, with a complication profile unique to this pathophysiology. However, decision-making in this population must incorporate end-of-life goals of care given limited prognosis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Radiation therapy is a cornerstone of brain metastasis (BrM) management but carries the risk of radiation necrosis (RN), which can require resection for palliation or diagnosis. We sought to determine the relationship between extent of resection (EOR) of pathologically-confirmed RN and postoperative radiographic and symptomatic outcomes., Methods: A single-center retrospective review was performed at an NCI-designated Comprehensive Cancer Center to identify all surgically-resected, previously-irradiated necrotic BrM without admixed recurrent malignancy from 2003 to 2018. Clinical, pathologic and radiographic parameters were collected. Volumetric analysis determined EOR and longitudinally evaluated perilesional T2-FLAIR signal preoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months postoperatively when available. Rates of time to 50% T2-FLAIR reduction was calculated using cumulative incidence in the competing risks setting with last follow-up and death as competing events. The Spearman method was used to calculate correlation coefficients, and continuous variables for T2-FLAIR signal change, including EOR, were compared across groups., Results: Forty-six patients were included. Most underwent prior stereotactic radiosurgery with or without whole-brain irradiation (N = 42, 91%). Twenty-seven operations resulted in gross-total resection (59%; GTR). For the full cohort, T2-FLAIR edema decreased by a mean of 78% by 6 months postoperatively that was durable to last follow-up (p < 0.05). EOR correlated with edema reduction at last follow-up, with significantly greater T2-FLAIR reduction with GTR versus subtotal resection (p < 0.05). Among surviving patients, a significant proportion were able to decrease their steroid use: steroid-dependency decreased from 54% preoperatively to 15% at 12 months postoperatively (p = 0.001)., Conclusions: RN resection conferred both durable T2-FLAIR reduction, which correlated with EOR; and reduced steroid dependency., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Historically, the prognosis for patients who have melanoma brain metastasis (MBM) has been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in those with advanced melanoma. Therefore, MBM presentation, prognosis, and the use of multimodality central nervous system (CNS)-directed treatment were reassessed., Methods: In this retrospective study, the authors evaluated patients with MBM who received treatment at Memorial Sloan Kettering Cancer Center between 2010 and 2019. Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis and time-dependent multivariable Cox modeling were used to assess prognostic variables and to associate CNS-directed treatments with OS., Results: Four hundred twenty-five patients with 2488 brain metastases were included. The median OS after an MBM diagnosis was 8.9 months (95% CI, 7.9-11.3 months). Patients who were diagnosed with MBM between 2015 and 2019 experienced longer OS compared to those who were diagnosed between 2010 and 2014 (OS, 13.0 months [95% CI, 10.47-17.06 months] vs 7.0 months [95% CI, 6.1-8.3 months]; P = .0003). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination (P < .0001), increasing numbers of brain metastases at diagnosis (P < .0001), earlier MBM diagnosis year (P = .0008), higher serum levels of lactate dehydrogenase (P < .0001), receipt of immunotherapy before MBM diagnosis (P = .003), and the presence of extracranial disease (P = .02). The use of different CNS-directed treatment modalities was associated with presenting symptoms, diagnosis year, number and size of brain metastases, and the presence of extracranial disease. Multivariable analysis demonstrated improved survival for patients who underwent craniotomy (P = .01)., Conclusions: The prognosis for patients with MBM has improved within the last 5 years, coinciding with the approval of PD-1 immune checkpoint blockade and combined BRAF/MEK targeting. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM., Lay Summary: Historically, melanoma brain metastases (MBM) have carried a poor survival prognosis of 4 to 6 months; however, the introduction of immunotherapy and targeted precision medicines has altered the survival curve for advanced melanoma. In this large, single-institution, contemporary cohort, the authors demonstrate a significant increase in survival of patients with MBM to 13 months within the last 5 years of the study. A worse prognosis for patients with MBM was significantly associated with the number of metastases at diagnosis, previous exposure to immunotherapy, spread of disease to the leptomeningeal compartment, serum lactate dehydrogenase elevation, and the presence of extracranial disease. The current age of systemic treatments has also been accompanied by shifts in the use of central nervous system-directed therapies., (© 2021 American Cancer Society.)

Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Nelson S. MossConsulting or Advisory Role: AstraZeneca Research Funding: GT Medical Technologies No other potential conflicts of interest were reported.

Background: Quantifying the degree to which spinal involvement of metastatic renal cell carcinoma (mRCC) is a locoregional phenomenon vs. a hematogenous, bone-specific affinity has implications for prognosis and antimetastatic therapy., Objective: To investigate the distribution of spinal metastasis in mRCC and to explore relationships between clinical factors and patterns of spinal spread., Methods: Patients with mRCC and spinal involvement from June 2005 to November 2018 were identified. Clinical and biologic features including primary tumor size and degree of spinal and nonbony metastatic involvement were collected. Spinal distributions were evaluated by the permutation test, with the null hypothesis that metastases are distributed uniformly across levels., Results: One hundred patients with 685 spinal levels involved by mRCC were evaluated. A nonuniform spatial distribution was observed across the cohort (P < 0.001); a preponderance of thoracolumbar involvement was noted with the mode at L3. No significant deviation in metastatic distribution from uniform was observed in right- or left-sided tumors, subgroups of distant or local metastases, or histology. Patients with smaller tumors (<4 cm) and local spread had distribution of spinal metastases not significantly different from uniform (P = 0.292 and P = 0.126, respectively)., Conclusions: These data support a dominant locoregional as opposed to arterial hematogenous mechanism for early spinal dissemination of mRCC. Characterizations of the biologic molecular features contributing to osseous tropism and aggressive tumor biology (as seen in the subset of outlier patients with small tumors who appear to have more uniform spread), have implications for surveillance and are an area of active investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Adjuvant stereotactic radiosurgery (SRS) improves the local control of resected brain metastases (BrM). However, the dependency of long-term outcomes on SRS timing relative to surgery remains unclear., Methods: Retrospective analysis of patients treated with metastasectomy-plus-adjuvant SRS at Memorial Sloan Kettering Cancer Center (MSK) between 2013 and 2016 was conducted. Kaplan-Meier methodology was used to describe overall survival (OS) and cumulative incidence rates were estimated by type of recurrence, accounting for death as a competing event. Recursive partitioning analysis (RPA) and competing risks regression modeling assessed prognostic variables and associated events of interest., Results: Two hundred and eighty-two patients with BrM had a median OS of 1.5 years (95% CI: 1.2-2.1) from adjuvant SRS with median follow-up of 49.8 months for survivors. Local surgical recurrence, other simultaneously SRS-irradiated site recurrence, and distant central nervous system (CNS) progression rates were 14.3% (95% CI: 10.1-18.5), 4.9% (95% CI: 2.3-7.5), and 47.5% (95% CI: 41.4-53.6) at 5 years, respectively. Median time-to-adjuvant SRS (TT-SRS) was 34 days (IQR: 27-39). TT-SRS was significantly associated with surgical site recurrence rate ( P = 0.0008). SRS delivered within 1 month resulted in surgical site recurrence rate of 6.1% (95% CI: 1.3-10.9) at 1-year, compared to 9.2% (95% CI: 4.9-13.6) if delivered between 1 and 2 months, or 27.3% (95% CI: 0.0-55.5) if delivered >2 months after surgery. OS was significantly lower for patients with TT-SRS >~2 months. Postoperative length of stay, discharge to a rehabilitation facility, urgent care visits, and/or disease recurrence between surgery and adjuvant SRS associated with increased TT-SRS., Conclusions: Adjuvant SRS provides durable local control. However, delays in initiation of postoperative SRS can decrease its efficacy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.

Brain metastases (BrM) affect up to 20% of patients with cancer and represent an increasing portion of patients with surgical brain tumors owing to improving prognoses of cancer patients in general and in many cases even of those with brain metastases. With advances in molecular biology and targeted therapy, the indications for neurosurgical sampling and specifically stereotactic biopsy are likely to change in the future. In this review the authors address some of the scientific advances in BrM biology, the clinical rationale and range of techniques currently used to perform stereotactic biopsy, and how the advent of molecular interrogation may potentially alter the way patients with BrM are managed in the future., Competing Interests: Disclosure NM has consulted for AstraZeneca. KY has consulted for BrainLab AG., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [ 18 F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes., Methods: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [ 18 F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [ 18 F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry., Results: In a preclinical mouse model, we illustrated that [ 18 F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [ 18 F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen., Conclusions: Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [ 18 F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: Intraventricular metastatic brain tumors account for a small, but challenging, fraction of metastatic brain tumors (0.9%-4.5%). Metastases from renal cell carcinoma (RCC) account for a large portion of these intraventricular tumors. Although patient outcomes have been assumed to be poor, these have not been reported in a modern series with a multimodality treatment paradigm of radiotherapy (RT), resection, and cerebrospinal fluid (CSF) diversion. We have presented the first case series of patients with intraventricular metastatic tumors from RCC., Methods: We performed a single-institution retrospective review of patients with intraventricular RCC metastases treated from January 2003 to January 2019. Volumetric analysis was used to delineate the tumor size and the Kaplan-Meier method to evaluate the survival data., Results: A total of 22 intraventricular RCC metastases were identified in 19 patients with 61.3 patient-years of follow-up. The median patient age was 64 years, and the median tumor volume was 2.2 cm 3 . Overall, 19 metastases had been treated initially with RT. Of these, 16 had received stereotactic body RT and 3 had received whole brain RT. Three tumors were surgically excised and had received adjuvant stereotactic body RT in the upfront setting. Although 5 patients had presented with obstructive hydrocephalus, none had required CSF diversion. After treatment, 5 metastases had progressed, resulting in 1- and 3-year progression-free survival rates of 81.6% and 68%, respectively. The median overall survival was 2.8 years, with 1- and 5-year overall survival rates of 76.7% and 28.3%, respectively. Leptomeningeal carcinomatosis was not observed., Conclusions: Despite the relatively limited overall survival for this population with metastatic cancer, comparable to contemporary parenchymal brain metastasis cohorts, reasonable local central nervous system control was achieved in most patients using a paradigm of focal RT and resection, where indicated. Finally, CSF diversion was not required even in patients presenting with hydrocephalus., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chordomas are malignant, highly recurrent tumors of the midline skeleton that arise from the remnants of the notochord. The development of systemic therapy is critically important to ultimately managing this tumor. Several ongoing trials are attempting to use molecular targeted therapies for mutated pathways in recurrent and advanced chordomas and have shown promise. In addition, immunotherapies, including brachyury-directed vaccination and checkpoint inhibition, have also been attempted with encouraging results. This article discusses the major pathways that have been implicated in the pathogenesis of chordoma with an emphasis on molecular vulnerabilities that future therapies are attempting to exploit., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Statistical challenges exist when using diffusion tensor imaging (DTI) to assess traumatic axonal injury (TAI) in individual concussed athletes. The authors examined active professional American football players over a 6-year time period to study potential TAI after concussion and assess optimal methods to analyze DTI at the individual level., Methods: Active American professional football players recruited prospectively were assessed with DTI, conventional MRI, and standard clinical workup. Subjects underwent an optional preseason baseline scan and were asked to undergo a scan within 5 days of concussion during gameplay. DTI from 25 age- and sex-matched controls were obtained. Both semiautomated region-of-interest analysis and fully automated tract-based spatial statistics (TBSS) were used to examine DTI at individual and group levels. Statistical differences were assessed comparing individual DTI data to baseline imaging versus a normative database. Group-level comparisons were also performed to determine if longer exposure to professional-level play or prior concussion cause white matter microstructural integrity changes., Results: Forty-nine active professional football players were recruited into the study. Of the 49 players, 7 were assessed at baseline during the preseason and after acute concussion. An additional 18 players were assessed after acute concussion only. An additional 24 players had only preseason baseline assessments. The results suggest DTI is more sensitive to suspected TAI than conventional MRI, given that 4 players demonstrated decreased fractional anisotropy (FA) in multiple tracts despite normal conventional MRI. Furthermore, the data suggest individual assessment of DTI data using baseline premorbid imaging is more sensitive than typical methods of comparing data to a normative control group. Among all subjects with baseline data, 1 reduced FA tract (± 2.5 standard deviations) was found using the typical normative database reference versus 10 statistically significant (p < 0.05) reduced FA tracts when referencing internal control baseline data. All group-level comparisons were statistically insignificant (p > 0.05)., Conclusions: Baseline premorbid DTI data for individual DTI analysis provides increased statistical sensitivity. Specificity using baseline imaging also increases because numerous potential etiologies for reduced FA may exist prior to a concussion. These data suggest that there is a high potential for false-positive and false-negative assessment of DTI data using typical methods of comparing an individual to normative groups given the variability of FA values in the normal population.

Thirty-four cardiac and 22 sudden noncardiac deaths in men were examined with an injection, radiographic, and dissection autopsy technique to obtain as many coronary narrowings as possible for study. The narrowest sites in each of the major coronary vessels (LAD, LCX, and RCA) from each subject were identified histologically for analysis. The parameters studied were size of lumen, estimated as percentage of vessel cross-section, vs. the age of subject and the grades of chronic inflammatory cell infiltrate, of neovascularization, of intimal haemorrhage, and of pultaceous cholesterol-rich deposit in the wall. Genstat statistical analysis revealed that the significant explanatory variables for the reduction in arterial lumen were active inflammation and cardiac cause of death. Neither age nor cholesterol-rich deposits had significant explanatory power. A pathogenic role for inflammation may well be possible and efforts will be made in the future to investigate its etiology.

Using morphologic criteria to distinguish between myocardial infarction and lesions that selectively involve myocardial cells, the authors found evidence of ongoing selective myocardial necrosis in 88% of 50 individuals dying suddenly. Acute coronary thrombosis was rare. Since the morphological characteristics of the cell injury differ significantly from that seen in infarction and since the lesion may occur in individuals without significant epicardial coronary disease, factors other than permanent vascular obstruction are indicated as having a role in sudden cardiac death. Some other yet-unidentified process may alter susceptible myocardial cells.

Cells derived from human atherosclerotic plaques and from arterial media were compared with cells obtained from human leiomyomata and myometrium with respect to growth behavior in long-term cell culture. None of numerous variations in culture media, including alterations of serum concentration and source, improved the rate of cell multiplication or in vitro longevity. Both uterine cell types, but neither arterial cell type, multiplied after tissue dissociation with enzymes (elastase, collagenase, hyaluronidase). The replicative life-span of each of eight samples of arterial plaque cells was equal to or less than that of the corresponding medial cells. A similar relationship was observed for eight paired sets of leiomyoma and myometrial cells. The results indicate that, under the conditions of culture in vitro, cells of a bona fide smooth muscle tumor have a finite replicative life-span and smooth muscle cells of atherosclerotic plaques behave in a similar manner.

Clinical and pathologic changes in 87 patients who could not be resuscitated from an episode of sudden cardiovascular collapse are described and compared with observations from patients in the same community who were successfully resuscitated from ventricular fibrillation. Findings in patients who died suddenly generally did not differ when the patients were groups by electrocardiographic rhythm on arrival of the mobile coronary aid unit. The pathologic changes of acute thrombosis and recent myocardial infarction did not occur with sufficient frequency in the entire group to be considered causally related to the sudden collapse, occurring in 10 and 5 percent of cases, respectively. Although most patients had evidence of obstructive coronary disease and old myocardial infarction, 8 percent had no significant vascular disease, acute thrombosis, myocarditis or valve disease that might be implicated as a factor in sudden death. There was no relation between age and severity of obstructive coronary disease or frequency of old myocardial infarction in patients who died suddenly. Complete atherosclerotic occlusion in one or more coronary vessels occurred in 51 of 87 (59 percent) and old myocardial infarction in 48 of 87 (55 percent). Although the mean age of this autopsy population was similar to that of all patients in the community who have had ventricular fibrillation on arrival of the aid unit, the nonsurvivors had a greater incidence of myocardial infarction and symptomatic heart disease (73 of 87) than did survivors. Comparison of this autopsy group with persons from the community who were resuscitated from ventricular fibrillation and subsequently had coronary angiograms indicates that the severity of coronary stenosis does not distinguish between survivors and nonsurvivors of an episode of ventricular fibrillation and suggests that other factors influence the outcome of an episode of ventricular fibrillation.