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OBJECTIVE Microsurgical resection of arteriovenous malformations (AVMs) can be aided by staged treatment consisting of stereotactic radiosurgery followed by resection in a delayed fashion. This approach is particularly useful for high Spetzler-Martin (SM) grade lesions because radiosurgery can reduce flow through the AVM, downgrade the SM rating, and induce histopathological changes that additively render the AVM more manageable for resection. The authors present their 28-year experience in managing AVMs with adjunctive radiosurgery followed by resection. METHODS The authors retrospectively reviewed records of patients treated for cerebral AVMs at their institution between January 1990 and August 2019. All patients who underwent stereotactic radiosurgery (with or without embolization), followed by resection, were included in the study. Of 1245 patients, 95 met the eligibility criteria. Univariate and multivariate regression analyses were performed to assess relationships between key variables and clinical outcomes. RESULTS The majority of lesions treated (53.9%) were high grade (SM grade IV–V), 31.5% were intermediate (SM grade III), and 16.6% were low grade (SM grade I–II). Hemorrhage was the initial presenting sign in half of all patients (49.5%). Complete resection was achieved among 84% of patients, whereas 16% had partial resection, the majority of whom received additional radiosurgery. Modified Rankin Scale (mRS) scores of 0–2 were achieved in 79.8% of patients, and 20.2% had poor (mRS scores 3–6) outcomes. Improved (44.8%) or stable (19%) mRS scores were observed among 63.8% of patients, whereas 36.2% had a decline in mRS scores. This includes 22 patients (23.4%) with AVM hemorrhage and 6 deaths (6.7%) outside the perioperative period but prior to AVM obliteration. CONCLUSIONS Stereotactic radiosurgery is a useful adjunct in the presurgical management of cerebral AVMs. Multimodal therapy allowed for high rates of AVM obliteration and acceptable morbidity rates, despite the predominance of high-grade lesions in this series of patients.

OBJECTIVE The CyberKnife (CK) has emerged as an effective frameless and noninvasive method for treating a myriad of neurosurgical conditions. Here, the authors conducted an extensive retrospective analysis and review of the literature to elucidate the trend for CK use in the management paradigm for common neurosurgical diseases at their institution. METHODS A literature review (January 1990–June 2019) and clinical review (January 1999–December 2018) were performed using, respectively, online research databases and the Stanford Research Repository of patients with intracranial and spinal lesions treated with CK at Stanford. For each disease considered, the coefficient of determination (r2) was estimated as a measure of CK utilization over time. A change in treatment modality was assessed using a t-test, with statistical significance assessed at the 0.05 alpha level. RESULTS In over 7000 patients treated with CK for various brain and spinal lesions over the past 20 years, a positive linear trend (r2 = 0.80) in the system's use was observed. CK gained prominence in the management of intracranial and spinal arteriovenous malformations (AVMs; r2 = 0.89 and 0.95, respectively); brain and spine metastases (r2 = 0.97 and 0.79, respectively); benign tumors such as meningioma (r2 = 0.85), vestibular schwannoma (r2 = 0.76), and glomus jugulare tumor (r2 = 0.89); glioblastoma (r2 = 0.54); and trigeminal neuralgia (r2 = 0.81). A statistically significant difference in the change in treatment modality to CK was observed in the management of intracranial and spinal AVMs (p < 0.05), and while the treatment of brain and spine metastases, meningioma, and glioblastoma trended toward the use of CK, the change in treatment modality for these lesions was not statistically significant. CONCLUSIONS Evidence suggests the robust use of CK for treating a wide range of neurological conditions.

OBJECTIVES We investigated differences in quality of life (QoL) in patients enrolled on a phase I/II dose-escalation study of 3-fraction resection cavity stereotactic radiosurgery (SRS) for large brain metastases. METHODS Eligible patients had 1 to 4 brain metastases, one of which was a resection cavity 4.2 to 33.5 cm3. European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires core-30 (QLQ-30) and brain cancer specific module (QLQ-BN20) were obtained before SRS and at each follow-up. Nine scales were analyzed (global health status; physical, social, and emotional functioning; motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty). QoL was assessed with mixed effects models. Differences ≥10 points with q-value (adjusted P-value to account for multiplicity of testing)

BACKGROUND To better counsel vestibular schwannoma patients, it is necessary to understand the tumor control rates of stereotactic radiosurgery (SRS). OBJECTIVES To determine tumor control rates, factors determining control and complication rates following SRS. METHODS Tertiary hospital retrospective cohort. RESULTS 579 tumors (576 patients) were treated with SRS. 477 tumors (474 patients, 82%) had ≥1 year follow up and 60% (344) ≥3 years follow up. 88% of tumors had primary SRS and 6.7% salvage SRS. Median follow up time was 4.6 years. At 3 years, the tumor control rate of primary SRS was 89% (258 of 290) in sporadic tumors compared to 43% in Neurofibromatosis type II (3 of 17) (p

Objective Financial toxicity associated with cancer treatment has a deleterious impact on patient outcomes but has not been well characterized among patients with metastatic cancers. We characterize the extent of financial toxicity among this population and identify factors associated with financial toxicity. Methods We prospectively surveyed adult patients with brain and spine metastases who received radiosurgery at a large academic medical center between January 2018 and December 2019. Financial toxicity was measured with the Personal Financial Wellness (PFW) scale. Results In total, 93 patients were included, with a median survival of 17.7 months. Most patients had private insurance (47%) or Medicare with supplementary insurance (42%), whereas 11% of patients were uninsured or insured by Medicaid/Medicare/Veterans Affairs. Of patients, 60% were primary income earners, of whom 52% had dependents. The median PFW score was 7.0 (interquartile range, 5.1–9.1), with financial toxicity reported in 23 patients (25%). After adjusting for age and education level, private insurance (odds ratio [OR], 0.28; P = 0.080) was associated with a lower likelihood of financial toxicity. Having ≥1 emergency department visit (OR, 3.87; P = 0.024) and a cancer-related change in employment status (OR, 3.63; P = 0.036) were associated with greater likelihood of reporting financial toxicity. Conclusions Most patients with cancer with brain and spine metastases with a poor prognosis treated at a tertiary center are primary income earners and experience financial toxicity. Further studies are warranted to assess the longitudinal impact of financial toxicity in patients with metastatic cancer, particularly those with ≥1 emergency department visit and a cancer-related change in employment status.

Background Radiation therapy for intracranial lesions is constrained by dose to neurologic organs at risk. Case Description We report 2 cases, a newly diagnosed chondrosarcoma and a previously irradiated meningioma, with tumors that abutted the optic chiasm following subtotal resection. Definitive radiotherapy would have required either undercoverage of the tumor or treatment of the chiasm with doses posing an unacceptable risk of blindness. Therefore, the patients underwent open surgery with placement of an abdominal fat autograft to provide space between the tumor and the optic structures at risk. Patients received definitive fractionated stereotactic radiotherapy. For each patient, we retrospectively compared the treated plan (with fat autograft) to a second plan generated using the pre-autograft imaging, maintaining similar tumor coverage. For the chondrosarcoma, the fat autograft reduced the optic chiasm maximum dose by 21% (70.4 Gy to 55.3 Gy). For the reirradiated peri-optic meningioma, the optic chiasm maximum dose was reduced by 10% (50.8 Gy to 45.9 Gy), the left optic nerve by 17% (48.9 Gy to 40.4 Gy), and the right optic nerve by 30% (32.3 Gy to 22.6 Gy). Conclusions We demonstrate the utility of abdominal fat autograft placement to maximize coverage of tumor while minimizing dose to intracranial organs at risk.

Objective Immunotherapy for patients with melanoma with brain metastasis has significantly improved outcomes; however, it has also been characterized by potentially dangerous immune-related adverse events (IRAEs). Several reports have suggested that these reactions can precede improved treatment responses. For intracranial disease control, we sought to identify if such an association exists. Methods We conducted a retrospective chart review of patients with melanoma who underwent immunotherapy treatment after diagnosis of brain metastasis. The study cohort was then stratified into 2 groups based on their history of developing an IRAE that prompted discontinuation of that regimen. The primary outcome variable included intracranial progression-free survival (PFS). Kaplan-Meier and Cox proportional hazard analyses were used to evaluate survival and predictors of outcomes. Results Fifty-two patients met the inclusion criteria, 17 of whom experienced severe IRAEs that led to discontinuation of immunotherapy. Median intracranial PFS was 19.9 versus 10.5 months (P = 0.053) in patients who did and did not experience severe IRAEs prompting discontinuation, respectively. No additional outcome benefits were identified for systemic PFS or overall survival (mean, 33.1 months and 27.6 months, respectively). Multivariable analysis identified BRAF mutation status as a negative prognosticator of brain progression (P = 0.013; hazard ratio, 3.90). Initial treatment with BRAF inhibitor was also a negative predictor of all-cause mortality (P = 0.015; hazard ratio, 10.73). Conclusions Immune-related adverse events may signify an underlying immunogenic response that has intracranial disease control benefits. Despite their associated side effects, immunotherapies continue to show promising outcomes as a first-line agent for melanoma with brain metastasis.

Introduction Dural arteriovenous fistulae (DAVF) are vascular lesions with arteriovenous shunting that may be treated with surgical obliteration or endovascular embolization. Some DAVF, such as anterior cranial fossa DAVF (AC-DAVF) derive their arterial supply from ophthalmic artery branches in nearly all cases, and trans-arterial embolization carries a risk of vision loss. We determined the efficacy and safety of trans-ophthalmic artery embolization of DAVF. Materials and methods We performed a retrospective cohort study of all patients with DAVF treated by trans-ophthalmic artery embolization from 2012 to 2020. Primary outcome was angiographic cure of the DAVF. Secondary outcomes included vision loss, visual impairment, orbital cranial nerve injury, stroke, modified Rankin Scale at 90-days, and mortality. Results 12 patients met inclusion criteria (9 males; 3 females). 10 patients had AC-DAVF. Patient age was 59.7 ± 9.5 (mean ± SD) years. Patients presented with intracranial hemorrhage (4 patients), headache (4 patients), amaurosis fugax (1 patients), or were incidentally discovered (2 patients). DAVF Cognard grades were: II (1 patient), III (6 patients), and IV (5 patients). DAVF were embolized with Onyx (10 patients), nBCA glue (1 patient), and a combination of coils and Onyx (1 patient). DAVF cure was achieved in 11 patients (92%). No patients experienced vision loss, death, or permanent disability. One patient experienced a minor complication of blurry vision attributed to posterior ischemic optic neuropathy. 90-day mRS was 0 (10 patients) and 1 (2 patients). Conclusions Trans-ophthalmic artery embolization is an effective and safe treatment for DAVF.

Purpose Although consensus guidelines for postresection stereotactic radiosurgery (SRS) for brain metastases recommend the surgical corridor leading to the resection cavity be included in the SRS plan, no study has reported patterns of tumor recurrence based on inclusion or exclusion of the corridor as a target. We reviewed tumor control and toxicity outcomes of postresection SRS for deep brain metastases based on whether or not the surgical corridor was targeted. Materials and Methods We retrospectively reviewed patients who had resected brain metastases treated with SRS between 2007 and 2018 and included only “deep” tumors (defined as located ≥1.0 cm from the pial surface before resection). Results In 66 deep brain metastases in 64 patients, the surgical corridor was targeted in 43 (65%). There were no statistical differences in the cumulative incidences of progression at 12 months for targeting versus not targeting the corridor, respectively, for overall local failure 2% (95% confidence interval [CI], 0%-11%) versus 9% (95% CI, 1%-25%; P = .25), corridor failure 0% (95% CI, 0%-0%) versus 9% (95% CI, 1%-25%; P = .06), cavity failure 2% (95% CI, 0%-11%) versus 0% (95% CI, 0%-0%; P = .91), and adverse radiation effect 5% (95% CI, 1%-15%) versus 13% (95% CI, 3%-30%; P = .22). Leptomeningeal disease (7%; 95% CI, 2%-18%) versus 26% (95% CI, 10%-45%; P = .03) was higher in those without the corridor targeted. Conclusions Omitting the surgical corridor in postoperative SRS for resected brain metastases was not associated with statistically significant differences in corridor or cavity recurrence or adverse radiation effect. As seen in recent prospective trials of postresection SRS, the dominant pattern of progression is within the resection cavity; omission of the corridor would yield a smaller SRS volume that could allow for dose escalation to potentially improve local cavity control.

Head and neck paragangliomas (HNPs) are rare, usually benign hyper vascularized neuroendocrine tumors that traditionally have been treated by surgery, with or without endovascular embolization, or, more recently stereotactic radiosurgery (SRS). The aim of our study is to determine the clinical and radiographic effectiveness of SRS for treatment of HNPs. A systematic search of electronic databases was performed, and 37 articles reporting 11,174 patients (1144 tumors) with glomus jugulare (GJT: 993, 86.9%), glomus tympanicum (GTT: 94, 8.2%), carotid body tumors (CBTs: 28, 2.4%), and glomus vagale (GVT: 16, 1.4%) treated with SRS definitively or adjuvantly were included. The local control (LC) was estimated from the pooled analysis of the series, and its association with SRS technique as well as demographic and clinical factors was analyzed. The median age was 56 years (44–69 years). With a median clinical and radiological follow-up of 44 months (9–161 months), LC was 94.2%. Majority of the patients (61.0%) underwent Gamma Knife Radiosurgery (GKS), but there was no statistically significant difference in LC depending upon the SRS technique (p = 0.9). Spearmen’s correlation showed that LC was strongly and negatively correlated with multiple parameters, which included female gender (r = − 0.4, p = 0.001), right-sided tumor (r = − 0.3, p = 0.03), primary SRS (r = − 0.5, p ≤ 0.001), and initial clinical presentation of hearing loss (r = − 0.4, p = 0.001). To achieve a LC ≥ 90%, a median marginal dose (Gy) of 15 (range, 12–30 Gy) was required. The results corroborate that SRS in HNPs is associated with good clinical and radiological outcome.

Background and purpose Brain arteriovenous malformation (AVM) treatment by stereotactic radiosurgery (SRS) is effective, but AVM obliteration following SRS may take two years or longer. MRI with arterial-spin labeling (ASL) may detect brain AVMs with high sensitivity. We determined whether brain MRI with ASL may accurately detect residual AVM following SRS treatment. Materials and methods We performed a retrospective cohort study of patients who underwent brain AVM evaluation by DSA between June 2010 and June 2015. Inclusion criteria were: (1) AVM treatment by SRS, (2) follow-up MRI with ASL at least 30 months after SRS, (3) DSA within 3 months of the follow-up MRI with ASL, and (4) no intervening AVM treatment between the MRI and DSA. Four neuroradiologists blindly and independently reviewed follow-up MRIs. Primary outcome measure was residual AVM indicated by abnormal venous ASL signal. Results 15 patients (12 females, mean age 29 years) met inclusion criteria. There were three posterior fossa AVMs and 12 supratentorial AVMs. Spetzler–Martin (SM) Grades were: SM1 (8%), SM2 (33%), SM3 (17%), SM4 (25%), and SM5 (17%). DSA demonstrated residual AVM in 10 patients. The pooled sensitivity, specificity, positive predictive value, and negative predictive value of venous ASL signal for predicting residual AVM were 100% (95% CI: 0.9-1.0), 95% (95% CI: 0.7–1.0), 98% (95% CI: 0.9–1.0), and 100% (95% CI: 0.8–1.0), respectively. High inter-reader agreement as found by Fleiss’ Kappa analysis (k = 0.92; 95% CI: 0.8–1.0; P Conclusions ASL is highly sensitive and specific in the detection of residual cerebral AVM following SRS treatment.

Background Historically, it is stated that large intracranial tumors, herein defined as a maximum dimension of ≥3 cm or tumor volume ≥14.2 cm3, are not candidates for stereotactic radiosurgery (SRS). We report outcomes of patients with large benign intracranial tumors treated with SRS. Methods With institutional review board approval, we retrospectively identified 74 patients with large benign intracranial tumors (59 meningiomas, 9 vestibular schwannomas, and 6 glomus jugulare tumors) treated with robotic SRS (2007–2018). Patients received definitive SRS in 47.3% of the cases, adjuvant to surgical resection in 44.6%, and salvage after past radiation treatment in 8.1%. A median tumor volume of 16.0 cm3 (range, 10.1–65.5 cm3) received a median dose of 24.0 Gy (range, 14.0–30.0 Gy) in a median of 3 fractions (range, 1–5), for a median single fraction equivalent dose (with alpha/beta of 3) of 14.8 Gy (range, 11.3–18.0 Gy). The Kaplan-Meier estimate of tumor local control (LC) was calculated from date of SRS. Results With a median clinical follow-up of 32.8 months (range, 0.6–125.9 months) and median radiologic follow-up of 28.5 months (range, 0.6–121.4 months), LC was 96.5% (95% confidence interval, 92.4%–100%) at 3 years and 91.7% (95% confidence interval, 87.6%–95.7%) at 5 years. Adverse radiation effect (ARE) was seen in 10 patients (13.5%) at a median of 13.5 months (range, 7.8–34.5 months). ARE occurred in 9% of those with prior treatment compared with 5% who were radiation-naive (P = 0.23). With 236.4 person-years of follow-up, no secondary malignancies were seen. Conclusions Despite the historical adage, we find that SRS provides high rates of LC for these large tumors, with rates of ARE similar to historical reports of SRS for smaller benign tumors.

OBJECTIVEArteriovenous malformations (AVMs) of the basal ganglia and thalamus are particularly difficult lesions to treat, accounting for 3%–13% of all AVMs in surgical series and 23%–44% of malformations in radiosurgery series. The goal of this study was to report the results of multimodal management of basal ganglia and thalamic AVMs and investigate the factors that influence radiographic cure and good clinical outcomes.METHODSThis study was a retrospective analysis of a prospectively maintained database of all patients treated at the authors’ institution. Clinical, radiological, follow-up, and outcome data were analyzed. Univariate and multivariate analyses were conducted to explore the influence of various factors on outcome.RESULTSThe results and data analysis pertaining to 123 patients treated over 32 years are presented. In this cohort, radiographic cure was achieved in 50.9% of the patients. Seventy-five percent of patients had good clinical outcomes (stable or improved performance scores), whereas 25% worsened after treatment. Inclusion of surgery and radiosurgery independently predicted obliteration, whereas nidus diameter and volume predicted clinical outcomes. Nidus volume/diameter and inclusion of surgery predicted the optimal outcome, i.e., good clinical outcomes with lesion obliteration.CONCLUSIONSGood outcomes are possible with multimodal treatment in these complex patients. Increasing size and, by extension, higher Spetzler-Martin grade are associated with worse outcomes. Inclusion of multiple modalities of treatment as indicated could improve the chances of radiographic cure and good outcomes.

Background Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used together to manage brain metastases (BMs). We assessed adverse radiation effect, disease control, and overall survival in patients with BMs who received SRS with anticytotoxic T-lymphocyte–associated protein 4 and/or anti– programmed cell death protein receptor/ligand therapies. Methods We retrospectively reviewed the records of patients with intact or resected BMs treated with SRS and ICIs within 5 months of SRS between 2010 and 2018. Patients were defined as receiving concurrent SRS and ICI if a dose of ICI was given within 4 weeks of SRS. Local failure, distant intracranial failure, extracranial failure, and adverse radiation effect were assessed using cumulative incidence rates and competing risk regressions with death as a competing risk. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazards models. Results A total of 97 patients with 580 BMs were included in our analysis. Competing risk analyses showed that concurrent SRS-ICI therapy is associated with higher rates of adverse radiation effect (6.4% vs. 2.0% at 1 year; multivariable hazard ratio [HR], 4.47; 95% confidence interval [CI], 1.57–12.73; P = 0.005), lower rates of extracranial failure (69.7% vs. 80.8% at 1 year; multivariable HR, 0.60; 95% CI, 0.42–0.87; P = 0.007), and better overall survival (48.6% vs. 25.4% at 1 year; multivariable HR, 0.57; 95% CI, 0.33–0.99; P = 0.044) compared with nonconcurrent therapy. SRS-ICI timing was not associated with local failure or distant intracranial failure. Conclusions Concurrent SRS-ICI therapy has a tolerable adverse event profile and may improve extracranial disease control and overall survival, supporting concurrent use in the management of BMs.

Introduction The CyberKnife, a frameless, robotic, stereotactic device, has been developed to radiosurgically treat arteriovenous malformations (AVMs). While most AVMs are obliterated within two-to-three years, a subset remain recalcitrant; long-term data on these difficult to treat AVMs are limited in the neurosurgical literature. Materials and methods A retrospective analysis of all patients who underwent CyberKnife treatment for intracranial AVMs at a single U.S. institution between 2002 and 2012, whose AVMs had failed to obliterate within 48 months or longer from the treatment start date, were eligible for inclusion. Results Eleven patients (9 AVMs; 7 males, 2 females) were followed for an average of 85.2 months (range 56.2–119.4). The median lesion size was 3.5 cm (range: 2.8–8.0 cm) and median Spetzler-Martin grade was 3 (range: 2–5). All AVMs were treated with one radiation dose (median prescribed dose was 18.0 Gy; median Dmax: 23.7 Gy). Six (66.7%) were obliterated in a median time of 84 months (range: 52–94 months), while 3 (33.3%) remained active after a median of 90.8 months (range 69.7–119.4). Transient, post-radiosurgery adverse radiation effects occurred in 5 (55.6%) cases. One (11.1%) patient had an acute hemorrhage from the AVM after radiosurgery. Four (44.4%) patients underwent repeat radiosurgery and/or embolization. Three of these lesions eventually obliterated, while 1 did not. Conclusion The median time to obliteration was 84 months. Two-thirds of AVMs which persisted for over 4 years following initial radiosurgery treatment eventually obliterated. Transient post-radiosurgery adverse effects were common; delayed hemorrhages were rare in our case series.

Introduction Since Lars Leksell developed the first stereotactic radiosurgery (SRS) device in 1951, there has been growth in the technologies available and clinical indications for SRS. This expansion has been reflected in the medical literature, which is built upon key articles and institutions that have significantly impacted SRS applications. Our aim was to identify these prominent works and provide an educational tool for training and further inquiry. Method A list of search phrases relating to central nervous system applications of stereotactic radiosurgery was compiled. A topic search was performed using PubMed and Scopus databases. The journal, year of publication, authors, treatment technology, clinical subject, study design and level of evidence for each article were documented. Influence was proposed by citation count and rate. Results Our search identified a total of 10,211 articles with the top 10 publications overall on the study of SRS spanning 443–1313 total citations. Four articles reported on randomized controlled trials, all of which evaluated intracranial metastases. The most prominent subtopics included SRS for arteriovenous malformation, glioblastoma, and acoustic neuroma. Greatest representation by treatment modality included Gamma Knife, LINAC, and TomoTherapy. Conclusions This systematic reporting of the influential literature on SRS for intracranial and spinal pathologies underscores the technology’s rapid and wide reaching clinical applications. Moreover the findings provide an academic guide to future health practitioners and engineers in their study of SRS for neurosurgery.

Background Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data. Objective To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors. Methods We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy. Results Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed. Conclusion Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

Purpose Foramen magnum meningiomas (FMMs) are a major surgical challenge, due to relevant surgical morbidity and mortality. The paper aims to review the clinical (symptomatic improvement, complication rate, length of hospital stay) and radiological outcome (completeness of resection) of microsurgical resection of FMMs, and to identify predictors of complications. Methods A multi-institutional retrospective review of prospectively maintained database of FMMs included 51 patients (74.5% females) with a median tumor volume of 8.18 cm3 (range, 1.77–57.9 cm3) and median follow-up of 36 months (range, 0.30–180.0 months). Tumors were resected though suboccipital approach (58.8%) or transcondylar approach (39.3%). Results Gross-total resection (GTR) was achieved in 80.4%, while local tumor control in 98% of cases. Clinical symptoms improved in 34 patients (66.7%) and worsened in 5 (9.8%). The median length of hospital stay was 5 days. Mortality was null. Postoperative complications developed in 15 patients (29.4%), with cerebrospinal fluid leak (7.8%) and lower cranial nerves deficits (7.8%) as the most frequent. Craniospinal location (p = 0.03), location anterior to the dentate ligament (DL) (p = 0.02), involvement of vertebral artery (VA) (p = 0.03) were significantly associated with complication rate. These three elements allow calculating the Foramen Magnum Meningioma Risk Score (FRMMRS), to estimate the risk of post-operative complications. Conclusion Microsurgical resection allows for high GTR rate and local tumor control rate, despite complications in one third of the patients. The FMMRS allows classifying FMMs and estimating the risk of post-operative complications.

INTRODUCTION: Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described. METHODS: We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed. RESULTS: A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 versus 10 months (p=0.004), systemic TTF (15 versus 4 months, p

BackgroundDrug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual’s mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual’s mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations.MethodsThe present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels forALK,BRCA1,EGFR, andERBB2/HER2.ResultsResults indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%,p p = 0.0001) and [A+B] cybrids (24.67%,p = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B],p = 0.0270). (4) The expression levels decreased forALKin L (p p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased forEGFRin [A+B] cybrids (p = 0.0246) compared to untreated cybrids.ConclusionOur findings suggest that an individual’s mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment.

Background Brain arteriovenous malformations (AVMs) are rare, potentially devastating cerebrovascular lesions that can occur in both children and adults. AVMs are largely sporadic and the basic disease biology remains unclear, limiting advances in both detection and treatment. This study aimed to investigate human brain AVMs for endothelial‐to‐mesenchymal transition (EndMT), a process recently implicated in cerebral cavernous malformations (CCMs). Methods We used 29 paraffin‐embedded and 13 fresh/frozen human brain AVM samples to profile expression of panels of EndMT‐associated proteins and RNAs. CCMs, a cerebrovascular disease also characterized by abnormal vasculature, were used as a primary comparison, given that EndMT specifically contributes to CCM disease biology. AVM‐derived cell lines were isolated from three fresh, surgical AVM samples and characterized by protein expression. Results We observed high collagen deposition, high PAI‐1 expression, and expression of EndMT‐associated transcription factors such as KLF4, SNAI1, and SNAI2 and mesenchymal‐associated markers such as VIM, ACTA2, and S100A4. SMAD‐dependent TGF‐β signaling was not strongly activated in AVMs and this pathway may be only partially involved in mediating EndMT. Using serum‐free culture conditions, we isolated myofibroblast‐like cell populations from AVMs that expressed a unique range of proteins associated with mature cell types and with EndMT. Conditioned medium from these cells led to increased proliferation of HUVECs and SMCs. Conclusions Collectively, our results suggest a role for EndMT in AVM disease. This may lead to new avenues for disease models to further our understanding of disease mechanisms, and to the development of improved diagnostics and therapeutics.

Benign spinal tumors are rare clinical conditions, including meningiomas, schwannomas, and neurofibromas. Although these tumors are usually treated with open surgical resection, spinal stereotactic radiosurgery may be a safe and effective alternative to surgery in selected patients.

Background We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). Methods We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3–5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. Results From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51–86 y). The median target volume was 60 cm3 (range, 14.7–137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1–2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2–12.6 mo). No grades 3–5 ARE occurred. With a median follow-up of 13.8 months (range 1.7–64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6–10.5); overall survival, 14.8 months (95% CI: 10.9–19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5–33.5) versus 11.3 months (95% CI: 8.9–17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2–48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9–17.6) for no ARE (P = 0.08). Conclusions The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1–2 and did not statistically impact survival.

The development of cavernous malformations many years following conventionally fractionated brain irradiation is well recognized and commonly reported. However, cavernous malformation induction following stereotactic radiosurgery (SRS) is largely unreported. Herein, we describe two cases of cavernous malformation formation years following SRS for brain metastases. A 20-year-old woman with breast cancer brain metastases received treatment with whole brain radiotherapy (WBRT), then salvage SRS 1.4 years later for progression of a previously treated metastasis. This lesion treated with SRS had hemorrhagic enlargement 3.0 years after SRS. Resection revealed a cavernous malformation. A 25-year-old woman had SRS for a brain metastasis from papillary thyroid carcinoma. Resection of a progressive, hemorrhagic lesion within the SRS field 2 years later revealed both recurrent carcinoma as well as cavernous malformation. As patients with brain metastases live longer following SRS, our cases highlight that the differential diagnosis of an enlarging enhancing lesion within a previous SRS field includes not only cerebral necrosis and tumor progression but also cavernous malformation induction.

Introduction Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods Patients with histologically-confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson’s Chi-square and Fisher’s exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001 to 0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02 to 0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001 to 0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1 to 79.6] months vs 5.45 [1.8 to 26.3], p = 0.0092) and OS (median 56.73 months [7.8 to 104.5] vs 14.83 [3.8 to 29.1], p = 0.0252). Conclusion Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

OBJECTIVE Cavernous sinus meningioma (CSM) can affect visual function and require expeditious treatment to prevent permanent visual loss. Authors of this retrospective study sought to determine the factors associated with visual functional outcomes in CSM patients treated with surgery, stereotactic radiosurgery (SRS), or stereotactic radiation therapy (SRT), alone or in combination. METHODS Consecutive patients with CSM who had presented at an academic tertiary care hospital from 2000 to 2018 were identified through retrospective chart review. Visual function—visual eye deficit (VED), optic disc (OD) appearance, intraocular pressure (IOP), and extraocular movement (EOM)—was assessed before and after treatment for CSM. VED with visual acuity (VA) ≤ 20/200 and visual field defect ≥ −11 dB, pale OD appearance in the ipsilateral or contralateral eye, increased ipsilateral IOP, and/or EOM restriction were defined as a poor visual functional outcome. Multivariable logistic regression was used to evaluate the associations between pretreatment visual functional assessment and posttreatment visual outcomes. RESULTS The study cohort included 44 patients (73% female; median age 55 years), with a median clinical follow-up of 14 months. Ipsilateral VED improved, remained stable, or worsened, respectively, in 0%, 33.4%, and 66.6% of the patients after subtotal resection (STR) alone; in 52.6%, 31.6%, and 15.8% after STR plus radiation treatment; in 28.5%, 43.0%, and 28.5% after gross-total resection (GTR) alone; and in 56.3%, 43.7%, and 0% after radiation treatment (SRS or SRT) alone. Contralateral VED remained intact in all the patients after STR alone and those with radiation treatment (SRS or SRT) alone; however, it improved, remained stable, or worsened in 10.5%, 84.2%, and 5.3% after STR plus radiation treatment and in 43.0%, 28.5%, and 28.5% after GTR alone. EOM remained intact, fully recovered, remained stable, and worsened, respectively, in 0%, 50%, 50%, and 0% of the patients after STR alone; in 36.8%, 47.4%, 15.8%, and 0% of the patients after STR with radiation treatment; in 57.1%, 0%, 28.6%, and 14.3% of the patients after GTR alone; and in 56.2%, 37.5%, 6.3%, and 0% of the patients after radiation treatment (SRS or SRT) alone. In multivariable analyses adjusted for age, tumor volume, and treatment modality, initial ipsilateral poor VED (OR 10.1, 95% CI 1.05–97.2, p = 0.04) and initial ipsilateral pale OD appearance (OR 21.1, 95% CI 1.6–270.5, p = 0.02) were associated with poor ipsilateral VED posttreatment. Similarly, an initial pale OD appearance (OR 15.7, 95% CI 1.3–199.0, p = 0.03), initial poor VED (OR 21.7, 95% CI 1.2–398.6, p = 0.03), and a higher IOP in the ipsilateral eye (OR 55.3, 95% CI 1.7–173.9, p = 0.02) were associated with an ipsilateral pale OD appearance posttreatment. Furthermore, a higher initial ipsilateral IOP (OR 35.9, 95% CI 3.3–400.5, p = 0.004) was indicative of a higher IOP in the ipsilateral eye posttreatment. Finally, initial restricted EOM was indicative of restricted EOM posttreatment (OR 20.6, 95% CI 18.7–77.0, p = 0.02). CONCLUSIONS Pretreatment visual functional assessment predicts visual outcomes in patients with CSM and can be used to identify patients at greater risk for vision loss.

CyberKnife stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) administers nonisometric, conformational high-dose radiation to the trigeminal nerve with risk of subsequent hypoesthesia.We performed a retrospective, single-institution review of 66 patients with TGN treated with CyberKnife SRS to compare outcomes from 2 distinct treatment periods: standard dosing (n = 38) and reduced dosing (n = 28). Standard and reduced dosing permitted a maximum brainstem dose of 45 Gy and 25 Gy, respectively, each with a prescription dose of 60 Gy. Primary and secondary outcomes were Barrow Neurologic Institute pain and numbness scores. Maximum brainstem dose, prepontine nerve length, and treatment history were recorded for their predictive contributions by logistic regression.After matching, patients in the standard dosing and reduced dosing groups were followed for a median of 25 months and 19.5 months, respectively. Mean trigeminal nerve length was 8.55 mm in the standard dosing group and 9.46 mm in the reduced dosing group. Baseline rates of poorly controlled pain were 97% and 88%, respectively, which improved to 23.4% and 8.3%, respectively (P0.001 for both). The baseline rates of bothersome numbness were null in both groups, and increased to 25% in the standard group (P = 0.006) and to 21% in the reduced group (P = 0.07). Regression analyses suggested that reduced brainstem exposure (P = 0.01), as well as a longer trigeminal nerve (P = 0.01), were predictive of durable pain control.These outcomes demonstrate that a lower maximum brainstem dose can provide excellent pain control without affecting facial numbness. Longer nerves may achieve better long-term outcomes and help optimize individual plans.

Surgery is the primary treatment for acromegaly. However, surgery may not be curative of some tumors, particularly invasive macroadenomas. Adjuvant radiation, specifically robotic stereotactic radiosurgery (rSRS), may improve the endocrine outcome. We retrospectively reviewed hormonal and radiological data of 22 acromegalic patients with invasive macroadenomas treated with rSRS at Stanford University Medical Center between 2000 and 2016. Prior to treatment, the tumor's median maximal diameter was 19 mm (2.5-50 mm). Cavernous sinus invasion occurred in 19 patients (86.3%) and compression of the optic chiasm in 2 (9.0%). At last follow up, with an average follow up of 43.2 months, all patients had a reduction in their IGF-1 levels (median IGF-1% upper limit of normal (ULN) baseline: 136% vs last follow up: 97%; p = 0.05); 9 patients (40.9%) were cured, and 4 (18.1%) others demonstrated biochemical control of acromegaly. The median time to cure was 50 months and the mean interval to cure or biochemical control was 30.3 months (± 24 months, range 6-84 months). Hypopituitarism was present in 8 patients (36.3%) and new pituitary deficits occurred in 6 patients with a median latency of 31.6 ± 14.5 months. At final radiologic follow-up, 3 tumors (13.6%) were smaller and 19 were stable in size. The mean biologically effective dose (BED) was higher in subjects cured compared to those with persistent disease, 163 Gy3 (± 47) versus 111 Gy3 (± 43), respectively (p = 0.01). No patient suffered visual deterioration. Robotic SRS is a safe and effective treatment for acromegaly: radiation-induced visual complications and hypopituitarism is rare.

Hemangioblastomas are rare, benign, vascular tumors of the central nervous system (CNS), often associated with von-hippel lindau (VHL) disease. Current therapeutic options include microsurgical resection or stereotactic radiosurgery (SRS). With no randomized controlled studies and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. We completed a Pubmed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year progression free survival (PFS). The pooled 5-year PFS across all eligible studies was 88.4%. No difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease. Adverse events were associated with increasing marginal dose, independent of tumor volume. VHL status, sex, radiosurgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. Multiple studies show excellent tumor control at 5-year follow up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.

PurposeTo determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.Materials and methodsIn this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2cm, were enrolled in a phase 1, 3+3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400mg orally once daily for 14days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30days.ResultsFrom 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12months (range, 1-64months), Kaplan-Meier overall survival was 13months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2months after SRS.ConclusionsThe MTD of vorinostat with concurrent SRS was established as 400mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.

Embolization has been proposed to reduce the size of the arteriovenous malformation (AVM) nidus in advance of radiosurgical treatment. Embolization followed by radiosurgery for brain AVMs, however, is controversial.We assessed the impact of embolization on nidal size before radiosurgical treatment and evaluated cure rates and complications by using embolization followed by radiosurgery.A retrospective review of our institutional AVM database identified 91 patients treated from 1995 to 2009 with embolization followed by radiosurgery. Pre- and postembolization AVM volumes were measured with angiography, and the modified radiation-based AVM scores (RBAS) also were calculated pre- and postembolization. RBAS determined from pre-embolization volumes were correlated with postradiosurgical obliteration.Median AVM volume declined from 18.8 mL (interquartile range, 10.2-32.2 mL) to 9.9 mL (3.1-19.2 mL) after embolization, P0.00003. Median RBAS scores decreased from 2.6 mL (1.8-3.9 mL) to 1.8 mL (1.0-2.8 mL), P0.00003. Two of 91 (2.2%) had new fixed deficits after embolization; however, no patient had new disabling deficits (modified Rankin Scale score2). A total of 71 of 91 (79%) have had3 years' follow-up, and 40 (56%) had complete obliteration, with 38 (53%) having excellent outcomes (complete obliteration without neurologic decline). Excellent outcome was seen in 90% of patients with modified RBAS score1, 66% of patients with score 1-1.5, 50% patients with score 1.5-2, and 43% of patients with score2.These data suggest that embolization of brain AVMs can safely and effectively reduce the treatment volume before radiosurgery. Combined therapy with embolization and radiosurgery does not appear to adversely affect rates of excellent outcome.

OBJECTIVEColorectal cancer (CRC) and other gastrointestinal (GI) cancers are believed to have greater radioresistance than other histologies. The authors report local control and toxicity outcomes of stereotactic radiosurgery (SRS) to spinal metastases from GI primary cancers.METHODSA retrospective single-center review was conducted of patients with spinal metastases from GI primary cancers treated with SRS from 2004 to 2017. Patient demographics and lesion characteristics were summarized using medians, interquartile ranges (IQRs), and proportions. Local failure (LF) was estimated using the cumulative incidence function adjusted for the competing risk of death and compared using Gray’s test for equality. Multivariable analyses were conducted using Cox proportional hazard models, adjusting for death as a competing risk, on a per-lesion basis. Patients were stratified in the Cox model to account for repeated measures for clustered outcomes. Median survival was calculated using the Kaplan-Meier method.RESULTSA total of 74 patients with 114 spine lesions were included in our analysis. The median age of the cohort was 62 years (IQR 53–70 years). Histologies included CRC (46%), hepatocellular carcinoma (19%), neuroendocrine carcinoma (13%), pancreatic carcinoma (12%), and other (10%). The 1- and 2-year cumulative incidence rates of LF were 24% (95% confidence interval [CI] 16%–33%) and 32% (95% CI 23%–42%), respectively. Univariable analysis revealed that older age (p = 0.015), right-sided primary CRCs (p = 0.038), and single fraction equivalent dose (SFED; α/β = 10) < 20 Gy (p = 0.004) were associated with higher rates of LF. The 1-year cumulative incidence rates of LF for SFED < 20 Gy10 versus SFED ≥ 20 Gy10 were 35% and 7%, respectively. After controlling for gross tumor volume and prior radiation therapy to the lesion, SFED < 20 Gy10 remained independently associated with worse LF (hazard ratio 2.92, 95% CI 1.24–6.89, p = 0.014). Toxicities were minimal, with pain flare observed in 6 patients (8%) and 15 vertebral compression fractures (13%).CONCLUSIONSSpinal metastases from GI primary cancers have high rates of LF with SRS at a lower dose. This study found that SRS dose is a significant predictor of failure and that prescribed SFED ≥ 20 Gy10 (biological equivalent dose ≥ 60 Gy10) is associated with superior local control.

Postoperative stereotactic radiosurgery (SRS) has less detrimental effect on cognition and quality of life compared with whole brain radiation therapy (WBRT) and is increasingly used for resected brain metastases (BMs). Postoperative SRS techniques are not standardized, and there is a concern for a different pattern of failure after postoperative SRS compared with WBRT. We aim to study the efficacy, toxicity, and failure pattern of postoperative SRS.We retrospectively reviewed outcomes of patients with resected BMs treated with postoperative SRS between 2007 and 2018. Overall survival and cumulative incidences of local failure, overall distant intracranial failure (distant parenchymal failure, nodular leptomeningeal disease [nLMD], classical leptomeningeal disease [cLMD]), and adverse radiation effect were reported. Neurologic death was determined for patients with leptomeningeal disease (LMD).A total of 442 patients with 501 resected BMs were treated over 475 total SRS courses. Median clinical follow-up and overall survival after SRS were 10.1 months (interquartile range, 3.6-20.7 months) and 13.9 months (95% confidence interval [CI], 11.8-15.2 months), respectively. At 12 months, event rates were 7% (95% CI, 5%-10%) for local failure, 9% (95% CI, 7%-12%) for adverse radiation effect, 44% (95% CI, 40%-49%) for overall distant intracranial failure, 37% (95% CI, 33%-42%) for distant parenchymal failure, and 13% (95% CI, 10%-17%) for LMD. The overall incidence of LMD was 15.8% (53% cLMD, 46% nLMD). cLMD was associated with shorter survival than nLMD (2.0 vs 11.2 months, P.01) and a higher proportion of neurologic death (67% vs 41%, P = .02). A total of 15% of patients ultimately received WBRT.We report the largest clinical experience of postoperative SRS for resected BMs, showing excellent local control and low toxicity. Intracranial failure was predominantly distant, with a rising incidence of LMD.

International audience; We formulated an ultra-small, gadolinium-based nanoparticle (AGuIX) with theranostic properties to simultaneously enhance MRI tumor delineation and radiosensitization in a glioma model. The 9L glioma cells were orthotopically implanted in 10-week-old Fischer rats. The intra-tumoral accumulation of AGuIX was quantified using MRI T1-maps. Rats randomized to intervention cohorts were subsequently treated with daily temozolomide for five consecutive days before radiotherapy treatment. Collectively, a series of 32 rats were divided into untreated (n = 7), temozolomide-only (n = 7), temozolomide and MRT (n = 9), AGuIX and MRT (n = 7), and triple therapy (temozolomide, AGuIX NPs, and MRT; n = 9) cohorts. AGuIX nanoparticles achieved a maximum intra-tumoral concentration (expressed as concentration of Gd3+) at 1 h after intravenous injection, reaching a mean of 227.9 ± 60 lM. This was compared to concentrations of 10.5 ± 9.2 lM and 62.9 ± 24.7 lM in the contralateral hemisphere and cheek, respectively. There was a slower washout in the intra-tumor region, with sustained tumor-to-contralateral ratio of AGuIX, up to 14-fold, for each time point. The combination of AGuIX or temozolomide with MRT improved the median survival time (40 days) compared to the MeST of control rats (25 days) (p < 0.002). There was a trend towards further increased survival when the three treatments were combined (MeST of 46 days). This study demonstrated the selective accumulation of AGuIX in high grade glioma, as well as the potential survival benefits when combined with chemoradiation.

A retrospective data review.To evaluate the efficacy of CyberKnife (CK) stereotactic radiosurgery (SRS) for thyroid spinal metastasis (SMs).Thyroid carcinoma is an infrequent cause of SM. The absolute efficacy of SRS generally and CK in particular remains poorly characterized for thyroid SM. The current study is the first to specifically evaluate the efficacy of CK SRS for thyroid SMs.A retrospective review of patients at our institution between 2003 and 2013 was done. Details about tumor location, radiographic findings before and after CK SRS, tumor recurrence, prescription isodose level, total and maximum dose, number of fractions, and gross tumor volume coverage were similarly collected. For comparison with other studies, the biologically effective dose and the equivalent total dose in 2 Gy fractions were calculated. Each patient was assessed for survival and local disease control from the time of the first CK session and survival analysis was carried out using the Kaplan-Meier method. Risk factors for local failure were assessed using multivariate logistic regression.A total of 12 patients with 32 spinal metastases from thyroid carcinoma that were treated with CK SRS were identified. Survival for 1, 2, and 3 years was 55%, 44%, and 33%, and local control was 67%, 56%, and 34% respectively. The study found that the single strongest factor associated with local control was prior radiotherapy (β-coefficient -27.72, P = 0.01). No complications occurred in the immediate or late follow-up period.This was the first study to specifically investigate the efficacy of CK for treatment of thyroid SMs. Our findings suggest that CK can be safely used to treat spinal SMs from thyroid cancer and is associated with a high rate of local control.4.

Objective/Background: We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma. Methods: We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method. Results: Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2–157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11–43) and 42% (95% CI 22–60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects. Conclusions: SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.

Gross total resection of large intracranial meningiomas (LIMs) can be challenging and cause significant morbidity and mortality. The aim of this systematic review is to determine the clinical effectiveness and safety of stereotactic radiosurgery (SRS) either as primary or adjuvant therapy for LIMs with tumors ≥2.5 cm in maximum dimension (tumor volume ≥8.1 cm3). A total of 452 tumors in 496 patients (350 female [69.3%] and 146 male [30.6%]) with median age 60 years (48–65 years) were included. The median tumor volume at the time of diagnosis was 16.7 cm3 (10–53.3 cm3). The tumors typically were located in the skull base (77.2%), whereas only 14.6% were in the supratentorial space. The median follow-up after SRS was 54 months (18–90 months). In total, 87.8% of patients were treated with single-session (SS) Gamma Knife radiosurgery (GKS), whereas the remaining 12.1% patients received non-SS GKS. Of 452 LIMs assessed for clinical response, 45.1% showed improvement and 15.7% deteriorated after SRS. Radiographic tumor control at last follow-up (2–7.5 years) ranged from 84% to 100%. Overall, radiation-induced toxicity occurred in 23% of patients, with the most common adverse effect being cranial nerve neuropathy (5.5%) and peritumoral edema (5.3%). Subgroup analysis revealed that there is 2-fold greater likelihood of improvement in clinical symptoms in patients with non-SS GKS than SS GKS (odds ratio 2.47; 95% confidence interval 1.38–4.44; P = 0.002). SRS is safe and effective in the treatment of LIMs as primary or adjuvant treatment. Further prospective studies are required to validate our results.

OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.

Cerebral arteriovenous malformations (AVMs) are vascular lesions consisting of abnormal connections between arteries and veins with no intermediate capillary network. With an annual spontaneous rupture rate of approximately 2–4%, they represent a significant source of hemorrhagic stroke and neurologic morbidity and mortality in young patients. The current treatment paradigms for AVMs include microsurgery, stereotactic radiosurgery (SRS), and embolization, all of which aim to abolish the risk of hemorrhage by obliterating the AVM nidus. Stereotactic radiosurgery is a minimally invasive and effective treatment option that is particularly suitable for small- to medium-sized AVMs located in deep or eloquent brain regions. Obliteration is achieved in 70–80% of cases, following a latency period of approximately 1–3-year posttreatment. SRS carries a unique complication profile including a sustained risk of hemorrhage during the latency period, as well as adverse radiation effects with associated neurologic deficits. AVM lesions vary widely in their natural histories and their suitability for treatment with SRS, based on characteristics such as size, location, and rupture status. For large AVMs, adjunct techniques such as endovascular embolization or volume and dose staging may be utilized to make the lesions appropriate targets for SRS. In the case of unruptured AVMs, early data from recent prospective trials have suggested that conservative medical management may result in better short-term outcomes than interventional treatment. Thus, the risks and complications associated with SRS therapy for individual AVMs must be carefully balanced against the morbidities associated with the natural history of the disease. Here we discuss the salient clinical and pathophysiologic indications for the use of SRS, review data on treatment efficacy and outcomes, and profile the major complications.

Purpose Pseudarthrosis within the spine tumor population is increased from perioperative radiation and complex stabilization for invasive and recurrent pathology. We report the radiographic and clinical rates of pseudarthrosis following multiple courses of instrumented fusion and perioperative stereotactic radiosurgery (SRS). Methods We performed a single institution review of 418 patients treated with non-isocentric SRS for spine between October 2002 and January 2013, identifying those with spinal instrumentation and greater than six months of follow-up. Surgical history, radiation planning, and radiographic outcomes were documented. Results Eleven patients who met criteria for inclusion underwent 21 sessions of spinal SRS and 16 instrumented operations. Radiographic follow-up was 48.9 months; 3/11 (27%) were with radiographic hardware failure, and one (9%) separate case ultimately warranted externalization due to tumor recurrence. SRS was administered to treat progression of disease in 12/21 (57%) procedures, and residual lesions in 7/11 (64%) procedures. Following first and second SRS, 8/11 (73%) and 2/7 (29%) patients were with symptomatic improvement, respectively. Conclusion Risk of pseudarthrosis following SRS for patients with oncologic spinal lesions will become increasingly apparent with the optimized management of and survival from spinal pathologies. We highlight how the need for local control outpaces the risk of instrumentation failure.

Magnetic particle imaging (MPI) is a novel radiation-free tomographic imaging method that provides a background-free, signal attenuation-free, direct quantification of the spatial distribution of superparamagnetic iron-oxide nanoparticles (SPIONs) with high temporal resolution (milliseconds), high spatial resolution (1 mm), and extreme sensitivity (μmol). The technique is based on nonlinear magnetization of the SPIONs when exposed to an oscillating magnetic field. MPI was first described in 2001. Since then, the technique has been applied to experimental imaging of diseases affecting different organs in the human body. The aim of this paper is to review the potential applications of MPI in the field of neurosurgery.A nonsystematic review of the existing literature on the use of MPI in neurosurgical diseases was performed.MPI has been used for the detection of locoregional invasion of brain tumors, tracking, and monitoring the viability of neural stem cells implanted for neuroregenerative purposes, diagnosis of cerebral ischemia, and diagnosis and morphofunctional assessment of brain aneurysms.MPI is at a preclinical stage. In the future, human-sized MPI scanners, along with the optimal toxicity profile of SPIONs will allow diagnostic applications in neurosurgical diseases.

Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

OBJECT Metastatic disease to the craniovertebral junction (CVJ) is rare but presents unique management challenges. To date, studies on using stereotactic radiosurgery (SRS) for CVJ metastases have been limited to case reports and small case series. The aim of this analysis was to evaluate the utility of SRS in the management of these secondary lesions. METHODS Clinical and radiological information from the charts of 25 patients with metastatic disease of the CVJ who were treated with SRS between 2005 and 2013 at the Stanford CyberKnife Center were retrospectively reviewed. RESULTS Seven male and 18 female patients with a median age of 58 years (range 34–94 years) were identified. The most common primary tumors were breast cancer (n = 5) and non-small cell lung cancer (n = 5), and the most frequent symptom was neck pain (n = 17). The average tumor volume treated was 15.9 cm3 (range 0.16–54.1 cm3), with a mean marginal radiation dose of 20.3 Gy (range 15–25.5 Gy). The median follow-up was 18 months (range 1–81 months), though 1 patient was lost to follow-up. SRS provided radiographic tumor stability in over 80% of patients, offered pain alleviation in nearly two-thirds of patients, and produced no serious complications. Moreover, SRS preserved spinal stability in all but 1 patient, in whom pre-SRS stability was established. There was no evidence of radiation toxicity in the patient population. Median survival was 28 months (range 2–81 months), with survival of 13.3% at 5 years. CONCLUSIONS In the absence of unstable pathological fracture and spinal cord compression, metastatic tumors of the CVJ can be safely and effectively treated with SRS. This treatment option offers palliative pain relief and can halt tumor progression with only a low risk of complications or spinal instability.