Faculty Bibliography

Melanoma in the head and neck is known to metastasize to cranial nerves. Prompt treatment is critical for preventing progression and reducing neuropathy. We report a patient who presented with cranial neuropathy related to a malignant skull base lesion that originated as lentigo maligna. The diagnosis was challenging, requiring two surgeries to obtain tissue and neither biopsy leading to a definitive diagnosis. Pathological analyses demonstrated positive immunoreactivity for SOX10 and S100, preservation of H3K27me3, and PTEN and STK11 mutations. The patient was managed with Gamma Knife Radiosurgery and combination immunotherapy. Imaging at 9 months post-SRS showed resolution of the mass lesion. Clinically, the patient has occasional left-sided facial pain requiring no medication and denies facial numbness. We favor a diagnosis of desmoplastic neurotropic melanoma due to the neurotropic spread and response to melanoma-targeted immunotherapy.

BACKGROUND:Stereotactic radiosurgery (SRS) is a highly effective management approach for patients with vestibular schwannomas (VS), with 10-yr control rates up 98%. When it fails, however, few data are available to guide management. OBJECTIVE:To perform a retrospective analysis of patients who underwent 2 SRS procedures on the same VS to assess the safety and efficacy of this practice. METHODS:This study was opened to centers of the International Gamma Knife Research Foundation (IGKRF). Data collected included patient characteristics, clinical symptoms at the time of SRS, radiosurgery dosimetric data, imaging response, clinical evolution, and survival. Actuarial analyses of tumor responses were performed. RESULTS:Seventy-six patients from 8 IGKRF centers were identified. Median follow-up from the second SRS was 51.7 mo. Progression after the first SRS occurred at a median of 43 mo. Repeat SRS was performed using a median dose of 12 Gy. Actuarial tumor control rates at 2, 5, and 10 yr following the second SRS were 98.6%, 92.2%, and 92.2%, respectively. Useful hearing was present in 30%, 8%, and 5% of patients at first SRS, second SRS, and last follow-up, respectively. Seventy-five percent of patients reported stable or improved symptoms following the second SRS. Worsening of facial nerve function attributable to SRS occurred in 7% of cases. There were no reports of radionecrosis, radiation-associated edema requiring corticosteroids, radiation-related neoplasia, or death attributable to the repeat SRS procedure. CONCLUSION/CONCLUSIONS:Patients with progressing VS after radiosurgery can be safely and effectively managed using a second SRS procedure.

BACKGROUND:Intraosseous petrous apex schwannomas are an exceedingly rare entity; little is known about their epidemiology, natural history, and post-operative outcomes. CASE DESCRIPTION/METHODS:Here, we present the fourth known case of a primary intraosseous schwannoma of the petrous apex: a 68-year-old woman presenting with diplopia, facial numbness, progressive intermittent vertigo, tinnitus, diminished hearing, and ataxia. She underwent a transtemporal approach for subtotal resection of the tumor with subsequent stereotactic radiosurgery. CONCLUSIONS:Our two-year follow-up demonstrates slow growth and success of multimodal management in the treatment of these tumors. We review the three prior reports of petrous apex schwannomas, and identify unifying radiographic and clinical characteristics in order to aid in future diagnostic considerations of lesions of the petrous apex.

Background and Purpose- The effects of prior hemorrhage on stereotactic radiosurgery (SRS) outcomes for pediatric arteriovenous malformations (AVMs) are not well defined. The aim of this multicenter, retrospective cohort study is to compare the SRS outcomes for unruptured versus ruptured pediatric AVMs. Methods- The International Radiosurgery Research Foundation pediatric AVM database from 1987 to 2018 was reviewed retrospectively. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. Associations between prior hemorrhage and outcomes were adjusted for baseline differences, inverse probability weights, and competing risks. Results- The study cohort comprised 153 unruptured and 386 ruptured AVMs. Favorable outcome was achieved in 48.4% and 60.4% of unruptured and ruptured AVMs, respectively (adjusted odds ratio, 1.353; P=0.190). Cumulative AVM obliteration probabilities were 51.2%, 59.4%, 64.2%, and 70.0% for unruptured and 61.0%, 69.3%, 74.0%, and 79.3% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.311; P=0.020). Cumulative post-SRS hemorrhage probabilities were 4.5%, 5.6%, 5.6%, and 9.8% for unruptured and 4.7%, 6.1%, 6.1%, and 10.6% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.086; P=0.825). Probabilities of AVM obliteration (adjusted subhazard ratio, 0.968; P=0.850) and post-SRS hemorrhage (adjusted subhazard ratio, 1.663; P=0.251) were comparable between the 2 cohorts after inverse probability weight adjustments. Symptomatic (15.8% versus 8.1%; adjusted odds ratio, 0.400; P=0.008) and permanent (9.2% versus 5.0%; adjusted odds ratio, 0.441; P=0.045) radiation-induced change were more common in unruptured AVMs. Conclusions- The overall outcomes after SRS for unruptured versus ruptured pediatric AVMs are comparable. However, symptomatic and permanent radiation-induced change occur more frequently in pediatric patients with unruptured AVMs.

OBJECTIVE:There remains a large discrepancy among surgeons in expectations of vestibular schwannoma (VS) growth. The anticipated growth rate of a VS and its potential clinical impact are important factors when deciding whether to observe the lesion over time or to intervene. Previous studies of VS natural growth remain limited, mostly confined to linear measurements, often without high-resolution, thin-sequence imaging. The present study comprehensively assessed natural tumor growth rates using volumetric measurements. METHODS:Between 2012 and 2018, 212 treatment-naïve patients diagnosed with a unilateral VS were evaluated. A total of 699 MR images were assessed, with a range of 2-11 MR images per patient. All MR images preceded any intervention, with patients subsequently being observed through completion of data analysis (36%) or treated with stereotactic radiosurgery (32%) or microsurgical resection (32%). To determine precise tumor volumes, the tumor area was outlined on every slice, and the products of the area and slice thickness were summed (99% of scans were ≤ 1-mm slice thickness). A multilevel model with random effects was used to assess the mean volume change over time. Each tumor was categorized as one of the following: growing (volume increase by more than 20% per year), fast growing (volume increase by more than 100% per year), stable (volume change between 20% decrease and 20% increase per year), and shrinking (volume decrease by more than 20% per year). RESULTS:The mean VS volumetric growth rate was 33.5% per year (95% CI 26.9%-40.5%, p < 0.001). When assessing the frequencies of individual tumor annual growth rates, 66% demonstrated growth (30% fast growing), 33% were stable, and 1% exhibited shrinking over an average interval of 25 months. Larger tumors were associated with increased absolute growth, but there was no relationship between tumor size and proportional growth rate. There was also no relationship between patient age and tumor growth rate. CONCLUSIONS:This study comprehensively assessed VS volumetric growth rates using high-resolution images and was conducted in a large and diverse patient sample. The majority of the tumors exhibited growth, with about one-third growing at a rate of 100% per year. These findings may contribute to a consensus understanding of tumor behavior and inform clinical decisions regarding whether to intervene or observe.

OBJECTIVE:The most common functioning pituitary adenoma is prolactinoma. Patients with medically refractory or residual/recurrent tumors that are not amenable to resection can be treated with stereotactic radiosurgery (SRS). The aim of this multicenter study was to evaluate the role of SRS for treating prolactinomas. METHODS:This retrospective study included prolactinomas treated with SRS between 1997 and 2016 at ten institutions. Patients' clinical and treatment parameters were investigated. Patients were considered to be in endocrine remission when they had a normal level of prolactin (PRL) without requiring dopamine agonist medications. Endocrine control was defined as endocrine remission or a controlled PRL level ≤ 30 ng/ml with dopamine agonist therapy. Other outcomes were evaluated including new-onset hormone deficiency, tumor recurrence, and new neurological complications. RESULTS:The study cohort comprised 289 patients. The endocrine remission rates were 28%, 41%, and 54% at 3, 5, and 8 years after SRS, respectively. Following SRS, 25% of patients (72/289) had new hormone deficiency. Sixty-three percent of the patients (127/201) with available data attained endocrine control. Three percent of patients (9/269) had a new visual complication after SRS. Five percent of the patients (13/285) were recorded as having tumor progression. A pretreatment PRL level ≤ 270 ng/ml was a predictor of endocrine remission (p = 0.005, adjusted HR 0.487). An increasing margin dose resulted in better endocrine control after SRS (p = 0.033, adjusted OR 1.087). CONCLUSIONS:In patients with medically refractory prolactinomas or a residual/recurrent prolactinoma, SRS affords remarkable therapeutic effects in endocrine remission, endocrine control, and tumor control. New-onset hypopituitarism is the most common adverse event.

Stereotactic radiosurgery emerged as a neurosurgical discipline in order to utilize energy for the manipulation of brain or nerve tissue, with the goal of minimal access and safe and effective care of a spectrum of neurosurgical disorders. Perhaps no other branch of neurosurgery has been so disruptive across the entire discipline of brain tumor care, treatment of vascular disorders, and management of functional problems. Radiosurgery is mainstream, supported by thousands of peer-reviewed outcomes reports. This article reviews current practice with a focus on challenges, emerging trends, and areas of investigation.

INTRODUCTION/BACKGROUND:Seizures are the second most common clinical presentation in patients with brain arteriovenous malformations (AVMs), and they are the most common presentation of unruptured AVMs. The aim of this multicenter, retrospective cohort study was to identify predictors of seizure presentation in AVM patients treated with stereotactic radiosurgery (SRS). METHODS:We performed a retrospective review of AVM patients treated with SRS at eight participating International Radiosurgery Research Foundation sites. Patient and AVM characteristics were compared between those with versus without seizure presentation in univariable and multivariable models. Subgroup analysis of patients with cortical AVMs was performed. RESULTS:The study cohort comprised 2,333 AVM patients, including 419 (18%) with and 1,914 (82%) without seizure presentation. Prior AVM resection (OR=7.65, p=0.001), lack of prior AVM hemorrhage (OR=0.004, p<0.001), cortical AVM location (OR=1559.42, p<0.001), lower Spetzler-Martin (SM) grade (OR=0.51, p=0.007), and higher Virginia Radiosurgery AVM Score (VRAS; OR=1.46, p=0.008) were independent predictors of seizure presentation. The rate of seizure presentation in patients with cortical AVMs was 27%. Prior AVM resection (OR=8.36, p<0.001), lack of prior AVM hemorrhage (OR=0.004, p<0.001), and temporal AVM location (OR=4.15, p<0.001) were independent predictors of seizure presentation for cortical AVMs. CONCLUSION/CONCLUSIONS:We identified multiple factors associated with seizure presentation in AVM patients selected to undergo SRS. Prior AVM resection, cortical AVM location and lack of prior AVM hemorrhage were the strongest predictors of pre-SRS seizures. SM grade and VRAS may have a role in seizure risk stratification. Among cortical AVMs, temporal lobe localization was predictive of seizure presentation.

Background and Purpose- Understanding the hemorrhage risks associated with brain arteriovenous malformations (AVMs) before and after stereotactic radiosurgery (SRS) is important. The aims of this multicenter, retrospective cohort study are to evaluate and compare the rates of pre- and post-SRS AVM hemorrhage and identify risk factors. Methods- We pooled AVM SRS data from 8 institutions participating in the International Radiosurgery Research Foundation. Predictors of post-SRS hemorrhage were determined using a multivariate logistic regression model. Pre- and post-SRS hemorrhage rates were compared using Fisher exact test. Ruptured and unruptured AVMs were matched in a 1:1 ratio using propensity scores, and their outcomes were compared. Results- The study cohort comprised 2320 AVM patients who underwent SRS. Deep AVM location (odds ratio, 1.86; 95% CI, 1.19-2.92; P=0.007), the presence of an AVM-associated arterial aneurysm (odds ratio, 2.44; 95% CI, 1.63-3.66; P<0.001), and lower SRS margin dose (odds ratio, 0.93; 95% CI, 0.88-0.98; P=0.005) were independent predictors of post-SRS hemorrhage. The post-SRS hemorrhage rate was lower for obliterated versus patent AVMs (6.0 versus 22.3 hemorrhages/1000 person-years; P<0.001). The AVM hemorrhage rate decreased from 15.4 hemorrhages/1000 person-years before SRS to 11.9 after SRS ( P=0.001). The outcomes of the matched ruptured versus unruptured AVM cohorts were similar. Conclusions- SRS appears to reduce the risk of AVM hemorrhage, although this effect is predominantly driven by obliteration. Deep-seated AVMs are more likely to rupture during the latency period after SRS. AVM-associated aneurysms should be considered for selective occlusion before SRS of the nidus to ameliorate the post-SRS hemorrhage rate of these lesions.

BACKGROUND:The BRAF mutation has been identified as a potent target for the treatment of metastatic melanoma and BRAF inhibitors (BRAFi) have demonstrated promising results against melanoma brain metastases (BM). OBJECTIVE:To further investigate the effectiveness of this combined treatment regimen. METHODS:In this multicenter retrospective cohort study, 198 patients with known BRAF mutation status and treated with stereotactic radiosurgery (SRS) between 2011 and 2015 were identified. Kaplan-Meier methodology and multivariate regression analysis was then used to compare survival based on each parameter. RESULTS:The median survival after the diagnosis of BM in patients with BRAF mutation who received BRAFi was increased compared to survival in patients with wild-type BRAF (BRAF wt). In multivariate analysis, the BRAF mutation was an independent, positive prognostic factor with a hazard ratio of 0.59. BRAF mutated Patients who received BRAFi following SRS had improved survival compared to patients who received it before (P < .001) or concurrently (P = .007). PD-1 inhibitors improved survival, with more pronounced effect in patients not carrying the BRAF mutation. Among the patients who were treated with BRAFi, 10.4% developed intracerebral hematoma (ICH), in comparison to 3% of patients who were not treated with BRAFi (P = .03). CONCLUSION/CONCLUSIONS:In the setting of widespread use of BRAFi, the presence of a BRAF mutation is an independent predictor of better prognosis in patients with melanoma BM that underwent SRS. The effect of BRAFi is optimal when treatment is initiated at least 1 wk following SRS. BRAFi may increase the frequency of asymptomatic ICH.