Faculty Bibliography

BACKGROUND:Differentiating brain metastasis progression from radiation effects or radiation necrosis (RN) remains challenging. Golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced MRI provides high spatial and temporal resolution to analyze tissue enhancement, which may differ between tumor progression (TP) and RN. OBJECTIVE:To investigate the utility of longitudinal GRASP MRI in distinguishing TP from RN after gamma knife stereotactic radiosurgery (SRS). METHODS:We retrospectively evaluated 48 patients with brain metastasis managed with SRS at our institution from 2013 to 2020 who had GRASP MRI before and at least once after SRS. TP (n = 16) was pathologically confirmed. RN (n = 16) was diagnosed on either resected tissue without evidence of tumor or on lesion resolution on follow-up. As a reference, we included a separate group of patients with non-small-cell lung cancer that showed favorable response with tumor control and without RN on subsequent imaging (n = 16). Mean contrast washin and washout slopes normalized to the superior sagittal sinus were compared between groups. Receiver operating characteristic analysis was performed to determine diagnostic performance. RESULTS:After SRS, progression showed a significantly steeper washin slope than RN on all 3 follow-up scans (scan 1: 0.29 ± 0.16 vs 0.18 ± 0.08, P = .021; scan 2: 0.35 ± 0.19 vs 0.18 ± 0.09, P = .004; scan 3: 0.32 ± 0.12 vs 0.17 ± 0.07, P = .002). No significant differences were found in the post-SRS washout slope. Post-SRS washin slope differentiated progression and RN with an area under the curve (AUC) of 0.74, a sensitivity of 75%, and a specificity of 69% on scan 1; an AUC of 0.85, a sensitivity of 92%, and a specificity of 69% on scan 2; and an AUC of 0.87, a sensitivity of 63%, and a specificity of 100% on scan 3. CONCLUSION:Longitudinal GRASP MRI may help to differentiate metastasis progression from RN.

INTRODUCTION/BACKGROUND:Clinical trial data comparing outcomes after administration of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) to patients with brain metastases (BM) suggest that SRS better preserves cognitive function and quality of life without negatively impacting overall survival. Here, we estimate the maximum number of BM that can be treated using single and multi-session SRS while limiting the dose of radiation delivered to normal brain tissue to that associated with WBRT. METHODS:Multiple-tumor SRS was simulated using a Monte Carlo - type approach and a pre-calculated dose kernel method. Tumors with diameters ≤36 mm were randomly placed throughout the contoured brain parenchyma until the brain mean dose reached 3 Gy, equivalent to the radiation dose delivered during a single fraction of a standard course of WBRT (a total dose of 30 Gy in 10 daily fractions of 3 Gy). Distribution of tumor sizes, dose coverage, selectivity, normalization, and maximum dose data used in the simulations were based on institutional clinical metastases data. RESULTS:The mean number of tumors treated, mean volume of healthy brain tissue receiving > 12 Gy (V12) per tumor, and total tumor volume treated using mixed tumor size distributions were 12.7 ± 4.2, 2.2 cc, and 12.9 cc, respectively. Thus, we estimate that treating 12-13 tumors per day over 10 days would deliver the dose of radiation to healthy brain tissue typically associated with a standard course of WBRT. CONCLUSION/CONCLUSIONS:Although in clinical practice, treatment with SRS is often limited to patients with ≤15 BM, our findings suggest that many more lesions could be targeted while still minimizing the negative impacts on quality of life and neurocognition often associated with WBRT. Results from this in silico analysis require clinical validation.

BACKGROUND:The development of accurate machine learning algorithms requires sufficient quantities of diverse data. This poses a challenge in health care because of the sensitive and siloed nature of biomedical information. Decentralized algorithms through federated learning (FL) avoid data aggregation by instead distributing algorithms to the data before centrally updating one global model. OBJECTIVE:To establish a multicenter collaboration and assess the feasibility of using FL to train machine learning models for intracranial hemorrhage (ICH) detection without sharing data between sites. METHODS:Five neurosurgery departments across the United States collaborated to establish a federated network and train a convolutional neural network to detect ICH on computed tomography scans. The global FL model was benchmarked against a standard, centrally trained model using a held-out data set and was compared against locally trained models using site data. RESULTS:A federated network of practicing neurosurgeon scientists was successfully initiated to train a model for predicting ICH. The FL model achieved an area under the ROC curve of 0.9487 (95% CI 0.9471-0.9503) when predicting all subtypes of ICH compared with a benchmark (non-FL) area under the ROC curve of 0.9753 (95% CI 0.9742-0.9764), although performance varied by subtype. The FL model consistently achieved top three performance when validated on any site's data, suggesting improved generalizability. A qualitative survey described the experience of participants in the federated network. CONCLUSION/CONCLUSIONS:This study demonstrates the feasibility of implementing a federated network for multi-institutional collaboration among clinicians and using FL to conduct machine learning research, thereby opening a new paradigm for neurosurgical collaboration.

PURPOSE/UNASSIGNED:Eccrine gland carcinoma (EC) is a rare skin neoplasm that uncommonly spreads to the brain or pituitary gland. We describe the role of multiple stereotactic radiosurgery (SRS) procedures to manage recurrent brain metastases of this rare disease. MATERIALS AND METHODS/UNASSIGNED:Retrospective chart review was completed to obtain details for this report. The study was performed under IRB study on medical record only and was exempt from patient's consent. RESULTS AND CONCLUSIONS/UNASSIGNED:A 59-year-old female underwent surgical excision of a right parietal scalp EC. Over the next 13 years, the patient underwent initial fractionated whole brain radiation therapy after she developed multiple brain metastases followed by systemic chemotherapy for extracranial disease. Because of repeated development of new brain disease, three SRS procedures were performed to treat a total of 50 brain metastases and a pituitary metastasis (PM). The patient expired from progressive systemic cancer spread 13 years after her initial surgical excision. Due to the rarity of metastatic EC to the brain, no standard treatment paradigm has emerged. Using multimodality options that included local excision of the original skin tumor, followed by radiation, systemic chemotherapy, and three SRS procedures, long-term survival was possible in this unusual case.

BACKGROUND:Melanoma brain metastases are commonly treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs). However, the toxicity of these 2 treatments is largely unknown when administered concurrently. OBJECTIVE:To evaluate the risk of radiation necrosis (RN) with concurrent and nonconcurrent SRS and ICIs. METHODS:The guidelines from the Strengthening the Reporting of Observational Studies in Epidemiology checklist were used. Inverse probability of treatment weighting, univariable and multivariable logistic regression, and the Kaplan-Meier method was utilized. RESULTS:There were 203 patients with 1388 brain metastases across 11 international institutions in 4 countries with a median follow-up of 15.6 months. The rates of symptomatic RN were 9.4% and 8.2% in the concurrent and nonconcurrent groups, respectively ( P =.766). On multivariable logistic regression, V12 ≥ 10 cm 3 (odds ratio [OR]: 2.76; P =.006) and presence of BRAF mutation (OR: 2.20; P =.040) were associated with an increased risk of developing symptomatic RN; the use of concurrent over nonconcurrent therapy was not associated with an increased risk (OR: 1.06; P =.877). There were 20 grade 3 toxic events reported, and no grade 4 events reported. One patient experienced a grade 5 intracranial hemorrhage. The median overall survival was 36.1 and 19.8 months for the concurrent and nonconcurrent groups (log-rank P =.051), respectively. CONCLUSION/CONCLUSIONS:Concurrent administration of ICIs and SRS are not associated with an increased risk of RN. Tumors harboring BRAF mutation, or perhaps prior exposure to targeted agents, may increase this risk. Radiosurgical optimization to maintain V12 < 10 cm 3 is a potential strategy to reduce the risk of RN.

Purpose/Objective(s): Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases (BrM), particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Materials/Methods: Patients with BrM from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Recursive partitioning analysis (RPA) was utilized for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected.
Result(s): Six hundred fifty-seven patients with 4,182 BrM across 11 international institutions were analyzed. Rates of RN and symptomatic RN (SRN) for all patients were 10% and 6.8%, respectively. The highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified using V12 Gy: (1) < 12 cm³; (2) 20 cm³ <= V12 Gy >= 12 cm³; (3) > 20 cm³. Odds ratios for RN and SRN with cases of V12 Gy >= 12 cm³ compared with < 12 cm³ were 3.05 (p < 0.001) and 3.72 (p < 0.001), respectively. Rates of RN and SRN are presented in the table below. Concurrent ICI use rates were equivalent among these resulting groups, and the addition of concurrent ICI use did not improve the model's fidelity. Using RPA, 80% of the highest-fidelity models failed to incorporate concurrent ICI as a predictive variable. Even after exclusion of V12 Gy as a candidate variable, concurrent ICI remained unused in 85% of the highest-fidelity models. These models yielded 94% accuracy for the validation set and 92% accuracy for the test set.
Conclusion(s): Utilization of SRS and ICI results in a low risk of RN and SRN. This risk is not increased when ICI and SRS are administered concurrently. Therefore, ICI can safely be administered within 4-weeks of SRS. In patients receiving SRS and ICI, three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.
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BACKGROUND: While most meningiomas are considered benign tumors, a subset of these tumors are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgical and radiotherapeutic options, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in neuroendocrine tumors. Here we report the results of the interim analysis of an ongoing clinical trial (NCT03971461) that is evaluating the effect of 177Lu-DOTATATE in treating progressive intracranial meningiomas.
METHOD(S): In this Simon two-stage design phase II study, adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every eight weeks for four doses. 68Ga-DOTATATE PET-MRI was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass.
RESULT(S): Fourteen patients (F = 11, M = 3) with progressive meningiomas (WHO I = 3, II = 10, III = 1) have been enrolled. Median age was 63.1 (range 49-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, no treatment-limiting toxicities were observed. Six of 14 patients (42%) achieved PFS-6. Radiographically, all six patients had achieved Stable Disease. A functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging was observed in three patients.
CONCLUSION(S): Treatment with SSTR2- targeting 177Lu-DOTATATE is well tolerated. In this interim analysis, six of 14 patients achieved PFS-6. This exceeds the predefined threshold to continue to stage two of this study. This clinical trial is now open to patient enrollment at two study sites in the US

OBJECTIVE: Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRIC) are a frequently observed clinical manifestation and are commonly classified as radiographic radiation necrosis. However, these findings are not well characterized and may predict for response to SRS and ICI.
METHOD(S): The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRIC were determined based upon MRI, PET/CT, or MR spectroscopy and a consensus by local clinical providers was required.
RESULT(S): The analysis included 697 patients with 4,536 brain metastases across 11 institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years, 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% were non-small cell lung cancer, melanoma, and renal cell carcinoma (RCC) histology, respectively. TRIC were observed in 9.8%. On univariable analysis, Karnofsky Performance Status (KPS) (hazard ratio [HR]: 0.98; p < 0.001), presence of TRIC (HR: 0.67; p = 0.03), female sex (HR: 0.67; p < 0.001), and prior resection (HR: 0.60; p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR: 0.98; p < 0.001) and the presence of TRIC (HR: 0.66; p = 0.03) were associated with improved OS. A V12 Gy >= 10 cm3 (Odds Ratio [OR]: 2.78; p < 0.001), prior whole brain radiation therapy (OR: 3.46; p = 0.006), and RCC histology (OR: 3.10; p = 0.01) were associated with an increased probability of developing TRIC. The median OS in patients with and without TRIC was 29.0 and 23.1 months, respectively (log-rank p = 0.03).
CONCLUSION(S): TRIC following ICI and SRS are associated with a median OS benefit of approximately 6 months. Further prospective study is warranted to further elucidate the role and etiology of this common clinical scenario

BACKGROUND:For patients with vestibular schwannoma (VS), stereotactic radiosurgery (SRS) has proven effective in controlling tumor growth while hearing preservation remains a key goal. OBJECTIVE:To evaluate hearing outcomes in the modern era of cochlear dose restriction. METHODS:During the years 2013 to 2018, 353 patients underwent Gamma knife surgery for VS at our institution. We followed 175 patients with pre-SRS serviceable hearing (Gardner-Robertson Score, GR 1 and 2). Volumetric and dosimetry data were collected, including biological effective dose, integral doses of total and intracanalicular tumor components, and hearing outcomes. RESULTS:The mean age was 56 years, 74 patients (42%) had a baseline GR of 2, and the mean cochlear dose was 3.5 Gy. The time to serviceable hearing loss (GR 3-4) was 38 months (95% CI 26-46), with 77% and 62% hearing preservation in the first and second years, respectively. Patients optimal for best hearing outcomes were younger than 58 years with a baseline GR of 1, free canal space ≥0.041 cc (diameter of 4.5 mm), and mean cochlear dose <3.1 Gy. For such patients, hearing preservation rates were 92% by 12 months and 81% by 2 years, staying stable for >5 years post-SRS, significantly higher than the rest of the population. CONCLUSION/CONCLUSIONS:Hearing preservation after SRS for patients with VS with serviceable hearing is correlated to the specific baseline GR score (1 or 2), age, cochlear dose, and biological effective dose. Increased tumor-free canal space correlates with better outcomes. The most durable hearing preservation correlates with factors commonly associated with smaller tumors away from the cochlea.