Ultrasound-guided resection of cerebellar racemose neurocysticercosis: novel insights from a unique scenario.

Racemose neurocysticercosis (RNC) is a malignant form of Taenia solium infection. It carries high mortality due to widespread intraparenchymal invasion, mass effect, and cyst rupture. Cerebellar RNC is unusual and constitutes a surgical challenge. Scarce applications of ultrasound (US) -guided resection have been reported for RNC of the posterior fossa. We report the case of a 66-year-old woman who presented with ataxia and dysmetria. Her past medical history was relevant for seizures and hydrocephalus secondary to neurocysticercosis. Because of the increasing cyst invasion and threatening mass effect in the posterior fossa, the patient underwent US-guided resection of lesions. Postoperative computed tomography (CT) demonstrated complete excision of cysts, and a 2-year follow-up magnetic resonance imaging (MRI) showed no recurrence. On neurological examination, the patient had persistent ataxia without new-onset neurological deficits. The present case study illustrates the feasibility and cost-effective approach of US-guided resection to provide enhanced operative visualization and achieve complete cyst resection.

Extent of Surgical Resection as a Predictor of Tumor Progression in Skull Base Chordomas: A Multicenter Volumetric Analysis.

INTRODUCTION: Skull-base chordomas are aggressive tumors with a propensity for recurrence/progression. Even with standard of care (SoC), 5-year recurrence rates are variable (19%-54%). This high recurrence/progression rate correlates with increased morbidity and mortality. We sought to analyze a multicenter cohort of skull base chordomas to identify predictors of progression in patients receiving SoC. METHODS: The [Blinded]-Neurosurgery data registry was queried for skull base chordomas treated from 2008-2020. Patients with the histopathologic diagnosis of chordoma were included. The cohort was composed of patients with preoperative and postoperative magnetic resonance imaging. Tumor volume and radiologic characteristics were obtained from axial T2 sequences using a Digital Imaging and Communications in Medicine viewer. Survival analysis was performed using Kaplan-Meier method, and time-to-event multivariate regression was performed to identify independent predictors of progression. RESULTS: The cohort included 195 patients, of which 66 patients met inclusion criteria; median age was 44, and 28 (42%) were females. Fifty-four (82%) received SoC, 7 (11%) resection only, and 5 (8%) radiotherapy only. Median preoperative and postoperative tumor volumes were 11.55 cm3 (0.33-54.89) and 0.34 cm3 (0-42.52), respectively. Recurrence rate with SoC was 37%. Postoperative tumor volume (P = 0.010) correlated with progression. A postoperative volume of >4.9 cm3 (P = 0.044), ≤81.3% of tumor resection (P = 0.02), and lower-clivus location (P < 0.005) correlated with decreased time to progression. CONCLUSIONS: Skull base chordomas can be challenging to resect. Even though maximal resection and radiotherapy improve rate of tumor progression, many of these lesions eventually recur. We have identified a postoperative tumor volume of ≥4.9 cm3 and extent of resection of ≤81.3% in this cohort as predictors of progression in patients receiving SoC.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

PURPOSE: Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. METHODS: A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). RESULTS: The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). CONCLUSION: The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Absence of the torcular, review of venous sinus anatomy, and the simplified dural sinus classification.

BACKGROUND: Classically, the torcular Herophili is described as the symmetric junction between the superior sagittal sinus (SSS), transverse sinuses (TSs), and straight sinus (SS). However, finding this pattern in practice is not standard. Anatomical variations are common, and different drainage patterns should be expected. Existing literature proposes highly detailed descriptions and classifications of this region. Still, a simplified and practical categorization is not available. METHODS: We present an anatomical finding of the torcular Herophili discovered on a cadaveric dissection. Then, we conducted a retrospective study examining the 100 most recent cranial magnetic resonance venographies (MRVs) from the Mayo Clinic, labeling them with a new proposed dural sinus classification system. Images were initially classified by two authors and further validated by a board-certified neurosurgeon and a board-certified neuroradiologist from our institution. To measure consistency in image identification, two additional international neurosurgeons were asked to classify a subset of the same MRV images, and their answers were compared. RESULTS: Of the MRV cohort, 33 patients were male and 67 were female. Their ages ranged from 18 to 86 years, with a mean of 47.35 years and a median of 49 years. Upon examination, 53 patients presented as confluent (53%), 9 as SSS divergent (9%), 25 as SS divergent (25%), 11 as circular (11%), and 2 as trifurcated (2%). The inter-rater reliability ranked very good; agreement between the two neurosurgeons was 83% (κ = 0.830, p < 0.0005). CONCLUSION: The confluence of the venous sinuses is a highly variable anatomical area that is rarely evaluated with neuroimaging before surgery. The classic textbook configuration is not the rule. Using a simplified classification system may increase awareness and hopefully patient safety by preparing the physician for anatomical variations that they will encounter in a surgical or clinical scenario.

SARS-CoV2 entry factors are expressed in primary human glioblastoma and recapitulated in cerebral organoid models.

PURPOSE: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults with a median overall survival of only 14.6 months despite aggressive treatment. While immunotherapy has been successful in other cancers, its benefit has been proven elusive in GBM, mainly due to a markedly immunosuppressive tumor microenvironment. SARS-CoV-2 has been associated with the development of a pronounced central nervous system (CNS) inflammatory response when infecting different cells including astrocytes, endothelial cells, and microglia. While SARS-CoV2 entry factors have been described in different tissues, their presence and implication on GBM aggressiveness or microenvironment has not been studied on appropriate preclinical models. METHODS: We evaluated the presence of crucial SARS-CoV-2 entry factors: ACE2, TMPRSS2, and NRP1 in matched surgically-derived GBM tissue, cells lines, and organoids; as well as in human brain derived specimens using immunohistochemistry, confocal pixel line intensity quantification, and transcriptome analysis. RESULTS: We show that patient derived-GBM tissue and cell cultures express SARS-CoV2 entry factors, being NRP1 the most crucial facilitator of SARS-CoV-2 infection in GBM. Moreover, we demonstrate that, receptor expression remains present in our GBM organoids, making them an adequate model to study the effect of this virus in GBM for the potential development of viral therapies in the future. CONCLUSION: Our findings suggest that the SARS-CoV-2 virus entry factors are expressed in primary tissues and organoid models and could be potentially utilized to study the susceptibility of GBM to this virus to target or modulate the tumor microenviroment.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases.

PURPOSE: Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. METHODS AND MATERIALS: Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. RESULTS: Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P = .03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P < 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. CONCLUSIONS: The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.

Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics.

Imaging-defined necrosis after treatment with single-fraction stereotactic radiosurgery and immune checkpoint inhibitors and its potential association with improved outcomes in patients with brain metastases: an international multicenter study of 697 patients.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRICs) are a frequently observed clinical manifestation and are commonly classified as imaging-defined radiation necrosis. However, these findings are not well characterized and may predict a response to SRS and ICIs. The objective of this study was to investigate predictors of TRICs and their impact on patient survival. METHODS: This retrospective multicenter cohort study was conducted through the International Radiosurgery Research Foundation. Member institutions submitted de-identified clinical and dosimetric data for patients with non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) brain metastases that had been treated with SRS and ICIs. Data were collected from March 2020 to February 2021. Univariable and multivariable Cox and logistic regression analyses were performed. The Kaplan-Meier method was used to evaluate overall survival (OS). The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRICs were determined on the basis of MRI, PET/CT, or MR spectroscopy, and consensus by local clinical providers was required. RESULTS: The analysis included 697 patients with 4536 brain metastases across 11 international institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years (IQR 58-73 years), 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% of tumors were NSCLC, melanoma, and RCC, respectively. All patients had undergone single-fraction radiosurgery to a median margin dose of 20 Gy (IQR 18-20 Gy). TRICs were observed in 9.8% of patients. The median OS for all patients was 24.5 months. On univariable analysis, Karnofsky Performance Status (KPS; HR 0.98, p < 0.001), TRICs (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 TRICs (HR 0.66, p = 0.03) were associated with improved OS. A brain volume receiving ≥ 12 Gy of radiation (V12Gy) ≥ 10 cm3 (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 TRICs. The median OS rates in patients with and without TRICs were 29.0 and 23.1 months, respectively (p = 0.03, log-rank test). CONCLUSIONS: TRICs following ICI and SRS were associated with a median OS benefit of approximately 6 months in this retrospective multicenter study. Further prospective study and additional stratification are needed to validate these findings and further elucidate the role and etiology of this common clinical scenario.

Brain radiotoxicity-related 15CAcBRT gene expression signature predicts survival prognosis of glioblastoma patients.

BACKGROUND: Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. METHODS: RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. RESULTS: We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. CONCLUSIONS: 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.

Preoperative stereotactic radiosurgery in the management of brain metastases and gliomas.

Stereotactic radiosurgery (SRS) is the delivery of a high dose ionizing radiation in a highly conformal manner, which allows for significant sparing of nearby healthy tissues. It is typically delivered in 1-5 sessions and has demonstrated safety and efficacy across multiple intracranial neoplasms and functional disorders. In the setting of brain metastases, postoperative and definitive SRS has demonstrated favorable rates of tumor control and improved cognitive preservation compared to conventional whole brain radiation therapy. However, the risk of local failure and treatment-related complications (e.g. radiation necrosis) markedly increases with larger postoperative treatment volumes. Additionally, the risk of leptomeningeal disease is significantly higher in patients treated with postoperative SRS. In the setting of high grade glioma, preclinical reports have suggested that preoperative SRS may enhance anti-tumor immunity as compared to postoperative radiotherapy. In addition to potentially permitting smaller target volumes, tissue analysis may permit characterization of DNA repair pathways and tumor microenvironment changes in response to SRS, which may be used to further tailor therapy and identify novel therapeutic targets. Building on the work from preoperative SRS for brain metastases and preclinical work for high grade gliomas, further exploration of this treatment paradigm in the latter is warranted. Presently, there are prospective early phase clinical trials underway investigating the role of preoperative SRS in the management of high grade gliomas. In the forthcoming sections, we review the biologic rationale for preoperative SRS, as well as pertinent preclinical and clinical data, including ongoing and planned prospective clinical trials.

Concurrent Administration of Immune Checkpoint Inhibitors and Stereotactic Radiosurgery Is Well-Tolerated in Patients With Melanoma Brain Metastases: An International Multicenter Study of 203 Patients.

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: 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.

MicroRNA delivery systems in glioma therapy and perspectives: A systematic review.

Gliomas are the deadliest of all primary brain tumors, and they constitute a serious global health problem. MicroRNAs (miRNAs) are gene expression regulators associated with glioma pathogenesis. Thus, miRNAs represent potential therapeutic agents for treating gliomas. However, miRNAs have not been established as part of the regular clinical armamentarium. This systemic review evaluates current molecular and pre-clinical studies with the aim of defining the most appealing supramolecular platform for administering therapeutic miRNA to patients with gliomas. An integrated analysis suggested that cationic lipid nanoparticles, functionalized with octa-arginine peptides, represent a potentially specific, practical, non-invasive intervention for treating gliomas. This supramolecular platform allows loading both hydrophilic (miRNA) and hydrophobic (anti-tumor drugs, like temozolomide) molecules. This systemic review is the first to describe miRNA delivery systems targeted to gliomas that integrate several types of molecules as active ingredients. Further experimental validation is warranted to confirm the practical value of miRNA delivery systems.

Skull Base Meningiomas in Patients with Neurofibromatosis Type 2: An International Multicenter Study Evaluating Stereotactic Radiosurgery.

Objective Meningiomas are the second most common tumors in neurofibromatosis type 2 (NF-2). Microsurgery is challenging in NF-2 patients presenting with skull base meningiomas due to the intrinsic risks and need for multiple interventions over time. We analyzed treatment outcomes and complications after primary Gamma Knife radiosurgery (GKRS) to delineate its role in the management of these tumors. Methods An international multicenter retrospective study approved by the International Radiosurgery Research Foundation was performed. NF-2 patients with at least one growing and/or symptomatic skull base meningioma and 6-month follow-up after primary GKRS were included. Clinical and radiosurgical parameters were recorded for analysis. Results In total, 22 NF-2 patients with 54 skull base meningiomas receiving GKRS as primary treatment met inclusion criteria. Median age at GKRS was 38 years (10-79 years). Most lesions were located in the posterior fossa (55.6%). Actuarial progression free survival (PFS) rates were 98.1% at 2 years and 90.0% at 5 and 10 years. The median follow-up time after initial GKRS was 5.0 years (0.6-25.5 years). Tumor volume at GKRS was a predictor of tumor control. Lesions >5.5 cc presented higher chances to progress after radiosurgery ( p = 0.043). Three patients (13.64%) developed adverse radiation effects. No malignant transformation or death due to meningioma or radiosurgery was reported. Conclusions GKRS is effective and safe in the management of skull base meningiomas in NF-2 patients. Tumor volume deserve greater relevance during clinical decision-making regarding the most appropriate time to treat. GKRS offers a minimally invasive approach of particular interest in this specific group of patients.

The Extent of Resection in Gliomas-Evidence-Based Recommendations on Methodological Aspects of Research Design.

OBJECTIVE: Modern neurosurgery has established maximal safe resection as a cornerstone in the management of diffuse gliomas. Evaluation of the extent of resection (EOR), and its association with certain outcomes or interventions, heavily depends on an adequate methodology to draw strong conclusions. We aim to identify weaknesses and limitations that may threaten the internal validity and generalizability of studies involving the EOR in patients with glioma and to suggest methodological recommendations that may help mitigate these threats. METHODS: A systematic search was performed by querying PubMed, Web of Science, and Scopus since inception to April 30, 2021 using PICOS/PRISMA guidelines. Articles were then screened to identify high-impact studies evaluating the EOR in patients diagnosed with diffuse gliomas in accordance with predefined criteria. We identify common weakness and limitations during the evaluation of the EOR in the selected studies and then delineate potential methodological recommendations for future endeavors dealing with the EOR. RESULTS: We identified 31 high-impact studies and found several research design issues including inconsistencies regarding EOR terminology, measurement, data collection, analysis, and reporting. Although some of these issues were related to now outdated reporting standards, many were still present in recent publications and deserve attention in contemporary and future research. CONCLUSIONS: There is a current need to focus more attention to the methodological aspects of glioma research. Methodological inconsistencies may introduce weaknesses into the internal validity of the studies and hamper comparative analysis of cohorts from different institutions. We hope our recommendations will eventually help develop stronger methodological designs in future research endeavors.

Preoperative Stereotactic Radiosurgery for Glioblastoma.

Glioblastoma is a devastating primary brain tumor with a median overall survival of approximately 15 months despite the use of optimal modern therapy. While GBM has been studied for decades, modern therapies have allowed for a reduction in treatment-related toxicities, while the prognosis has largely been unchanged. Adjuvant stereotactic radiosurgery (SRS) was previously studied in GBM; however, the results were disappointing. SRS is a highly conformal radiation technique that permits the delivery of high doses of ionizing radiation in 1-5 sessions while largely sparing surrounding healthy tissues. Furthermore, studies have shown that the delivery of ablative doses of ionizing radiation within the central nervous system is associated with enhanced anti-tumor immunity. While SRS is commonly used in the definitive and adjuvant settings for other CNS malignancies, its role in the preoperative setting has become a topic of great interest due to the potential for reduced treatment volumes due to the treatment of an intact tumor, and a lower risk of nodular leptomeningeal disease and radiation necrosis. While early reports of SRS in the adjuvant setting for glioblastoma were disappointing, its role in the preoperative setting and its impact on the anti-tumor adaptive immune response is largely unknown. In this review, we provide an overview of GBM, discuss the potential role of preoperative SRS, and discuss the possible immunogenic effects of this therapy.

Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study.

BACKGROUND: Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. METHODS: RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. RESULTS: Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. CONCLUSIONS: Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.

Minimally Invasive Transforaminal Lumbar Interbody Fusion: Cost of a Surgeon's Learning Curve.

BACKGROUND: Minimally invasive transforaminal interbody fusion has become an increasingly common approach in adult degenerative spine disease but is associated with a steep learning curve. We sought to evaluate the impact of the learning experience on mean procedure time and mean cost associated with each procedure. METHODS: We studied the first 100 consecutive minimally invasive transforaminal interbody fusion procedures of a single surgeon. We performed multivariable linear regression models, modeling operating time, and costs in function of the procedure order adjusted for patients' age, sex, and number of surgical levels. The number of procedures necessary to attain proficiency was determined through a k-means cluster analysis. Finally, the total excess operative time and total excess cost until obtaining proficiency was evaluated. RESULTS: Procedure order was found to impact procedure time and mean costs, with each successive case being associated with progressively less procedure time and cost. On average, each successive case was associated with a reduction in procedure time of 0.97 minutes (95% confidence interval 0.54-1.40; P < 0.001) and an average adjusted reduction in overall costs of $82.75 (95% confidence interval $35.93-129.57; P < 0.001). An estimated 58 procedures were needed to attain proficiency, translating into an excess procedure time of 2604.2 minutes (average of 45 minutes per case), overall costs associated with the learning experience of $226,563.8 (average of $3974.80 per case), and excess surgical cost of $125,836.6 (average of $2207.66 per case). CONCLUSIONS: Successive cases were associated with progressively less procedure time and mean overall and surgical costs, until a proficiency threshold was attained.

Adipose-Derived Stem Cells Therapy for Radiation-Induced Skin Injury.

BACKGROUND: Radiation-induced skin injuries have been treated with different medical therapies and have shown diverse outcomes. We aim to evaluate the effect of adipose-derived stem cells (ADSCs) therapy on radiation-induced skin injury. METHODS: We performed a review by querying PubMed, Ovid MEDLINE, and EMBASE databases from inception to April 2020 following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The MeSH terms "adipose-derived stem cells," "wound healing," "radiation," and synonyms in combinations determined our search strategy. Experimental peer-reviewed articles describing the protocol and comparing the results with controls were included. Non-English studies were excluded. RESULTS: Our search recorded a total of 137 articles. Only 8 studies met our inclusion criteria and were included in this review. Five studies evaluated the use of ADSC alone, whereas the others evaluated the efficacy of ADSC seeded in scaffolds. Adipose-derived stem cell-based therapies, either alone or seeded in scaffolds, were shown to improve wound healing in most studies when compared with controls. CONCLUSIONS: There is evidence supporting the positive benefits from ADSC-based therapies in radiation-induced skin injury. However, further studies are needed to standardize the method of ADSC extraction, radiation-induced skin injury experimental model, and increase the time of follow-up to evaluate the results accurately.

Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma.

Radiotherapy (RT) is one of the cornerstones in the current treatment paradigm for glioblastoma (GBM). However, little has changed in the management of GBM since the establishment of the current protocol in 2005, and the prognosis remains grim. Radioresistance is one of the hallmarks for treatment failure, and different therapeutic strategies are aimed at overcoming it. Among these strategies, nanomedicine has advantages over conventional tumor therapeutics, including improvements in drug delivery and enhanced antitumor properties. Radiosensitizing strategies using nanoparticles (NP) are actively under study and hold promise to improve the treatment response. We aim to describe the basis of nanomedicine for GBM treatment, current evidence in radiosensitization efforts using nanoparticles, and novel strategies, such as preoperative radiation, that could be synergized with nanoradiosensitizers.

Initial Observation among Patients with Vestibular Schwannoma.

Introduction Vestibular schwannomas (VS) are slow growing tumors. Although there are a wide variety of available treatment options, these tumors are often initially observed. We aimed to establish the presenting symptoms and outcomes of patients treated with initial observation at our institution. Methods The medical records of patients with radiographically diagnosed VS were reviewed from 1989 to 2018. Actuarial estimates of radiographic tumor control and freedom of local therapy were calculated and compared using Cox regression analyses. Results A total of 360 patients were diagnosed with VS at our institution from 1989 through 2018 with a median age of 59.9 years. After radiographic diagnosis, 243 patients (67.5%) opted for initial observation. Local control at 1, 5, and 10 years was 91, 67, and 58%, respectively. On multivariable analysis, factors associated with shorter time to radiographic tumor progression included younger patient age ( p = 0.016) and tumors with an extracanalicular component ( p = 0.032). Regarding time until definitive treatment only larger baseline American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) tumor size predicted for earlier initiation of therapy ( p < 0.001), although this was restricted to tumors with an extracanalicular component ( p = 0.004), as opposed to purely internal auditory canal tumors ( p = 0.839). Conclusion Many patients who were initially observed continued to have satisfactory local control rates at 10 years. In patients with extracanalicular tumors, larger AAO-HNS tumor measurements were associated with earlier radiographic tumor progression and shorter time to local therapy, with 7 mm serving as a potential threshold value for extracanalicular tumors. Younger patients and tumors with primarily an extracanalicular portion may warrant closer observation.