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We previously published a novel strategy for management of postcraniotomy bone flap infection consisting of single stage debridement, bone flap removal, and immediate titanium mesh cranioplasty.Postcraniotomy patients with surgical site infections treated with surgical debridement, bone flap removal, and immediate titanium mesh cranioplasty were retrospectively reviewed. The primary outcome measure was reoperation due to persistent infection or wound healing complications from the titanium mesh.We included 48 patients, of which 15 (31.3%) were female. The most common primary diagnoses were glioblastoma (31.3%), meningioma (18.8%), and vascular/trauma (16.7%). Most patients had a history of same-site craniotomy prior to the surgery complicated by surgical site infection and 47.9% had prior cranial radiation. Thirty-six (75.0%) patients achieved resolution of their infection and did not require a second operation. Twelve (25.0%) patients required reoperation: 6 (12.5%) patients were found to have frank intraoperative purulence on reoperation, whereas 6 (12.5%) had reoperation for poor wound healing without any evidence of persistent infection. Cochran Armitage trend test revealed that patients with increasing number of wound healing risk factors had significantly higher risk of reoperation (P = 0.001). Prior intensity modulated radiotherapy alone was a significant risk factor for reoperation (6.5 [1.40-30.31], P = 0.002). Median follow-up time was 20.5 weeks.Immediate titanium mesh cranioplasty at the time of debridement and bone flap removal is an acceptable option in the management of post-craniotomy bone flap infection. Patients with multiple wound healing risk factors are at higher risk for reoperation.

In addition to established prognostic factors in low-grade glioma (LGG), studies suggest a sexual dimorphism with male sex portending worse prognosis. Our objective was to identify the effect of sex on presentation and outcomes in LGG.We conducted a retrospective cohort study of adults (aged ≥18 years) diagnosed with LGG (World Health Organization 2016 grade 2 glioma). Patients with IDH wild-type tumors were excluded. Patients were matched between male and female sex by age, treatment, and surgery via propensity score matching. Patient, tumor, and treatment characteristics were analyzed by sex. Endpoints included overall survival (OS), next intervention-free survival (NIFS), progression-free survival, and malignant transformation-free survival. Kaplan-Meier analyses and Cox proportional hazards regression multivariable analysis with backward elimination were completed.Of the 532 patients identified, 258 (48%) were men. Men were more likely to present with seizure (69.38% vs 56.57%, P = .002), but no other statistically significant differences between sexes at presentation were identified. Five-year OS was higher in women at 87% (95% confidence interval [CI], 83%-91%) versus 78% (95% CI, 73%-84%) in men (P = .0045). NIFS was significantly higher in female patients at 68% (95% CI, 62%-74%) versus 57% (95% CI, 51%-64%) in men (P = .009). On multivariable analysis, female sex was independently associated with improved OS (hazard ratio [HR], 1.54; 95% CI, 1.16-2.05; P = .002), NIFS (HR, 1.42; 95% CI, 1.42; P = .004), and malignant transformation-free survival (HR, 1.62; 95% CI, 1.24-2.12; P = .0004). In patients with molecularly defined LGG (IDH and 1p19q status; n = 291), female sex remained independently associated with improved OS (HR, 1.79; 95% CI, 1.16-2.77; P = .008) and NIFS (HR, 1.45; 95% CI, 1.07-1.96; P = .016).In this study, female sex was independently associated with improved outcomes. These findings support intrinsic sex-specific differences in LGG behavior, justifying further studies to optimize management and therapeutics based on sex.

Surgery is the treatment of choice for large vestibular schwannomas (VS). Stereotactic radiosurgery (SRS) has been suggested as an alternative to resection in selected patients. However, the safety and efficacy of SRS in Koos grade IV patients ≤ 45 years old has not been evaluated. The aim of this study is to describe the clinical and radiological outcomes of Koos grade IV in young patient managed with a single-session SRS.This retrospective, multicenter analysis included SRS-treated patients, ≤ 45 years old presenting with non-life threatening or incapacitating symptoms due to a Koos Grade IV VS and with follow-up ≥ 12 months. Tumor control and neurological outcomes were evaluated.176 patients [median age of 36.0 (IQR 9) and median tumor volume of 9.3 cmSingle-session SRS is a safe and effective alternative to surgical resection in selected patients ≤ 45 years old particularly those with medical co-morbidities and those who decline resection. Longer term follow up is warranted.

Supplementary Data

Supplementary Information

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies.Significance:Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas.This article is highlighted in the In This Issue feature, p. 1611

Purpose:Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment—including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment—has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined.Experimental Design:We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM.Results:Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles.Conclusions:These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.

Supplementary Figures 1-18

PDF file - 223K, Aptamer high tumor cells display preferential invasion.

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PDF file - 42K, Aptamer Sequences.

PDF file - 279K, Aptamer A4 high cells have a differential genetic profile associated with downregulation of genes involved in cellular development.

PDF file - 87K, TIC-specific aptamers preferentially bind TICs in comparison to non-TICs or U87MG cells.

PDF file - 86K, TIC- specific aptamers display specificity for TICs.

PDF file - 226K, TIC-specific apatmers internalize specifically into TICs.

OBJECTIVE The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children. METHODS Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed. RESULTS A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications. CONCLUSIONS SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

Surgery is the preferred treatment for large vestibular schwannomas (VS). Good tumor control and cranial nerve outcomes were described in selected Koos IV VS after single-session stereotactic radiosurgery (SRS), but outcomes in elderly patients have never been specifically studied. The aim of this study is to report clinical and radiological outcomes after single-session SRS for Koos IV VS in patients ≥ 65 years old.This multicenter, retrospective study included patients ≥ 65 years old, treated with primary, single-session SRS for a Koos IV VS, and at least 12 months of follow-up. Patients with life-threatening or incapacitating symptoms were excluded. Tumor control rate, hearing, trigeminal, and facial nerve function were studied at last follow-up.One-hundred and fifty patients (median age of 71.0 (IQR 9.0) years old with a median tumor volume of 8.3 cc (IQR 4.4)) were included. The median prescription dose was 12.0 Gy (IQR 1.4). The local tumor control rate was 96.0% and 86.2% at 5 and 10 years, respectively. Early tumor expansion occurred in 6.7% and was symptomatic in 40% of cases. A serviceable hearing was present in 16.1% prior to SRS and in 7.4% at a last follow-up of 46.5 months (IQR 55.8). The actuarial serviceable hearing preservation rate was 69.3% and 50.9% at 5 and 10 years, respectively. Facial nerve function preservation or improvement rates at 5 and 10 years were 98.7% and 91.0%, respectively. At last follow-up, the trigeminal nerve function was improved in 14.0%, stable in 80.7%, and worsened in 5.3% of the patients. ARE were noted in 12.7%. New hydrocephalus was seen in 8.0% of patients.SRS can be a safe alternative to surgery for selected Koos IV VS in patients ≥ 65 years old. Further follow-up is warranted.

Purpose Surgery is the treatment of choice for large vestibular schwannomas (VS). Stereotactic radiosurgery (SRS) has been suggested as an alternative to resection in selected patients. However, the safety and efficacy of SRS in Koos grade IV patients ≤45 years old has not been evaluated. The aim of this study is to describe the clinical and radiological outcomes of Koos grade IV in young patient managed with a single-session SRS. Methods This retrospective, multicenter analysis included SRS-treated patients, ≤45 years old presenting with non-life threatening or incapacitating symptoms due to a Koos Grade IV VS and with follow-up ≥ 12 months. Tumor control and neurological outcomes were evaluated. Results 176 patients (median age of 36.0 (IQR 9) and median tumor volume of 9.3 cm3 (IQR 4.7)) were included. The median prescription dose was 12 Gy (IQR 0.5). Median follow-up period was 37.5 (IQR 53.5) months. The 5- and 10-year progression-free survival was 90.9 and 86.7%. Early tumor enlargement occurred in 10.9% of cases and was associated with tumor progression at the last follow-up. The probability of serviceable hearing preservation at 5- and 10-years was 56.8% and 45.2%, respectively. The probability of improvement or preservation of facial nerve function was 95.7% at 5 and 10-years. Adverse radiation effects were noted in 19.9%. New-onset hydrocephalus occurred in 4.0%. Conclusion Single-session SRS is a safe and effective alternative to surgical resection in selected patients ≤45 years old particularly those with medical co-morbidities and those who decline resection. Longer term follow up is warranted.

Background Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by “planned LITT+SRT” versus “LITT alone” versus “repeat SRT alone.” Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0–30.5), age of 60 years (range: 37–86), Karnofsky Performance Status (KPS) of 80 (range: 60–100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7–19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004). Conclusions These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

Steroids are often utilized to manage patients with non-small cell lung cancer brain metastases (NSCLCBM). Steroids and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with decreased overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI). We retrospectively investigated patients treated with ICI after the diagnosis of NSCLCBM at a single tertiary care institution examing the impact of steroids and NLR. Overall survival (OS) and intracranial progression-free survival (PFS) were analyzed. 171 patients treated with ICI for NSCLCBM were included. Thirty-six received steroids within 30 days of the start of ICI, and 53 patients had an NLR ≥ 5 before the start of ICI. Upfront steroids was associated with decreased OS on multivariable analysis (median OS 10.5 vs. 17.9 months, p = .03) and intracranial PFS (5.0 vs. 8.7 months, p = .045). NLR ≥ 5 was indicative of worse OS (10.5 vs. 18.4 months, p = .04) but not intracranial PFS (7.2 vs. 7.7 months, p = .61). When NLR and upfront steroids are modeled together, there is a strong interaction (p = .0008) indicating that the impact of steroids depended on the patient’s NLR. In a subgroup analysis, only in patients with NLR p = .032). The impact of steroids on the efficacy of ICI in patients with NSCLCBM is dependent on the patient's NLR underscoring its importance in these patients. Patients with a low NLR, steroid use decreases the efficacy of ICI. These results can inform clinicians about the impact of steroids in patients treated with ICI.

The optimal modality of radiation—intensity-modulated radiation therapy (IMRT) or stereotactic radiosurgery (SRS)—in patients with recurrent WHO grade II meningiomas is not well-established. The purpose of this study was to compare progression-free survival (PFS) in patients undergoing salvage IMRT vs SRS. We compared PFS in those with and without history of prior radiation. Forty-two patients with 71 tumor recurrences treated with IMRT or SRS were retrospectively reviewed. Thirty-two salvage treatments were performed on recurrent tumors never treated with prior radiation (‘radiation-naive’ cohort), whereas 39 salvage treatments were performed on recurrent tumors previously treated with radiation (‘re-treatment cohort’). In the ‘radiation-naive’ cohort, 3-year PFS for IMRT and SRS was 68.8% and 60.7%, respectively (p = 0.61). The median tumor volume for patients treated with IMRT was significantly larger than for patients treated with SRS (5.7 vs 2.2 cm3; p = 0.04). The 3-year PFS for salvage IMRT or SRS in the ‘re-treatment’ cohort was 45.4% vs 65.8% in the ‘radiation-naive’ cohort (p = 0.008). When analyzing the outcome of multiple re-treatments, median PFS was 47 months for 1st or 2nd salvage radiation (IMRT or SRS) compared to 16 months for the 3rd or greater salvage radiation treatment (p = 0.003). For salvage radiation of recurrent grade II tumors that are ‘radiation-naive’, comparable 3-year PFS rates were found between IMRT and SRS, despite the IMRT group having significantly larger tumors. Salvage radiation overall was less successful in the ‘re-treatment’ cohort compared with the ‘radiation-naive’ cohort. Additionally, the effectiveness of radiation significantly declines with successive salvage radiation treatments.

Purpose: Glioblastoma (GBM) immunotherapy clinical trials are generally initiated after standard-of-care treatment—including surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment—has either begun or failed. However, the impact of these interventions on the antitumoral immune response is not well studied. While discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated into clinical trial design, the impact of surgical resection and steroids on the antitumor immune response has yet to be determined. Experimental Design: We developed a murine model integrating tumor resection and steroid treatment and used flow cytometry to analyze systemic and local immune changes. These mouse model findings were validated in a cohort of 95 patients with primary GBM. Results: Using our murine resection model, we observed a systemic reduction in lymphocytes corresponding to increased tumor volume and decreased circulating lymphocytes that was masked by dexamethasone treatment. The reduction in circulating T cells was due to reduced CCR7 expression, resulting in T-cell sequestration in lymphoid organs and the bone marrow. We confirmed these findings in a cohort of patients with primary GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Finally, we demonstrated that peripheral lymphocyte content varies with progression-free survival and overall survival, independent of tumor volume, steroid use, or molecular profiles. Conclusions: These data reveal that prior to intervention, increased tumor volume corresponds with reduced systemic immune function and that peripheral lymphocyte counts are prognostic when steroid treatment is taken into account.

Secretory meningioma (SM) is a rare subtype of benign meningioma reported to cause significant peritumoral brain edema (PTBE). Therefore, patients with SM may have more severe presenting symptoms and possibly increased postoperative complications. Our aim was to perform a statistically rigorous comparison of patients with SM with other nonsecretory World Health Organization grade I meningiomas and examine PTBE, postsurgical outcomes, and recurrence in a large series of cases.A retrospective review of all patients at our institution with pathologically confirmed SM between 2000 and 2017 was performed. A control group of nonsecretory grade I meningiomas was matched 1:1 according to tumor location and size. Study groups were compared on clinical characteristics and outcomes using logistic, cumulative logit, and normal linear generalized estimating equations regression models.Fifty-five patients with SM met inclusion criteria and were matched with 55 control patients. After adjusting for size and location, the odds of a patient with SM having a more severe T2 edema grade were 8.9 (95% confidence interval, 3.8-21.1; P 0.001) times higher, and the odds of any T2 edema were 6.2 (95% confidence interval, 2.2-17.6; P 0.001) times higher. Significance remained even when adjusting for age. Postoperative complications, Simpson grade resection, neurologic outcome, and recurrence were not significantly different.Patients with SM have significantly greater odds of having PTBE compared with patients with nonsecretory World Health Organization grade I meningiomas of a similar size and location. Despite this situation, surgical outcome and recurrence rates are similar.

Clear cell meningioma (CCM) is a rare WHO grade II meningioma variant, characterized by aggressive features and a high tumor recurrence rate. In this study, we compared overall and progression-free survivals between CCMs and other WHO grade II meningiomas. A retrospective institutional database review was performed to identify all patients who underwent surgical resection of a WHO grade II meningioma between 1997 and 2019. Overall survival and progression-free survival were compared between patients with clear cell meningiomas and patients with other WHO grade II meningiomas. Multivariable Cox proportional-hazards analysis was used to identify independent predictors of tumor recurrence and survival. We included a total of 214 patients in this study (43 CCMs, 171 other WHO grade II meningiomas). Patients with CCMs had significantly shorter progression-free (p = 0.001) and overall (p = 0.026) survivals than patients with other grade II meningiomas. In multivariable analysis, clear cell histology was a significant and powerful independent predictor of tumor recurrence (HR 1.93; 95% CI 1.14–3.26) when controlling for tumor location, extent of resection, and adjuvant radiation. In multivariable analysis, clear cell histology correlated with increased mortality (HR 1.96, 95% CI 0.97–3.94), though this was not statistically significant. This is the first study to compare overall and progression-free survivals between CCMs and other WHO grade II meningiomas. Clear cell histology predicts a higher risk of tumor recurrence and mortality than other grade II histologies. Future studies may help to understand the impact of these findings and the treatment implications.

WHO grade II meningiomas behave aggressively, with recurrence rates as high as 60%. Although complete resection in low-grade meningiomas is associated with a relatively low recurrence rate, the impact of complete resection for WHO grade II meningiomas is less clear. We studied the association of extent of resection with overall and progression-free survivals in patients with WHO grade II meningiomas. A retrospective database review was performed to identify all patients who underwent surgical resection for intracranial WHO grade II meningiomas at our institution between 1995 and 2019. Kaplan–Meier analysis was used to compare overall and progression-free survivals between patients who underwent gross total resection (GTR) and those who underwent subtotal resection (STR). Multivariable Cox proportional-hazards analysis was used to identify independent predictors of tumor recurrence and mortality. Of 214 patients who underwent surgical resection for WHO grade II meningiomas (median follow-up 53.4 months), 158 had GTR and 56 had STR. In Kaplan–Meier analysis, patients who underwent GTR had significantly longer progression-free (p = 0.002) and overall (p = 0.006) survivals than those who underwent STR. In multivariable Cox proportional-hazards analysis, GTR independently predicted prolonged progression-free (HR 0.57, p = 0.038) and overall (HR 0.44, p = 0.017) survivals when controlling for age, tumor location, and adjuvant radiation. Extent of resection independently predicts progression-free and overall survivals in patients with WHO grade II meningiomas. In an era of increasing support for adjuvant treatment modalities in the management of meningiomas, our data support maximal safe resection as the primary goal in treatment of these patients.

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies. Significance: Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas. This article is highlighted in the In This Issue feature, p. 1611

OBJECTIVEStereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs.METHODSThe authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared.RESULTSThe overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation.CONCLUSIONSApproximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.

Background Surgical options for patients with thalamic brain tumors are limited. Traditional surgical resection is associated with a high degree of morbidity and mortality. Laser interstitial thermal therapy (LITT) utilizes a stereotactically placed laser probe to induce thermal damage to tumor tissue. LITT provides a surgical cytoreduction option for this challenging patient population. We present our experience treating thalamic brain tumors with LITT. Objective To describe our experience and outcomes using LITT on patients with thalamic tumors. Methods We analyzed 13 consecutive patients treated with LITT for thalamic tumors from 2012 to 2017. Radiographic, clinical characteristics, and outcome data were collected via review of electronic medical records. Results Thirteen patients with thalamic tumors were treated with LITT. Most had high-grade gliomas, including glioblastoma (n = 9) and anaplastic astrocytoma (n = 2). The average tumor volume was 12.0 cc and shrank by 42.9% at 3 mo. The average hospital stay was 3.0 d. Median ablation coverage as calculated by thermal damage threshold (TDT) lines was 98% and 95% for yellow (>43°C for >2 min) or blue (>10 min), respectively. Median disease-specific progression-free survival calculated for 8 patients in our cohort was 6.1 mo (range: 1.1-15.1 mo). There were 6 patients with perioperative morbidity and 2 perioperative deaths because of intracerebral hematoma. Conclusion LITT is a feasible treatment for patients with thalamic tumors. LITT offers a cytoreduction option in this challenging population. Patient selection is key. Close attention should be paid to lesion size to minimize morbidity. More studies comparing treatment modalities of thalamic tumors need to be performed.

Laser interstitial thermal therapy (LITT) is a minimally invasive therapy that have been used for brain tumors, epilepsy, chronic pain, and other spine pathologies. This therapy is performed under imaging and stereotactic guidance to precisely direct the probe and ablate the area of interest using real-time magnetic resonance (MR) thermography. LITT has gained popularity as a treatment for glioma because of its minimally invasive nature, small skin incision, repeatability, shorter hospital stay, and the possibility of receiving adjuvant therapy shortly after surgery instead of several weeks as required after open surgical resection. Several reports have demonstrated the usefulness of LITT in the treatment of newly-diagnosed and recurrent gliomas. In this review, we will summarize the recent evidence of this therapy in the field of glioma surgery and the future perspectives of the use of LITT combined with other treatment strategies for this devastating disease.

Background Laser interstitial thermal therapy (LITT) is a stereotactic-guided technique, which is increasingly being performed for brain lesions. The aim of our study was to report the national trends and factors predicting the clinical outcomes following LITT using the Nationwide Inpatient Sample. Methods We extracted data from 2011–2016 using ICD-9/10 codes. Patients with a primary procedure of LITT were included. Patient demographics, complications, length of hospital stay, discharge disposition, and index-hospitalization charges were analyzed. Results A cohort of 1768 patients was identified from the database. Mean length of hospital stay was 3.2 days, 82% of patients were discharged to home, and in-hospitalization cost was $124,225. Complications and mortality were noted in 12.9% and 2.5% of patients following LITT, respectively. Non-Caucasian patients (estimate ratio [ER] 4.26), those with other insurance (compared with commercial, ER: 5.35), 3 and 4+ comorbidity indexes, patients with higher quartile median household income (second, third, and fourth quartile compared with first quartile), and those who underwent nonelective procedures were likely to have higher complications and less likely to be discharged home. Patients with 4+ comorbidity indexes were likely to have longer length of hospital stay (ER 1.39) and higher complications (ER: 7.95) and were less likely to be discharged home (ER: 0.17) and have higher in-hospitalization cost (ER: 1.21). Conclusions LITT is increasingly being performed with low complication rates. Non-Caucasian race, higher comorbidity index, noncommercial insurance, and nonelective procedures were predictors of higher complications and being less likely to be discharged home. In-hospitalization charges were higher in patients with higher comorbidity index and those with noncommercial insurance.

OBJECTIVEContrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).METHODSThe authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.RESULTSThe study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.CONCLUSIONSAVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

Objective To evaluate the role of apparent diffusion coefficient (ADC) in differentiating radiation necrosis (RN) from recurrent tumor after Gamma Knife radiosurgery (GKRS) for brain metastases (BMs). Methods Forty-one patients with BM who underwent surgical intervention after GKRS at Cleveland Clinic (2006–2017) were included in this retrospective study. The ADC values of the growing lesions and the contralateral hemisphere were calculated using picture archiving and communication system. These values were correlated to the percentage of RN identified on pathologic evaluation of the surgical specimen. Results The median age of the patients was 59 years (range, 25–86 years), and lung cancer (63.4%) was the most common malignancy. Median initial (pre-GKRS) target volume of the lesions was 5.4 cc (range, 0.135–45.6 cc), and median GKRS dose was 18.0 Gy. Surgical resection or biopsy was performed at a median of 176 days after GKRS. Two variables were statistically significant predictors of predominate RN (75%–100%) in the surgical specimen: 1) ADC of the lesion on the preresection magnetic resonance imaging (MRI) and 2) initial pre-GKRS target volume. ADC >1.5 × 10−3 mm2/s within the lesion on MRI predicted significant RN on pathologic evaluation of the lesion (P 10 cc), the risk of identifying significant necrosis in the pathologic specimen was elevated (P Conclusions Our data suggest that the combination of lesion ADC on MRI prior to surgical intervention and the initial target volume can predict RN with reasonable accuracy.

OBJECTIVEWith increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases.METHODSPatients with HER2+ breast cancer brain metastases who underwent SRS from 1997–2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival.RESULTSOne hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival.CONCLUSIONSFor patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.

OBJECTIVEThe object of this retrospective study was to investigate the impact of targeted therapies on overall survival (OS), distant intracranial failure, local failure, and radiation necrosis among patients treated with radiation therapy for renal cell carcinoma (RCC) metastases to the brain.METHODSAll patients diagnosed with RCC brain metastasis (BM) between 1998 and 2015 at a single institution were included in this study. The primary outcome was OS, and secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. The timing of targeted therapies was recorded. Multivariate Cox proportional-hazards regression was used to model OS, while multivariate competing-risks regression was used to model local failure, distant intracranial failure, and radiation necrosis, with death as a competing risk.RESULTSThree hundred seventy-six patients presented with 912 RCC BMs. Median OS was 9.7 months. Consistent with the previously validated diagnosis-specific graded prognostic assessment (DS-GPA) for RCC BM, Karnofsky Performance Status (KPS) and number of BMs were the only factors prognostic for OS. One hundred forty-seven patients (39%) received vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Median OS was significantly greater among patients receiving TKIs (16.8 vs 7.3 months, p < 0.001). Following multivariate analysis, KPS, number of metastases, and TKI use remained significantly associated with OS.The crude incidence of local failure was 14.9%, with a 12-month cumulative incidence of 13.4%. TKIs did not significantly decrease the 12-month cumulative incidence of local failure (11.4% vs 14.5%, p = 0.11). Following multivariate analysis, age, number of BMs, and lesion size remained associated with local failure. The 12-month cumulative incidence of radiation necrosis was 8.0%. Use of TKIs within 30 days of SRS was associated with a significantly increased 12-month cumulative incidence of radiation necrosis (10.9% vs 6.4%, p = 0.04).CONCLUSIONSUse of targeted therapies in patients with RCC BM treated with intracranial SRS was associated with improved OS. However, the use of TKIs within 30 days of SRS increases the rate of radiation necrosis without improving local control or reducing distant intracranial failure. Prospective studies are warranted to determine the optimal timing to reduce the rate of necrosis without detracting from survival.

OBJECTIVE Though stereotactic radiosurgery (SRS) is an established safe treatment for small- and medium-sized vestibular schwannomas (VSs), its role in the management of Koos grade IV VS is still unclear. In this retrospective multicenter study, the authors evaluated tumor control and the patient outcomes of primary, single-session SRS treatment for Koos grade IV VS. METHODS This study included patients treated with primary, single-session SRS for Koos grade IV VS at 10 participating centers. Only those patients presenting with non–life-threatening or incapacitating symptoms and at least 12 months of clinical and neuroimaging follow-up were eligible for inclusion. Relevant data were collected, and the Kaplan-Meier method was used to perform time-dependent analysis for post-SRS tumor control, hearing preservation, and facial nerve function preservation. Univariate and multivariate analyses were performed for outcome measures using Cox regression analysis. RESULTS Six hundred twenty-seven patients (344 females, median patient age 54 [IQR 22] years) treated with primary SRS were included in this study. The median tumor volume was 8.7 (IQR 5) cm3. Before SRS, serviceable hearing, facial nerve weakness (House-Brackmann grade > I), and trigeminal neuropathy were present in 205 (33%), 48 (7.7%), and 203 (32.4%) patients, respectively. The median prescription dose was 12 (IQR 1) Gy. At a median radiological follow-up of 38 (IQR 54) months, tumor control was achieved in 94.1% of patients. Early tumor expansion occurred in 67 (10.7%) patients and was associated with a loss of tumor control at the last follow-up (p = 0.001). Serviceable hearing preservation rates at the 5- and 10-year follow-ups were 65% and 44.6%, respectively. Gardner-Robertson class > 1 (p = 0.003) and cochlear dose ≥ 4 Gy (p = 0.02) were risk factors for hearing loss. Facial nerve function deterioration occurred in 19 (3.0%) patients at the last follow-up and was associated with margin doses ≥ 13 Gy (p = 0.03) and early tumor expansion (p = 0.04). Post-SRS, 33 patients developed hydrocephalus requiring shunting. Adverse radiation effects occurred in 92 patients and were managed medically or surgically in 34 and 18 cases, respectively. CONCLUSIONS SRS is a safe and effective method of obtaining tumor control in patients with Koos grade IV VS presenting with non–life-threatening or debilitating symptoms, especially those with surgical comorbidities that contraindicate resection. To decrease the incidence of post-SRS facial palsy, a prescription dose < 13 Gy is recommended.