Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.

Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor ß. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy.

Glioblastoma Stem Cell Targeting Peptide Isolated Through Phage Display Binds Cadherin 2.

Glioblastoma stem cells (GSCs) have unique properties of self-renewal and tumor initiation that make them potential therapeutic targets. Development of effective therapeutic strategies against GSCs requires both specificity of targeting and intracranial penetration through the blood-brain barrier. We have previously demonstrated the use of in vitro and in vivo phage display biopanning strategies to isolate glioblastoma targeting peptides. Here we selected a 7-amino acid peptide, AWEFYFP, which was independently isolated in both the in vitro and in vivo screens and demonstrated that it was able to target GSCs over differentiated glioma cells and non-neoplastic brain cells. When conjugated to Cyanine 5.5 and intravenously injected into mice with intracranially xenografted glioblastoma, the peptide localized to the site of the tumor, demonstrating intracranial tumor targeting specificity. Immunoprecipitation of the peptide with GSC proteins revealed Cadherin 2 as the glioblastoma cell surface receptor targeted by the peptides. Peptide targeting of Cadherin 2 on GSCs was confirmed through ELISA and in vitro binding analysis. Interrogation of glioblastoma databases demonstrated that Cadherin 2 expression correlated with tumor grade and survival. These results confirm that phage display can be used to isolate unique tumor-targeting peptides specific for glioblastoma. Furthermore, analysis of these cell specific peptides can lead to the discovery of cell specific receptor targets that may serve as the focus of future theragnostic tumor-homing modalities for the development of precision strategies for the treatment and diagnosis of glioblastomas.

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Microsurgical versus endovascular treatment of ethmoidal dural arteriovenous fistulas: systematic review and meta-analysis with a single-center case series.

OBJECTIVE: Ethmoidal dural arteriovenous fistulas (DAVFs) are often associated with cortical venous drainage (CVD) and a higher incidence of hemorrhage compared with DAVFs in other locations. They may be treated with open surgical disconnection or with endovascular treatment (EVT). In this systematic review and meta-analysis, the authors compare the outcomes of ethmoidal DAVFs treated with open microsurgery versus EVT and report four additional cases of ethmoidal DAVFs treated with open microsurgery in their institution. METHODS: A literature search of the PubMed and Scopus databases was conducted between December 2021 and May 2022 to identify relevant articles published between 1990 and 2021 using the PRISMA guidelines. References were reviewed and screened by two authors independently, and disagreements were resolved through consensus. Exclusion criteria included non-English-language studies, those with an incorrect study design, those reporting DAVFs in a nonethmoidal location, and studies whose outcomes were not stratified based on DAVF location. Inclusion criteria were any studies reporting on ethmoidal DAVFs treated by either microsurgery or EVT. A risk of bias assessment was performed using the Newcastle-Ottawa Scale. The authors performed a pooled proportional meta-analysis to compare patient outcomes. RESULTS: Twenty studies were included for analysis. Of 224 patients, 142 were treated with surgery, while 103 were treated with EVT. Seventy percent (148/210) of the patients were symptomatic at presentation, with hemorrhage being the most common presentation (48%). CVD was present in 98% of patients and venous ectasia in 61%. The rates of complete DAVF obliteration with surgery and EVT were 89% and 70%, respectively (95% CI -30% to -10%, p < 0.03). Twenty percent (21/103) of endovascularly treated fistulas required subsequent surgery. Procedure-related complications occurred in 10% of the surgical cases, compared with 13% of the EVT cases. The authors' case series included 4 patients with ethmoidal DAVFs treated surgically with complete obliteration, without any postoperative complications. CONCLUSIONS: The complete obliteration rates of ethmoidal DAVF appear to be higher and more definitive with microsurgical intervention than with EVT. While complication rates between the two procedures seem similar, patients treated with EVT may require further interventions for definitive treatment. The limitations of this study include its retrospective nature, the quality of studies included, and the continued evolving technologies of EVT. Future studies should focus on the association between venous drainage pattern and the proclivity toward venous ectasia or rate of hemorrhage at presentation.

The role of endoscopic endonasal salvage surgery in recurrent or residual craniopharyngioma after a transcranial approach: a systematic review.

BACKGROUND: The management of craniopharyngiomas is challenging due to their high rate of recurrence following resection. Excision of recurrent tumors poses further surgical challenges due to loss of arachnoidal planes and adherence to anatomical structures. The endoscopic endonasal approach (EEA) offers a favorable alternative to transcranial approaches for primary craniopharyngiomas. However, the safety and efficacy of EEA for recurrent tumors, specifically after a prior transcranial approach, needs further investigation. METHODS: We performed a systematic review using PubMed to develop a database of cases of recurrent craniopharyngiomas previously treated with a transcranial approach. RESULTS: Fifteen articles were included in this review with a total of 75 cases. There were 50 males and 25 females with a mean age of 38 years (range 2-80). One prior transcranial surgery was done in 80.0% of cases, while 8.0% had two and 12.0% had more than two prior surgeries. Radiotherapy after transcranial resection was given in 18 cases (24.0%). Following EEA, vision improved in 60.0% of cases, and vision worsened in 8.6% of the cases. Of cases, 64.4% had pre-existing anterior hypopituitarism, and 43.8% had diabetes insipidus prior to EEA. New anterior hypopituitarism and diabetes insipidus developed in 24.6% and 21.9% of cases, respectively following EEA. Gross total resection (GTR) was achieved in 64.0%, subtotal resection in 32.0%, and partial resection in 4.0% revision EEA cases. GTR rate was higher in cases with no prior radiotherapy compared to cases with prior radiotherapy (72.0% vs 39.0%, p = 0.0372). The recurrence rate was 17.5% overall but was significantly lower at 10.0% following GTR (p = 0.0019). The average follow-up length was 41.2 months (range, 1-182 months). CONCLUSION: The EEA can be utilized for resection of recurrent or residual craniopharyngiomas previously managed by a transcranial approach.

Development of a "Geo-Tagged" tumor sample registry: intra-operative linkage of sample location to imaging.

PURPOSE: There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation. METHODS: This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon). RESULTS: Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected. CONCLUSION: We are using the results of this analysis to develop a prospective sample collection protocol.

Phage display targeting identifies EYA1 as a regulator of glioblastoma stem cell maintenance and proliferation.

Glioblastoma (GBM) ranks among the most lethal of human malignancies with GBM stem cells (GSCs) that contribute to tumor growth and therapeutic resistance. Identification and isolation of GSCs continue to be a challenge, as definitive methods to purify these cells for study or targeting are lacking. Here, we leveraged orthogonal in vitro and in vivo phage display biopanning strategies to isolate a single peptide with GSC-specific binding properties. In silico analysis of this peptide led to the isolation of EYA1 (Eyes Absent 1), a tyrosine phosphatase and transcriptional coactivator. Validating the phage discovery methods, EYA1 was preferentially expressed in GSCs compared to differentiated tumor progeny. MYC is a central mediator of GSC maintenance but has been resistant to direct targeting strategies. Based on correlation and colocalization of EYA1 and MYC, we interrogated a possible interaction, revealing binding of EYA1 to MYC and loss of MYC expression upon targeting EYA1. Supporting a functional role for EYA1, targeting EYA1 expression decreased GSC proliferation, migration, and self-renewal in vitro and tumor growth in vivo. Collectively, our results suggest that phage display can identify novel therapeutic targets in stem-like tumor cells and that an EYA1-MYC axis represents a potential therapeutic paradigm for GBM.

Patient satisfaction and cost savings analysis of the telemedicine program within a neuro-oncology department.

PURPOSE: Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person visits within a Neuro-Oncology Program to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. METHODS: 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) by surgical and medical neuro-oncology patients between 04/01/2020 and 06/30/2021 were reviewed. Survey results were divided into 4 categories (Access, Provider, Technology (telemedicine only), and Overall Satisfaction). Results were analyzed for the impact of telemedicine versus in-person visits, and gender, age, insurance, and specialty. Cost savings were calculated based on potential travel distance and lost productivity. RESULTS: Survey results from telemedicine visits demonstrated that patients with private insurance returned higher scores in the Provider (p = 0.0089), Technology (p = 0.00187), and Overall (p = 0.00382) categories. Surgical patients returned higher scores for Access (p = 0.0015), Technology (p = 0.0002), and Overall (p = 0.0019). When comparing telemedicine to in-person scores, in-person scored higher in Provider (p = 0.0092) for all patients, while in-person scored higher in Access (p = 0.0252) amongst surgical patients. Cost analysis revealed that telemedicine allowed patients to save an average of 4.1 to 5.6 h per visit time and a potential cost savings of up to $223.3 ± 171.4. CONCLUSION: Telemedicine yields equivalent patient satisfaction when employed in surgical as compared to medical Neuro-Oncology patients with the potential to lessen the financial and time burden on neuro-oncology patients.

Patient frailty association with cerebral arteriovenous malformation microsurgical outcomes and development of custom risk stratification score: an analysis of 16,721 nationwide admissions.

OBJECTIVE: Patient frailty is associated with poorer perioperative outcomes for several neurosurgical procedures. However, comparative accuracy between different frailty metrics for cerebral arteriovenous malformation (AVM) outcomes is poorly understood and existing frailty metrics studied in the literature are constrained by poor specificity to neurosurgery. This aim of this paper was to compare the predictive ability of 3 frailty scores for AVM microsurgical admissions and generate a custom risk stratification score. METHODS: All adult AVM microsurgical admissions in the National (Nationwide) Inpatient Sample (2002-2017) were identified. Three frailty measures were analyzed: 5-factor modified frailty index (mFI-5; range 0-5), 11-factor modified frailty index (mFI-11; range 0-11), and Charlson Comorbidity Index (CCI) (range 0-29). Receiver operating characteristic curves were used to compare accuracy between metrics. The analyzed endpoints included in-hospital mortality, routine discharge, complications, length of stay (LOS), and hospitalization costs. Survey-weighted multivariate regression assessed frailty-outcome associations, adjusting for 13 confounders, including patient demographics, hospital characteristics, rupture status, hydrocephalus, epilepsy, and treatment modality. Subsequently, k-fold cross-validation and Akaike information criterion-based model selection were used to generate a custom 5-variable risk stratification score called the AVM-5. This score was validated in the main study population and a pseudoprospective cohort (2018-2019). RESULTS: The authors analyzed 16,271 total AVM microsurgical admissions nationwide, with 21.0% being ruptured. The mFI-5, mFI-11, and CCI were all predictive of lower rates of routine discharge disposition, increased perioperative complications, and longer LOS (all p < 0.001). Their AVM-5 risk stratification score was calculated from 5 variables: age, hydrocephalus, paralysis, diabetes, and hypertension. The AVM-5 was predictive of decreased rates of routine hospital discharge (OR 0.26, p < 0.001) and increased perioperative complications (OR 2.42, p < 0.001), postoperative LOS (+49%, p < 0.001), total LOS (+47%, p < 0.001), and hospitalization costs (+22%, p < 0.001). This score outperformed age, mFI-5, mFI-11, and CCI for both ruptured and unruptured AVMs (area under the curve [AUC] 0.78, all p < 0.001). In a pseudoprospective cohort of 2005 admissions from 2018 to 2019, the AVM-5 remained significantly associated with all outcomes except for mortality and exhibited higher accuracy than all 3 earlier scores (AUC 0.79, all p < 0.001). CONCLUSIONS: Patient frailty is predictive of poorer disposition and elevated complications, LOS, and costs for AVM microsurgical admissions. The authors' custom AVM-5 risk score outperformed age, mFI-5, mFI-11, and CCI while using threefold less variables than the CCI. This score may complement existing AVM grading scales for optimization of surgical candidates and identification of patients at risk of postoperative medical and surgical morbidity.

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

Breast cancer subtype predicts clinical outcomes after stereotactic radiation for brain metastases.

PURPOSE: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). METHODS: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. RESULTS: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001). CONCLUSIONS: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.

Subacute vision loss after microvascular decompression for trigeminal neuralgia.

Microvascular decompression is the surgery of choice for typical trigeminal neuralgia (TN) that fails conservative medical management. Visual loss after MVD is a rare complication that has not been reported. In this article, we present a patient who developed delayed visual loss and papilledema from transverse sinus stenosis resulting from bone wax compression after MVD for TN. While waxing the edges of a retrosigmoid craniotomy may seem mundane, meticulous care should be taken to ensure that there is no compression of the venous sinuses, as this could lead to intracranial hypertension.

The historical evolution of microvascular decompression for trigeminal neuralgia: from Dandy's discovery to Jannetta's legacy.

Although the symptoms of trigeminal neuralgia (TN) have been well described throughout the history of medicine, its etiology was initially not well understood by most surgeons. The standard procedure used to treat TN today, microvascular decompression (MVD), evolved due to the efforts of numerous neurosurgeons throughout the twentieth century. Walter Dandy was the first to utilize the cerebellar (suboccipital) approach to expose the trigeminal nerve for partial sectioning. He made unique observations about the compression of the trigeminal nerve by nearby structures, such as vasculature and tumors, in TN patients. In the 1920s, Dandy unintentionally performed the first MVD of the trigeminal nerve root. In the 1950s, Palle Taarnhøj treated a TN patient by performing the first intentional decompressive procedure on the trigeminal nerve root solely through the removal of a compressive tumor. By the 1960s, W. James Gardner was demonstrating that the removal of offending lesion(s) or decompression of nearby vasculature alleviated pressure on the trigeminal nerve and the pain associated with TN. By the 1990s, Peter Jannetta proved Dandy's original hypothesis; he visualized the compression of the trigeminal nerve at the root entry zone in TN patients using an intraoperative microscope. In this paper, we recount the historical evolution of MVD for the treatment of TN.

Efficacy of simultaneous pericranial and nasoseptal "double flap" reconstruction of anterior skull base defects after combined transbasal and endoscopic endonasal approaches.

BACKGROUND: The "double flap" reconstruction technique, comprised of a simultaneous vascularized pedicled pericranial flap (PCF) and pedicled nasoseptal flap (NSF), can be used to repair anterior skull base defects after a combined cranionasal or transbasal-endoscopic endonasal approach (EEA) has been performed to remove malignant anterior skull base tumors. The use of two vascularized flaps may potentially decrease the incidence of post-radiation flap necrosis and postoperative cerebrospinal fluid (CSF) leaks after radiation therapy. METHODS: We conducted a retrospective review of a prospective skull base database on patients who underwent the double flap reconstruction technique after a combined transbasal-EEA approach. Data collected for each patient included demographics, method of tumor resection and repair, complications, tumor recurrence, and follow-up. RESULTS: Nine patients who underwent a combined transbasal-EEA approach for resection of anterior skull base tumors with significant intracranial extension followed by reconstruction of the cranial base using the double flap technique. Four were men and five were women, with a mean age of 49 years (range, 15-68 years). There was no postoperative CSF leakage detected or complications of infection, meningitis, mucocele, or tension pneumocephalus after a mean follow-up of 35.7 months (range, 4.5-98 months). Seven of the nine patients underwent adjuvant radiation without flap necrosis. Local tumor recurrence was not observed in any of the patients at last follow-up; however, one patient developed distant brain metastasis. CONCLUSION: The simultaneous PCF and NSF double flap reconstruction is an effective technique in preventing postoperative CSF leakage and post-radiation necrosis when repairing anterior skull base defects after combined transbasal-EEA approaches. This technique may be useful in patients anticipated to undergo postoperative radiation therapy.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. METHODS: A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). RESULTS: A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. CONCLUSIONS: Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

Transbasal versus endoscopic endonasal versus combined approaches for olfactory groove meningiomas: importance of approach selection.

OBJECTIVE There has been much debate regarding the optimal surgical approach for resecting olfactory groove meningiomas (OGMs). In this paper, the authors analyzed the factors involved in approach selection and reviewed the surgical outcomes in a series of OGMs. METHODS A retrospective review of 28 consecutive OGMs from a prospective database was conducted. Each tumor was treated via one of 3 approaches: transbasal approach (n = 15), pure endoscopic endonasal approach (EEA; n = 5), and combined (endoscope-assisted) transbasal-EEA (n = 8). RESULTS The mean tumor volume was greatest in the transbasal (92.02 cm3) and combined (101.15 cm3) groups. Both groups had significant lateral dural extension over the orbits (transbasal 73.3%, p < 0.001; combined 100%), while the transbasal group had the most cerebral edema (73.3%, p < 0.001) and vascular involvement (66.7%, p < 0.001), and the least presence of a cortical cuff (33.3%, p = 0.019). All tumors in the combined group were recurrent tumors that invaded into the sinonasal cavity. The purely EEA group had the smallest mean tumor volume (33.33 cm3), all with a cortical cuff and no lateral dural extension. Gross-total resection was achieved in 80% of transbasal, 100% of EEA, and 62.5% of combined cases. Near-total resection (> 95%) was achieved in 20% of transbasal and 37.5% of combined cases, all due to tumor adherence to the critical neurovascular structures. The rate of CSF leakage was 0% in the transbasal and combined groups, and there was 1 leak in the EEA group (20%), resulting in an overall CSF leakage rate of 3.6%. Olfaction was preserved in 66.7% in the transbasal group. There was no significant difference in length of stay or 30-day readmission rate between the 3 groups. The mean modified Rankin Scale score was 0.79 after the transbasal approach, 2.0 after EEA, and 2.4 after the combined approach (p = 0.0604). The mean follow-up was 14.5 months (range 1-76 months). CONCLUSIONS The transbasal approach provided the best clinical outcomes with the lowest rate of complications for large tumors (> 40 mm) and for smaller tumors (< 40 mm) with intact olfaction. The role of EEA appears to be limited to smaller, appropriately selected tumors in which olfaction is already absent. EEA also plays an important adjunctive role when combined with the transbasal approach for recurrent OGMs invading the sinonasal cavity. Careful patient selection using an individualized, tailored strategy is important to optimize surgical outcomes.

Extended middle fossa approach with anterior petrosectomy for resection of upper petroclival meningioma involving Meckel's cave: operative video and technical nuances.

The surgical management of petroclival meningiomas remains a formidable challenge. These tumors are deep in the base of the skull and arise medial to the fifth cranial nerve. In this operative video, the author demonstrates the extended middle fossa approach with anterior petrosectomy to resect an upper petroclival meningioma extending into Meckel's cave with brainstem compression. This approach is very useful for accessing deep tumors located above and below the tentorium, and between the fifth and seventh cranial nerves. Access to Meckel's cave is readily achieved by opening the fibrous ring of the porous trigeminus. This video demonstrates the operative technique and surgical nuances of the skull base approach, useful anatomic landmarks of the middle fossa rhomboid for safe petrosectomy drilling, pearls for cranial nerve and neuro-otologic preservation, and exposure of Meckel's cave. A gross-total resection was achieved, and the patient was neurologically intact. In summary, the extended middle fossa approach with anterior petrosectomy is an important strategy in the armamentarium for surgical management of petroclival meningiomas. The video can be found here: https://youtu.be/jttwJIYPHC8 .

Combined bi-occipital suboccipital transsinus transtentorial approach for resection of a pineal region falcotentorial meningioma: operative video and technical nuances.

Large deep-seated meningiomas of the falcotentorial region present a formidable surgical challenge. In this operative video, the author demonstrates the combined bi-occipital suboccipital transsinus transtentorial approach for microsurgical resection of a large falcotentorial meningioma. This approach involves division of the less dominant transverse sinus after assessment of the venous pressure before and after clipping of the sinus with continuous neurophysiologic monitoring. Mild retraction of the occipital lobe and cerebellum results in a wide supra- and infratentorial exposure of extensive pineal region tumors. This video atlas demonstrates the operative technique and surgical nuances, including patient positioning, supra- and infratentorial craniotomy, transsinus transtentorial incision, and tumor removal with preservation of the vein of Galen complex. In summary, the combined bi-occipital suboccipital transsinus transtentorial approach provides a wide supra- and infratentorial surgical corridor for removal of select falcotentorial meningiomas. The video can be found here: https://youtu.be/3aD8h2uwBAo .