Facial Nerve Schwannoma Treatment with Stereotactic Radiosurgery (SRS) versus Resection followed by SRS: Outcomes and a Management Protocol.

Background Stereotactic radiosurgery (SRS) and resection are treatment options for patients with facial nerve schwannomas without mass effect. Objective This article evaluates outcomes of patients treated with SRS versus resection + SRS. Method We retrospectively compared 43 patients treated with SRS to 12 patients treated with resection + SRS. The primary study outcome was unfavorable combined endpoint, defined as worsening or new clinical symptoms, and/or tumor radiological progression. SRS (38.81 ± 5.3) and resection + SRS (67.14 ± 11.8) groups had similar clinical follow-ups. Results At the time of SRS, the tumor volumes of SRS (mean ± standard error; 1.83 ± 0.35 mL) and resection + SRS (2.51 ± 0.75 mL) groups were similar. SRS (12.15 ± 0.08 Gy) and resection + SRS (12.16 ± 0.14 Gy) groups received similar radiation doses. SRS group (42/43, 98%) had better local tumor control than the resection + SRS group (10/12, 83%, p = 0.04). Most of SRS (32/43, 74%) and resection + SRS (10/12, 83%) group patients reached a favorable combined endpoint following SRS ( p = 0.52). Considering surgical associated side effects, only 2/10 patients of the resection + SRS group reached a favorable endpoint ( p < 0.001). Patients of SRS group, who are > 34 years old ( p = 0.02), have larger tumors (> 4 mL, 0.04), internal auditory canal (IAC) segment tumor involvement ( p = 0.01) were more likely to reach an unfavorable endpoint. Resection + SRS group patients did not show such a difference. Conclusion While resection is still needed for larger tumors, SRS offers better clinical and radiological outcomes compared to resection followed by SRS for facial schwannomas. Younger age, smaller tumors, and non-IAC situated tumors are factors that portend a favorable outcome.

Social media insights for neurosurgical oncologists: a survey of the American Association of Neurological Surgeons and Congress of Neurological Surgeons Joint Section on Tumors.

PURPOSE: There is a paucity in the literature regarding the characteristics and attitudes of social media (SM) utilization in a professional manner by neurosurgical oncologists. METHODS: A 34-question electronic survey was created using Google Forms and disseminated via email to members of the AANS/CNS Joint Section on Tumors. Demographic data were compared amongst those who utilize social media versus those who do not. Factors associated with positive effects of professional SM use and with having more followers on SM were analyzed. RESULTS: The survey received 94 responses, of which 64.9% reported that they currently use SM in a professional manner. Age < 50 years was found to be associated with SM use (p = 0.038). Facebook (54.1%), Twitter (60.7%), Instagram (41%), and LinkedIn (60.7%) were the most used SM platforms. Having a higher number of followers was associated with practicing in academics (p = 0.005), using Twitter (p = 0.013), posting about their own research publications (p = 0.018), posting interesting cases (p = 0.022), and posting about upcoming events (p = 0.001). Having a higher number of followers on SM was also associated with positive effects, specifically new patient referrals (p = 0.04). CONCLUSION: Neurosurgical oncologists can benefit by using social media professionally for increased patient engagement and networking within the medical community. Practicing in academics, making use of Twitter, and posting about interesting cases, upcoming academic events, and one's own research publications can help gain followers. In addition, having a large following on social media could lead to positive effects such as new patient referrals.

Project Confirm: Accelerated Drug Approvals for Chronic Myeloid Leukemia.

The FDA has an accelerated approval program for drugs that have been identified as promising treatments for serious conditions when the available data suggest that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here, a group of academic CML experts, patient panelists, and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.

Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021.

Importance: Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered. Observations: Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021. Conclusions and Relevance: Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.

Distinct immune signature predicts progression of vestibular schwannoma and unveils a possible viral etiology.

BACKGROUND: The management of sub-totally resected sporadic vestibular schwannoma (VS) may include observation, re-resection or irradiation. Identifying the optimal choice can be difficult due to the disease's variable progression rate. We aimed to define an immune signature and associated transcriptomic fingerprint characteristic of rapidly-progressing VS to elucidate the underpinnings of rapidly progressing VS and identify a prognostic model for determining rate of progression. METHODS: We used multiplex immunofluorescence to characterize the immune microenvironment in 17 patients with sporadic VS treated with subtotal surgical resection alone. Transcriptomic analysis revealed differentially-expressed genes and dysregulated pathways when comparing rapidly-progressing VS to slowly or non-progressing VS. RESULTS: Rapidly progressing VS was distinctly enriched in CD4+, CD8+, CD20+, and CD68+ immune cells. RNA data indicated the upregulation of anti-viral innate immune response and T-cell senescence. K - Top Scoring Pair analysis identified 6 pairs of immunosenescence-related genes (CD38-KDR, CD22-STAT5A, APCS-CXCR6, MADCAM1-MPL, IL6-NFATC3, and CXCL2-TLR6) that had high sensitivity (100%) and specificity (78%) for identifying rapid VS progression. CONCLUSION: Rapid progression of residual vestibular schwannoma following subtotal surgical resection has an underlying immune etiology that may be virally originating; and despite an abundant adaptive immune response, T-cell immunosenescence may be associated with rapid progression of VS. These findings provide a rationale for clinical trials evaluating immunotherapy in patients with rapidly progressing VS.

Endoscopic closure of the Eustachian tube orifice for refractory lateral skull base cerebrospinal fluid leak using autologous fat graft: illustrative case.

BACKGROUND: Rhinorrhea due to lateral skull base cerebrospinal fluid (CSF) leaks can be a challenge to manage. Multiple strategies exist for treating CSF leaks in this region including direct repair, posterior Eustachian tube packing, and CSF diversion. Endonasal closure of the Eustachian tube has been reported using cerclage and mucosal flaps. OBSERVATIONS: We present the first reported case of endoscopic autologous fat packing of the Eustachian tube orifice to repair a CSF leak. In this case a 42-year-old woman who underwent middle fossa meningioma resection 20 years ago presented with refractory CSF rhinorrhea despite blind sac closure of the ear canal. This persisted after CSF diversion and only resolved after endoscopic endonasal Eustachian tube closure described herein. LESSONS: This technique is simple to perform with minimal risk of morbidity. Eustachian tube orifice fat packing may be particularly useful for patients with refractory CSF rhinorrhea with low CSF pressure.

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.

Endolymphatic Sac Tumor Screening and Diagnosis in von Hippel-Lindau Disease: A Consensus Statement.

Objective Endolymphatic sac tumors (ELSTs) are a frequent cause of hearing loss and other audiovestibular dysfunction in patients with von Hippel-Lindau disease (VHL). Unified screening recommendations for VHL patients have not been established. To develop consensus guidelines, the VHL Alliance formed an expert committee to define evidence-based clinical screening recommendations. Patients and Methods Recommendations were formulated by using the Grading of Recommendations, Assessment, Development, and Evaluation framework after a comprehensive literature review. Results Diagnosis of ELSTs in VHL requires a combination of clinical evaluation and imaging and audiometric findings. Audiovestibular signs/symptoms are often an early feature of small ELSTs, including those that are not visible on imaging. Diagnostic audiograms have the greatest sensitivity for the detection of ELST-associated sensorineural hearing loss and can help confirm clinically relevant lesions, including those that may not be radiographically evident. Magnetic resonance imaging (MRI) can be a more specific test for ELSTs in VHL particularly when supplemented with computed tomography imaging for the identification of small tumors. VHL patients between the ages 10 and 60 years carry high preponderance for ELST presentation. Conclusion We recommend that clinical evaluation (yearly) and diagnostic audiograms (every other year) be the primary screening tools for ELSTs in VHL. We suggest that screening be performed between the ages 11 and 65 years or with the onset of audiovestibular signs/symptoms for synchronicity with other testing regimens in VHL. We recommend that baseline imaging (MRI of the internal auditory canals) can be performed between the ages of 15 and 20 years or after positive screening.

FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors.

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.

The Role of Intra-Operative Duplex Ultrasonography Following Translabyrinthine Approach for Vestibular Schwannoma.

Objective: Sigmoid sinus (SS) stenosis is a complication of translabyrinthine approach. Velocity changes in the SS measured by intra-operative doppler ultrasound may help in identifying patients at risk for sinus occlusion. Patients: SS velocity was measured using doppler ultrasound prior to opening dura and again prior to placement of the abdominal fat graft. Intervention: Data collected included: patient age, surgical side, sinus dominance, tumor volume, intra-operative doppler ultrasound measurements, post-operative venous sinus imaging, anticoagulation, and morbidities and mortalities. Main Outcome Measure: SS patency and velocity. Results: Eight patients were included in the analysis (22 to 69 years). Four had left-sided and four had right-sided craniotomies. Sigmoid sinuses were either right-side dominant or co-dominant. The mean velocity ± standard deviation (SD) prior to dura opening and abdominal fat packing was 23.2 ± 11.3 and 25.5 ± 13.9 cm/s, respectively, p = 0.575. Post-operative Magnetic Resonance Venography (MRV) imaging showed four sigmoid sinus occlusions; seven patients showed sigmoid sinus stenosis, and one internal jugular vein occlusion. One patient had post-operative Computed Tomography Venography (CTV) only. Of the four patients with MRV occlusions, CTVs were performed with three showing occlusion and all four-showing stenosis. One patient with internal jugular vein occlusion on MRV received warfarin anticoagulation. There was one cerebrospinal fluid leak requiring ear closure, one small cerebellar infarct, and one with facial nerve palsy (House-Brackman Grade 3). Conclusion: SS velocity changes before and after tumor resection were not predictive of sinus occlusion. We hypothesize that sinus occlusion may be caused by related factors other than thrombosis, such as external compression of the sinus secondary to abdominal fat grafting.

Predictors of hearing functional outcome following surgery for cerebellopontine angle meningioma.

OBJECTIVE: Cerebellopontine angle (CPA) meningiomas can affect hearing function and require expeditious treatment to prevent permanent hearing loss. The authors sought to determine the factors associated with functional hearing outcome in CPA meningioma patients treated with surgery and/or radiation therapy in the form of either stereotactic radiosurgery or stereotactic radiation therapy. METHODS: Consecutive patients with CPA meningiomas who had presented at our hospital from 2008 to 2018 were identified through retrospective chart review. Hearing function (as defined by pure tone average (PTA) and speech discrimination score (SDS) on Audiogram) was assessed before and after surgery for CPA meningioma. Audiograms with PTA > 50 dB and SDS < 69% were defined as poor hearing functional outcome. Multivariable Cox Proportional Hazards Regression Model was used to assess the associations between pre-operative hearing functional assessment and post-operative hearing functional outcomes. RESULTS: The study cohort included 31 patients (80.6% females, with a mean age of 61.3 ± 15.2 years) with a median clinical follow-up of 5 months (range: 1 week-98 months). The mean pre-operative PTA and SDS were 23.8 ± 11.2 dB and 64.4 ± 22.2% respectively. At the last visit, there was significant hearing recovery, with an improvement of 29.7 ± 18.0 dB (p < 0.001) and 87.6 ± 17.8% (p < 0.001) in PTA and SDS respectively. After adjusting for age, gender, tumor volume, location, and tumor classification, Multivariable Cox Proportional Hazards Regression Model was conducted which revealed that patients undergoing surgery through retro sigmoid approach [Hazards Ratio (HR): 32.1, 95% Confidence Interval (CI): 2.11-491.0, p = 0.01] and gross total resection (GTR) (HR: 2.99, 95% CI: 1.09-9.32, p = 0.05) had significantly higher risk of poor hearing functional outcome compared to petrosal approach and near/subtotal resection. Moreover, patients with poor preoperative hearing had 85% higher chance of poor hearing functional outcome postoperatively (HR: 0.15, 95%CI: 0.03-0.59, p = 0.007). CONCLUSION: Postoperative improvement in hearing is a reasonable expectation following surgery for CPA meningioma. Preoperative hearing, surgical approach and extent of surgical resection are predictive factors of postoperative hearing function outcome and can therefore aid in identification of patients at higher risk of hearing loss.

The neurosurgical management of sinonasal malignancies involving the anterior skull base: a 28-year experience at The MD Anderson Cancer Center.

OBJECTIVE: Sinonasal malignancies that extend to the anterior skull base frequently require neurosurgical intervention. The development of techniques for craniofacial resection revolutionized the management of these neoplasms, but modern and long-term data are lacking, particularly those related to the incorporation of endoscopic techniques and novel adjuvant chemotherapeutics into management schema. The present study was performed to better define the utility of surgical management and to determine factors related to outcome. METHODS: Patients who underwent surgery between 1993 and 2020 were included in this retrospective cohort study. Only patients with greater than 6 months of clinical and radiological follow-up were included. Outcome measures included progression, survival, and treatment-related complications. RESULTS: Two hundred twenty-five patients were included. The mean clinical follow-up was 6.5 years. The most common histological diagnosis was olfactory neuroblastoma (33%). Overall, metastatic disease and brain invasion were present in 8% and 19% of patients, respectively, at the time of surgery. A lumbar drain was used in 54% of patients. When stratified by decade, higher-stage disease at surgery became more frequent over time (15% of patients had metastatic disease in the 3rd decade of the study period vs 4% in the 1st decade). Despite the inclusion of patients with progressively higher-stage disease, median overall survival (OS) remained stable in each decade at approximately 10 years (p = 0.16). OS was significantly worse in patients with brain invasion (p = 0.006) or metastasis at the time of surgery (p = 0.014). Complications occurred after 28% of operations, but typically resulted in no long-term negative sequelae. Use of a lumbar drain was a significant predictor of complications (p = 0.02). Permanent ophthalmological disabilities were observed after 4% of surgical procedures. One patient died during the perioperative period. Finally, major complications (Clavien-Dindo grade ≥ IIIb) decreased from 27% of patients in the 1st decade to 10% in the 3rd decade (p = 0.007). CONCLUSIONS: The surgical management of sinonasal malignancies with anterior skull base involvement is effective and generally safe. Surgical management, however, is only one facet of the overall multimodal management paradigms created to optimize patient outcomes. Survival outcomes have remained stable despite more extensive disease at surgery in patients who have presented in recent decades. The safety of such surgery has improved over time owing to the incorporation of endoscopic surgical techniques and the avoidance of lumbar spinal drainage with open resection.

Neurofibromatosis type 2-associated meningiomas: an international multicenter study of outcomes after Gamma Knife stereotactic radiosurgery.

OBJECTIVE: The management of neurofibromatosis type 2 (NF2)-associated meningiomas is challenging. The role of Gamma Knife radiosurgery (GKRS) in the treatment of these tumors remains to be fully defined. In this study, the authors aimed to examine the role of GKRS in the treatment of NF2-associated meningiomas and to evaluate the outcomes and complications after treatment. METHODS: Seven international medical centers contributed data for this retrospective cohort. Tumor progression was defined as a ≥ 20% increase from the baseline value. The clinical features, treatment details, outcomes, and complications were studied. The median follow-up was 8.5 years (range 0.6-25.5 years) from the time of initial GKRS. Shared frailty Cox regression was used for analysis. RESULTS: A total of 204 meningiomas in 39 patients treated with GKRS were analyzed. Cox regression analysis showed that increasing the maximum dose (p = 0.02; HR 12.2, 95% CI 1.287-116.7) and a lower number of meningiomas at presentation (p = 0.03; HR 0.9, 95% CI 0.821-0.990) were predictive of better tumor control in both univariable and multivariable settings. Age at onset, sex, margin dose, location, and presence of neurological deficit were not predictive of tumor progression. The cumulative 10-year progression-free survival was 94.8%. Radiation-induced adverse effects were noted in 4 patients (10%); these were transient and managed medically. No post-GKRS malignant transformation was noted in 287 person-years of follow-up. CONCLUSIONS: GKRS achieved effective tumor control with a low and generally acceptable rate of complications in NF2-associated meningiomas. There did not appear to be an appreciable risk of post-GKRS-induced malignancy in patients with NF2-treated meningiomas.

Role of cerebral digital subtraction angiography in the evaluation of pulse synchronous tinnitus.

OBJECTIVES: The aim of this study was to evaluate the value of digital subtraction angiography (DSA) in the diagnostic evaluation of a highly selected patient population presenting with pulse-synchronous tinnitus (PST). METHODS: We retrospectively reviewed the charts of all patients referred for evaluation of possible vascular etiology of pulsatile tinnitus. Patients were evaluated with regards to presenting signs, comorbidities, non-invasive imaging results, angiographic findings and outcomes. RESULTS: Fifteen patients underwent cerebral DSA. Dural arteriovenous fistula (dAVF) was identified in six patients, and five patients had other significant vascular pathology identified on DSA. Seven patients with 'negative' non-invasive imaging were found to have significant pathology on DSA. CONCLUSIONS: Catheter angiography may have a significant yield in appropriately selected patients presenting with pulse synchronous tinnitus.