MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma.

Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan-Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19-93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT-sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45-2.95; p < 0.0001) and males (1.51; 95% CI, 1.14-2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01-1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG-sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.

The Role of EGFR Amplification in Deep Venous Thrombosis Occurrence in IDH Wild-Type Glioblastoma.

Introduction: Glioblastoma (GBM) patients have a 20-30 incidence of venous thromboembolic events. EGFR is a widely used prognostic marker for many cancers. Recent lung cancer studies have described relationships between EGFR amplification and an increased incidence of thromboembolic complications. We aim to explore this relationship in glioblastoma patients. Methods: Two hundred ninety-three consecutive patients with IDH wild-type GBM were included in the analysis. The amplification status of EGFR was measured using fluorescence in situ hybridization (FISH). Centromere 7 (CEP7) expression was recorded to calculate the EGFR-to-CEP7 ratio. All data were collected retrospectively through chart review. Molecular data were obtained through the surgical pathology report at the time of biopsy. Results: There were 112 subjects who were EGFR-amplified (38.2%) and 181 who were non-amplified (61.8%). EGFR amplification status was not significantly correlated with VTE risk overall (p = 0.2001). There was no statistically significant association between VTE and EGFR status after controlling for Bevacizumab therapy (p = 0.1626). EGFR non-amplified status was associated with an increased VTE risk in subjects greater than 60 years of age (p = 0.048). Conclusions: There was no significant difference in occurrence of VTE in patients with glioblastoma, regardless of EGFR amplification status. Patients older than 60 years of age with EGFR amplification experienced a lower rate of VTE, contrary to some reports on non-small-cell lung cancer linking EGFR amplification to VTE risk.

Enhanced recovery after surgery in patients with normal pressure hydrocephalus undergoing ventriculoperitoneal shunting procedures.

OBJECTIVE: Patients with idiopathic normal pressure hydrocephalus (iNPH) who undergo ventriculoperitoneal shunt (VPS) placement often belong to an older demographic, putting them at increased risk of postoperative delirium and related complications. Recent literature documenting the use of Enhanced Recovery After Surgery (ERAS) protocols in various disciplines of surgery has shown improved clinical outcomes, faster discharge, and lower readmission rates. Early return to a familiar environment (i.e., discharged home) is a well-known predictor of reduced postoperative delirium. However, ERAS protocols are uncommon in neurosurgery, especially intracranial procedures. We developed a novel ERAS protocol for patients with iNPH undergoing VPS placement to gain further insight regarding postoperative complications, specifically delirium. METHODS: We studied 40 patients with iNPH with indications for VPS. Seventeen patients were selected at random to undergo the ERAS protocol, and twenty-three patients underwent the standard VPS protocol. The ERAS protocol consisted of measures to reduce infection, manage pain, minimize invasiveness, confirm procedural success with imaging, and shorten the length of stay. Pre-operative American Society of Anesthesiologists (ASA) grade was collected for each patient to indicate baseline risk. Rates of readmission and postoperative complications, including delirium and infection, were collected at 48 h, 2 weeks, and 4 weeks postoperatively. RESULTS: There were no perioperative complications among the 40 patients. There was no postoperative delirium in any of the ERAS patients. Postoperative delirium was observed in 10 of 23 non-ERAS patients. There was no statistically significant difference between the ASA grade between the ERAS and non-ERAS groups. CONCLUSIONS: We described a novel ERAS protocol for patients with iNPH receiving VPS focusing on an early discharge. Our data suggest that ERAS protocols in VPS patients might reduce the incidence of delirium without increasing the risk of infection or other postoperative complications.

Safety of craniotomy for brain tumor resection in octogenarians and older patients - a matched - cohort analysis.

INTRODUCTION: The incidence of brain tumors has increased in elderly population overtime. Their eligibility to a major surgery remains a questionable subject. This study evaluated prognostic factors and 30-days morbidity and mortality in octogenarian population who underwent craniotomy for resection of brain tumor. MATERIALS AND METHODS: A total of 154 patients were divided into two different groups: patients above 80 years old and patients below 65 years old. In both groups, patients were stratified based on diagnosis with benign tumors [meningioma] and malignant tumors [high-grade gliomas and metastases]. Multivariable logistic regression model with backward elimination method was utilized to identify the independent risk factors for 30-days readmission and post-operative complications. RESULTS: The analysis revealed no significant difference in 30-day readmission (p = 0.7329), 30-day mortality (0.6854) or in post-operative complication (p = 0.3291) between age ≥ 80 and age ≤ 65 groups. A longer length of stay (LOS) was observed in the older patients (p = 0.0479). There was a significant difference in the pre-post KPS between the two groups (p < 0.0001). ASA (p = 0.0315) and KPS (p = 0.071) were found as important prognostic factors associated with post-operative mortality in both groups. CONCLUSION: Octogenarians can withstand craniotomy without any significant increase in 30-day readmission, 30-day mortality and post-operative complications as compared to patients younger than age 65. The ASA score (>3) and/or KPS (<70) were the most important prognostic factors for 30-days readmission and mortality.

Trigeminal Neuralgia-Step-by-Step DYNA-Computed Tomography-Assisted Balloon Compression Rhizotomy.

Trigeminal nerve balloon compression (TNBC)1-3 can provide immediate therapeutic relief to patients suffering from trigeminal neuralgia. This is a particularly effective treatment option for patients who are not eligible for surgical procedures (i.e., elderly patients or patients with multiple comorbidities) or for patients who have had an insufficient response to microvascular decompression. TNBC can also be used as a bridge treatment before stereotactic radiosurgery. Use of intraoperative computed tomography-like images using a C-arm system (DYNA-CT) imaging facilitates the TNBC procedure.4,5 Three-dimensional DYNA-CT imaging with needle guidance allows for precise needle advancement and insertion through the foramen ovale. DYNA-CT enables the direct visualization and avoidance of vascular structures such as the carotid or internal maxillary arteries and results in decreased procedure times and complications. The authors present a step-by-step video demonstrating the use of intraoperative DYNA-CT needle guidance for TNBC (Video 1). A Siemens Artis Zee Biplane system is used for the procedure. A comprehensive description of all elements of the procedure is provided including balloon preparation, needle trajectory planning, needle advancement, 3-dimensional confirmation of the needle's depth and path, balloon placement, balloon inflation, and balloon removal. Tips and optimal strategies are presented. Advantages of using DYNA-CT for needle guidance include the reduction of fluoroscopy dose and fluoroscopy time. The average dose area product during conventional percutaneous balloon compression in prior studies was 1137 mGycm2, with a mean fluoroscopic time of 62 seconds.6 In our experience, the mean fluoroscopy dose is 274 mGycm2 and the total fluoroscopic time is about 45 seconds. Furthermore, during the DYNA-CT acquisition, the neurointerventional team stays outside the room during the DYNA-CT, which reduces the cumulative radiation to the operator. DYNA-CT needle guidance facilitates precise advancement of the needle into the foramen ovale and positioning of the balloon in the Meckel cave during TNBC. It is a safe and feasible technique that allows for the visualization and avoidance of important structures such as the internal carotid artery or the internal maxillary artery, resulting in decreased procedure times and complications.

Wide Dissection Trans-Sulcal Approach for Resection of Deep Intra-Axial Lesions in Eloquent Brain Areas.

Introduction: Resection of intra-axial tumors (IaT) in eloquent brain regions risks major postoperative neurological deficits. Awake craniotomy is often used to navigate these areas; however, some patients are ineligible for awake procedures. The trans-sulcal approach (TScal) was introduced to reduce parenchymal trauma during tumor resection. We report our experiences utilizing TScal for resection of deep IaT located in eloquent areas. Materials and Methods: This is a single-center retrospective analysis of patients who underwent IaT resection in eloquent areas via TScal from January 2013 to April 2021. Seventeen cases were reviewed, and relevant data was collected. Fluorescence-guided surgery with 5-aminolevulinic acid (ALA) and intraoperative ultrasound was performed in some cases. Results: Seventeen patients (10 males, 7 females) averaging 61.2 years-old (range, 21-76) were included in this study. Average length of stay was 4.8 days, and only 2 patients (11.8%) required hospital readmission within 30 days. Gross total resection (GTR) was achieved in 15 patients (88.2%), while subtotal resection occurred in 2 patients (11.8%). Eleven patients (64.7%) reported full resolution of symptoms, 4 patients (23.5%) reported deficit improvement, and 2 patients (11.8%) experienced no change from their preoperative deficits. No patient developed new permanent deficits postoperatively. Discussion: GTR, preoperative deficit reduction, and complications were comparable to awake craniotomy and other TScal studies. Ancillary intraoperative techniques, such as brain mapping, 5-ALA and intraoperative ultrasound, are afforded by TScal to improve resection rates and overall outcomes. Conclusions: TScal can be an option for patients with deep lesions in eloquent areas who are not candidates for awake surgeries.

Blood Supply of Cranial Nerves Passing Through the Cavernous Sinus: An Anatomical Study and Its Implications for Microsurgical and Endoscopic Cavernous Sinus Surgery.

BACKGROUND: Despite improvements in surgical techniques, cranial nerve (CN) deficits remain the most frequent cause of disability following cavernous sinus (CS) surgery. The most common tumor affecting the CS is meningioma. They originate from lateral wall and have their blood supply from meningohypophyseal trunk (MHT) and inferolateral trunk (ILT). Pituitary adenomas commonly invade the CS through its medial wall and receive blood supply form medial branches of the internal carotid artery (ICA) (superior and inferior hypophyseal arteries). Some tumors may grow within the CS (e.g. trigeminal schwannomas, hemangiomas). These tumors are fed by all the intracavernous ICA branches. Tumors involving the CS may also displace the neurovascular structures, therefore, a better understanding of intracavernous neurovascular anatomy may reduce the postoperative morbidity associated with approaching CS tumors. In this anatomical study, the anatomic variations and their clinical implications of the intracavernous CNs' blood supply were evaluated through transcranial and endonasal routes. METHODS: Twenty sides of ten adult cadaveric formalin-fixed, latex-injected specimens were dissected in stepwise fashion under microscopic and endoscopic magnification. The origin and course of the intracavernous ICA branches supplying the intracavernous CNs are studied. RESULTS: The proximal segment of the oculomotor nerve receives blood supply from the ILT in 85%, and the tentorial artery of the MHT in 15% of specimens. The distal segment is exclusively supplied by the ILT. The proximal trochlear nerve receives blood supply from the ILT (75%) and the tentorial artery (25%); the distal segment is exclusively supplied by the superior orbital branch. The proximal third of the abducens nerve receives its vascularity exclusively from the dorsal meningeal artery, and its middle and distal thirds from the ILT. The ophthalmic and proximal maxillary segments of the trigeminal nerve also receive blood supply from the ILT. The distal maxillary segment is supplied by the artery of the foramen rotundum. All ILT branches terminate on the inferomedial aspects of the intra-cavernous CNs. Extensive anastomoses are found between ILT branches and the branches arising from external carotid artery. CONCLUSION: Understanding the anatomy of the intracavernous ICA's branches is important to improving surgical outcomes with tumors involving the CS.

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases.

Immune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p < 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials.

Microsurgical resection of petroclival meningiomas treated with stereotactic radiosurgery to address persistent post-treatment trigeminal pain.

BACKGROUND: Petroclival meningiomas (PCM) are challenging tumors to manage. Observation, Stereotactic radiosurgery (SRS) and surgical resection have typically been offered as treatment options. A percentage of patients with PCMs present with trigeminal pain. We present four patients with small PCMs presenting with Trigeminal neuralgia (TN) that were treated with radiosurgery and continued to have debilitating trigeminal pain afterwards. All of them underwent microsurgical resection (MR) of their tumor to manage their trigeminal pain. OBJECTIVE: Trigeminal Neuralgia in the setting of PCM is rare. Oftentimes in these subset of patients TN pain persists after radiation and medical therapy. We explore the possibility of addressing intractable TN pain with microsurgical resection. METHODS: Patients with petroclival meningiomas presenting with trigeminal pain and having persistent pain after treatment with radiosurgery were included in our review. Those patients were treated with microsurgical resection of their tumor to help control their persistent pain. The patients' demographics, clinical, and radiological data were reviewed. The primary aim of the review was to assess the patients' Barrow Neurological Institute (BNI) trigeminal neuralgia scores following microsurgical resection. RESULTS: Four female patients were identified. The tumors were locally controlled after SRS, however all four patients continued to have debilitating trigeminal pain despite medical management. All patients had complete resolution of their TN pain in the immediate postoperative period, with a BNI score of I on their last follow up. CONCLUSION: Microsurgical resection is an appropriate option for patient's petroclival meningiomas with persistent facial pain after treatment with SRS.

A Case of Takotsubo Cardiomyopathy After Local Anesthetic and Epinephrine Infiltration.

Takotsubo cardiomyopathy (TC) is a non-ischemic cardiomyopathy that is accompanied by sudden left ventricular myocardial stunning, dilation and dysfunction. It often results from severe emotional or physical stress. We present the case of a 41-year-old female patient who had general anesthesia induced uneventfully for an elective bladder sling procedure. After an intravaginal injection of local anesthesia (lidocaine 2%; epinephrine 1:100,000) just prior to the surgical incision, the patient had cardiovascular collapse for which cardiopulmonary resuscitation (CPR) was performed. The patient was eventually stabilized but transesophageal echocardiography showed impairment in cardiac motion and remarkably reduced ejection fraction. Troponin levels were elevated but coronary angiography was unremarkable. The ejection fraction returned to normal the next day. Local anesthetic with epinephrine administration can lead to TC, and with optimal management, long-term cardiac sequela can be avoided.