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Meningiomas are largely indolent tumors with a benign clinical course, but a minority exhibit aggressive behavior characterized by rapid growth, neurologic deficits, and increased mortality. Identifying high-risk patients requiring intervention is challenging, but recent insights into meningioma biology provide a useful guide for decision making. Standard of care for recurrent or biologically aggressive tumors consists of surgery and radiation therapy. Systemic therapies targeting vascular endothelial growth factor signaling and somatostatin analogues are potential options for those with refractory disease but display only modest activity. New paradigms in meningioma clinical trial design provide hope for improved options in the future.

Background Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management. Methods We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms. Results We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score. Conclusion We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

Gliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma. Sequencing data was obtained from 35 gliosarcoma patients from Genomics Evidence Neoplasia Information Exchange (GENIE) 5.0, a database curated by the American Association of Cancer Research (AACR). We analyzed genomic alterations in gliosarcomas and compared them to GBM (n = 1,449) and soft tissue sarcoma (n = 1,042). 30 samples were included (37% female, median age 59 [IQR: 49–64]). Nineteen common genes were identified in gliosarcoma, defined as those altered in > 5% of samples, including TERT Promoter (92%), PTEN (66%), and TP53 (60%). Of the 19 common genes in gliosarcoma, 6 were also common in both GBM and soft tissue sarcoma, 4 in GBM alone, 0 in soft tissue sarcoma alone, and 9 were more distinct to gliosarcoma. Of these, BRAF harbored an OncoKB level 1 designation, indicating its status as a predictive biomarker of response to an FDA-approved drug in certain cancers. EGFR, CDKN2A, NF1, and PTEN harbored level 4 designations in solid tumors, indicating biological evidence of these biomarkers predicting a drug-response. Gliosarcoma contains molecular features that overlap GBM and soft tissue sarcoma, as well as its own distinct genomic signatures. This may play a role in disease classification and inclusion criteria for clinical trials. Gliosarcoma mutations with potential therapeutic indications include BRAF, EGFR, CDKN2A, NF1, and PTEN.

Background Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy. Methods Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO. Conclusion Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.

Esthesioneuroblastoma (ENB) is an uncommon primary sinonasal tumor which can extend intracranially. Exactly how to classify them pathologically still remains discrepant; the Hyams grading system, for example, has not been universally adopted. This individual patient data (IPD) meta-analysis aimed to investigate the prognostic implication of each Hyams grade on patient outcomes. We accessed two electronic databases including PubMed and Web of Science. Raw patient data from potential articles were extracted. To examine the associations of various clinicopathological factors with the Hyams grades, we utilized Chi-square, t-test, and Mann–Whitney, as appropriate. Log-rank test and Cox regression analysis were used to elucidate the impact of the Hyams grades on recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS) of ENB patients. We included 33 studies with 492 ENB patients. We found significant associations of Kadish stages, Dulguerov stages, rates of recurrence, metastasis, and patient mortality with Hyams grade. Log-rank tests and Cox regression models demonstrated significant differences in RFS and OS of Hyams grade I – II, grade III, and grade IV patients. There was no statistical difference in RFS and OS of Hyams grade I and II. Radiotherapy was only effective in grade III – IV ENBs and chemotherapy showed no benefits to patients. We verify that the Hyams grading system appears to be a reliable prognostic indicator to assess ENB patient outcomes. Consolidating the Hyams grading system into a three-tier system based on similar clinical outcomes of grades I and II may simplify this classification schema.

Introduction Meningioma is the most common primary brain tumor. Most meningiomas are benign; however, a subset of these tumors can be aggressive, presenting with early or multiple tumor recurrences that are refractory to neurosurgical resection and radiotherapy. There is no standard systemic therapy for these patients, and post-surgical management of these patients is usually complicated due to lack of accurate prediction for tumor progression. Methods In this review, we summarise the crucial immunosuppressive role of checkpoint regulators, including PD-1 and PD-L1 interacting in the tumor microenvironment, which has led to efforts aimed at targeting this axis. Results Since their discovery, checkpoint inhibitors have significantly improved the outcome in many types of cancers. Currently, targeted therapy for PD-1 and PD-L1 proteins are being tested in several ongoing clinical trials for brain tumors such as glioblastoma. More recently, there have been some reports implicating increased PD-L1 expression in high-grade (WHO grades II and III) meningiomas. Several clinical trials are underway to assess the efficacy of checkpoint inhibitors in the therapeutic management of patients with aggressive meningiomas. Here, we review the immune suppressive microenvironment in meningiomas, and then focus on clinical and pathological characterization and tumor heterogeneity with respect to PD-L1 expression as well as challenges associated with the assessment of PD-L1 expression in meningioma. Conclusion We conclude with a brief review of ongoing clinical trials using checkpoint inhibitors for the treatment of high-grade and refractory meningiomas.

Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities. 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed. Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors. Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.

Endoscopic endonasal skull base surgery has emerged as the treatment modality of choice for a range of skull base lesions, particularly pituitary adenomas. However, navigation and manipulation of the nasal corridor and paranasal sinuses requires that surgeons are aware of effective techniques to maximize patient outcomes and avoid sinonasal morbidity postoperatively. This paper is a narrative review aimed to provide an updated and consolidated report on the perioperative management of the nasal corridor and paranasal sinuses in the setting of endoscopic skull base surgery for pituitary disease. Anatomic variants and common surgical techniques are discussed. Post-operative complications are evaluated in detail. Understanding the structural implications of the endonasal approach to the sphenoid is crucial to optimization of the surgical outcomes. We propose guidelines for perioperative management of endoscopic endonasal skull base surgery for pituitary diseases. Standardized treatment algorithms can improve patient satisfaction, and increase the comparability and the quality of reported information across research studies.

Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of the present study was to determine the prognostic value of atypical histopathological features across all nonmalignant meningiomas (World Health Organization [WHO] grade I-II).The data from 334 patients with WHO grade I (n = 275) and grade II (n = 59) meningiomas who had undergone surgical resection from 2001 to 2015 at 2 academic centers were pooled. Progression/recurrence (P/R) was determined radiographically and measured from the date of surgery.The median follow-up was 52 months. The patients were stratified by the number of atypical features: 0 (n = 151), 1 (n = 71), 2 (n = 66), 3 (n = 22), and 4 or 5 (n = 24). The risk of P/R increased with an increasing number of atypical features (log-rank test, P = 0.001). The 5-year actuarial rates of P/R stratified by the number of atypical features were as follows: 0, 16.3% (95% confidence interval [CI], 10.7-24.4); 1, 21.7% (95% CI, 12.8-35.2); 2, 28.2% (95% CI, 18.4-41.7); 3, 30.4% (95% CI, 13.8-58.7); and 4 or 5, 51.4% (95% CI, 31.7-74.5). On univariate analysis, the presence of high nuclear/cytoplasmic ratio (P = 0.007), prominent nucleoli (P = 0.007), and necrosis (P0.00005) were associated with an increased risk of P/R. On multivariate analysis, the number of atypical features (hazard ratio [HR], 1.30; 95% CI, 1.03-1.63; P = 0.03), ≥4 mitoses per high-power fields (HR, 2.45; 95% CI, 1.17-5.15; P = 0.02), subtotal resection (HR, 3.9; 95% CI, 2.5-6.3; P0.0005), and the lack of adjuvant radiotherapy (HR, 2.40; 95% CI, 1.19-4.80; P = 0.01) were associated with an increased risk of P/R.An increased number of atypical features, ≥4 mitoses per 10 high-power fields, subtotal resection, and the lack of adjuvant radiotherapy were independently associated with P/R of WHO grade I-II meningiomas. Patients with these features might benefit from intensified therapy.

Objective Esthesioneuroblastoma (ENB) is a rare malignancy of the sinonasal tract and its infrequency has confounded efforts at clearly describing the survival trends associated with this neoplasm over the years. In this study, we reviewed survival trends in ENB and investigated the impact of treatment extent and modality on patient outcomes. Methods We accessed the Surveillance, Epidemiology, and End Result (SEER) program to identify ENB cases from 1998 to 2016. A χ2 test was used to compare the categorical covariates and a t test or Mann-Whitney U test was utilized for continuous variables. The impact of prognostic factors on survival was computed using a Kaplan-Meier analysis and multivariate Cox proportional hazards model. We divided ENB patients into 4 periods including 1998–2002, 2003–2007, 2008–2012, and 2013–2016, and investigated survival trends using the Kaplan-Meier curve and log-rank test. Results ENB patients who underwent biopsy alone were associated with older age, larger tumor diameter, increased rates of tumor extension, nodal/distant metastases, and advanced stages as compared with patients undergoing tumor resection. Our results also demonstrated that surgical resection and adjuvant radiotherapy could confer survival advantages, whereas chemotherapy was associated with reduced survival in patients with ENB. Over the past 2 decades, surprisingly, there has been no change in survival rates for patient with ENB (P = 0.793). Conclusions Despite advanced diagnostic studies and modernized treatment approaches, ENB survival has remained unchanged over the years, calling for improved efforts to develop appropriate individualized interventions for this rare tumor entity. Our results also confirmed that surgery and adjuvant radiotherapy is associated with improved patient survival whereas the use of chemotherapy should be considered carefully.

Background Distant metastases (DM) at presentation in meningiomas is a very rare event, and the incidence and factors predicting this are uncertain. This population-based study also aimed to investigate the prognostic implication of DM at presentation and clinical parameters to prognosticate the overall survival (OS) of meningiomas presenting with DM (M1). Methods We accessed the Surveillance, Epidemiology, and End Results program to search for patients who were diagnosed with meningioma between 2004 and 2016. The log-rank test was used to compare Kaplan–Meier survival curves and multivariate Cox regression model was utilized to evaluate the prognostic parameters of meningiomas with DM at presentation. Results The incidence of DM at presentation among all meningiomas was 0.18%. Clinical variables associated with this event were male gender, large tumor size, and WHO grade III. The presence of DM at diagnosis conferred a shorter survival in comparison to those without DM (HR = 2.015; 95% CI = 1.600–2.536). Older patient age, male gender, malignant histology, and the lesser extent of resection were independent prognostic factors that could negatively impact OS of M1 meningiomas. Radiotherapy and chemotherapy were not associated with an improved outcome for these patients. Conclusion Our study highlighted the clinical and prognostic factors of M1 meningiomas. These data suggest that a greater extent of resection is associated with increased OS across a nationwide analysis and emphasize the need to establish the standards of care in these patients.

The diagnosis and management of mixed intracranial germ cell tumors may be complicated by the diversity present within this tumor category. Mixed germ cell tumors demonstrate variable natural histories which may be altered by the inclusion of even the most minute immature histological components. We report the case of an 18-year-old male who presented with a 3-month history of progressive headache and nausea leading to lethargy. Imaging revealed a giant pineal region mass extending superiorly from the roof of the fourth ventricle into the lateral ventricle, with resultant obstructive hydrocephalus. No spinal lesions were noted. Following gross total resection, the patient experienced marked improvement. Pathologic analysis identified an uncommon tumor composition: mature teratoma (96%), immature teratoma (2%), and germinoma (2%). Guided by the immature component, chemotherapy and radiation were added post-operatively to provide this patient with the greatest chance of long-term survival. Intracranial pathology, including germ cell tumors, should be included in the differential for any young patient presenting with new and progressive headache and nausea. This case emphasizes the benefit of a multimodal approach to mixed germ cell tumors of the pineal region and the importance of careful pathologic review of all submitted material.

To evaluate surgical resection with brachytherapy placement as a salvage treatment in patients with recurrent high-grade meningioma who exhausted prior external beam treatment options. Single-center retrospective review of our institutional experience of brachytherapy implantation from 2012 to 2018. The primary outcome of the study was progression free survival (PFS). Secondary outcomes included overall survival (OS) and complications. A matched cohort of patients not treated with brachytherapy over the same time period was evaluated as a control group. All patients had received prior radiation treatment and underwent planned gross total resection (GTR) surgery. A total of 27 cases were evaluated. Compared with prior treatment, brachytherapy implantation demonstrated a statistically significant improvement in tumor control [HR 0.316 (0.101 − 0.991), p = 0.034]. PFS-6 and PFS-12 were 92.3% and 84.6%, respectively. Compared with the matched control cohort, brachytherapy treatment demonstrated improved PFS [HR 0.310 (0.103 − 0.933), p = 0.030]. Overall survival was not statistically significantly different between groups [HR 0.381 (0.073 − 1.982), p = 0.227]. Overall postoperative complications were comparable between groups, although there was a higher incidence of radiation necrosis in the brachytherapy cohort. Brachytherapy with planned GTR improved PFS in recurrent high-grade meningioma patients who exhausted prior external beam radiation treatment options. Future improvement of brachytherapy dose delivery methods and techniques may continue to prolong control rates and improve outcomes for this challenging group of patients.

Background Although microvascular decompression (MVD) is a durable treatment for medically refractory trigeminal neuralgia, hemifacial spasm, or glossopharyngeal neuralgia attributable to neurovascular conflict, few national studies have analyzed predictors of postoperative complications. Objective To determine the incidence and risk factors for adverse events after MVD. Methods Patients who underwent MVD were extracted from the prospectively collected National Surgical Quality Improvement Program registry (2006–2017). Multivariable logistic regression identified predictors of 30-day adverse events and unplanned readmission; multivariable linear regression analyzed predictors of a longer hospital stay. Results Among the 1005 patients evaluated, the mortality was 0.3%, major neurologic complication rate 0.4%, and 2.8% had a nonroutine hospital discharge. Patient age was not a predictor of any adverse events. Statistically significant independent predictors both of any adverse event (9.2%) and of a longer hospitalization were American Society of Anesthesiologists (ASA) classification III–IV designation and longer operative duration (P ≤ 0.03) The 30-day readmission rate was 6.8%, and the most common reasons were surgical site infections (22.4%) and cerebrospinal fluid leakage (14.3%). Higher ASA classification, diabetes mellitus, and operative time were predictors of readmission (P Conclusions In this National Surgical Quality Improvement Program analysis, postoperative morbidity and mortality after MVD was low. Patient age was not a predictor of postoperative complications, whereas higher ASA classification, diabetes mellitus, and longer operative duration were predictive of any adverse event and readmission. ASA classification provided superior risk stratification compared with the total number of patient comorbidities or laboratory values. These data can assist with preoperative patient counseling and risk stratification.

Background Brain metastases commonly manifest in patients with cancer, with ∼20%–50% presenting with 1 intracranial lesion. Among patients with 1, small brain metastasis and controlled or absent extracranial disease, it remains unclear whether aggressive intracranial management using neurosurgical resection plus cavity stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) rather than SRS/SRT alone is beneficial. In patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size, we evaluated the effect of surgery plus SRS/SRT compared with SRS/SRT on oncologic outcomes, including overall survival. Methods We retrospectively identified 86 patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size who had been treated from 2000 to 2015 at our institution. We examined differences in the rates of local and distant failure, use of salvage treatment, and other oncologic outcomes, including all-cause mortality. Results The baseline characteristics were similar between the 2 cohorts. The median follow-up period for the surviving patients was 38 months. On multivariable analysis, surgical resection plus cavity SRS/SRT was associated with a lower risk of all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.19–1.00; P = 0.05) compared with SRS/SRT alone. The 1- and 2-year rates of overall survival were 100% and 88% versus 74% and 52% for surgery plus cavity SRS/SRT versus SRS/SRT alone, respectively. Conclusions Aggressive, local therapy, including neurosurgical resection, might benefit patients with 1 brain metastasis in the context of controlled or absent systemic disease, even if the lesion in question is small. Further studies are needed to evaluate these associations.

Readmission and reoperation are risks in the resection of benign cranial nerve tumors (BCNTs). This report analyzes the impact of patient-level and surgical factors on these adverse outcomes.This retrospective cohort review comprised patients with a diagnosis of BCNT enrolled in the American College of Surgeons National Surgical Quality Improvement Program registry from 2011 to 2015. Multivariate logistic regression was used to determine the impact of select medical and operative factors on the primary outcomes of readmission and reoperation within 30 days, adjusted for relevant covariates.We identified 996 patients who underwent resection of a BCNT. The most frequent major complications were readmission (11%), reoperation (8%), surgical site infections (2.6%), and venous thromboembolism (1.5%). The most frequent indications for readmission were management of infection (2.5%), cerebrospinal fluid leak (2.3%), and hydrocephalus (0.5%). Repair of cranial and meningeal defects (3.0%), correction of lagophthalmos (1.2%), and repair of middle ear defects (1.0%) were the most common indications for reoperation. Logistic regression revealed that extremes of age were associated with readmission, whereas preoperative steroid usage, long operative time, and postoperative length of stay3 days were associated with reoperation (P0.05). Obesity trended toward an association with readmission and reoperation.Extremes of age were associated with readmission; preoperative steroid use, long operative time, and postoperative length of stay3 days were associated with reoperation. Surgeons should consider these factors when assessing risk of postoperative complications for BCNTs.

The effect of adjuvant radiotherapy in management for high‐grade meningiomas, especially atypical meningiomas, remains controversial. We aimed to explore the role of adjuvant radiotherapy in this population. A total of 162 adults with high‐grade meningiomas (99 atypical meningiomas and 63 anaplastic meningiomas) were treated from 2003 to 2008 at Huashan Hospital. One hundred and seventeen patients presented with primary and 45 with recurrent disease. One hundred and fifteen patients (70.9%) were treated with adjuvant radiotherapy after surgical resection. The median follow‐up was 76.5 months (range 1‐142 months). Kaplan‐Meier survival curve and Cox proportional hazards modeling were used for analyses. Adjuvant radiotherapy was associated with prolonged progression‐free survival (PFS) and overall survival (OS) in patients with newly diagnosed anaplastic meningiomas irrespective of extent of resection (PFS, P = .001; OS, P = .003). Gross total resection was the only independent prognostic factor for those with newly diagnosed atypical meningiomas (PFS, P

IntroductionBrain metastases are the most common brain tumors in adults, whose management remains nuanced. Improved understanding of risk factors for surgical complications and mortality may guide treatment decisions.MethodsA nationwide, multicenter analysis was conducted with a retrospective cohort. Adult patients in the 2012-2015 American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) databases who received a craniotomy for resection of brain metastasis were included.Results3500 cases were analyzed, of which 17% were considered frail and 24% were infratentorial. The most common 30-day medical complications were venous thromboembolism (3%, median time-to-event [TTE] 4.5 days), pneumonia (4%, median TTE 6 days), and urinary tract infections (2%, median TTE 5 days). Reoperation and unplanned readmission occurred in 5% and 12% of patients, respectively. Infratentorial approach and frailty were associated with reoperation before discharge (OR 2.0 for both; p=0.01 and p=0.03 respectively), but not after discharge. Infratentorial approaches conferred heightened risk for readmission for hydrocephalus (OR 5.1, p=0.02) and reoperation for cerebrospinal fluid diversion (OR 7.1, pConclusionsOptimization of metrics contributing to patient frailty and heightened surveillance in patients with infratentorial metastases may be considered in the peri-operative period.

Background: Metastases to the bilateral occipital lobes pose a difficult clinical scenario due to risk of debilitating visual loss. We sought to characterize clinical outcomes following different treatment modalities to help guide management in this challenging situation. Methods: We retrospectively reviewed brain metastases patients treated at a single institution between 2008 and 2017 and assessed visual symptoms before and after treatment, the tumor and peritumoral edema volumes before treatment, and clinical outcomes including mortality. Results: Eighteen patients with metastases affecting both occipital lobes were identified. Lung cancer represented the most common primary (n = 10). Visual deficits were present in 12 patients at the time of diagnosis of bilateral occipital metastases (67%). Patients received radiotherapy (n = 5) or combined surgical resection and radiotherapy (n = 13). Among symptomatic patients, two received radiation and 10 received combined surgery and radiation. Nine patients had improved visual symptoms after treatment with no new visual deficits reported as a result of treatment. Among asymptomatic patients, three were treated with radiation alone and three with resection and radiation. Three of these patients developed new visual symptoms following treatment, including one patient with Balint’s syndrome. Conclusion: Patients with symptomatic bilateral occipital lobe metastases may experience visual improvement following intervention, especially if symptoms stem from compression or edema. Those without visual symptoms are at risk of developing new visual deficits during treatment, which should be included in the decision-making process and when counseling patients. Visual deficits improved after surgery in the majority of patients, with no cases of immediate visual deterioration.

Background: Pineal cysts are common entities, with a reported prevalence between 10 and 54%. Management of pineal cysts has historically been expectant, with surgical treatment of these lesions usually reserved for patients with a symptomatic presentation secondary to mass effect. The appropriate management of pineal cysts in patients presenting with headache in the absence of hydrocephalus – often the most common clinical scenario – has been more ambiguous. Here, we report the results of a comprehensive systematic review of headache outcomes for surgically treated, non-hydrocephalic pineal cyst patients without signs of increased intracranial pressure (ICP). Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to construct a systematic review. A comprehensive search of the PubMed, Embase, Scopus, and Web of Science databases was conducted from through June 2020. Relevant English-language articles were identified using the search terms “pineal cyst” and “headache.” The following eligibility criteria were applied: the inclusion of at least one surgically-treated, non-hydrocephalic pineal cyst patient presenting with headache in the absence of hemorrhage or signs and symptoms of increased ICP. Patient demographics and post-operative headache outcomes for the included studies were extracted and summarized. Results: A total of 24 pineal cyst cases meeting our selection criteria were identified across 11 included studies. Postoperative improvement or resolution of headaches was reported for 23/24 patients. Our systematic review of the literature demonstrates that non-hydrocephalic patients with pineal cysts have a high rate of headache improvement following surgical intervention. Conclusion: The results indicate a need for further investigation of the link between headache and pineal cysts in the non-hydrocephalic patient.

Background There are controversial results concerning the prognostic implication of TERT promoter mutation in glioma patients concerning MGMT status. In this meta-analysis, we investigated whether there are any interactions of these two genetic markers on the overall survival (OS) of glioma patients. Methods Electronic databases including PubMed and Web of Science were searched for relevant studies. Hazard ratio (HR) and its 95% confidence interval (CI) for OS adjusted for selected covariates were calculated from the individual patient data (IPD), Kaplan-Meier curve (KMC), or directly obtained from the included studies. Results A total of nine studies comprising 2819 glioma patients were included for meta-analysis. Our results showed that TERT promoter mutation was associated with a superior outcome in MGMT-methylated gliomas (HR = 0.73; 95% CI = 0.55–0.98; p-value = 0.04), whereas this mutation was associated with poorer survival in gliomas without MGMT methylation (HR = 1.86; 95% CI = 1.54–2.26; p-value TERT-mutated glioblastoma (GBM) patients with MGMT methylation benefited from temozolomide (TMZ) treatment (HR = 0.33; 95% CI = 0.23–0.47; p-value TERT-wild type GBMs (HR = 0.80; 95% CI = 0.56–1.15; p-value = 0.23). Conclusions The prognostic value of TERT promoter mutation may be modulated by MGMT methylation status. Not all MGMT-methylated GBM patients may benefit from TMZ; it is possible that only TERT-mutated GBM with MGMT methylation, in particular, may respond.

Chordomas are rare tumors that are notoriously refractory to chemotherapy and radiotherapy when radical surgical resection is not achieved or upon recurrence after maximally aggressive treatment. The study of chordomas has been complicated by small patient cohorts and few available model systems due to the rarity of these tumors. Emerging next-generation sequencing technologies have broadened understanding of this disease by implicating novel pathways for possible targeted therapy. Mutations in cell-cycle regulation and chromatin remodeling genes have been identified in chordomas, but their significance remains unknown. Investigation of the immune microenvironment of these tumors suggests that checkpoint protein expression may influence prognosis, and adjuvant immunotherapy may improve patient outcome. Finally, growing evidence supports aberrant growth factor signaling as potential pathogenic mechanisms in chordoma. In this review, we characterize the impact on treatment opportunities offered by the genomic and immunologic landscape of this tumor.

Encouraging clinical results using immune checkpoint therapies to target the PD-1 axis in a variety of cancer types have paved the way for new immune therapy trials in brain tumor patients. However, the molecular mechanisms that regulate expression of the PD-1 pathway ligands, PD-L1 and PD-L2, remain poorly understood. To address this, we explored the cell-intrinsic mechanisms of constitutive PD-L1 and PD-L2 expression in brain tumors. PD-L1 and PD-L2 expression was assessed by flow cytometry and qRT-PCR in brain tumor cell lines and patient tumor-derived brain tumor-initiating cells (BTICs). Immunologic effects of PD-L2 overexpression were evaluated by IFN-γ ELISPOT. CD274 and PDCD1LG2 cis-regulatory regions were cloned from genomic DNA and assessed in full or by mutating and/or deleting regulatory elements by luciferase assays. Correlations between clinical responses and PD-L1 and PD-L2 expression status were evaluated in TCGA datasets in LGG and GBM patients. We found that a subset of brain tumor cell lines and BTICs expressed high constitutive levels of PD-L1 and PD-L2 and that PD-L2 overexpression inhibited neoantigen specific T cell IFN-γ production. Characterization of novel cis-regulatory regions in CD274 and PDCD1LG2 lead us to identify that GATA2 is sufficient to drive PD-L1 and PD-L2 expression and is necessary for PD-L2 expression. Importantly, in TCGA datasets, PD-L2 correlated with worse clinical outcomes in glioma patients.. By perturbing GATA2 biology, targeted therapies may be useful to decrease inhibitory effects of PD-L2 in the microenvironment.

INTRODUCTION: Surgical outcomes and healthcare utilization have been shown to vary based on patient insurance status. We analyzed whether patients’ insurance affects case urgency for and readmission after craniotomy for meningioma resection, using benign meningioma as a model system to minimize confounding from the disease-related characteristics of other neurosurgical pathologies. METHODS: We analyzed 90-day readmission for patients who underwent resection of a benign meningioma in the Nationwide Readmission Database from 2014–2015. RESULTS: A total of 9783 meningioma patients with private insurance (46%), Medicare (39%), Medicaid (10%), self-pay (2%), or another scheme (3%) were analyzed. 72% of all cases were elective; with 78% of cases in privately insured patients being elective compared to 71% of Medicare (p>0.05), 59% of Medicaid patients (OR 2.3, p

To evaluate surgical resection with brachytherapy placement as a salvage treatment in patients with recurrent high-grade meningioma who exhausted prior external beam treatment options. Single-center retrospective review of our institutional experience of brachytherapy implantation from 2012 to 2018. The primary outcome of the study was progression free survival (PFS). Secondary outcomes included overall survival (OS) and complications. A matched cohort of patients not treated with brachytherapy over the same time period was evaluated as a control group. All patients had received prior radiation treatment and underwent planned gross total resection (GTR) surgery. A total of 27 cases were evaluated. Compared with prior treatment, brachytherapy implantation demonstrated a statistically significant improvement in tumor control [HR 0.316 (0.101 − 0.991), p = 0.034]. PFS-6 and PFS-12 were 92.3% and 84.6%, respectively. Compared with the matched control cohort, brachytherapy treatment demonstrated improved PFS [HR 0.310 (0.103 − 0.933), p = 0.030]. Overall survival was not statistically significantly different between groups [HR 0.381 (0.073 − 1.982), p = 0.227]. Overall postoperative complications were comparable between groups, although there was a higher incidence of radiation necrosis in the brachytherapy cohort. Brachytherapy with planned GTR improved PFS in recurrent high-grade meningioma patients who exhausted prior external beam radiation treatment options. Future improvement of brachytherapy dose delivery methods and techniques may continue to prolong control rates and improve outcomes for this challenging group of patients.

Meningiomas are the most common primary tumor of the central nervous system, with ~28,000 new diagnoses annually in the United States1. Currently, there are no approved systemic therapies for meningiomas that recur following local treatment: chemotherapy and hormonal agents have demonstrated minimal benefit in numerous clinical trials2–4. Meningioma comprises a heterogeneous group of neoplasms driven by mutations in a wide array of tumor suppressor genes and oncogenes5–17. Characterization of these mutations has revealed opportunities for rational therapy18–20. For example, a durable therapeutic response has been reported for a metastatic AKT1(E17K)-mutant meningioma treated with a pan-AKT inhibitor.21 Studies also suggest the potential for treating meningioma with immune checkpoint modulators22–24: programmed death receptor 1 ligand (PD-L1) is expressed in a subset of meningiomas and the tumor microenvironment is immunosuppressive22–28. Higher-grade meningiomas also harbor mutations predicted to generate neoantigens, which may foster susceptibility to immunotherapies29. Based on these data, we initiated a phase II study of nivolumab, a humanized IgG4 PD-1 blocking monoclonal antibody, in patients with higher-grade meningiomas that recurred following surgery and radiotherapy ({"type":"clinical-trial","attrs":{"text":"NCT02648997","term_id":"NCT02648997"}}NCT02648997). We report here a patient with an atypical meningioma that was not controlled by repeated surgery and radiation but which was highly response to nivolumab.

Updated multi-institutional database studies assessing perioperative risk factors on 30-day morbidity and mortality after skull base surgeries are limited. We aim to identify perioperative risk factors and report the incidence of 30-day morbidity and mortality in adult patients after skull base surgery.We queried the 2007-2016 American College of Surgeons National Surgical Quality Improvement program database to identify patients who underwent anterior, middle, or posterior skull base surgery. We performed multivariable logistic regression to identify risk factors associated with 30-day morbidity and mortality. Postoperative events were compared between propensity score matched cohorts (no morbidity versus 30-day morbidity).The final analysis included 1028 adult (≥18 years old) patients. The incidence of 30-morbidity and mortality was 14.6% and 1.6%, respectively. Postoperative ventilator dependence (52.9%) followed by pneumonia (23.5%) and unplanned intubation (23.5%) had the highest prevalence among those with 30-day mortality. The adjusted odds of 30-day morbidity was significantly higher among patients with functional dependency, American Society of Anesthesiologists Physical Status ≥4, hyponatremia, and anemia (p 0.05). The adjusted odds of 30-day mortality was significantly increased among patients with sepsis, bleeding disorder, disseminated cancer, and older age (p 0.05).Clinical perioperative factors are significantly associated with 30-day morbidity and mortality after skull base surgery. The reported rate of 30-day morbidity and mortality was similar to earlier studies and therefore highlights the need for continued quality improvement.

Leiomyosarcomas, neoplasms of smooth muscle, are rarely found within the orbit. Orbital leiomyosarcoma may be primary, metastatic, or secondary to radiation. When they are metastatic, patients almost exclusively have a history of a primary leiomyosarcoma, often occurring in the spermatic cord, skin, gastrointestinal tract, or the uterus. We present the case of 48-year-old woman who presented with a metastatic orbital leiomyosarcoma, which was identified before the primary tumor.

QUESTION 1 What surgical approaches for vestibular schwannomas (VS) are best for complete resection and facial nerve (FN) preservation when serviceable hearing is present? RECOMMENDATION There is insufficient evidence to support the superiority of either the middle fossa (MF) or the retrosigmoid (RS) approach for complete VS resection and FN preservation when serviceable hearing is present. QUESTION 2 Which surgical approach (RS or translabyrinthine [TL]) for VS is best for complete resection and FN preservation when serviceable hearing is not present? RECOMMENDATION There is insufficient evidence to support the superiority of either the RS or the TL approach for complete VS resection and FN preservation when serviceable hearing is not present. QUESTION 3 Does VS size matter for facial and vestibulocochlear nerve preservation with surgical resection? RECOMMENDATION Level 3: Patients with larger VS tumor size should be counseled about the greater than average risk of loss of serviceable hearing. QUESTION 4 Should small intracanalicular tumors (

Background: Surgical techniques for stabilization of the occipital cervical junction have traditionally consisted of screw-based techniques applied in conjunction with occipital plating and rods connected to subaxial instrumentation in the form of pars, pedicle, or lateral mass screws. In patients with type 1 Chiari malformation (CM-1) and evidence of occipital cervical junction instability who have undergone posterior decompression, the occipital condyle (OC) represents a potential alternative cranial fixation point. To date, this technique has only been described in pediatric case reports and morphometric cadaver studies. Methods: Patients underwent posterior fossa decompression for treatment of CM. Subsequently, patients received occipital cervical stabilization using OC screws. Results: Patients were successfully treated with no post-operative morbidity. Patient 2 was found to have pseudoarthrosis and underwent revision. Both patients continue to do well at 1-year follow-up. Conclusion: Placement of the OC screw offers advantages over traditional plate-based occipital fixation in that bone removal for suboccipital decompression is not compromised by the need for hardware placement, screws are hidden underneath ample soft tissue in patients with thin skin which prevents erosion, and the OC consists of primarily cortical bone which provides for robust tricortical fixation. These cases demonstrate the novel application of the OC screw fixation technique to the treatment of occipital cervical junction instability in adult patients undergoing simultaneous posterior fossa decompression.

Background: Basilar invagination (BI) is a complex condition characterized by prolapse of the odontoid into the brain stem/upper cervical cord. This lesion is often associated with Chiari malformations, and rheumatoid arthritis (RA). Treatment options for BI typically include cervical traction, an isolated anterior transoral odontoidectomy, anterior endonasal odontoidectomy, an isolated posterior fusion, or combined anterior/ posterior surgical approach. Case Description: A 45-year-old female with a Chiari I malformation and RA underwent a combined posterior C0-C5 posterior decompression/fusion, followed by an anterior odontoidectomy (i.e. endoscopic/endonasal under neuronavigation). Postoperatively, the patient’s symptoms and neurological signs resolved. Conclusion: BI in was successfully managed with a combined posterior C0-C5 decompression/fusion followed by an anterior endoscopic/endonasal odontoidectomy performed under neuronavigation.

While salvage re-irradiation is often used for recurrent high-grade glioma (HGG), there have been few comparisons between various re-radiation dose/fractionation schedules or with bevacizumab alone. We analyzed patients with recurrent HGG who received re-irradiation at Dana-Farber Cancer Institute and Brigham and Women's Hospital from 2010 to 2014 (n = 67), as well as those who received bevacizumab alone (n = 177). Cox proportional hazards modeling was used to examine factors associated with overall survival (OS). Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Median time from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionations used were 6 Gy × 5 (36%), 3.5 Gy × 10 (21%), 2.67 Gy × 15 (15%), and 18-20 Gy × 1 (15%). No early or late toxicities >grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 and 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR] 1.6; 95% CI, 1.1-2.3; p = .007), and recurrence in a new brain location (vs. local-only; AHR 7.4; 95% CI, 2.4-23.1; p

Background Carotid injury during anterior skull base approaches is promptly recognizable and mandates immediate treatment; likewise, development of pseudoaneurysms after such injuries is anticipated and managed. Methods We report here on the delayed development of a pseudoaneurysm as the result of avulsion of clival meningeal arteries that manifests as unalarming intraoperative bleeding. Results and Conclusions The bleeding is brisk and arterial but easily controlled. Immediate postoperative angiography is negative, necessitating repeated angiography to depict the delayed formation. It is best treated by endovascular means that maintains patency of the carotid artery, calling for the development of a suitable device that obliterates the opening of the pseudoaneurysm while maintaining carotid flow that is deployable in the tortuous carotid artery.

OBJECTIVEIdiopathic normal pressure hydrocephalus (iNPH) is characterized by ventriculomegaly, gait difficulty, incontinence, and dementia. The symptoms can be ameliorated by CSF drainage. The object of this study was to identify factors associated with shunt-responsive iNPH.METHODSThe authors reviewed the medical records of 529 patients who underwent shunt placement for iNPH at their institution between July 2001 and March 2015. Variables associated with shunt-responsive iNPH were identified using bivariate and multivariate analyses. Detailed alcohol consumption information was obtained for 328 patients and was used to examine the relationship between alcohol and shunt-responsive iNPH. A computerized patient registry from 2 academic medical centers was queried to determine the prevalence of alcohol abuse among 1665 iNPH patients.RESULTSBivariate analysis identified associations between shunt-responsive iNPH and gait difficulty (OR 4.59, 95% CI 2.32–9.09; p < 0.0001), dementia (OR 1.79, 95% CI 1.14–2.80; p = 0.01), incontinence (OR 1.77, 95% CI 1.13–2.76; p = 0.01), and alcohol use (OR 1.98, 95% CI 1.23–3.16; p = 0.03). Borderline significance was observed for hyperlipidemia (OR 1.56, 95% CI 0.99–2.45; p = 0.054), a family history of hyperlipidemia (OR 3.09, 95% CI 0.93–10.26, p = 0.054), and diabetes (OR 1.83, 95% CI 0.96–3.51; p = 0.064). Multivariate analysis identified associations with gait difficulty (OR 3.98, 95% CI 1.81–8.77; p = 0.0006) and alcohol (OR 1.94, 95% CI 1.10–3.39; p = 0.04). Increased alcohol intake correlated with greater improvement after CSF drainage. Alcohol abuse was 2.5 times more prevalent among iNPH patients than matched controls.CONCLUSIONSAlcohol consumption is associated with the development of shunt-responsive iNPH.

// Grace J. Young 1, * , Wenya Linda Bi 1, 2, * , Winona W. Wu 1 , Tanner M. Johanns 3, 4 , Gavin P. Dunn 4, 5 and Ian F. Dunn 1 1 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 3 Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA 4 Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA 5 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA * These authors contributed equally to this work Correspondence to: Ian F. Dunn, email: idunn@partners.org Gavin P. Dunn, email: gpdunn@wustl.edu Keywords: intracranial melanoma, BRAF inhibition, targeted therapy, immunotherapy, anti-PD1 Received: October 04, 2016 Accepted: April 24, 2017 Published: July 13, 2017 ABSTRACT Melanoma is the most lethal of skin cancers, in part because of its proclivity for rapid and distant metastasis. It is also potentially the most neurotropic cancer in terms of probability of CNS metastasis from the primary lesion. Despite surgical resection and radiotherapy, prognosis remains guarded for patients with brain metastases. Over the past five years, a new domain of personalized therapy has emerged for advanced melanoma patients with the introduction of BRAF and other MAP kinase pathway inhibitors, immunotherapy, and combinatory therapeutic strategies. By targeting critical cellular signaling pathways and unleashing the adaptive immune response against tumor antigens, a subset of melanoma patients have demonstrated remarkable responses to these treatments. Over time, acquired resistance to these modalities inexorably develops, providing new challenges to overcome. We review the rapidly evolving terrain for intracranial melanoma treatment, address likely and potential mechanisms of resistance, as well as evaluate promising future therapeutic approaches currently under clinical investigation.

BACKGROUND Reoperation has been increasingly utilized as a metric evaluating quality of care. OBJECTIVE To evaluate the rate of, reasons for, and predictors of unplanned reoperation after craniotomy for tumor in a nationally accrued population. METHODS Patients who underwent cranial tumor resection were extracted from the prospective National Surgical Quality Improvement Program registry (2012-2014). Multivariate logistic regression examined predictors of unplanned cranial reoperation. Predictors screened included patient age, sex, tumor location and histology, functional status, comorbidities, preoperative laboratory values, operative urgency, and time. RESULTS Of the 11 462 patients included, 3.1% (n = 350) underwent an unplanned cranial reoperation. The most common reasons for cranial reoperation were intracranial hematoma evacuation (22.5%), superficial or intracranial surgical site infections (11.9%), re-resection of tumor (8.4%), decompressive craniectomy (6.1%), and repair of cerebrospinal fluid leakage (5.6%). The strongest predictor of any cranial reoperation was preoperative thrombocytopenia (less than 100 000/μL, odds ratio [OR] = 2.51, 95% confidence interval [CI]: 1.23-5.10, P = .01). Thrombocytopenia, hypertension, emergent surgery, and longer operative time were predictors of reoperation for hematoma (P ≤ .004), while dependent functional status, morbid obesity, leukocytosis, and longer operative time were predictors of reoperation for infection (P < .05). Although any unplanned cranial reoperation was not associated with differential odds of mortality (OR = 1.68, 95% CI: 0.94-3.00, P = .08), hematoma evacuation was significantly associated with thirty-day death (P = .04). CONCLUSION In this national analysis, unplanned cranial reoperation was primarily associated with operative indices, rather than preoperative characteristics, suggesting that reoperation may have some utility as a quality indicator. However, hypertension and thrombocytopenia were potentially modifiable predictors of reoperation.

Background Giant hypervascular intracranial tumors represent a formidable challenge because their size limits surgical control of the blood supply and debulking poses the risk of critical blood loss. Embolization facilitates resection but carries the risk of life-threatening tumor infarction, hemorrhage, or swelling if performed preoperatively. Endovascular intraoperative embolization avoids the fatal risk and allows the surgeon to attend instantly if any complication occurs. Methods and Results We report 2 cases in which combining intraoperative embolization with microsurgical resection in the hybrid operating room was used to safely and successfully remove giant hypervascular tumors. Conclusions Intraoperative embolization facilitates the safe resection of giant hypervascular tumors and mitigates the consequences of potential tumor infarction, hemorrhage, or swelling from embolization. These cases exemplify the benefits of combining expertise in endovascular and microsurgical techniques with the capabilities of modern hybrid operating rooms allowing for their simultaneous application.

Background Skull base chordomas in children are extremely rare. Their course, management, and outcome have not been defined. Objective To describe the preeminent clinical and radiological features in a series of pediatric patients with skull base chordomas and analyze the outcome of a cohort who underwent uniform treatment. We emphasize predictors of overall survival and progression-free survival, which aligns with Collins' law for embryonal tumors. Methods Thirty-one patients with a mean age of 10.7 yr (range 0.8-22) harboring skull base chordomas were evaluated. We retrospectively analyzed the outcomes and prognostic factors for 18 patients treated by the senior author, with uniform management of surgery with the aim of gross total resection and adjuvant proton-beam radiotherapy. Mean follow-up was 119.2 mo (range 8-263). Results Abducens nerve palsy was the most common presenting symptom. Imaging disclosed large tumors that often involve multiple anatomical compartments. Patients undergoing gross total resection had significantly increased progression-free survival (P = .02) and overall survival (P = .05) compared with those having subtotal resection. Those who lived through the period of risk for recurrence without disease progression had a higher probability of living entirely free of progression (P = .03; odds ratio = 16.0). Age, sex, and histopathological variant did not yield statistical significance in survival. Conclusion Long-term overall and progression-free survival in children harboring skull base chordomas can be achieved with gross surgical resection and proton-beam radiotherapy, despite an advanced stage at presentation. Collins' law does apply to pediatric skull base chordomas, and children with this disease have a high hope for cure.

Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified a number of genetic determinants of pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether pituitary tumors could be stratified based on objective molecular characteristics using a clinical genomics assay. We performed a retrospective analysis of patients operated on at the Brigham and Women's Hospital from 2012 to 2016 whose pituitary tumors were profiled using multiplexed next-generation sequencing. We analyzed 127 pituitary tumors, including 114 adenomas, 5 craniopharyngiomas, and 8 tumors of other histologies. We observed recurrent BRAFV600E mutations in papillary craniopharyngiomas, CTNNB1 mutations in adamantinomatous craniopharyngiomas, and activating GNAS mutations in growth hormone–secreting adenomas. Furthermore, we validated the presence of two distinct genomic subclasses in adenomas (i.e., those with disrupted or quiet copy-number profiles) and the significant association of disruption with functional hormone status (P < 0.05). We report the clinical implementation of next-generation sequencing of pituitary tumors. We confirmed previously identified molecular subclasses for these tumors and show that routine screening as part of clinical practice is both feasible and informative. This large-scale proof-of-principle study may help to guide future institutional efforts for pituitary tumor classification as well as the incorporation of such techniques into prospective analysis as part of clinical trials.

Purpose: Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood. Experimental Design: We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent. Results: We identified mutations, insertions/deletions, and copy-number alterations. Nearly one-third of samples (29%) had chromosome arm-level copy-number alterations across large fractions of the genome. Despite such widespread genomic disruption, these tumors had few focal events, which is unusual among highly disrupted cancers. The other 71% of tumors formed a distinct molecular class, with somatic copy number alterations involving less than 6% of the genome. Among the highly disrupted group, 75% were functional adenomas or atypical null-cell adenomas, whereas 87% of the less-disrupted group were nonfunctional adenomas. We confirmed this association between functional subtype and disruption in a validation dataset of 87 pituitary adenomas. Analysis of previously published expression data from an additional 50 adenomas showed that arm-level alterations significantly impacted transcript levels, and that the disrupted samples were characterized by expression changes associated with poor outcome in other cancers. Arm-level losses of chromosomes 1, 2, 11, and 18 were significantly recurrent. No significantly recurrent mutations were identified, suggesting no genes are altered by exonic mutations across large fractions of pituitary macroadenomas. Conclusions: These data indicate that sporadic pituitary adenomas have distinct copy-number profiles that associate with hormonal and histologic subtypes and influence gene expression. Clin Cancer Res; 23(7); 1841–51. ©2016 AACR.

Background and Purpose— Previous clinical trials were not designed to discern the optimal timing of decompressive craniectomy for stroke, and the ideal surgical timing in patients with space-occupying infarction who do not exhibit deterioration within 48 hours is debated. Methods— Patients undergoing decompressive craniectomy for stroke were extracted from the Nationwide Inpatient Sample (2002–2011). Multivariable logistic regression evaluated the association of surgical timing with mortality, discharge to institutional care, and poor outcome (a composite end point including death, tracheostomy and gastrostomy, or discharge to institutional care). Covariates included patient demographics, comorbidities, year of admission, and hospital characteristics. However, standard stroke severity scales and infarct volume were not available. Results— Among 1301 admissions, 55.8% (n=726) underwent surgery within 48 hours. Teaching hospital admission was associated with earlier surgery ( P =0.02). The timing of intervention was not associated with in-hospital mortality. However, when evaluated continuously, later surgery was associated with increased odds of discharge to institutional care (odds ratio, 1.17; 95% confidence interval, 1.05–1.31, P =0.005) and of a poor outcome (odds ratio, 1.12; 95% confidence interval, 1.02–1.23; P =0.02). When evaluated dichotomously, the odds of discharge to institutional care and of a poor outcome did not differ at 48 hours after hospital admission, but increased when surgery was pursued after 72 hours. Subgroup analyses found no association of surgical timing with outcomes among patients who had not sustained herniation. Conclusion s—In this nationwide analysis, early decompressive craniectomy was associated with superior outcomes. However, performing decompression before herniation may be the most important temporal consideration.

OBJECTIVE Although there is a growing body of research highlighting the negative impact of obesity and malnutrition on surgical outcomes, few studies have evaluated these parameters in patients undergoing intracranial surgery. The goal of this study was to use a national registry to evaluate the association of body mass index (BMI) and hypoalbuminemia with 30-day outcomes after craniotomy for tumor. METHODS Adult patients who underwent craniotomy for tumor were extracted from the prospective National Surgical Quality Improvement Program registry. Patients were stratified by body habitus according to the WHO classification, as well as by preoperative hypoalbuminemia (< 3.5 g/dl). Multivariable logistic regression evaluated the association of body habitus and hypoalbuminemia with 30-day mortality, complications, and discharge disposition. Covariates included patient age, sex, race or ethnicity, tumor histology, American Society of Anesthesiology class, preoperative functional status, comorbidities (including hypertension and diabetes mellitus), and additional preoperative laboratory values. RESULTS Among the 11,510 patients included, 28.7% were classified as normal weight (BMI 18.5–24.9 kg/m2), 1.9% as underweight (BMI < 18.5 kg/m2), 33.4% as overweight (BMI 25.0–29.9 kg/m2), 19.1% as Class I obese (BMI 30.0–34.9 kg/m2), 8.3% as Class II obese (BMI 35.0–39.9 kg/m2), 5.5% as Class III obese (BMI ≥ 40.0 kg/m2), and 3.1% had missing BMI data. In multivariable regression models, body habitus was not associated with differential odds of mortality, postoperative stroke or coma, or a nonroutine hospital discharge. However, the adjusted odds of a major complication were significantly higher for Class I obese (OR 1.28, 99% CI 1.01–1.62; p = 0.008), Class II obese (OR 1.53, 99% CI 1.13–2.07; p < 0.001), and Class III obese (OR 1.67, 99% CI 1.19–2.36; p < 0.001) patients compared with those of normal weight; a dose-dependent effect was seen, with increased effect size with greater adiposity. The higher odds of major complications was primarily due to significantly increased odds of a venous thromboembolism in overweight and obese patients, as well as of a surgical site infection in those with Class II or III obesity. Additionally, 41.0% of patients had an albumin level ≥ 3.5 g/dl, 9.6% had hypoalbuminemia, and 49.4% had a missing albumin value. Hypoalbuminemia was associated with significantly higher odds of mortality (OR 1.91, 95% CI 1.41–2.60; p < 0.001) or a nonroutine hospital discharge (OR 1.46, 95% CI 1.21–1.76; p < 0.001). CONCLUSIONS In this National Surgical Quality Improvement Program analysis evaluating patients who underwent craniotomy for tumor, body habitus was not associated with differential mortality or neurological complications. However, obese patients had increased odds of a major perioperative complication, primarily due to higher rates of venous thromboembolic events and surgical site infections. Preoperative hypoalbuminemia was associated with increased odds of mortality and a nonroutine hospital discharge, suggesting that serum albumin may have utility in stratifying risk preoperatively in patients undergoing craniotomy.

Pituitary tumor apoplexy can result from either hemorrhagic or infarctive expansion of pituitary adenomas, and the related mass effect can result in compression of critical neurovascular structures. The time course of recovery of visual field deficits, headaches, ophthalmoparesis, and pituitary dysfunction after endoscopic transsphenoidal surgery has not been well established.Medical records were retrospectively reviewed for all patients who underwent endoscopic transsphenoidal surgery for pituitary tumor apoplexy from April 2008 to November 2014.Of 578 patients who underwent transsphenoidal surgery, pituitary tumor apoplexy was identified in 44 patients (7.6%). Two patients had prior surgery, leaving 42 patients for final analysis. These included infarction-related apoplexy in 7 (14.4%) patients, and hemorrhagic apoplexy in 35 (85.6%) patients. Hemorrhagic adenomas had a larger axial tumor diameter than patients with infarctive adenomas (4.4 ± 4.1 cm vs. 1.8 ± 0.8 cm; P0.01), but were otherwise equivalent. At an average last follow-up of 2.52 years (range, 0.1-6.7 years), resolution of ophthalmoparesis as a result of pituitary tumor apoplexy demonstrated the longest recovery course (range, 2.4 ± 2.2 months) compared with visual field deficits (range, 8.0 ± 9.9 days), headaches (range, 1.9 ± 3.0 days), or pituitary dysfunction (range, 2.0 ± 1.8 weeks; P0.01). All patients who presented with headaches (n = 37) and/or visual disturbances (n = 22) had complete resolution of symptoms at last follow-up, whereas 83.3% of patients who presented with ophthalmoplegia experienced resolution. Endocrinologic dysfunction remained relatively consistent after surgery.Endoscopic transsphenoidal surgery can provide durable resolution of symptoms for patients presenting with pituitary tumor apoplexy. Recovery from headaches, visual, and pituitary dysfunction may be more rapid compared with ophthalmoparesis.

Background Functional gonadotroph adenomas (FGAs) are rare tumors of the pituitary gland that secrete biologically active gonadotropins. Objective To advance clinical understanding of FGAs. Methods We performed a retrospective review of adult patients who underwent resection of a pituitary lesion between August 1997 and October 2014 and remain under care at our center. We identified patients who had pathologic and biochemical confirmation of FGAs, as defined by a lack of serum follicle-stimulating hormone/luteinizing hormone suppression in the setting of elevated gonadal steroids, associated clinical symptoms, or both. Results FGAs were documented in 7 patients (5 men, 2 women) over a 17-year period. Clinical findings at presentation included visual field deficits in 5 patients, headache in 3, sexual dysfunction in 3, and ovarian cysts in both women. Each patient underwent lesion resection (6 via the endonasal transsphenoidal approach and 1 via a craniotomy with transsphenoidal reoperation). Analysis of tumor samples revealed immunopositivity for follicle-stimulating hormone/luteinizing hormone in 5 patients and FSH only in 2 patients. Postoperative follow-up (median, 10 months; range, 4-213 months) indicated remission in 6 of 7 patients. Conclusion An FGA can pose both a diagnostic and a therapeutic challenge. The tumor is often diagnosed as a nonfunctioning macroadenoma after presenting with nonspecific symptoms and is the cause of significant morbidity. An FGA should be considered in the differential diagnosis of patients harboring pituitary adenomas with reproductive dysfunction. Transsphenoidal resection is the initial treatment of choice and can reduce endocrine dysfunction, resolve headaches, improve visual impairment, and provide tissue for detailed analysis. Abbreviations FGA, functional gonadotroph adenomaFSH, follicle-stimulating hormoneLH, luteinizing hormoneTSH, thyroid-stimulating hormone.

Background Falcine meningiomas have unique characteristics including their high rates of recurrence, association with high grade pathology, increased male prevalence, and potential for diffuse involvement of the falx. Objective To address these issues in a substantial series of falcine meningiomas and report on the impact of extent of resection for this distinct meningioma entity. Methods Retrospective analysis of characteristics and outcomes of 59 falcine meningioma patients who underwent surgery with the senior author. A "Grade Zero" category was used when an additional resection margin of 2 to 3 cm from the tumor insertion was achieved. Results For de novo falcine meningiomas, gross total resection (GTR) was associated with significantly decreased recurrence incidence compared with subtotal resection (P ≤ .0001). For recurrent falcine meningiomas, median progression-free survival (PFS) was significantly improved for GTR cases (37 mo vs 12 mo; P = .017, hazard ratio (HR) .243 (.077-.774)). "Grade Zero" resection demonstrated excellent durability for both de novo and recurrent cases, and PFS was significantly improved with "Grade Zero" resection for recurrent cases (P = .003, HR 1.544 (1.156-2.062)). The PFS benefit of "Grade Zero" resection did not achieve statistical significance over Simpson grade 1 during the limited follow-up period (mean 2.8 yr) for these groups. Conclusion The recurrence of falcine meningiomas is related to the diffuse presence of tumor between the leaflets of the falx. Increased extent of resection including, when possible, a clear margin of falx surrounding the tumor base was associated with the best long-term outcomes in our series, particularly for recurrent tumors.

Background: The vast majority of pituitary tumors are benign and behave accordingly; however, a fraction are invasive and are more aggressive, with a very small fraction being frankly malignant. The cellular pathways that drive transformation in pituitary neoplasms are poorly characterized, and current classification methods are not reliable correlates of clinical behavior. Novel techniques in epigenetics, the study of alterations in gene expression without changes to the genetic code, provide a new dimension to characterize tumors, and may hold implications for prognostication and management. Methods: We conducted a review of primary epigenetic studies of pituitary tumors with a focus on histone modification, DNA methylation, and transcript modification. Results: High levels of methylation have been identified in invasive and large pituitary tumors. DNA methyltransferase overexpression has been detected in pituitary tumors, especially in macroadenomas. Methylation differences at CpG sites in promoter regions may distinguish several types of tumors from normal pituitary tissue. Histone modifications have been linked to increased p53 expression and longer progression-free survival in pituitary tumors; sirtuins are expressed at higher values in GH-expressing compared to nonfunctional adenomas and correlate inversely with size in somatotrophs. Upregulation in citrullinating enzymes may be an early pathogenic marker of prolactinomas. Numerous genes involved with cell growth and signaling show altered methylation status for pituitary tumors, including cell cycle regulators, components of signal transduction pathways, apoptotic regulators, and pituitary developmental signals. Conclusions: The limited clinical predictive capacity of the current pituitary tumor classification system suggests that tumor subclasses likely remain to be discovered. Ongoing epigenetic studies could provide a basis for adding methylation and/or acetylation screening to standard pituitary tumor workups. Identifying robust correlations between tumor epigenetics and corresponding histological, radiographic, and clinical course information could ultimately inform clinical decision-making.