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Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma

Sameer Agnihotri, Kenneth D. Aldape, and Gelareh Zadeh

Diffuse gliomas and secondary glioblastomas (GBMs) that develop from low-grade gliomas are a common and incurable class of brain tumor. Mutations in the metabolic enzyme glioblastomas (IDH1) represent a distinguishing feature of low-grade gliomas and secondary GBMs. IDH1 mutations are one of the most common and earliest detectable genetic alterations in low-grade diffuse gliomas, and evidence supports this mutation as a driver of gliomagenesis. Here, the authors highlight the biological consequences of IDH1 mutations in gliomas, the clinical and therapeutic/diagnostic implications, and the molecular subtypes of these tumors. They also explore, in brief, the non-IDH1–mutated gliomas, including primary GBMs, and the molecular subtypes and drivers of these tumors. A fundamental understanding of the diversity of GBMs and lower-grade gliomas will ultimately allow for more effective treatments and predictors of survival.

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Introduction. Big data and its impact on the future of neurosurgery

Michael Y. Wang, Jang W. Yoon, Gelareh Zadeh, Paul Park, Erica F. Bisson, and Daniel M. Sciubba

Free access

Introduction: Glioblastoma: an update on pathophysiology and management strategies

Mitchel S. Berger, Jeffrey N. Bruce, Thomas C. Chen, and Gelareh Zadeh

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Management and outcome of recurrent adult craniopharyngiomas: an analysis of 42 cases with long-term follow-up

Mazda K. Turel, Georgios Tsermoulas, Lior Gonen, George Klironomos, Joao Paulo Almeida, Gelareh Zadeh, and Fred Gentili

OBJECTIVE

The treatment of recurrent and residual craniopharyngiomas is challenging. In this study the authors describe their experience with these tumors and make recommendations on their management.

METHODS

The authors performed an observational study of adult patients (≥ 18 years) with recurrent or residual craniopharyngiomas that were managed at their tertiary center. Retrospective data were collected on demographics and clinical, imaging, and treatment characteristics from patients who had a minimum 2-year follow-up. Descriptive statistics were used and the data were analyzed.

RESULTS

There were 42 patients (27 male, 15 female) with a mean age of 46.3 ± 14.3 years. The average tumor size was 3.1 ± 1.1 cm. The average time to first recurrence was 3.6 ± 5.5 years (range 0.2–27 years). One in 5 patients (8/42) with residual/recurrent tumors did not require any active treatment. Of the 34 patients who underwent repeat treatment, 12 (35.3%) had surgery only (transcranial, endoscopic, or both), 9 (26.5%) underwent surgery followed by adjuvant radiation therapy (RT), and 13 (38.2%) received RT alone. Eighty-six percent (18/21) had a gross-total (n = 4) or near-total (n = 14) resection of the recurrent/residual tumors and had good local control at last follow-up. One of 5 patients (7/34) who underwent repeat treatment had further treatment for a second recurrence. The total duration of follow-up was 8.6 ± 7.1 years. The average Karnofsky Performance Scale score at last follow-up was 80 (range 40–90). There was 1 death.

CONCLUSIONS

Based on this experience and in the absence of guidelines, the authors recommend an individualized approach for the treatment of symptomatic or growing tumors. This study has shown that 1 in 5 patients does not require repeat treatment of their recurrent/residual disease and can be managed with a “scan and watch” approach. On the other hand, 1 in 5 patients who had repeat treatment for their recurrence in the form of surgery and/or radiation will require further additional treatment. More studies are needed to best characterize these patients and predict the natural history of this disease and response to treatment.

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Testing the radiosurgery-based arteriovenous malformation score and the modified Spetzler—Martin grading system to predict radiosurgical outcome

Yuri M. Andrade-Souza, Gelareh Zadeh, Meera Ramani, Daryl Scora, May N. Tsao, and Michael L. Schwartz

Object. The aim of this study was to validate the radiosurgery-based arteriovenous malformation (AVM) score and the modified Spetzler—Martin grading system to predict radiosurgical outcome.

Methods. One hundred thirty-six patients with brain AVMs were randomly selected. These patients had undergone a linear accelerator radiosurgical procedure at a single center between 1989 and 2000. Patients were divided into four groups according to an AVM score, which was calculated from the lesion volume, lesion location, and patient age (Group 1, AVM score < 1; Group 2, AVM score 1–1.49; Group 3, AVM score 1.5–2; and Group 4, AVM score > 2). Patients with a Spetzler—Martin Grade III AVM were divided into Grades IIIA (lesion > 3 cm) and IIIB (lesion < 3 cm). Sixty-two female (45.6%) and 74 male (54.4%) patients with a median age of 37.5 years (mean 37.5 years, range 5–77 years) were followed up for a median of 40 months. The median tumor margin dose was 15 Gy (mean 17.23 Gy, range 15–25 Gy). The proportions of excellent outcomes according to the AVM score were as follows: 91.7% for Group 1, 74.1% for Group 2, 60% for Group 3, and 33.3% for Group 4 (chi-square test, degrees of freedom (df) = 3, p < 0.001). Based on the modified Spetzler—Martin system, Grade I lesions had 88.9% excellent results; Grade II, 69.6%; Grade IIIB, 61.5%; and Grades IIIA and IV, 44.8% (chi-square test, df = 3, p = 0.047).

Conclusions. The radiosurgery-based AVM score can be used accurately to predict excellent results following a single radiosurgical treatment for AVM. The modified Spetzler—Martin system can also predict radiosurgical results for AVMs, thus making it possible to use this system while deciding between surgery and radiosurgery.

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Long-term outcomes of transsphenoidal surgery for management of growth hormone–secreting adenomas: single-center results

Mohammed J. Asha, Hirokazu Takami, Carlos Velasquez, Selfy Oswari, Joao Paulo Almeida, Gelareh Zadeh, and Fred Gentili

OBJECTIVE

Transsphenoidal surgery is advocated as the first-line management of growth hormone (GH)–secreting adenomas. Although disease control is defined by strict criteria for biochemical remission, the length of follow-up needed is not well defined in literature. In this report, the authors present their long-term remission rate and identify various predictive factors that might influence the clinical outcome.

METHODS

The authors conducted a single-institute retrospective analysis of all transsphenoidal procedures for GH-secreting adenomas performed from January 2000 to June 2016. The primary outcome was defined as biochemical remission according to the 2010 consensus criteria and measured at the 1-year postoperative mark as well as on the last recorded follow-up appointment.

Secondary variables included recurrence rate, patterns of clinical presentation, and outcome of adjuvant therapy (including repeat surgery). Subgroup analysis was performed for patients who had biochemical or radiological “discordance”—patients who achieved biochemical remission but with incongruent insulin-like growth factor 1 (IGF-1)/GH or residual tumor on MRI. Recurrence-free survival analysis was conducted for patients who achieved remission at 1 year after surgery.

RESULTS

Eighty-one patients (45 female and 36 male) with confirmed acromegaly treated with transsphenoidal surgery were included. In 62 cases the patients were treated with a pure endoscopic approach and in 19 cases an endoscopically assisted microscopic approach was used.

Primary biochemical remission after surgery was achieved in 59 cases (73%) at 1 year after surgery. However, only 41 patients (51%) remained in primary surgical remission (without any adjuvant treatment) at their last follow-up appointment, indicating a recurrence rate of 31% (18 of 59 patients) over the duration of follow-up (mean 100 ± 61 months). Long-term remission rates for pure endoscopic and endoscopically assisted cases were not significantly different (48% vs 52%, p = 0.6). Similarly, no significant difference in long-term remission was detected between primary surgery and repeat surgery (54% vs 33%, p = 0.22).

Long-term remission was significantly influenced by extent of resection, cavernous sinus invasion (radiologically as well as surgically reported), and preoperative and early postoperative GH and IGF-1 levels (within 24–48 hours after surgery) as well as by clinical grade, with lower remission rates in patients with dysmorphic features and/or medical comorbidities (grade 2–3) compared to minimally symptomatic or silent cases (grade 1).

CONCLUSIONS

The long-term surgical remission rate appears to be significantly less than “early” remission rates and is highly dependent on the extent of tumor resection. The authors advocate a long-term follow-up regimen and propose a clinical grading system that may aid in predicting long-term outcome in addition to the previously reported anatomical factors. The role of repeat surgery is highlighted.

Open access

DNA methylation profiling of a lipomatous meningioma: illustrative case

Zeel Patel, Justin Z. Wang, Zamir Merali, Vikas Patil, Farshad Nassiri, Qingxia Wei, Julio Sosa, Claire Coire, and Gelareh Zadeh

BACKGROUND

Lipomatous meningiomas are an extremely rare, benign meningioma subtype subcategorized under metaplastic meningioma in the most recent 2021 update to the World Health Organization classification. They make up less than 0.3% of all meningiomas and, to date, less than 70 cases have been reported in the literature, none of which have undergone molecular profiling. This study aims to promote the utility of molecular profiling to better diagnose these rare tumors.

OBSERVATIONS

The authors present the first case of a lipomatous meningioma with DNA methylation profiling that both confirmed its benign biology and uncovered unique cytogenetic changes. Molecular characterization of a lipomatous meningioma confirmed its diagnosis as a distinct, benign meningioma subtype and revealed several copy number variations on chromosome 8 and in NF2 and SMARCB1. Here we discuss some of the radiological and histopathological features of lipomatous meningiomas, how they can be used to distinguish from other meningiomas and other similarly presenting tumors, and a brief literature review discussing the pathophysiology and presentation of this rare tumor.

LESSONS

This study provides evidence supporting the use of molecular profiling to diagnose lipomatous meningiomas and guide their clinical management more accurately.

Free access

Cross-sectional analysis of women in neurosurgery: a Canadian perspective

Catherine Veilleux, Nardin Samuel, Han Yan, Victoria Bass, Rabab Al-Shahrani, Ann Mansur, James T. Rutka, Gelareh Zadeh, Mojgan Hodaie, and Geneviève Milot

OBJECTIVE

Although the past decades have seen a steady increase of women in medicine in general, women continue to represent a minority of the physician-training staff and workforce in neurosurgery in Canada and worldwide. As such, the aim of this study was to analyze the experiences of women faculty practicing neurosurgery across Canada to better understand and address the factors contributing to this disparity.

METHODS

A historical, cross-sectional, and mixed-method analysis of survey responses was performed using survey results obtained from women attending neurosurgeons across Canada. A web-based survey platform was utilized to collect responses. Quantitative analyses were performed on the responses from the study questionnaire, including summary and comparative statistics. Qualitative analyses of free-text responses were performed using axial and open coding.

RESULTS

A total of 19 of 31 respondents (61.3%) completed the survey. Positive enabling factors for career success included supportive colleagues and work environment (52.6%); academic accomplishments, including publications and advanced degrees (36.8%); and advanced fellowship training (47.4%). Perceived barriers reported included inequalities with regard to career advancement opportunities (57.8%), conflicting professional and personal interests (57.8%), and lack of mentorship (36.8%). Quantitative analyses demonstrated emerging themes of an increased need for women mentors as well as support and recognition of the contributions to career advancement of personal and family-related factors.

CONCLUSIONS

This study represents, to the authors’ knowledge, the first analysis of factors influencing career success and satisfaction in women neurosurgeons across Canada. This study highlights several key factors contributing to the low representation of women in neurosurgery and identifies specific actionable items that can be addressed by training programs and institutions. In particular, female mentorship, opportunities for career advancement, and increased recognition and integration of personal and professional roles were highlighted as areas for future intervention. These findings will provide a framework for addressing these factors and improving the recruitment and retention of females in this specialty.

Open access

Adult isocitrate dehydrogenase–mutant brainstem glioma: illustrative case

Vincent C. Ye, Alexander P. Landry, Teresa Purzner, Aristotelis Kalyvas, Nilesh Mohan, Philip J. O’Halloran, Andrew Gao, and Gelareh Zadeh

BACKGROUND

Adult brainstem gliomas are rare entities that demonstrate heterogeneous biology and appear to be distinct from both their pediatric counterparts and adult supratentorial gliomas. Although the role of histone 3 mutations is being increasingly understood in this disease, the effect of isocitrate dehydrogenase (IDH) mutations remains unclear, largely because of limited data.

OBSERVATIONS

The authors present the case of a 29-year-old male with an IDH1-mutant, World Health Organization grade III anaplastic astrocytoma in the dorsal medulla, and they provide a review of the available literature on adult IDH-mutant brainstem glioma. The authors have amassed a cohort of 15 such patients, 7 of whom have survival data available. Median survival is 56 months in this small cohort, which is similar to that for IDH wild-type adult brainstem gliomas.

LESSONS

The authors’ work reenforces previous literature suggesting that the role of IDH mutation in glioma differs between brainstem and supratentorial lesions. Therefore, the authors advocate that adult brainstem gliomas be studied in terms of major molecular subgroups (including IDH mutant) because these gliomas may exhibit fundamental differences from each other, from pediatric brainstem gliomas, and from adult supratentorial gliomas.

Free access

Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas

Alireza Mansouri, Soroush Larjani, George Klironomos, Normand Laperriere, Michael Cusimano, Fred Gentili, Michael Schwartz, and Gelareh Zadeh

OBJECT

In this paper, the authors’ aim was to determine short-term volumetric and diametric tumor growth and identify clinical, radiological, and dosimetric predictors of adverse radiation events (AREs) following stereotactic radiosurgery (SRS) for intracranial WHO Grade I meningiomas.

METHODS

This is a retrospective review of all WHO Grade I meningiomas that were treated with SRS (primary or adjuvant) between December 2005 and June 2012 at the University Health Network. Seventy-five patients had at least 24 months of both clinical and radiological follow-up and were, therefore, included in this study. Tumor growth was defined as any volumetric or diametric change greater than 10% per year. Any variation less than +10% was considered growth stability. Volumetric measurements were made using T1-weighted gadolinium-enhanced 3-T MRI scans and ITK-SNAP software. Tumor growth rates were calculated using the specific growth rate (SGR). Univariate statistics were used to identify predictors of post-SRS AREs. All statistical analyses were performed using IBM SPSS.

RESULTS

Women accounted for 69.3% of patients, and the mean treatment age was 58.6 years. Median follow-up was 36.2 months. Twenty-one (28%) patients had undergone prior resection. Two (3%) patients required salvage surgical intervention following SRS. The majority of the lesions (56%) were skull base tumors. Median tumor volume and diameter were 5.2 cm3 and 27.5 mm, respectively. The absence of tumor growth was observed in 39 cases (52%) based on the volumetric measurements, while the absence of tumor growth was observed in 69 cases (92%) based on the diametric measurements. Twenty-six patients (34.6%) experienced new-onset AREs, including headache (17.3%), cranial neuropathy (10.6%), speech impairment (2.7%), tremors (2.7%), and ataxia (1.3%). Fourteen patients (18.7%) experienced new-onset edema, and 4 of these patients were symptomatic. A lower conformity index (1.24 vs 1.4) was significantly associated with the development of edema (p < 0.001 power > 0.8). Patients with meningiomas that had growth rates of more than 10% per year were more likely to experience long-term headaches after SRS (p = 0.022).

CONCLUSIONS

Volume-based reporting of SRS outcomes for meningiomas may be a more accurate method given the complex morphology of some lesions. The conformity index was identified as a predictor of edema following radiosurgery.