Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Congress of Neurological Surgeons systematic review and evidence­based guidelines on the management of recurrent diffuse low-grade glioma: update.

Target population These recommendations apply to adult patients with recurrent WHO grade 2 infiltrative diffuse glioma (oligodendroglioma, astrocytoma).Questions and Recommendations:Imaging Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, do advanced imaging techniques using magnetic resonance spectroscopy, perfusion weighted imaging, diffusion weighted imaging or PET provide superior assessment of tumor recurrence and histologic progression compared to standard MRI neuroimaging?Recommendation Level III: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, advanced imaging techniques using magnetic resonance spectroscopy, perfusion weighted imaging, diffusion weighted imaging or PET are suggested for identification of tumor recurrence or histologic progression.Pathology Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, is molecular testing for IDH-1, IDH-2, and TP53 Mutations and MGMT promotor methylation mutation warranted for predicting survival and formulating treatment recommendations?Recommendation Level III: It is suggested that IDH mutation status be determined for diagnostic purposes. TP53 mutations occur early in WHO grade 2 diffuse glioma pathogenesis, remain stable, and are not suggested as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. Assessment of MGMT status is suggested as an adjunct to assessing prognosis. Assessment of CDK2NA status is suggested since this is associated with malignant progression of WHO grade 2 diffuse gliomas.Q2: In adult patients with suspected recurrence of histologically proven WHO Grade 2 diffuse glioma, is testing of proliferation indices (MIB-1 and/or BUdR) warranted for predicting survival and formulating treatment recommendations?Recommendation Level III: It is suggested that proliferative indices (MIB-1 or BUdR) be measured in WHO grade 2 diffuse glioma as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival.Chemotherapy Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, does addition of temozolomide (TMZ), other cytotoxic agents or targeted agents to their treatment regimen improve PFS and/or OS?Recommendation Level III: Temozolomide is suggested in the therapy of recurrent WHO grade 2 diffuse glioma as it may improve clinical symptoms. PCV is suggested in the therapy of WHO grade 2 diffuse glioma at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. TMZ is suggested as the initial choice for recurrent WHO grade 2 diffuse glioma. Carboplatin is not suggested as there is no significant benefit from carboplatin as single agent therapy for recurrent WHO grade 2 diffuse gliomas. There is insufficient evidence to make any recommendations regarding other agents in the management of recurrent WHO grade 2 diffuse glioma.Radiotherapy Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, does addition of radiotherapy to treatment regimen improve PFS and/or OS?Recommendation Level III: Radiation is suggested at recurrence if there was no previous radiation treatment. Q2: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma after previous radiotherapy, does addition of re-irradiation or proton therapy to the treatment regimen improve PFS and/or OS?Recommendation Level III: It is suggested that re-irradiation be considered in the setting of WHO grade 2 diffuse glioma recurrence as it may provide benefit in PFS and OS.Surgery Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, does surgical resection improve PFS and/or OS?. There is insufficient evidence to make any new specific recommendations regarding the value of surgery or extent of resection in relationship to survival for recurrent WHO grade 2 diffuse glioma.

Breast cancer brain metastases localization and risk of hydrocephalus: a single institution experience.

PURPOSE: Brain metastases occur in up to one-third of patients with breast cancer. aromatase, a marker for estrogen activity that has been shown to promote such metastasis, heavily concentrates in certain midline structures of brain. We hypothesize that breast cancer metastasizes more often to brain areas with higher aromatase activity and that these patients have a higher risk of developing obstructive hydrocephalus. METHODS: In our retrospective review of 709 patients who underwent stereotactic radiosurgery (January 2014-May 2020), we identified 358 patients treated for metastatic breast or lung cancer. The MRI scan that first showed evidence of brain metastases was reviewed and number of metastases counted by location. Procedures used to treat obstructive hydrocephalus were recorded. Chi square test was used for statistical analysis. RESULTS: Of 358 patients, 99 patients with breast cancer had 618 brain metastases and 259 patients with lung cancer had 1487 brain metastases. Compared with expected distribution of brain metastases based on regional brain volumes and metastatic lung carcinoma as a control, patients with breast cancer more often had metastases to the cerebellum, diencephalon, medulla, and parietal lobe, and underwent significantly more neurosurgical interventions for treatment of obstructive hydrocephalus. CONCLUSION: Brain metastases in patients with breast cancer occurred more often along midline structures of the brain, which we believe may be associated with the increased estrogen activity in these structures. This finding is important for physicians who treat patients with metastatic breast cancer given the higher possibility of developing obstructive hydrocephalus.

Concomitant Temozolomide plus radiotherapy for high-grade and recurrent meningioma: a retrospective chart review.

BACKGROUND: High-grade and recurrent meningiomas are often treatment resistant and pose a therapeutic challenge after surgical and radiation therapy (RT) failure. Temozolomide (TMZ) is a DNA alkylating agent that appears to have a radiosensitizing effect when used in combination with RT and may be worthwhile in meningioma treatment. Thus, we investigated the potential efficacy of concomitant RT plus TMZ compared to historical controls of just RT used in the treatment of high-grade and recurrent meningiomas. METHODS: We performed a retrospective analysis of patients with meningioma treated at the University of Colorado with TMZ chemoradiation. Progression free survival (PFS) and overall survival (OS) were calculated from the start of chemoradiation to local recurrence or death, respectively. RESULTS: Eleven patients (12 tumors) were treated with chemoradiation with a median follow-up of 41.5 months. There were two WHO grade 1, eight grade 2 and two grade 3 meningiomas. Three patients died during the follow-up period-one being disease related (11.1%). Two patients had meningioma recurrence-at 2.3 months (WHO grade 3), and 5.4 years (WHO grade 2). Three-year OS and PFS for grade 2 meningiomas were each 88%. Historical controls demonstrate a 3-year median OS and PFS of 83% and 75.8%, respectively. CONCLUSIONS: Treatment options are limited for meningiomas after local failure. In this study, TMZ chemoradiation demonstrated no significant difference in PFS and OS in the treatment of grade 2 meningiomas compared to historic controls. Further study is warranted to find novel methods for the treatment of malignant and recurrent meningiomas.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of targeted therapies and immunotherapies in the management of progressive glioblastoma.

The following questions and recommendations are pertinent to the following: TARGET POPULATION: These recommendations apply to adults with progressive GBM who have undergone standard primary treatment with surgery and/or chemoradiation. QUESTION 1: In adults with progressive glioblastoma is the use of bevacizumab as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: Level III: Treatment with bevacizumab is suggested in the treatment of progressive GBM, as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months, while not providing evidence for improvement in overall survival. QUESTION 2: In adults with progressive glioblastoma is the use of bevacizumab as combination therapy with cytotoxic agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: Level III: There is insufficient evidence to show benefit or harm of bevacizumab in combination with cytotoxic therapies in progressive glioblastoma due to a lack of evidence supporting a clearly defined benefit without significant toxicity. QUESTION 3: In adults with progressive glioblastoma is the use of bevacizumab as a combination therapy with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 4: In adults with progressive glioblastoma is the use of targeted agents as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 5: In adults with progressive glioblastoma is the use of targeted agents in combination with cytotoxic therapies superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 6: In adults with progressive glioblastoma is the use of immunotherapy monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 7: In adults with progressive glioblastoma is the use of immunotherapy in combination with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 8: In adults with progressive glioblastoma is the use of immunotherapy in combination with bevacizumab superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma in adults.

TARGET POPULATION: These recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM). QUESTION (Q1): In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy? RECOMMENDATION: Level III: Adult patients with pGBM might derive benefit in treatment with TMZ, especially those who progress after more than 5 months of TMZ-treatment free interval. LEVEL III: Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohyperthermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy. There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits. QUESTION (Q2): In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy? RECOMMENDATION: Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a recommendation about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen. QUESTION (Q3): In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy? RECOMMENDATION: Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM. LEVEL III: Other cytotoxic therapies like perillyl acohol or ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy. QUESTION (Q4): In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy? RECOMMENDATION: Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM. QUESTION (Q5): In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy? RECOMMENDATION: Level III: Oncolytic virotherapy is not suggested in patients with pGBM.

Caregiver burden by treatment and clinical characteristics of patients with glioblastoma.

BACKGROUND: Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL). METHODS: Caregiver-patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses. RESULTS: The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions. CONCLUSION: This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.

Cytoreductive surgery in the management of newly diagnosed glioblastoma in adults: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adults with newly diagnosed or suspected glioblastoma. QUESTION: What is the effect of extent of surgical resection on patient outcome in the initial management of adult patients with suspected newly diagnosed glioblastoma? RECOMMENDATION: Level II: Maximal cytoreductive surgery is recommended in adult patients with suspected newly diagnosed supratentorial glioblastoma with gross total resection defined as removal of contrast enhancing tumor. Level III: Biopsy, subtotal resection, or gross total resection is suggested depending on medical comorbidities, functional status, and location of tumor if maximal resection may cause significant neurologic deficit. QUESTION: What is the role of cytoreductive surgery in adults with newly diagnosed bi-frontal "butterfly" glioblastoma? RECOMMENDATION: Level III: Resection of newly diagnosed bi-frontal "butterfly" glioblastoma is suggested to improve overall survival over biopsy alone. QUESTION: What is the goal of cytoreductive surgery in elderly adult patients with newly diagnosed glioblastoma? RECOMMENDATION: Level III: Elderly patients (> 65 years) show survival benefit with gross total resection and it is suggested they undergo cytoreductive surgery. QUESTION: What is the role of advanced intraoperative guidance techniques in cytoreductive surgery in adults with newly diagnosed glioblastoma? RECOMMENDATION: Level III: The use of intraoperative guidance adjuncts such as intraoperative MRI (iMRI) or 5-aminolevulinic acid (5-ALA) are suggested to maximize extent of resection in newly diagnosed glioblastoma. There is insufficient evidence to make a suggestion on the use of fluorescein, indocyanine green, or intraoperative ultrasound.

The role of imaging for the management of newly diagnosed glioblastoma in adults: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven glioblastoma (GBM). QUESTION: What are the optimal imaging techniques to be used in the management of a suspected glioblastoma (GBM), specifically: which imaging sequences are critical for most accurately identifying or diagnosing a GBM and distinguishing this tumor from other tumor types? RECOMMENDATIONS: Critical Imaging for the Identification and Diagnosis of Glioblastoma Level II: In patients with a suspected GBM, it is recommended that the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted, FLAIR and pre- and post-gadolinium contrast enhanced T1 weighted imaging. The addition of diffusion and perfusion weighted MR imaging can assist in the assessment of suspected GBM for the purposes of distinguishing GBM from other tumor types. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage and also can be useful for subjects who are unable to undergo MR imaging. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. Improvement of diagnostic specificity with the addition of non-anatomic (physiologic imaging) to anatomic imaging Level II: One blinded prospective study and a significant number of case series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected GBM, for the purposes of distinguishing GBM from other tumor types (e.g., primary CNS lymphoma or metastases). Level III: It is suggested that magnetic resonance spectroscopy (MRS) and nuclear medicine imaging (PET 18F-FDG and 11C-MET) be used to provide additional support for the diagnosis of GBM.

Reliability of fluorescein-assisted stereotactic brain biopsies in predicting conclusive tissue diagnosis.

BACKGROUND: The purpose of this study was to assess the reliability of fluorescein sodium in predicting conclusive tissue diagnosis in stereotactic brain biopsies and to characterize features of contrast-enhancing and non-enhancing MRI lesions associated with fluorescence. METHODS: A total of 19 patients were studied, 14 of which had contrast-enhancing and 5 of which had non-enhancing lesions on preoperative T1 post-gadolinium MRI scan. All patients received 3 mg/kg fluorescein sodium during anesthesia induction. Biopsy specimens were photographed under the operating microscope, using the Yellow560 module, prior to histopathological analysis. Two observers blinded to the MRI scans and histopathological results categorized the photographs retrospectively as "fluorescent" or "not fluorescent." Inter-rater agreement was assessed using Cohen's kappa coefficient. Sensitivity, specificity, and positive predictive value of fluorescence reliability were calculated for MRI contrast-enhancing lesions and confirmed location-concordance of tumor pathology based on rater's fluorescence status assessment. Results were correlated finally with final results on permanent sections. RESULTS: Strength of inter-rater fluorescence status agreement was found to be "substantial" (kappa = 0.771). Sensitivity, specificity, and positive predictive value for "fluorescent" and "not fluorescent" specimen in comparison with MRI contrast-enhancing lesions were 97%, 40%, and 82%, respectively. Sensitivity, specificity, and positive predictive value for confirmed tumor pathology were 100%, 63%, and 91%, respectively. Permanent pathology revealed high-grade glioma n = 5, low-grade glioma n = 3, lymphoma n = 5, pineal tumor n = 2, hamartoma n = 1, and nonspecific hypercellularity n = 3. CONCLUSIONS: Fluorescein-assisted stereotactic brain biopsies demonstrated a high likelihood to manifest fluorescence in contrast-enhancing MRI lesions, while adequately predicting conclusive tumor pathology.

Prostatic adenocarcinoma CNS parenchymal and dural metastases: alterations in ERG, CHD1 and MAP3K7 expression.

BACKGROUND: Prostatic carcinoma metastatic to dura is commonly encountered at autopsy, but presenting as a dural or, especially parenchymal, brain metastasis during life is far less common. Our group has been interested in two immunohistochemical (IHC) markers previously shown to be downregulated in particularly aggressive primary prostatic carcinomas: CHD1 and MAP3K7. Here we assess protein expression in clinically-relevant CNS metastases. We also assessed how these two markers correlated with the most common genetic alteration in prostate cancer: TMPRSS2 fusion to ERG (40-60% of carcinomas at the primary site), which places ERG expression under the control of the androgen-regulated TMPRSS2 gene, increasing expression. DESIGN: Database query, 2000-2016, identified 16 metastases to dura, 5 to brain parenchyma. RESULTS: Four of five intraparenchymal metastases and 15/16 informative dural-based metastases were ERG-negative (90.5% overall). There was reduced expression of CHD1 in 8/21 and reduced MAP3K7 in 17/21 cases; 7/19 (37%) ERG-negative metastases had dual low expression of CHD1/MAP3K7. ERG-positive cases had high expression of one or both markers. CONCLUSION: Metastatic prostatic carcinoma to CNS demonstrates expression patterns consistent with particularly aggressive behavior. Lower ERG expression in dural and intraparenchymal metastases suggests a possibility that ERG-negative tumors with loss of MAP3K7 may become resistant to standard therapies and diffusely metastasize.

A brief history of cortical functional localization and its relevance to neurosurgery.

Modern cortical mapping is a cornerstone for safe supratentorial glioma resection in eloquent brain and allows maximal resection with improved functional outcomes. The unlocking of brain functionality through close observation and eventually via cortical stimulation has a fascinating history and was made possible by contributions from early physician-philosophers and neurosurgery's founding fathers. Without an understanding of brain function and functional localization, none of today's modern cortical mapping would be possible.

Progesterone-only contraception is associated with a shorter progression-free survival in premenopausal women with WHO Grade I meningioma.

The hormonally active nature of intracranial meningioma has prompted research examining the risk of tumorigenesis in patients using hormonal contraception. Studies exploring estrogen-only and estrogen/progesterone combination contraceptives have failed to demonstrate a consistent increased risk of meningioma. By contrast, the few trials examining progesterone-only contraceptives have shown higher odds ratios for risk of meningioma. With progesterone-only contraception on the rise, the risk of tumor recurrence with these specific medications warrants closer study. We sought to determine whether progesterone-only contraception increases recurrence rate and decreases progression-free survival in pre-menopausal women with surgically resected WHO Grade I meningioma. Comparative analysis of 67 pre-menopausal women taking hormone-based contraceptives (progesterone-only medication, n = 21; estrogen-only or estrogen/progesterone combination medication, n = 46) who underwent surgical resection of WHO Grade I intracranial meningioma was performed. Differences in demographics, degree of resection, adjuvant therapy and time to recurrence were compared between the two groups. Compared to patients taking combination or estrogen-only contraception, those taking progesterone-only contraception demonstrated a greater recurrence rate (33.3 vs. 19.6%) with a reduced time to recurrence (18 vs. 32 months, p = 0.038) despite a significantly shorter follow-up (p = 0.014). There were no significant demographic or treatment related differences. The results from this study suggest that exogenous progesterone-only medications may represent a specific contraceptive subgroup that should be avoided in patients with meningioma.

Overcoming barriers to neurosurgical training in Tanzania: international exchange, curriculum development, and novel methods of resource utilization and subspecialty development.

Tanzania sits on the Indian Ocean in East Africa and has a population of over 53 million people. While the gross domestic product has been increasing in recent years, distribution of wealth remains a problem, and challenges in the distribution of health services abound. Neurosurgery is a unique case study of this problem. The challenges facing the development of neurosurgery in Tanzania are many and varied, built largely out of the special needs of modern neurosurgery. Task shifting (training nonphysician surgical providers) and 2-tiered systems (fast-track certification of general surgeons to perform basic neurosurgical procedures) may serve some of the immediate need, but these options will not sustain the development of a comprehensive neurosurgical footprint. Ultimately, long-term solutions to the need for neurosurgical care in Tanzania can only be fulfilled by local government investment in capacity building (infrastructure and neurosurgical training), and the commitment of Tanzanians trained in neurosurgery. With this task in mind, Tanzania developed an independent neurosurgery training program in Dar es Salaam. While significant progress has been made, a number of training deficiencies remain. To address these deficiencies, the Muhimbili Orthopedic Institute (MOI) Division of Neurosurgery and the University of Colorado School of Medicine Department of Neurosurgery set up a Memorandum of Understanding in 2016. This relationship was developed with the perspective of a "collaboration of equals." Through this collaboration, faculty members and trainees from both institutions have the opportunity to participate in international exchange, join in collaborative research, experience the culture and friendship of a new country, and share scholarship through presentations and teaching. Ultimately, through this international partnership, mutual improvement in the care of the neurosurgical patient will develop, bringing programs like MOI out of isolation and obscurity. From Dar es Salaam, a center of excellence is developing to train neurosurgeons who can go well equipped throughout Tanzania to improve the care of the neurosurgical patient everywhere. The authors encourage further such exchanges to be developed between partnership training programs throughout the world, improving the scholarship, subspecialization, and teaching expertise of partner programs throughout the world.

Clinical potential of meningioma genomic insights: a practical review for neurosurgeons.

Meningiomas are among the most common intracranial pathological conditions, accounting for 36% of intracranial lesions treated by neurosurgeons. Although the majority of these lesions are benign, the classical categorization of tumors by histological type or World Health Organization (WHO) grade has not fully captured the potential for meningioma progression and recurrence. Many targeted treatments have failed to generate a long-lasting effect on these tumors. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor 4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least 6 distinct mutational classes of meningiomas. In addition, 6 methylation classes of meningioma have been appreciated, enabling improved prediction of prognosis compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin. However, despite these exciting findings, the clinical relevance of these findings remains elusive. The authors review the key findings from recent genomic studies in meningiomas, specifically focusing on how these findings relate to clinical insights for the practicing neurosurgeon.

A second chance--reoperation in patients with failed surgery for intractable epilepsy: long-term outcome, neuropsychology and complications.

OBJECT: Resective surgery is a safe and effective treatment of drug-resistant epilepsy. If surgery has failed reoperation after careful re-evaluation may be a reasonable option. This study was to summarise the risks and benefits of reoperation in patients with epilepsy. METHODS: This is a retrospective single centre study comprising clinical data, long-term seizure outcome, neuropsychological outcome and postoperative complications of patients, who had undergone a second resective epilepsy surgery from 1989 to 2009. RESULTS: A total of 66 patients with median follow-up of 10.3 years were included into the study. Fifty-one patients (77%) had surgery for temporal lobe epilepsy, the remaining 15 cases for extra-temporal lobe epilepsies. The most frequent histological findings were tumours (n=33, 50%), followed by dysplasia, gliosis (n=11, each) and hippocampus sclerosis (n=9). The main reasons for seizure recurrence were incomplete resection (59.1%) of the putative epileptogenic lesion. After reoperation 46 patients (69.7%) were completely seizure-free International League Against Epilepsy 1 (ILAE 1) at the last available follow-up. The neuropsychological evaluation demonstrated that repeated losses in the same cognitive domain, that is, successive changes from better to worse performance categories, were rare and that those losses after first surgery were followed by improvement rather than decline. However, reoperations lead to an increased rate of permanent neurological deficits (9%), overall surgical complications (9%) and visual field deficits (67%). CONCLUSIONS: Reoperation after failed resective epilepsy surgery led to approximately 70% long-time seizure freedom and reasonable neuropsychological outcome. There is an increased risk of permanent postoperative neurological deficits, which should be taken into consideration when counselling for reoperation.

Epilepsy surgery of the rolandic and immediate perirolandic cortex: surgical outcome and prognostic factors.

OBJECTIVE: Herein we present a single-center retrospective study of patients who underwent epilepsy surgery for seizures arising from the sensorimotor (rolandic) cortex. The goal was to find prognostic factors associated with better seizure outcome and to evaluate both surgical and neurologic outcomes. PATIENTS, METHODS, AND MATERIALS: A total of 66 patients fulfilled eligibility criteria and were included in the study. Patients were divided into two groups for analysis: patients with resections within rolandic cortex (RO group; n = 46), and patients with resections in immediate perirolandic cortex and simultaneous sensorimotor multiple subpial transections (IPR group; n = 20). RESULTS: Favorable postoperative seizure outcome (International League Against Epilepsy [ILAE]; ILAE1-ILAE3) was achieved in 42 patients (64%), 39 (59%) of whom were completely seizure-free (ILAE1). The favorable seizure outcome in the RO group (72%) was better than in the IPR group (45%) (p = 0.04, relative risk [RR] 0.51 [0.28-0.94, 95% CI]). Eighteen patients (34%) had a postoperative permanent neurologic deficit. Independent predictors for excellent seizure outcome (ILAE1) after multivariate regression analysis were complete resection of the lesion (p < 0.001), pathology (p = 0.009), age at surgery (p = 0.03), and the absence of preoperative simple partial seizures (p = 0.01). SIGNIFICANCE: With a 64% favorable seizure outcome, surgery for intractable epilepsy arising from sensorimotor cortex is possible and can be worthwhile. The increased risk for postoperative neurologic deficits is higher than in other locations, and this must be discussed with patients in detail prior to surgery. Best postoperative results can be achieved in cases in which a complete resection is possible without damaging eloquent cortical areas.

The role of cytotoxic chemotherapy in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: What is the impact of cytotoxic chemotherapy on disease control and survival in the adult patient with progressive glioblastoma? TARGET POPULATION: This recommendation applies to adults patients with progressive glioblastoma. RECOMMENDATIONS LEVEL II: Temozolomide is recommended as superior to procarbazine in patients with first relapse of glioblastoma after having received nitrosourea chemotherapy or no prior cytotoxic chemotherapy at the time of initial therapy. The use of BCNU-impregnated biodegradable polymer wafers is recommended in the management of progressive glioblastoma as a surgical adjunct when cytoreductive surgery is indicated, taking into account the associated toxicities seen with this modality. LEVEL III: Consideration of a variety of cytotoxic chemotherapy agents of uncertain benefit is recommended in the setting of progressive glioblastoma based on the judgment of the treating physician taking into account the individual patients prior treatment exposure, systemic health, and likelihood of tolerance of the toxicities of any given agent. It is recommended in such cases that enrollment in available clinical trials be encouraged.

The role of targeted therapies in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: What is the influence of targeted medical therapies on disease control and survival in the adult patient with progressive glioblastoma? TARGETED POPULATION: This recommendation applies to adult patients with progressive glioblastoma RECOMMENDATIONS: Level III Treatment with bevacizumab is recommended as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months. Given that there are a large number of therapies are available for progressive glioblastoma that may be applied under selected circumstances dependent on patient characteristics and treating physician judgment, it is strongly recommended that patients with progressive glioblastoma be enrolled in properly designed clinical investigations to provide convincing evidence of therapeutic value.