Intracranial WHO Grade Research Articles

Utilization of a Cogmed working memory training program in patients with neurocognitive impairment following the resection of intracranial meningioma: Case series and review of the literature

Meningioma is the most common primary brain tumor in adults. Patients may become symptomatic due to the resultant mass effect and the peritumoral vasogenic edema. The majority of existing research on neurocognitive impairment in patients with brain tumors has focused on gliomas while less research has been conducted on the effects of tumor and/or surgical intervention on neurocognitive function in patients with meningioma. We conducted a prospective study on the utilization of the Cogmed Working Memory Training (CWMT) program in patients who underwent surgical resection of WHO grade I intracranial meningioma and experienced neurocognitive impairment after surgery. All patients had a significant improvement in their post-CWMT neurocognitive function evaluation compared to their baseline post-surgical neurocognitive evaluation, and the improvement was maintained at a three-month follow-up. This study is the first to evaluate the effectiveness of a neurocognitive rehabilitation program in augmenting the neurocognitive functioning of patients with Intracranial WHO Grade I Meningioma. The results of this study demonstrate the efficacy of the CWMT program in improving postoperative impaired neurocognitive function and potentially improving the quality of life of our patients.

Male sex and presence of preoperative symptoms are associated with early recurrence of WHO grade I meningiomas after surgical resection: analysis from the nationwide Brain Tumor Registry of Japan.

This study aimed to assess the risk factors for the recurrence of WHO grade I intracranial meningiomas using the Brain Tumor Registry of Japan (BTRJ) database. We extracted the data of 4641 patients with intracranial WHO grade I meningiomas treated only by surgical resection between 2001 and 2008. We conducted complete data analysis (n = 3690) and multiple imputation analysis (n = 4641) to adjust for missing data on tumor size. The influence of factors including age, sex, size, extent of resection, location, and preoperative symptoms on PFS was assessed. Univariate analyses of the complete data set showed that age did not affect PFS; however, male sex (p < 0.001), tumor size ≥ 30mm (p < 0.001), low extent of resection, tumor location at the skull base (p < 0.001), and the presence of preoperative symptoms (p < 0.001) were risk factors for a significantly shorter PFS. Multivariate analysis demonstrated that male sex (p < 0.001) and presence of preoperative symptoms (p = 0.027) were independent risk factors for shorter PFS alongside large tumor size (p < 0.001) and non-gross total resection (p < 0.001). These results were confirmed for the imputed dataset. While most previous large nationwide studies of meningiomas have evaluated overall survival, progression-free survival has yet to be thoroughly examined. This study suggests that even histologically benign meningiomas may have a sex difference in postoperative behavior. This observation may provide clues to understanding the mechanism of meningioma cell proliferation.

Health-related quality of life and clinical outcome after radiotherapy of patients with intracranial meningioma

This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6% at 5 years and 75.9% at 10 years. Local control (LC) at 5 and 10 years was 82.4% and 73.4%, respectively. Local recurrence was observed in 22 patients (18.5%). Higher grade acute and chronic toxicities were observed in seven patients (5.9%) and five patients (4.2%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.

FORGE: A Novel Scoring System to Predict the MIB-1 Labeling Index in Intracranial Meningiomas.

Simple SummaryMeningiomas are predominantly benign intracranial tumors, and surgical therapy represents the treatment of choice. However, the risk of recurrence and scheduling of follow-up intervals are significantly influenced by immunohistochemical items such as the MIB-1 labeling index. To date, it is not possible to integrate this essential information into the pre- or intraoperative surgical decision making. In the present study, we therefore analyzed baseline variables associated with the MIB-1 labeling index. We found four easily identifiable and routinely recorded risk factors for an increased MIB-1 index and developed a simple and quick-to-use score that allows us to estimate the risk of an elevated MIB-1 index prior to the surgical resection. Furthermore, this score seems to predict the progression-free survival in intracranial meningiomas. We believe that this score might us to more reliably guide patients in preoperative surgical strategy planning and postoperative follow-up scheduling.The MIB-1 index is an essential predictor of progression-free-survival (PFS) in meningioma. To date, the MIB-1 index is not available in preoperative treatment planning. A preoperative score estimating the MIB-1 index in patients with intracranial meningiomas has not been investigated so far. Between 2013 and 2019, 208 patients with tumor morphology data, MIB-1 index data, and plasma fibrinogen and serum C-reactive protein (CRP) data underwent surgery for intracranial WHO grade I and II meningioma. An optimal MIB-1 index cut-off value (≥6/<6) in the prediction of recurrence was determined by ROC curve analysis (AUC: 0.71; 95% CI: 0.55–0.87). A high MIB-1 index (≥6%) was present in 50 cases (24.0%) and was significantly associated with male sex, peritumoral edema, low baseline CRP, and low fibrinogen level in the multivariate analysis. A scoring system (“FORGE”) based on sex, peritumoral edema, preoperative CRP value, and plasma fibrinogen level supports prediction of the MIB-1 index (sensitivity 62%, specificity 79%). The MIB-1 labeling index and the FORGE score are significantly associated with an increased risk of poor PFS time. We suggest a novel score (“FORGE”) to preoperatively estimate the risk of an increased MIB-1 index (≥6%), which might help in surgical decision making and follow-up interval determination and inform future trials investigating inflammatory burden and proliferative activity.

The Prognostic Value of Methylation Signatures and NF2 Mutations in Atypical Meningiomas.

Simple SummaryThe WHO 2016 classification of human meningiomas is debated due to the subjective evaluation of the histopathological diagnostics and grading. However, meningioma classification based on genome-wide DNA methylation profiling has become useful in classification of these tumors by being a better prognostic tool. The current pilot study was designed to test out genome-wide DNA methylation profiling on atypical meningiomas as these tumors have a highly variable risk of recurrence. Although we found that it had diagnostic value, further refinements on the methylation profile procedure are required. With this study we aim to motivate and impact researchers to continue to work and debate towards an improved meningioma classification including molecular and genetic biomarkers, which will benefit patients with such diagnoses.Background: Due to the solely subjective histopathological assessment, the WHO 2016 classification of human meningiomas is subject to interobserver variation. Consequently, the need for more reliable and objective markers are highly needed. The aim of this pilot study was to apply genome-wide DNA methylation analysis on a series of atypical meningiomas to evaluate the practical utility of this approach, examine whether prognostic subclasses are achieved and investigate whether there is an association between the methylation subclasses with poor prognosis and time to recurrence. NF1/2 mutation analyses were also performed to explore the prognostic value of such mutations in these atypical meningiomas. Methods: Twenty intracranial WHO grade II atypical meningiomas from adult patients were included. They consisted of 10 cases with recurrence (group I), and 10 cases without recurrence (group II). The formalin-fixed and paraffin-embedded tissues underwent standardized genome-wide DNA methylation analysis, and the profiles were matched with the reference library and tumor classifier from Heidelberg. NF1/2 somatic mutation analyses were performed using the CNSv1panel from Düsseldorf. Results: Eighteen out of 20 cases matched to the meningioma class using the common brain tumor classifier (v11b4). Four of these cases matched to a methylation subclass related to a prognostic subgroup based on a cut-off of 0.9. NF2 mutations were detected in 55% of cases across both groups, and the most prominent copy number alterations were chromosomal losses of 22q, 1p and 14q. No significant NF1 mutations were identified. Conclusions: Genome-wide DNA methylation profiling represents a useful tool in the diagnostics of meningiomas, however, methodological adjustments need to be addressed.

Determinants and predictors for the long-term disease burden of intracranial meningioma patients

IntroductionMeningioma is a heterogeneous disease and patients may suffer from long-term tumor- and treatment-related sequelae. To help identify patients at risk for these late effects, we first assessed variables associated with impaired long-term health-related quality of life (HRQoL) and impaired neurocognitive function on group level (i.e. determinants). Next, prediction models were developed to predict the risk for long-term neurocognitive or HRQoL impairment on individual patient-level.MethodsSecondary data analysis of a cross-sectional multicenter study with intracranial WHO grade I/II meningioma patients, in which HRQoL (Short-Form 36) and neurocognitive functioning (standardized test battery) were assessed. Multivariable regression models were used to assess determinants for these outcomes corrected for confounders, and to build prediction models, evaluated with C-statistics.ResultsData from 190 patients were analyzed (median 9 years after intervention). Main determinants for poor HRQoL or impaired neurocognitive function were patients’ sociodemographic characteristics, surgical complications, reoperation, radiotherapy, presence of edema, and a larger tumor diameter on last MRI. Prediction models with a moderate/good ability to discriminate between individual patients with and without impaired HRQoL (C-statistic 0.73, 95% CI 0.65 to 0.81) and neurocognitive function (C-statistic 0.78, 95%CI 0.70 to 0.85) were built. Not all predictors (e.g. tumor location) within these models were also determinants.ConclusionsThe identified determinants help clinicians to better understand long-term meningioma disease burden. Prediction models can help early identification of individual patients at risk for long-term neurocognitive or HRQoL impairment, facilitating tailored provision of information and allocation of scarce supportive care services to those most likely to benefit.

Intracranial WHO grade I meningioma: a competing risk analysis of progression and disease-specific survival.

Studies on meningioma are reported with inadequate allowance for competing causes of progression or death. The aim of this study was to describe the outcome of patients with intracranial WHO grade I meningioma and identify factors that may influence disease progression and cause-specific survival. Pathology reports and clinical data of 505 WHO grade I meningiomas treated between January 2003 and December 2017 were retrospectively reviewed at a single institution. We estimated a cumulative incidence function for progression and cause-specific mortality. A competing risk analysis was conducted on clinical and histological criteria. Median follow-up was 6.2 years. A total of 530 surgical resections were performed on 505 cases. Forty-one patients received radiotherapy (RT). At data collection, 84 patients had died of their meningioma disease or demonstrated a recurrence eventually treated by redo surgery or RT. The risks of recurrence or meningioma-related death at 5 years were 16.2%, 95%CI[12.5, 20], whereas 5-year overall survival was 86.1%, 95%CI[82.8, 89.6]. In the multivariable Fine-Gray regression for a competing risk model, venous sinus invasion (SHR = 1.8, 95%CI[1.1, 2.9], p0.028), extent of resection (SHR = 0.2, 95%CI[0.1, 0.3], p < 0.001), and progressing meningioma (SHR = 7, 95%CI[3.3, 14.8], p < 0.001) were established as independent prognostic factors of cause-specific death or meningioma progression. In contrast, age at diagnosis < 65 years (HR = 1.1, 95%CI[1, 1.1], p < 0.001) and redo surgery for meningioma recurrence (HR = 2.6, 95%CI[1.4, 5], p = 0.00252) were predictors of the overall survival. In this large series, WHO grade I meningioma treatment failure correlated with venous sinus invasion, incomplete resection, and progressing tumour; shorter survival correlated with increased age and redo surgery for recurrence. We recommend the cumulative incidence competing risk approach in WHO grade I meningioma studies where unrelated mortality may be substantial, as this approach results in more accurate estimates of disease risk and associated predictors.

The value of high-dose radiotherapy in intracranial ependymoma.

We sought to evaluate the impact of adjuvant radiotherapy dose on overall survival (OS) after surgical resection for localized intracranial ependymoma. The National Cancer Database (NCDB) was queried from 2004 to 2015 for patients of all ages with intracranial WHO grade II to III ependymoma treated with surgery and 4500 to 7000 cGy of adjuvant radiotherapy. Pearson χ2 test and multivariate logistic regression analyses were used to assess clinicodemographic factors and patterns of care. After propensity-score matching, OS was assessed with Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling. Of the 1153 patients meeting criteria, 529 (46%) received ≤ 5400 cGy and 624 (54%) received>5400 cGy. At a median follow-up of 54.5 months, an OS benefit was observed for>5400 cGy in pediatric patients aged 2-18 years (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.28-0.99, P=0.047). No OS difference was found between ≤ 5400 cGy and>5400 cGy in pediatric patients aged<2 years (P=0.819) or in adults (P=0.180). Increasing age, WHO grade III, subtotal resection, and receipt of chemotherapy portended worse OS. Age 2 to 18 years, WHO III grade, supratentorial location, and receipt of chemotherapy were associated with receiving>5400 cGy. Adjuvant radiotherapy dose>5400 cGy was associated with improved OS for children aged 2-18 years with WHO grade II-III intracranial ependymoma. No OS benefit was found with>5400 cGy in adults or children less than two years of age.

Advances in Management of Pediatric Ependymomas.

Ependymomas are a heterogeneous group of neuroepithelial tumors of children and adults. In pediatric cases, the standard of care has long consisted of neurosurgical resection to the greatest extent acceptable followed by adjuvant involved field irradiation. Complete macroscopic surgical resection has remained the only consistent clinical variable known to improve survival. Adjuvant chemotherapy has yet to predictably affect outcome, possibly due to the molecular heterogeneity of histologically similar tumors. The administration of chemotherapy subsequently remains limited to clinical trials. However, recent comprehensive genomic, transcriptomic, and epigenetic interrogations of ependymomas have uncovered unique molecular characteristics and subtypes that correlated with clinical features such as age, neuroanatomical location, and prognosis. These findings represent a potential paradigm shift and provide a biologic rationale for targeted therapeutic strategies and risk-adapted administration of conventional treatment modalities. In this review, we focus on intracranial WHO grade II and III ependymoma of children and discuss conventional management strategies, followed by recent biologic findings and novel therapeutics currently under investigation.

Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas

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. 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. 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). 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.

Adult intracranial WHO grade II ependymomas: long-term outcome and prognostic factor analysis in a series of 114 patients

Ependymomas account for 2% of all intracranial tumors in adults. Considerable controversy continues to exist with regard to their prognostic factors and therapeutic management due to the rarity and the heterogeneity of series reported so far. The authors report a retrospective study of a homogenous population of 114 adult patients harboring WHO grade II intracranial ependymomas from 32 French Neurosurgical Centers between 1990 and 2004. All clinico-radiological and follow-up data were analyzed, and a central pathologic review was performed by two confirmed neuropathologists. The 5- and 10-year overall survival (OS) rates were 86.1% and 81.0%, respectively; the 5- and 10-year progression-free survival (PFS) rates were 74.6% and 58.9%, respectively. On multivariate analysis, the OS rates were associated with preoperative KPS score (P = .027), extent of surgery (P = .008), and tumor location (supratentorial vs infratentorial, P = .012). The multivariate analysis also revealed that the risk of recurrence was associated with incomplete resection (P = .001) and supratentotrial location (P = .038). Moreover, adjuvant radiotherapy (RT) for patients with incompletely resected tumors is responsible for a significant improvement of both overall (P = .005) and progression-free (P = .002) survival. This study clearly supports the major prognostic impact of the extent of surgery in WHO grade II. Interestingly, tumor location also seems to have an actual impact on both OS and PFS. Finally, the prognostic impact of RT was found to be beneficial for incompletely resected tumors.