Comprehensive assessment of atypical and anaplastic pediatric meningiomas utilizing national cancer database: a retrospective cohort study.

PURPOSE: To examine demographic and clinical characteristics and their association with survival in grade 2 and 3 pediatric meningiomas in a large cohort using the National Cancer Database (NCDB). METHODS: We conducted a comprehensive analysis using data from NCDB between 2004 to 2018. Tumor-specific data included tumor grade and size. Treatment details, including surgical resection, extent of resection, and radiotherapy, were gathered. Our analytic approach incorporated logistic and Poisson regression, Kaplan-Meier survival estimates, and Cox proportional hazards models. RESULTS: Among the included 239 patients aged 0-21 years, age category distribution was significantly different between grade 2 and grade 3 tumors (p = 0.018). For grade 2 meningiomas, 51.5% of patients were female, and 76.7% were white. 85.3% of patients with grade 2 meningiomas underwent surgical resection, of which 67% underwent gross total resection. Overall survival (OS) was significantly different between resected and non-resected patients (p = 0.048). Uninsured patients were over seven times as likely to have prolonged length of stay (LOS) versus those with private insurance (OR = 7.663, p = 0.014). For grade 3 meningiomas, 51.4% of patients were male, and 82.9% were white. 91.4% of patients with grade 3 meningiomas underwent surgical resection, of which 53.3% underwent subtotal resection. OS was not significantly different between resected and non-resected patients (p = 0.659). CONCLUSION: In summary, there were significant differences in age, maximum tumor dimension, unplanned readmission, radiotherapy, and treatment combinations between grade 2 and 3 meningiomas. These findings highlight the intricacies of managing pediatric meningiomas and emphasize the necessity for tailored therapeutic approaches to enhance outcomes in the future.

Significance of Staining Intensity in Ki-67 Proliferation Index in Meningiomas, and a Critical Review of the Literature on Proliferation Index Assessment.

OBJECTIVE: Meningioma is the most common primary adult intracranial neoplasm, and proliferation indices (PI) rise with increasing grade from WHO CNS grade 1 to 3. Ki-67 immunohistochemistry (IHC) poses a variety of technical and interpretative challenges. Here, we specifically investigated the staining intensity and its effect on interpretation and final diagnosis. METHODS: 124 high and low-grade meningiomas of various grades were blindly evaluated using different counting strategies (CS) based on the staining intensity of the nuclei as darkest (CS1), darkest+intermediate (CS2), and any staining (CS3) in hot-spots (HS) and in the context of overall proliferative activity (OPA). RESULT: CSs in HS, OPA, and their average results were significantly different between low-grade and high-grade groups. PI obtained using CS3 yielded results that matched best with values expected for the corresponding WHO grade. CS had a profound impact on whether a LG meningioma would be diagnosed as one with a "high proliferation index." CONCLUSION: A large body of work exists on the counting methods, clinically significant cut-off values, and inter- and intra-observer variability for Ki-67 PI interpretation. We show that Ki-67 IHC staining intensity, which to our knowledge has not been previously systematically investigated, can have a significant effect on PI interpretation in settings that influence diagnostic and clinical management decisions.

[Ga68] DOTATATE PET/MRI-guided radiosurgical treatment planning and response assessment in meningiomas.

BACKGROUND: Our purpose was to determine the utility of [68Ga]-DOTATATE PET/MRI in meningioma response assessment following radiosurgery. METHODS: Patients with meningioma prospectively underwent postoperative DOTATATE PET/MRI. Co-registered PET and gadolinium-enhanced T1-weighted MRI were employed for radiosurgery planning. Follow-up DOTATATE PET/MRI was performed at 6-12 months post-radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVRSSS) referencing superior sagittal sinus (SSS) blood pool were obtained. Size change was determined by Response Assessment in Neuro-Oncology (RANO) criteria. Association of SUVRSSS change magnitude and progression-free survival (PFS) was evaluated using Cox regression. RESULTS: Twenty-seven patients with 64 tumors (26% World Health Organization [WHO]-1, 41% WHO-2, 26% WHO-3, and 7% WHO-unknown) were prospectively followed post stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT; mean dose: 30 Gy, modal dose 35 Gy, mean of 5 fractions). Post-irradiation SUV and SUVRSSS decreased by 37.4% and 44.4%, respectively (P < .0001). Size product decreased by 8.9%, thus failing to reach the 25% significance threshold as determined by RANO guidelines. Mean follow-up time was 26 months (range: 6-44). Overall mean PFS was 83% and 100%/100%/54% in WHO-1/-2/-3 subcohorts, respectively, at 34 months. At maximum follow-up (42-44 months), PFS was 100%/83%/54% in WHO-1/-2/-3 subcohorts, respectively. Cox regression analyses revealed a hazard ratio of 0.48 for 10-unit reduction in SUVRSSS in the SRS cohort. CONCLUSIONS: DOTATATE PET SUV and SUVRSSS demonstrated marked, significant decrease post-radiosurgery. Lesion size decrease was statistically significant; however, it was not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising imaging biomarker for response assessment in meningiomas treated with radiosurgery. CLINICALTRIALS.GOV IDENTIFIER: NCT04081701.

Utility of texture analysis for objective quantitative ex vivo assessment of meningioma consistency: method proposal and validation.

BACKGROUND: Tumor consistency is considered to be a critical factor for the surgical removal of meningiomas and its preoperative assessment is intensively studied. A significant drawback in the research of predictive methods is the lack of a clear shared definition of tumor consistency, with most authors resorting to subjective binary classification labeling the samples as "soft" and "hard." This classification is highly observer-dependent and its discrete nature fails to capture the fine nuances in tumor consistency. To compensate for these shortcomings, we examined the utility of texture analysis to provide an objective observer-independent continuous measure of meningioma consistency. METHODS: A total of 169 texturometric measurements were conducted using the Brookfield CT3 Texture Analyzer on meningioma samples from five patients immediately after the removal and on the first, second, and seventh postoperative day. The relationship between measured stiffness and time from sample extraction, subjectively assessed consistency grade and histopathological features (amount of collagen and reticulin fibers, presence of psammoma bodies, predominant microscopic morphology) was analyzed. RESULTS: The stiffness measurements exhibited significantly lower variance within a sample than among samples (p = 0.0225) and significant increase with a higher objectively assessed consistency grade (p = 0.0161, p = 0.0055). A significant negative correlation was found between the measured stiffness and the time from sample extraction (p < 0.01). A significant monotonic relationship was revealed between stiffness values and amount of collagen I and reticulin fibers; there were no statistically significant differences between histological phenotypes in regard to presence of psammoma bodies and predominant microscopic morphology. CONCLUSIONS: We conclude that the values yielded by texture analysis are highly representative of an intrinsic consistency-related quality of the sample despite the influence of intra-sample heterogeneity and that our proposed method can be used to conduct quantitative studies on the role of meningioma consistency.

Preoperative surgical risk assessment of meningiomas: a narrative review based on MRI radiomics.

Meningiomas are one of the most common intracranial primary central nervous system tumors. Regardless of the pathological grading and histological subtypes, maximum safe resection is the recommended treatment option for meningiomas. However, considering tumor heterogeneity, surgical treatment options and prognosis often vary greatly among meningiomas. Therefore, an accurate preoperative surgical risk assessment of meningiomas is of great clinical importance as it helps develop surgical treatment strategies and improve patient prognosis. In recent years, an increasing number of studies have proved that magnetic resonance imaging (MRI) radiomics has wide application values in the diagnostic, identification, and prognostic evaluations of brain tumors. The vital importance of MRI radiomics in the surgical risk assessment of meningiomas must be apprehended and emphasized in clinical practice. This narrative review summarizes the current research status of MRI radiomics in the preoperative surgical risk assessment of meningiomas, focusing on the applications of MRI radiomics in preoperative pathological grading, assessment of surrounding tissue invasion, and evaluation of tumor consistency. We further analyze the prospects of MRI radiomics in the preoperative assessment of meningiomas angiogenesis and adhesion with surrounding tissues, while pointing out the current challenges of MRI radiomics research.

Clinical and pathological impact of an optimal assessment of brain invasion for grade 2 meningioma diagnosis: lessons from a series of 291 cases.

Brain invasion has not been recognized as a standalone criterion for atypical meningioma by the WHO classification until 2016. Since the 2007 edition suggested that meningiomas harboring brain invasion could be classified as grade 2, brain invasion study was progressively strengthened in our center, based on a strong collaboration between neurosurgeons and neuropathologists regarding sample orientation and examination. Practice changes were considered homogeneous enough in 2011. The aim of the present study was to evaluate the impact of gross practice change on the clinical and pathological characteristics of intracranial meningiomas classified as grade 2.The characteristics of consecutive patients with a grade 2 meningioma surgically managed before (1998-2005, n = 125, group A) and after (2011-2014, n = 166, group B) practices changed were retrospectively reviewed.Sociodemographical and clinical parameters were comparable in groups A and B, and the median age was 62 years in both groups (p = 0.18). The 5-year recurrence rates (23.2% vs 29.5%, p = 0.23) were similar. In group A, brain invasion was present in 48/125 (38.4%) cases and was more frequent than in group B (14/166, 8.4%, p < 0.001). In group A, 33 (26.4%) meningiomas were classified as grade 2 solely based on brain invasion (group ASBI), and 92 harbored other grade 2 criteria (group AOCA). Group ASBI meningiomas had a similar median progression-free survival compared to groups AOCA (68 vs 80 months, p = 0.24) and to AOCA and B pooled together (n = 258, 68 vs 90 months, p = 0.42).An accurate assessment of brain invasion is mandatory as brain invasion is a strong predictor of meningioma progression.

The histopathological diagnosis of atypical meningioma: glass slide versus whole slide imaging for grading assessment.

Limited studies on whole slide imaging (WSI) in surgical neuropathology reported a perceived limitation in the recognition of mitoses. This study analyzed and compared the inter- and intra-observer concordance for atypical meningioma, using glass slides and WSI. Two neuropathologists and two residents assessed the histopathological features of 35 meningiomas-originally diagnosed as atypical-in a representative glass slide and corresponding WSI. For each histological parameter and final diagnosis, we calculated the inter- and intra-observer concordance in the two viewing modes and the predictive accuracy on recurrence. The concordance rates for atypical meningioma on glass slides and on WSI were 54% and 60% among four observers and 63% and 74% between two neuropathologists. The inter-observer agreement was higher using WSI than with glass slides for all parameters, with the exception of high mitotic index. For all histological features, we found median intra-observer concordance of ≥ 79% and similar predictive accuracy for recurrence between the two viewing modes. The higher concordance for atypical meningioma using WSI than with glass slides and the similar predictive accuracy for recurrence in the two modalities suggest that atypical meningioma may be safely diagnosed using WSI.

Impact of insurance on hospital course and readmission after resection of benign meningioma.

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 < 0.001), and 49% of self-pay patients (OR 3.4, p < 0.001). Medicare (OR 1.5, p = 0.002) and Medicaid (OR 1.4, p = 0.035) were both associated with higher likelihood of 90-day readmission compared to private insurance. In comparison, 30-day analyses did not unveil this discrepancy between Medicaid and privately insured, highlighting the merit for longer-term outcomes analyses in value-based care. Patients readmitted within 30 days versus those with later readmissions possessed different characteristics. CONCLUSIONS: Compared to patients with private insurance coverage, Medicaid and self-pay patients were significantly more likely to undergo non-elective resection of benign meningioma. Medicaid and Medicare insurance were associated with a higher likelihood of 90-day readmission; only Medicare was significant at 30 days. Both 30 and 90-day outcomes merit consideration given differences in readmitted populations.

Multi-parametric qualitative and quantitative MRI assessment as predictor of histological grading in previously treated meningiomas.

PURPOSE: Meningiomas are mainly benign tumors, though a considerable proportion shows aggressive behaviors histologically consistent with atypia/anaplasia. Histopathological grading is usually assessed through invasive procedures, which is not always feasible due to the inaccessibility of the lesion or to treatment contraindications. Therefore, we propose a multi-parametric MRI assessment as a predictor of meningioma histopathological grading. METHODS: Seventy-three patients with 74 histologically proven and previously treated meningiomas were retrospectively enrolled (42 WHO I, 24 WHO II, 8 WHO III) and studied with MRI including T2 TSE, FLAIR, Gradient Echo, DWI, and pre- and post-contrast T1 sequences. Lesion masks were segmented on post-contrast T1 sequences and rigidly registered to ADC maps to extract quantitative parameters from conventional DWI and intravoxel incoherent motion model assessing tumor perfusion. Two expert neuroradiologists assessed morphological features of meningiomas with semi-quantitative scores. RESULTS: Univariate analysis showed different distributions (p < 0.05) of quantitative diffusion parameters (Wilcoxon rank-sum test) and morphological features (Pearson's chi-square; Fisher's exact test) among meningiomas grouped in low-grade (WHO I) and higher grade forms (WHO II/III); the only exception consisted of the tumor-brain interface. A multivariate logistic regression, combining all parameters showing statistical significance in the univariate analysis, allowed discrimination between the groups of meningiomas with high sensitivity (0.968) and specificity (0.925). Heterogeneous contrast enhancement and low ADC were the best independent predictors of atypia and anaplasia. CONCLUSION: Our multi-parametric MRI assessment showed high sensitivity and specificity in predicting histological grading of meningiomas. Such an assessment may be clinically useful in characterizing lesions without histological diagnosis. Key points • When surgery and biopsy are not feasible, parameters obtained from both conventional and diffusion-weighted MRI can predict atypia and anaplasia in meningiomas with high sensitivity and specificity. • Low ADC values and heterogeneous contrast enhancement are the best predictors of higher grade meningioma.

Racial and socioeconomic correlates of treatment and survival among patients with meningioma: a population-based study.

BACKGROUND: Though meningioma is the most common primary brain tumor, there is a paucity of epidemiologic studies investigating disparities in treatment and patient outcomes. Therefore, we sought to explore how sociodemographic factors are associated with rates of gross total resection (GTR) and radiotherapy as well as survival. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was queried to identify adult patients with meningioma diagnosed between 2005 and 2015. Socioeconomic status (SES) was determined using a validated composite index in which patients were stratified into tertiles and quintiles. Multivariable logistic regression and Cox proportional hazards analyses were used to identify predictors of treatment and survival, respectively. RESULTS: 71,098 patients met our inclusion criteria. Low SES quintile was associated with reduced odds of receiving GTR (OR 0.76, 95% CI 0.69-0.83, p < 0.0001) and radiotherapy (OR 0.83, 95% CI 0.76-0.91, p < 0.0001) as well as worse survival (HR 1.48, 95% CI 1.41-1.56) as compared to the highest SES quintile. Black patients had reduced odds of GTR (OR 0.74, 95% CI 0.67-0.71, p < 0.0001) and worse survival (HR 1.23, 95% CI 1.18-1.29, p < 0.0001) as compared to white patients. CONCLUSIONS: This national study of patients with meningioma found socioeconomic status and race to be independent inverse correlates of likelihood of GTR, radiotherapy, and survival. Limited access to care may underlie these disparities in part, and future studies are warranted to identify specific causes for these findings.

Quantitative assessment and clinical relevance of VEGFRs-positive tumor cells in refractory brain tumors.

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-ß and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.

Variations in screening and management practices for subsequent asymptomatic meningiomas in childhood, adolescent and young adult cancer survivors.

INTRODUCTION: Childhood, adolescent and young adult (CAYA) cancer survivors treated with cranial radiotherapy are at risk for developing subsequent meningiomas. There is insufficient evidence concerning the benefits and harms of screening for subsequent meningiomas, and uncertainty about the most appropriate clinical management of asymptomatic meningiomas. Data describing current clinical decision-making is essential to formulate surveillance recommendations. METHODS: We created an online survey to identify the current international clinical practice regarding screening for and management of subsequent asymptomatic meningiomas among CAYA cancer survivors. Fifty-nine physicians from North America and Europe with expertise relevant to meningiomas were invited to participate. RESULTS: Thirty-four physicians (58%) completed the survey. The reported number of CAYA cancer survivors that physicians are willing to screen to detect one meningioma varied widely from 0 to 750 (median 50). Physicians expressed concerns regarding harms from MRI screening, including risks of unnecessary interventions (n = 25, 73%) and overdiagnosis (n = 19, 56%). Growth pattern (n = 33, 97%), location (n = 31, 91%) and size (n = 29, 85%) were endorsed as the most important factors influencing the decision to treat asymptomatic meningiomas. A challenging location (n = 14, 52%), indolent tumor growth pattern (n = 13, 48%), and absence of symptoms (n = 12, 44%) were endorsed as the main reasons to monitor without intervention. CONCLUSIONS: There is international variation in opinions and clinical practice regarding screening for subsequent asymptomatic meningiomas among at risk CAYA cancer survivors. Decision-making regarding interventions of asymptomatic meningiomas are largely driven by clinical characteristics. These valuable insights into current clinical practice will inform surveillance guidelines for CAYA cancer survivors.

Efficacy and toxicity of particle radiotherapy in WHO grade II and grade III meningiomas: a systematic review.

OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.

Determining the role of adjuvant radiotherapy in the management of meningioma: a Surveillance, Epidemiology, and End Results analysis.

OBJECTIVEThe aim of this study was to illustrate the demographic characteristics of meningioma patients and observe the effect of adjuvant radiation therapy on survival by using the Surveillance, Epidemiology, and End Results (SEER) database. More specifically, the authors aimed to answer the question of whether adjuvant radiotherapy following resection of atypical meningioma confers a cause-specific survival benefit. Additionally, they attempted to add to previous characterizations of the epidemiology of primary meningiomas and assess the effectiveness of the standard of care for benign and anaplastic meningiomas. They also sought to characterize the efficacy of various treatment options in atypical and anaplastic meningiomas separately since nearly all other analyses have grouped these two together despite varying treatment regimens for these behavior categories.METHODSSEER data from 1973 to 2015 were queried using appropriate ICD-O-3 codes for benign, atypical, and anaplastic meningiomas. Patient demographics, tumor characteristics, and treatment choices were analyzed. The effects of treatment were examined using a multivariate Cox proportional hazards model and Kaplan-Meier survival analysis.RESULTSA total of 57,998 patients were included in the analysis of demographic, meningioma, and treatment characteristics. Among this population, cases of unspecified WHO tumor grade were excluded in the multivariate analysis, leaving a total of 12,931 patients to examine outcomes among treatment paradigms. In benign meningiomas, gross-total resection (HR 0.289, p = 0.013) imparted a significant cause-specific survival benefit over no treatment. In anaplastic meningioma cases, adjuvant radiotherapy imparted a significant survival benefit following both subtotal (HR 0.089, p = 0.018) and gross-total (HR 0.162, p = 0.002) resection as compared to gross-total resection alone. In atypical tumors, gross-total resection plus radiotherapy did not significantly change the hazard risk (HR 1.353, p = 0.628) compared to gross-total resection alone. Similarly, it was found that adjuvant radiation did not significantly benefit survival after a subtotal resection (HR 1.440, p = 0.644).CONCLUSIONSThe results of this study demonstrate that the role of adjuvant radiotherapy, especially after the resection of atypical meningioma, remains somewhat unclear. Thus, given these results, prospective randomized clinical studies are warranted to provide clear information on the effects of adjuvant radiation in meningioma treatment.

Primary pulmonary meningioma: A rare case report of aspiration cytological features and immunohistochemical assessment.

Ectopic meningioma is a generally rare type of benign tumor that very rarely occurs in the lung. Here, we report the cytological findings of a primary pulmonary meningioma with a particular focus on immunohistochemical (IHC) assessment. A healthy 60-year-old woman visited our hospital with an asymptomatic nodule in the right lower lung lobe. She had no particular past-history and no other tumors in the central nervous system or elsewhere according to an imaging examination. Transbronchial fine-needle aspiration cytology revealed clusters of spindle cells in a whorled formation and psammoma bodies. The tumor cells exhibited spindle-shaped cytoplasm, small fusiform or round nuclei and numerous intranuclear cytoplasmic inclusions. IHC staining of the cytological specimen revealed that the tumor cells were positive for epithelial membrane antigen, negative for thyroid transcription factor-1 and p40, and equivocal for claudin-1. Progesterone receptor immunoreactivity of cytology specimen resulted negative at first by manual method but retrieved positive by an autostainer. Following segmentectomy, the pathological diagnosis was a meningothelial meningioma. The patient has remained well without recurrence for 36 months postoperatively. Because the cytological preparation exhibited characteristic findings of meningioma, a correct diagnosis based on pre-operative cytological findings with appropriate IHC would be possible. Here, we report the cytological and IHC features of this case and highlight the importance of IHC-quality assurance.

Proposed response assessment and endpoints for meningioma clinical trials: report from the Response Assessment in Neuro-Oncology Working Group.

No standard criteria exist for assessing response and progression in clinical trials involving patients with meningioma, and there is no consensus on the optimal endpoints for trials currently under way. As a result, there is substantial variation in the design and response criteria of meningioma trials, making comparison between trials difficult. In addition, future trials should be designed with accepted standardized endpoints. The Response Assessment in Neuro-Oncology Meningioma Working Group is an international effort to develop standardized radiologic criteria for treatment response for meningioma clinical trials. In this proposal, we present the recommendations for response criteria and endpoints for clinical trials involving patients with meningiomas.

Response assessment of meningioma: 1D, 2D, and volumetric criteria for treatment response and tumor progression.

BACKGROUND: Meningiomas are the most common primary brain tumors in adults. Due to their variable growth rates and irregular tumor shapes, response assessment in clinical trials remains challenging and no standard criteria have been defined. We evaluated 1D, 2D, and volume imaging criteria to assess whether a volumetric approach might be a superior surrogate for overall survival (OS). METHODS: In this retrospective multicenter study, we evaluated the clinical and imaging data of 93 patients with recurrent meningiomas treated with pharmacotherapy. One-dimensional (1D), 2D, and volumetric measurements of enhancing tumor on pre- and post-treatment MRI were compared at 6 and 12 months after treatment initiation. Cox proportional hazards models were used to examine the relationship between each imaging criterion and OS. RESULTS: The median age of the patient cohort is 51 years (range 12-88), with 14 World Health Organization (WHO) grade I, 53 WHO grade II, and 26 WHO grade III meningiomas. Volumetric increase of 40% and unidimensional increase by 10 mm at 6 months and 12 months provided the strongest association with overall survival (HR = 2.58 and 3.24 respectively, p<0.01). Setting a volume change threshold above 40% did not correlate with survival. The interobserver agreement of 1D, 2D, and volume criteria is only moderate (kappa = 0.49, 0.46, 0.52, respectively). None of the criteria based on tumor size reduction were associated with OS (P > 0.09). CONCLUSION: Compared with 1D (Response Evaluation Criteria In Solid Tumors 1.1) and 2D (Response Assessment in Neuro-Oncology) approaches, volumetric criteria for tumor progression has a stronger association with OS, although the differences were only modest. The interobserver variability is moderate for all 3 methods. Further validation of these findings in an independent patient cohort is needed.

World Health Organization Grade II Meningiomas: The Role of Adjuvant/Salvage Gamma Knife Surgery After Initial Surgery and Prognostic Factor Assessment.

OBJECTIVE: This study was performed to evaluate the efficiency of Gamma Knife surgery (GKS) on reducing recurrence of World Health Organization (WHO) grade II meningiomas after surgery and to define the risk factors associated with tumor recurrence/progression and patient's death. METHODS: This retrospective study included 75 patients who were diagnosed with WHO grade II meningiomas after initial surgery. The Kaplan-Meier method with a log-rank test was used to calculate the survival curves. Univariate and multivariate Cox proportional hazards model were used to identify the risk factors associated with tumor recurrence/progression and patient's death. RESULTS: The median follow-up period was 70 months. The overall survival (OS) was 97.2% at 2 years and 89.8% at 5 years. The progression-free survival (PFS) at 1, 3, and 5 years was 89.3%, 72.6%, and 59.3%, respectively. Comparing the effects on PFS and OS between different groups, there were no statistically significant differences between the surgery-alone group and the surgery with adjuvant/salvage GKS group (P = 0.512; P = 0.949). In multivariate Cox proportional hazards model analysis, extent of resection (P = 0.001) and tumor location (P = 0.015) were associated with tumor recurrence; only histologic subtypes (P = 0.005) were associated with patient's death. CONCLUSIONS: There was no significant PFS or OS benefit for patients with WHO grade II meningiomas treated with adjuvant/salvage GKS postoperatively. Convexity meningiomas with gross total resection tended to benefit PFS. We suggest trying to achieve maximum safe gross total resection for patients with WHO grade II meningiomas, then following up closely.

Meningiomas: Objective assessment of proliferative indices by immunohistochemistry and automated counting method.

BACKGROUND: The most reliable histological correlate of recurrence risk in meningiomas is increased mitotic activity. Proliferative index with Ki-67 immunostaining is a helpful adjunct to manual counting. However, both show considerable inter-observer variability. A new immunohistochemical method for counting mitotic figures, using antibody against the phosphohistone H3 (PHH3) protein was introduced. Similarly, a computer based automated counting for Ki-67 labelling index (LI) is available. AIMS AND OBJECTIVES: To study the use of these new techniques in the objective assessment of proliferation indices in meningiomas. MATERIALS AND METHODS: This was a retrospective study of intracranial meningiomas diagnosed during the year 2013.The hematoxylin and eosin (H and E) sections and immunohistochemistry (IHC) with Ki-67 were reviewed by two pathologists. Photomicrographs of the representative areas were subjected to Ki-67 analysis by Immunoratio (IR) software. Mean Ki-67 LI, both manual and by IR were calculated. IHC with PHH3 was performed. PHH3 positive nuclei were counted and mean values calculated. Data analysis was done using SPSS software. RESULTS: A total of 64 intracranial meningiomas were diagnosed. Evaluation on H and E, PHH3, Ki-67 LI (both manual and IR) were done in 32 cases (22 grade I and 10 grade II meningiomas). Statistically significant correlation was seen between the mitotic count in each grade and PHH3 values and also between the grade of the tumor and values of Ki-67 and PHH3. CONCLUSION: Both the techniques used in the study had advantage over, as well as, correlated well with the existing techniques and hence, can be applied to routine use.