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Intraoperative MRI is increasingly used in neurosurgery, although there is little evidence for its use. We aimed to assess efficacy of intraoperative MRI guidance on extent of resection in patients with glioma. In our prospective, randomised, parallel-group trial, we enrolled adults (≥18 years) with contrast enhancing gliomas amenable to radiologically complete resection who presented to Goethe University (Frankfurt, Germany). We randomly assigned patients (1:1) with computer-generated blocks of four and a sealed-envelope design to undergo intraoperative MRI-guided surgery or conventional microsurgery (control group). Surgeons and patients were unmasked to treatment group allocation, but an independent neuroradiologist was masked during analysis of all preoperative and postoperative imaging data. The primary endpoint was rate of complete resections as established by early postoperative high-field MRI (1·5 T or 3·0 T). Analysis was done per protocol. This study is registered with ClinicalTrials.gov, number NCT01394692. We enrolled 58 patients between Oct 1, 2007, and July 1, 2010. 24 (83%) of 29 patients randomly allocated to the intraoperative MRI group and 25 (86%) of 29 controls were eligible for analysis (four patients in each group had metastasis and one patient in the intraoperative MRI group withdrew consent after randomisation). More patients in the intraoperative MRI group had complete tumour resection (23 [96%] of 24 patients) than did in the control group (17 [68%] of 25, p=0·023). Postoperative rates of new neurological deficits did not differ between patients in the intraoperative MRI group (three [13%] of 24) and controls (two [8%] of 25, p=1·0). No patient for whom use of intraoperative MRI led to continued resection of residual tumour had neurological deterioration. One patient in the control group died before 6 months. Our study provides evidence for the use of intraoperative MRI guidance in glioma surgery: such imaging helps surgeons provide the optimum extent of resection. None.

Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery. Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption. In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks. The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced. ClinicalTrials.gov NCT01851733.

Background Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes. Methods Compliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS. Results A threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47–1.05) and OS (HR 0.67, 95% CI 0.45–0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. < 75%). Conclusion A compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

Purpose The data of 589 metastatic breast cancer (MBC) patients in a single institution were reviewed to determine the outcomes of patients with brain metastasis (BM) and assess the efficacy of BM screening. Methods The patients with BM among the 589 MBC patients who underwent treatment at Shizuoka Cancer Center (Shizuoka, Japan) from 09/2002 to 03/2014 were retrospectively analyzed. Results During the study period, BM developed in 187 (31.7%) patients. The tumor subtypes were as follows: luminal (hormone receptor [HR]+, HER2−), 44.9%; luminal-HER2 (HR+, HER2+), 14.9%; HER2 (HR−, HER2+), 21.3%; and triple-negative (TN), 16.0%. BM was detected in 48.6% of the patients by screening MRI. While 137 of 187 patients underwent local therapy, whole-brain irradiation was the most frequently applied therapy (63.5%). The median overall survival from the diagnosis of BM was as follows: luminal, 7.0 months (M); luminal-HER2, 13.3 M; HER2, 17.7 M; TN, 4.2 M. The HER2 status (hazard ratio [HR]: 0.58, 95% confidence interval [CI] 0.38–0.88) and nonprogressive extracranial lesion(s) (HR: 0.45, 95% CI 0.29–0.71) were identified as prognostic factors in a multivariate analysis. When limited to HER2-overexpressed MBC patients, the multivariate analysis revealed that non-progressive extracranial lesion(s) (HR: 0.20, 95% CI 0.088–0.47) and stereotactic irradiation (STI) as an initial treatment (HR: 0.18, 95% CI 0.061–0.56) were prognostic factors. Conclusions Our retrospective review showed that early detection of BM by screening MRI, followed by STI, improved the prognosis of HER2-overexpressed MBC patients with BM. A further prospective randomized study is needed to confirm our findings.

Objectives To investigate whether whole-body diffusion-weighted imaging (WB-DWI) alone is adequate for detecting metastases in melanoma patients, or if standard WB contrast-enhanced magnetic resonance imaging (WB-ceMRI) is required. Methods Seventy-one WB-DWI studies were performed quarterly along with whole-body MRI including contrast-enhanced sequences (WB-ceMRI) in 19 patients with advanced melanoma. The reference standard was biopsy, other imaging investigations, or changes observed on follow-up. Findings of metastasis in separate WB-DWI and WB-DWI + WB-ceMRI readings were compared using κ statistics. Additionally, the distribution of findings was examined and calculated per body region (brain, neck, chest, abdomen, liver, pelvis, subcutaneous tissues, bones) and diagnostic accuracy (DA), sensitivity, specificity, negative predictive value, and positive predictive value were calculated per patient. Results The eight examinations that were positive by the reference standard contained a total of 14 metastatic findings. With almost perfect agreement between techniques (κ = 85 %, 95 % CI 70–100 %) for detection of examinations with metastatic findings, and complete agreement in extracranial metastasis detection, 10 metastases were detected using WB-DWI and 13 using WB-DWI + WB-ceMRI. WB-DWI and WB-DWI + WB-MRI had equivalent per patient DA (79 %). Conclusions WB-DWI without additional WB-ceMRI sequences is promising for the detection of extracranial metastases in melanoma patients, but contrast-enhanced MRI is required for evaluating the brain. Key Points • Whole-body (WB) magnetic resonance imaging (MRI) is increasingly used for oncological disease assessment. • WB diffusion-weighted MRI detects extracranial metastases in melanoma patients. • Contrast-enhanced MRI is only required for detecting brain metastases. • WB-DWI is inferior to low-dose CT for detecting lung metastases.

ObjectiveTo differentiate brain pilocytic astrocytoma (PA) from glioblastoma (GBM) using contrast-enhanced magnetic resonance imaging (MRI) quantitative radiomic features by a decision tree model.MethodsSixty-six patients from two centres (PA, n = 31; GBM, n = 35) were randomly divided into training and validation data sets (about 2:1). Quantitative radiomic features of the tumours were extracted from contrast-enhanced MR images. A subset of features was selected by feature stability and Boruta algorithm. The selected features were used to build a decision tree model. Predictive accuracy, sensitivity and specificity were used to assess model performance. The classification outcome of the model was combined with tumour location, age and gender features, and multivariable logistic regression analysis and permutation test using the entire data set were performed to further evaluate the decision tree model.ResultsA total of 271 radiomic features were successfully extracted for each tumour. Twelve features were selected as input variables to build the decision tree model. Two features S(1, -1) Entropy and S(2, -2) SumAverg were finally included in the model. The model showed an accuracy, sensitivity and specificity of 0.87, 0.90 and 0.83 for the training data set and 0.86, 0.80 and 0.91 for the validation data set. The classification outcome of the model related to the actual tumour types and did not rely on the other three features (p < 0.001).ConclusionsA decision tree model with two features derived from the contrast-enhanced MR images performed well in differentiating PA from GBM.Key Points• MRI findings of PA and GBM are sometimes very similar.• Radiomics provides much more quantitative information about tumours.• Radiomic features can help to distinguish PA from GBM.

ObjectivesTexture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. This study aimed to evaluate the feasibility of texture analysis on preoperative conventional MRI images in predicting early malignant transformation from low- to high-grade glioma and compare its utility to histogram analysis alone.MethodsA total of 68 patients with low-grade glioma (LGG) were included in this study, 15 of which showed malignant transformation. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analyses were performed to obtain the most discriminant factor (MDF) values for both training and testing data. Receiver operating characteristic (ROC) curve analyses were performed on MDF values and 9 histogram parameters in the training data to obtain cutoff values for determining the correct rates of discrimination between two groups in the testing data.ResultsThe ROC analyses on MDF values resulted in an area under the curve (AUC) of 0.90 (sensitivity 85%, specificity 84%) for T2w FLAIR, 0.92 (86%, 94%) for ADC, 0.96 (97%, 84%) for T1w, and 0.82 (78%, 75%) for T1w + Gd and correctly discriminated between the two groups in 93%, 100%, 93%, and 92% of cases in testing data, respectively. In the astrocytoma subgroup, AUCs were 0.92 (88%, 83%) for T2w FLAIR and 0.90 (92%, 74%) for T1w + Gd and correctly discriminated two groups in 100% and 92% of cases. The MDF outperformed all 9 of the histogram parameters.ConclusionTexture analysis on conventional preoperative MRI images can accurately predict early malignant transformation of LGGs, which may guide therapeutic planning.Key Points• Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment.• Texture analysis based on conventional preoperative MR images can accurately predict early malignant transformation from low- to high-grade glioma.• Texture analysis is a clinically feasible technique that may provide an alternative and effective way of determining the likelihood of early malignant transformation and help guide therapeutic decisions.

To evaluate diffusion tensor imaging (DTI)-based functional neuronavigation in surgery of cerebral gliomas with pyramidal tract (PT) involvement with respect to both perioperative assessment and follow-up outcome. A prospective, randomized controlled study was conducted between 2001 and 2005. A consecutive series of 238 eligible patients with initial imaging diagnosis of cerebral gliomas involving PTs were randomized into study (n = 118) and control (n = 120) groups. The study cases underwent DTI and three-dimensional magnetic resonance imaging scans. The maps of fractional anisotropy were calculated for PT mapping. Both three-dimensional magnetic resonance imaging data sets and fractional anisotropy maps were integrated by rigid registration, after which the tumor and adjacent PT were segmented and reconstructed for presurgical planning and intraoperative guidance. The control cases were operated on using routine neuronavigation. There was a trend for high-grade gliomas (HGGs) in the study group to be more likely to achieve gross total resection (74.4 versus 33.3%, P < 0.001). There was no significant difference of low-grade gliomas resection between the two groups. Postoperative motor deterioration occurred in 32.8% of control cases, whereas it occurred in only 15.3% of the study cases (P < 0.001). The 6-month Karnofsky Performance Scale score of study cases was significantly higher than that of control cases (86 +/- 20 versus 74 +/- 28 overall, P < 0.001; 93 +/- 10 versus 86 +/- 17 for low-grade gliomas, P = 0.013; and 77 +/- 27 versus 53 +/- 32 for HGGs, P = 0.001). For 81 HGGs, the median survival of study cases was 21.2 months (95% confidence interval, 14.1-28.3 mo) compared with 14.0 months (95% confidence interval, 10.2-17.8 mo) of control cases (P = 0.048). The estimated hazard ratio for the effect of DTI-based functional neuronavigation was 0.570, representing a 43.0% reduction in the risk of death. DTI-based functional neuronavigation contributes to maximal safe resection of cerebral gliomas with PT involvement, thereby decreasing postoperative motor deficits for both HGGs and low-grade gliomas while increasing high-quality survival for HGGs.

Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.