Insights from a Multicenter Study on Adult H3 K27M-Mutated Glioma: Surgical Resection's Limited Influence on Overall Survival, ATRX as Molecular Prognosticator.

BACKGROUND: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 WHO classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. METHODS: We included molecularly confirmed H3 K27M-mutated glioma cases in patients >18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 + 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy.Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, p=0.007). Preoperative Karnofsky Performance Score (KPS) < 80 showed a reduced OS (4.2 vs. 18 months, p=0.02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, p=0.0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, p=0.4006). CONCLUSION: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.

Reconstruction of the Corticospinal Tract in Patients with Motor-Eloquent High-Grade Gliomas Using Multilevel Fiber Tractography Combined with Functional Motor Cortex Mapping.

BACKGROUND AND PURPOSE: Tractography of the corticospinal tract is paramount to presurgical planning and guidance of intraoperative resection in patients with motor-eloquent gliomas. It is well-known that DTI-based tractography as the most frequently used technique has relevant shortcomings, particularly for resolving complex fiber architecture. The purpose of this study was to evaluate multilevel fiber tractography combined with functional motor cortex mapping in comparison with conventional deterministic tractography algorithms. MATERIALS AND METHODS: Thirty-one patients (mean age, 61.5 [SD, 12.2] years) with motor-eloquent high-grade gliomas underwent MR imaging with DWI (TR/TE = 5000/78 ms, voxel size = 2 × 2 × 2 mm3, 1 volume at b = 0 s/mm2, 32 volumes at b = 1000 s/mm2). DTI, constrained spherical deconvolution, and multilevel fiber tractography-based reconstruction of the corticospinal tract within the tumor-affected hemispheres were performed. The functional motor cortex was enclosed by navigated transcranial magnetic stimulation motor mapping before tumor resection and used for seeding. A range of angular deviation and fractional anisotropy thresholds (for DTI) was tested. RESULTS: For all investigated thresholds, multilevel fiber tractography achieved the highest mean coverage of the motor maps (eg, angular threshold = 60°; multilevel/constrained spherical deconvolution/DTI, 25% anisotropy threshold = 71.8%, 22.6%, and 11.7%) and the most extensive corticospinal tract reconstructions (eg, angular threshold = 60°; multilevel/constrained spherical deconvolution/DTI, 25% anisotropy threshold = 26,485 mm3, 6308 mm3, and 4270 mm3). CONCLUSIONS: Multilevel fiber tractography may improve the coverage of the motor cortex by corticospinal tract fibers compared with conventional deterministic algorithms. Thus, it could provide a more detailed and complete visualization of corticospinal tract architecture, particularly by visualizing fiber trajectories with acute angles that might be of high relevance in patients with gliomas and distorted anatomy.

Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy.

BACKGROUND: Intratumoral heterogeneity at the cellular and molecular level is a hallmark of glioblastoma (GB) that contributes to treatment resistance and poor clinical outcome. Little is known regarding epigenetic heterogeneity and intratumoral phylogeny and their implication for molecular classification and targeted therapies. PATIENTS AND METHODS: Multiple tissue biopsies (238 in total) were sampled from 56 newly-diagnosed, treatment-naive GB patients from a prospective in-house cohort and publicly available data and profiled for DNA methylation using the Illumina MethylationEPIC array. Methylation-based classification using the glioma classifier developed by Ceccarelli et al. and estimation of the MGMT promoter methylation status via the MGMT-STP27 model were carried out. In addition, copy number variations (CNVs) and phylogeny were analyzed. RESULTS: Almost half of the patients (22/56, 39%) harbored tumors composed of heterogeneous methylation subtypes. We found two predominant subtype combinations: classic-/mesenchymal-like, and mesenchymal-/pilocytic astrocytoma-like. Nine patients (16%) had tumors composed of subvolumes with and without MGMT promoter methylation, whereas 20 patients (36%) were homogeneously methylated, and 27 patients (48%) were homogeneously unmethylated. CNV analysis revealed high variations in many genes, including CDKN2A/B, EGFR, and PTEN. Phylogenetic analysis correspondingly showed a general pattern of CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 during early stages of tumor development. CONCLUSIONS: (Epi)genetic intratumoral heterogeneity is a hallmark of GB, both at DNA methylation and CNV level. This intratumoral heterogeneity is of utmost importance for molecular classification as well as for defining therapeutic targets in this disease, as single biopsies might underestimate the true molecular diversity in a tumor.

Fully automated analysis combining [18F]-FET-PET and multiparametric MRI including DSC perfusion and APTw imaging: a promising tool for objective evaluation of glioma progression.

PURPOSE: To evaluate diagnostic accuracy of fully automated analysis of multimodal imaging data using [18F]-FET-PET and MRI (including amide proton transfer-weighted (APTw) imaging and dynamic-susceptibility-contrast (DSC) perfusion) in differentiation of tumor progression from treatment-related changes in patients with glioma. MATERIAL AND METHODS: At suspected tumor progression, MRI and [18F]-FET-PET data as part of a retrospective analysis of an observational cohort of 66 patients/74 scans (51 glioblastoma and 23 lower-grade-glioma, 8 patients included at two different time points) were automatically segmented into necrosis, FLAIR-hyperintense, and contrast-enhancing areas using an ensemble of deep learning algorithms. In parallel, previous MR exam was processed in a similar way to subtract preexisting tumor areas and focus on progressive tumor only. Within these progressive areas, intensity statistics were automatically extracted from [18F]-FET-PET, APTw, and DSC-derived cerebral-blood-volume (CBV) maps and used to train a Random Forest classifier with threefold cross-validation. To evaluate contribution of the imaging modalities to the classifier's performance, impurity-based importance measures were collected. Classifier performance was compared with radiology reports and interdisciplinary tumor board assessments. RESULTS: In 57/74 cases (77%), tumor progression was confirmed histopathologically (39 cases) or via follow-up imaging (18 cases), while remaining 17 cases were diagnosed as treatment-related changes. The classification accuracy of the Random Forest classifier was 0.86, 95% CI 0.77-0.93 (sensitivity 0.91, 95% CI 0.81-0.97; specificity 0.71, 95% CI 0.44-0.9), significantly above the no-information rate of 0.77 (p = 0.03), and higher compared to an accuracy of 0.82 for MRI (95% CI 0.72-0.9), 0.81 for [18F]-FET-PET (95% CI 0.7-0.89), and 0.81 for expert consensus (95% CI 0.7-0.89), although these differences were not statistically significant (p > 0.1 for all comparisons, McNemar test). [18F]-FET-PET hot-spot volume was single-most important variable, with relevant contribution from all imaging modalities. CONCLUSION: Automated, joint image analysis of [18F]-FET-PET and advanced MR imaging techniques APTw and DSC perfusion is a promising tool for objective response assessment in gliomas.

Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA.

INTRODUCTION: Malignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity. METHODS: We evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast-enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up. RESULTS: The median age was 61 years (range 27-80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7-14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7-11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant. CONCLUSION: The present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered.

Imaging glioma biology: spatial comparison of amino acid PET, amide proton transfer, and perfusion-weighted MRI in newly diagnosed gliomas.

PURPOSE: Imaging glioma biology holds great promise to unravel the complex nature of these tumors. Besides well-established imaging techniques such O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET and dynamic susceptibility contrast (DSC) perfusion imaging, amide proton transfer-weighted (APTw) imaging has emerged as a promising novel MR technique. In this study, we aimed to better understand the relation between these imaging biomarkers and how well they capture cellularity and vascularity in newly diagnosed gliomas. METHODS: Preoperative MRI and FET-PET data of 46 patients (31 glioblastoma and 15 lower-grade glioma) were segmented into contrast-enhancing and FLAIR-hyperintense areas. Using established cutoffs, we calculated hot-spot volumes (HSV) and their spatial overlap. We further investigated APTw and CBV values in FET-HSV. In a subset of 10 glioblastoma patients, we compared cellularity and vascularization in 34 stereotactically targeted biopsies with imaging. RESULTS: In glioblastomas, the largest HSV was found for APTw, followed by PET and CBV (p < 0.05). In lower-grade gliomas, APTw-HSV was clearly lower than in glioblastomas. The spatial overlap of HSV was highest between APTw and FET in both tumor entities and regions. APTw correlated significantly with cellularity, similar to FET, while the association with vascularity was more pronounced in CBV and FET. CONCLUSIONS: We found a relevant spatial overlap in glioblastomas between hotspots of APTw and FET both in contrast-enhancing and FLAIR-hyperintense tumor. As suggested by earlier studies, APTw was lower in lower-grade gliomas compared with glioblastomas. APTw meaningfully contributes to biological imaging of gliomas.

Evaluation of radiation-related invasion in primary patient-derived glioma cells and validation with established cell lines: impact of different radiation qualities with differing LET.

PURPOSE: Glioblastoma multiforme (GBM) is the most common primary brain tumor and has a very poor overall prognosis. Multimodal treatment is still inefficient and one main reason is the invasive nature of GBM cells, enabling the tumor cells to escape from the treatment area causing tumor progression. This experimental study describes the effect of low- and high-LET irradiation on the invasion of primary GBM cells with a validation in established cell systems. METHODS: Seven patient derived primary GBM as well as three established cell lines (LN229, LN18 and U87) were used in this study. Invasion was investigated using Matrigel® coated transwell chambers. Irradiation was performed with low- (X-ray) and high-LET (alpha particles) radiation. The colony formation assay was chosen to determine the corresponding alpha particle dose equivalent to the X-ray dose. RESULTS: 4 Gy X-ray irradiation increased the invasive potential of six patient derived GBM cells as well as two of the established lines. In contrast, alpha particle irradiation with an equivalent dose of 1.3 Gy did not show any effect on the invasive behavior. The findings were validated with established cell lines. CONCLUSION: Our results show that in contrast to low-LET irradiation high-LET irradiation does not enhance the invasion of established and primary glioblastoma cell lines. We therefore suggest that high-LET irradiation could become an alternative treatment option. To fully exploit the benefits of high-LET irradiation concerning the invasion of GBM further molecular studies should be performed.

Accuracy of CT-navigated pedicle screw positioning in the cervical and upper thoracic region with and without prior anterior surgery and ventral plating.

AIMS: We aimed to retrospectively assess the accuracy and safety of CT navigated pedicle screws and to compare accuracy in the cervical and thoracic spine (C2-T8) with (COMB) and without (POST) prior anterior surgery (anterior cervical discectomy or corpectomy and fusion with ventral plating: ACDF/ACCF). PATIENTS AND METHODS: A total of 592 pedicle screws, which were used in 107 consecutively operated patients (210 COMB, 382 POST), were analysed. The accuracy of positioning was determined according to the classification of Gertzbein and Robbins on post-operative CT scans. RESULTS: High accuracy was achieved in 524 screws (88.5%), 192 (87.7%) in the cervical spine and 332 (89%) in the thoracic spine, respectively. The results in the two surgical groups were compared and a logistic regression mixed model was performed to analyse the risk of low accuracy. Significantly lower accuracy was found in the COMB group with 82.9% versus 91.6% in the POST group (p = 0.036). There were no neurological complications, but two vertebral artery lesions were recorded. Three patients underwent revision surgery for malpositioning of a screw. Although the risk of malpositioning of a screw after primary anterior surgery was estimated to be 2.4-times higher than with posterior surgery alone, the overall rates of complication and revision were low. CONCLUSION: We therefore conclude that CT navigated pedicle screws can be positioned safely although greater caution must be taken in patients who have previously undergone anterior surgery. Cite this article: Bone Joint J 2017;99-B:1373-80.

Reliability of Semi-Automated Segmentations in Glioblastoma.

PURPOSE: In glioblastoma, quantitative volumetric measurements of contrast-enhancing or fluid-attenuated inversion recovery (FLAIR) hyperintense tumor compartments are needed for an objective assessment of therapy response. The aim of this study was to evaluate the reliability of a semi-automated, region-growing segmentation tool for determining tumor volume in patients with glioblastoma among different users of the software. METHODS: A total of 320 segmentations of tumor-associated FLAIR changes and contrast-enhancing tumor tissue were performed by different raters (neuroradiologists, medical students, and volunteers). All patients underwent high-resolution magnetic resonance imaging including a 3D-FLAIR and a 3D-MPRage sequence. Segmentations were done using a semi-automated, region-growing segmentation tool. Intra- and inter-rater-reliability were addressed by intra-class-correlation (ICC). Root-mean-square error (RMSE) was used to determine the precision error. Dice score was calculated to measure the overlap between segmentations. RESULTS: Semi-automated segmentation showed a high ICC (> 0.985) for all groups indicating an excellent intra- and inter-rater-reliability. Significant smaller precision errors and higher Dice scores were observed for FLAIR segmentations compared with segmentations of contrast-enhancement. Single rater segmentations showed the lowest RMSE for FLAIR of 3.3 % (MPRage: 8.2 %). Both, single raters and neuroradiologists had the lowest precision error for longitudinal evaluation of FLAIR changes. CONCLUSIONS: Semi-automated volumetry of glioblastoma was reliably performed by all groups of raters, even without neuroradiologic expertise. Interestingly, segmentations of tumor-associated FLAIR changes were more reliable than segmentations of contrast enhancement. In longitudinal evaluations, an experienced rater can detect progressive FLAIR changes of less than 15 % reliably in a quantitative way which could help to detect progressive disease earlier.

Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging.

Purpose: Brain metastases are a common complication of cancer and occur in about 15 - 40 % of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Materials and Methods: Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Results: Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADClymphoma 0.92 [0.83 - 1.07] vs. ADCno_lymphoma 1.35 [1.10 - 1.64] P = 0.001). Further differentiation between types of metastases was not possible using FA and ADC. Conclusion: There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis. Key Points: • Histopathological subtypes of brain metastases/CNS lymphomas show different morphologic features on MRI• Primary CNS lymphomas show significantly reduced ADC values• DTI is not a reliable tool for differentiation between brain metastases Citation Format: • Bette S, Wiestler B, Delbridge C et al. Discrimination of Different Brain Metastases and Primary CNS Lymphomas Using Morphologic Criteria and Diffusion Tensor Imaging. Fortschr Röntgenstr 2016; 188: 1134 - 1143.

Prediction of glioma recurrence using dynamic ¹8F-fluoroethyltyrosine PET.

BACKGROUND AND PURPOSE: Inter- and intratumor heterogeneity and the variable course of disease in patients with glioma motivate the investigation of new prognostic factors to optimize individual treatment. Here we explore the usefulness of standard static and more sophisticated dynamic (18)F-fluoroethyltyrosine-PET imaging for the assessment of patient prognosis. MATERIALS AND METHODS: Thirty-four consecutive patients with untreated, first-diagnosed, histologically proved glioma were included in this retrospective study. All patients underwent dynamic PET scans before surgery (± standard treatment) and were followed up clinically and by MR imaging. Static and dynamic tumor-to-background ratio, TTP, and slope-to-peak were obtained and correlated with progression-free survival. RESULTS: Twenty of 34 patients experienced progression, with a median progression-free survival of 28.0 ± 11.1 months. Dynamic TTP was highly prognostic for recurrent disease, showing a strong correlation with progression-free survival (hazard ratio, 6.050; 95% CI, 2.11-17.37; P < .001). Most interesting, this correlation also proved significant in the subgroup of low-grade glioma (hazard ratio, 5.347; 95% CI, 1.05-27.20; P = .044), but not when using established static imaging parameters, such as maximum tumor-to-background ratio and mean tumor-to-background ratio. In the high-grade glioma subgroup, both dynamic and static parameters correlated with progression-free survival. The best results were achieved by defining ROIs around "hot spots" in earlier timeframes, underlining the concept of intratumor heterogeneity. CONCLUSIONS: (18)F-fluoroethyltyrosine-PET can predict recurrence in patients with glioma, with dynamic analysis showing advantages over static imaging, especially in the low-grade subgroup.

Long-term follow-up of standard microdiscectomy versus minimal access surgery for lumbar disc herniations.

BACKGROUND: Surgery of lumbar disc herniations is one of the most common neurosurgical procedures. New surgical approaches and techniques are constantly evolving. We present our long-term follow-up results comparing standard open microdiscectomy (SOMD) and minimal access microdiscectomy (MAMD) for single-level lumbar disc herniations. METHODS: Patients were randomized in two groups receiving either MAMD or SOMD. Physical and mental health and pain relief were assessed (ODI, SF-36 questionnaire, VAS leg and back pain). In addition, all patients received MR imaging for morphological evaluation of postoperative peridural scar tissue formation. RESULTS: Of the 60 initial patients (SOMD: 30 pts, MAMD: 30 pts), 38 were available for long-term follow-up. Mean follow-up time was 33 months. Long-term follow-up revealed significant postoperative pain relief in both groups. Good to excellent results concerning physical and mental health and pain relief were achieved in both groups. Significantly less peridural scar tissue formation was observed in the MAMD patients, but without clinical impact. CONCLUSION: MAMD is a feasible alternative to the standard open approach. Both groups show significant and long-lasting pain relief and good to excellent results regarding health-related quality of life. Congruent to our short-term results, we observed slightly but not statistically significant better clinical results in the MAMD group when compared to the SOMD group.