PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression

INTRODUCTION The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. METHODS Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. RESULTS PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. CONCLUSIONS PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression

Limited efficacy of temozolomide alone for astrocytoma, IDH-mutant, CNS WHO grades 2 or 3

PURPOSE The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Radiotherapy might be superior to temozolomide. Recent studies have linked temozolomide with induction of hypermutation and poor clinical course in some IDH-mutant gliomas. METHODS In this retrospective study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 and diagnosed between 2001 and 2019 were included. Patients initially monitored by wait-and-scan strategies or treated with radiotherapy or temozolomide alone were studied. Patient data were correlated with outcome. Matched pair and subgroup analyses were conducted. RESULTS Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy lived longer than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in the wait-and-scan cohort than in the temozolomide cohort (not reached vs 10.7 years, p < 0.01). Patients from the wait-and-scan cohort receiving temozolomide at first progression had significantly shorter survival times than patients treated with any other therapy at first progression (p < 0.01). Post-surgical T2 tumor volume, contrast enhancement on MRI and WHO grade were associated with overall survival in univariate analyses (p < 0.01). CONCLUSION The results suggest superiority of radiotherapy over temozolomide and wait-and-scan strategies regarding progression-free survival and superiority of radiotherapy over temozolomide regarding overall survival. Our results are consistent with the notion that early temozolomide might compromise outcome in some patients

Prediction of TERTp-mutation status in IDH-wildtype high-grade gliomas using pre-treatment dynamic 18FFET PET radiomics

PURPOSE To evaluate radiomic features extracted from standard static images (20-40~min p.i.), early summation images (5-15~min p.i.), and dynamic 18FFET PET images for the prediction of TERTp-mutation status in patients with IDH-wildtype high-grade glioma. METHODS A total of 159 patients (median age 60.2~years, range 19-82~years) with newly diagnosed IDH-wildtype diffuse astrocytic glioma (WHO grade III or IV) and dynamic 18FFET PET prior to surgical intervention were enrolled and divided into a training (n = 112) and a testing cohort (n = 47) randomly. First-order, shape, and texture radiomic features were extracted from standard static (20-40~min summation images; TBR20-40), early static (5-15~min summation images; TBR5-15), and dynamic (time-to-peak; TTP) images, respectively. Recursive feature elimination was used for feature selection by 10-fold cross-validation in the training cohort after normalization, and logistic regression models were generated using the radiomic features extracted from each image to differentiate TERTp-mutation status. The areas under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value were calculated to illustrate diagnostic power in both the training and testing cohort. RESULTS The TTP model comprised nine selected features and achieved highest predictability of TERTp-mutation with an AUC of 0.82 (95{\%} confidence interval 0.71-0.92) and sensitivity of 92.1{\%} in the independent testing cohort. Weak predictive capability was obtained in the TBR5-15 model, with an AUC of 0.61 (95{\%} CI 0.42-0.80) in the testing cohort, while no predictive power was observed in the TBR20-40 model. CONCLUSIONS Radiomics based on TTP images extracted from dynamic 18FFET PET can predict the TERTp-mutation status of IDH-wildtype diffuse astrocytic high-grade gliomas with high accuracy preoperatively

L-type amino acid transporter (LAT) 1 expression in 18F-FET-negative gliomas

BACKGROUND O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30{\%} of low- and 5{\%} of high-grade gliomas do not present enhanced 18F-FET uptake at primary diagnosis ({\textquotedbl}18F-FET-negative gliomas{\textquotedbl}) and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18F-FET-negative gliomas and to compare them to a matched group of 18F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18F-FET-negative (tumour-to-background ratio (TBR) 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells ({\%}) and the staining intensity (range 0-2) were multiplied to an overall score (H-score; range 0-200) and correlated to PET findings as well as progression-free survival (PFS). RESULTS IHC staining of LAT1 expression was positive in both, 18F-FET-positive as well as 18F-FET-negative gliomas. No differences were found between the 18F-FET-negative and 18F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBRmax, neither in the overall group nor in the 18F-FET-positive group only (p = 0.651 and p = 0.140). CONCLUSION Although LAT1 is reported to mediate the uptake of 18F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18F-FET are necessary

Radiomic Analysis Reveals Prognostic Information in T1-Weighted Baseline Magnetic Resonance Imaging in Patients With Glioblastoma

Objectives The aim of this study was to investigate whether radiomic analysis with random survival forests (RSFs) can predict overall survival from T1-weighted contrast-enhanced baseline magnetic resonance imaging (MRI) scans in a cohort of glioblastoma multiforme (GBM) patients with uniform treatment. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was waived. The MRI scans from 66 patients with newly diagnosed GBM from a previous prospective study were analyzed. Tumors were segmented manually on contrast-enhanced 3-dimensional T1-weighted images. Using these segmentations, P = 208 quantitative image features characterizing tumor shape, signal intensity, and texture were calculated in an automated fashion. On this data set, an RSF was trained using 10-fold cross validation to establish a link between image features and overall survival, and the individual risk for each patient was predicted. The mean concordance index was assessed as a measure of prediction accuracy. Association of individual risk with overall survival was assessed using Kaplan-Meier analysis and a univariate proportional hazards model. Results Mean overall survival was 14 months (range, 0.8-85 months). Mean concordance index of the 10-fold cross-validated RSF was 0.67. Kaplan-Meier analysis clearly distinguished 2 patient groups with high and low predicted individual risk (P = 5.5 x 10(-5)). Low predicted individual mortality was found to be a favorable prognostic factor for overall survival in a univariate Cox proportional hazards model (hazards ratio, 1.038;95% confidence interval, 1.015-1.062;P = 0.0059). Conclusions This study demonstrates that baseline MRI in GBM patients contains prognostic information, which can be accessed by radiomic analysis using RSFs

PSMA Expression in Glioblastoma as a Basis for Theranostic Approaches: A Retrospective, Correlational Panel Study Including Immunohistochemistry, Clinical Parameters and PET Imaging

Aim: The aim of the current study was to enlighten the evolution of prostate-specific membrane antigen (PSMA) expression in glioblastoma between initial diagnosis and recurrence in order to provide preliminary insight for further clinical investigations into innovative PSMA-directed treatment concepts in neuro-oncology. Methods: Patients who underwent resection for de-novo glioblastoma (GBM) and had a re-resection in case of a recurrent tumor following radiochemotherapy and subsequent chemotherapy were included (n = 16). Histological and immunohistochemical stainings were performed at initial diagnosis and at recurrence (n = 96 tissue specimens). Levels of PSMA expression both in endothelial and non-endothelial cells as well as vascular density (CD34) were quantified via immunohistochemistry and changes between initial diagnosis and recurrence were determined. Immunohistochemical findings were correlated with survival and established clinical parameters. Results: PSMA expression was found to be present in all GBM tissue samples at initial diagnosis as well as in all but one case of recurrent tumor samples. The level of PSMA expression in glioblastoma varied inter-individually both in endothelial and non-endothelial cells. Likewise, the temporal evolution of PSMA expression highly varied in between patients. The level of vascular PSMA expression at recurrence and its change between initial diagnosis and recurrence was associated with post recurrence survival time: Patients with high vascular PSMA expression at recurrence as well as patients with increasing PSMA expression throughout the disease course survived shorter than patients with low vascular PSMA expression or decreasing vascular PSMA expression. There was no significant correlation of PSMA expression with MGMT promoter methylation status or Ki-67 labelling index. Conclusion: PSMA is expressed in glioblastoma both at initial diagnosis and at recurrence. High vascular PSMA expression at recurrence seems to be a negative prognostic marker. Thus, PSMA expression in GBM might present a promising target for theranostic approaches in recurrent glioblastoma. Especially PSMA PET imaging and PSMA-directed radioligand therapy warrant further studies in brain tumor patients

Voxel-wise analysis of dynamic F-18-FET PET: a novel approach for non-invasive glioma characterisation

Background: Glioma grading with dynamic F-18-FET PET (0-40 min p.i.) is typically performed by analysing the mean time-activity curve of the entire tumour or a suspicious area within a heterogeneous tumour. This work aimed to ensure a reader-independent glioma characterisation and identification of aggressive sub-volumes by performing a voxel-based analysis with diagnostically relevant kinetic and static 18F-FET PET parameters. One hundred sixty-two patients with a newly diagnosed glioma classified according to histologic and molecular genetic properties were evaluated. The biological tumour volume (BTV) was segmented in static 20-40 min p.i. F-18-FET PET images using the established threshold of 1.6 x background activity. For each enclosed voxel, the time-to-peak (TTP), the late slope (Slope(15-40)), and the tumour-to-background ratios (TBR5-15, TBR20-40) obtained from 5 to 15 min p.i. and 20 to 40 min p.i. images were determined. The percentage portion of these values within the BTV was evaluated with percentage volume fractions (PVFs) and cumulated percentage volume histograms (PVHs). The ability to differentiate histologic and molecular genetic classes was assessed and compared to volume-of-interest (VOI)-based parameters. Results: Aggressive WHO grades III and IV and IDH-wildtype gliomas were dominated by a high proportion of voxels with an early peak, negative slope, and high TBR, whereby the PVHs with TTP 2 yielded the most significant differences between glioma grades. We found significant differences of the parameters between WHO grades and IDH mutation status, where the effect size was predominantly higher for voxel-based PVHs compared to the corresponding VOI-based parameters. A low overlap of BTV sub-volumes defined by TTP ) (2)- and TBR20-40 (> 2)-defined hotspots was observed. Conclusions: The presented approach applying voxel-wise analysis of dynamic F-18-FET PET enables an enhanced characterisation of gliomas and might potentially provide a fast identification of aggressive sub-volumes within the BTV. Parametric 3D F-18-FET PET information as investigated in this study has the potential to guide individual therapy instrumentation and may be included in future biopsy studies

Deep Brain Stimulation: Current Applications and Future Prospects

Deep Brain Stimulation (DBS) has proven to be an effective and minimally invasive surgical treatment for a variety of neurological and psychiatric diseases such as Parkinson's Disease, essential tremor, dystonia, Tourette's Syndrome and depression. In contrast to early surgical lesioning procedures, DBS has a considerably lower side-effect rate and is usually reversible. Common targets include nuclei involved in the basal ganglia circuitry as well as its efferent and afferent pathways such as the subthalamic nucleus (STN), the globus pallidus internus (GPi) or the ventral striatal region. Despite the increasing application of DBS, the exact mechanism of action is still matter of debates. Current trials focus on establishing alternative targets, exploring new indications as well as on capturing cortical responses during DBS in order to improve individual stimulation parameters