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Purpose: Recent artificial intelligence algorithms aided intraoperative decision-making via stimulated Raman histology (SRH) during craniotomy. This study assesses deep learning algorithms for rapid intraoperative diagnosis from SRH images in small stereotactic-guided brain biopsies. It defines a minimum tissue sample size threshold to ensure diagnostic accuracy., Experimental Design: A prospective single-center study examined 121 SRH images from 84 patients with unclear intracranial lesions undergoing stereotactic brain biopsy. Unprocessed, label-free samples were imaged using a portable fiber laser Raman scattering microscope. Three deep learning models were tested to (i) identify tumorous/nontumorous tissue as qualitative biopsy control; (ii) subclassify into high-grade glioma (central nervous system World Health Organization grade 4), diffuse low-grade glioma (central nervous system World Health Organization grades 2-3), metastases, lymphoma, or gliosis; and (iii) molecularly subtype IDH and 1p/19q statuses of adult-type diffuse gliomas. Model predictions were evaluated against frozen section analysis and final neuropathologic diagnoses., Results: The first model identified tumorous/nontumorous tissue with 91.7% accuracy. Sample size on slides impacted accuracy in brain tumor subclassification (81.6%, κ = 0.72 frozen section; 73.9%, κ = 0.61 second model), with SRH images being smaller than hematoxylin and eosin images (4.1 ± 2.5 mm2 vs. 16.7 ± 8.2 mm2, P < 0.001). SRH images with more than 140 high-quality patches and a mean squeezed sample of 5.26 mm2 yielded 89.5% accuracy in subclassification and 93.9% in molecular subtyping of adult-type diffuse gliomas., Conclusions: Artificial intelligence-based SRH image analysis is non-inferior to frozen section analysis in detecting and subclassifying brain tumors during small stereotactic-guided biopsies once a critical squeezed sample size is reached. Beyond frozen section analysis, it enables valid molecular glioma subtyping, allowing faster treatment decisions in the future; however, refinement is needed for long-term application., (©2024 American Association for Cancer Research.)

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O -(2-[ 18 F]fluoroethyl)-l-tyrosine ( 18 F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18 F-FET uptake and the MRSI signals choline (Cho), N -acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18 F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18 F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18 F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18 F-FET PET., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The expression level of the programmed cell death ligand 1 (PD-L1) appears to be a predictor for response to immunotherapy using checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). As differences in terms of PD-L1 expression levels in the extracranial primary tumor and the brain metastases may occur, a reliable method for the non-invasive assessment of the intracranial PD-L1 expression is, therefore of clinical value. Here, we evaluated the potential of radiomics for a non-invasive prediction of PD-L1 expression in patients with brain metastases secondary to NSCLC., Patients and Methods: Fifty-three NSCLC patients with brain metastases from two academic neuro-oncological centers (group 1, n = 36 patients; group 2, n = 17 patients) underwent tumor resection with a subsequent immunohistochemical evaluation of the PD-L1 expression. Brain metastases were manually segmented on preoperative T1-weighted contrast-enhanced MRI. Group 1 was used for model training and validation, group 2 for model testing. After image pre-processing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. The radiomics model was trained and validated using random stratified cross-validation. Finally, the best-performing radiomics model was applied to the test data. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analyses., Results: An intracranial PD-L1 expression (i.e., staining of at least 1% or more of tumor cells) was present in 18 of 36 patients (50%) in group 1, and 7 of 17 patients (41%) in group 2. Univariate analysis identified the contrast-enhancing tumor volume as a significant predictor for PD-L1 expression (area under the ROC curve (AUC), 0.77). A random forest classifier using a four-parameter radiomics signature, including tumor volume, yielded an AUC of 0.83 ± 0.18 in the training data (group 1), and an AUC of 0.84 in the external test data (group 2)., Conclusion: The developed radiomics classifiers allows for a non-invasive assessment of the intracranial PD-L1 expression in patients with brain metastases secondary to NSCLC with high accuracy., (© 2023. The Author(s).)

Background: Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit., Methods: The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected., Results: We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with "maximal CE resection" (class 2) had superior outcome compared to patients with "submaximal CE resection" (class 3) or "biopsy" (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ("supramaximal CE resection"). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers., Conclusions: The proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such "supramaximal CE resection.", (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL., Methods: In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported HRQoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, involvement of white matter tracts or resting-state network nodes by different types of lesions and within-network rs-fMRI connectivity were analyzed in terms of their interaction with HRQoL scores., Results: Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2/FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits., Conclusion: In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2/FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients., (© 2023. The Author(s).)

Determining the presence of tumor in biopsies and the decision-making during resections is often dependent on intraoperative rapid frozen-section histopathology. Recently, stimulated Raman scattering microscopy has been introduced to rapidly generate digital hematoxylin-and-eosin-stained-like images (stimulated Raman histology) for intraoperative analysis. To enable intraoperative prediction of tumor presence, we aimed to develop a new deep residual convolutional neural network in an automated pipeline and tested its validity. In a monocentric prospective clinical study with 94 patients undergoing biopsy, brain or spinal tumor resection, Stimulated Raman histology images of intraoperative tissue samples were obtained using a fiber-laser-based stimulated Raman scattering microscope. A residual network was established and trained in ResNetV50 to predict three classes for each image: (1) tumor, (2) non-tumor, and (3) low-quality. The residual network was validated on images obtained in three small random areas within the tissue samples and were blindly independently reviewed by a neuropathologist as ground truth. 402 images derived from 132 tissue samples were analyzed representing the entire spectrum of neurooncological surgery. The automated workflow took in a mean of 240 s per case, and the residual network correctly classified tumor (305/326), non-tumorous tissue (49/67), and low-quality (6/9) images with an inter-rater agreement of 89.6% (κ = 0.671). An excellent internal consistency was found among the random areas with 90.2% (Cα = 0.942) accuracy. In conclusion, the novel stimulated Raman histology-based residual network can reliably detect the microscopic presence of tumor and differentiate from non-tumorous brain tissue in resection and biopsy samples within 4 min and may pave a promising way for an alternative rapid intraoperative histopathological decision-making tool., (© 2022. The Author(s).)

Background: The BRAF V600E mutation is present in approximately 50% of patients with melanoma brain metastases and an important prerequisite for response to targeted therapies, particularly BRAF inhibitors. As heterogeneity in terms of BRAF mutation status may occur in melanoma patients, a wild-type extracranial primary tumor does not necessarily rule out a targetable mutation in brain metastases using BRAF inhibitors. We evaluated the potential of MRI radiomics for a noninvasive prediction of the intracranial BRAF mutation status., Methods: Fifty-nine patients with melanoma brain metastases from two university brain tumor centers (group 1, 45 patients; group 2, 14 patients) underwent tumor resection with subsequent genetic analysis of the intracranial BRAF mutation status. Preoperative contrast-enhanced MRI was manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses., Results: Twenty-two of 45 patients (49%) in group 1, and 8 of 14 patients (57%) in group 2 had an intracranial BRAF V600E mutation. A linear support vector machine classifier using a six-parameter radiomics signature yielded an area under the ROC curve of 0.92 (sensitivity, 83%; specificity, 88%) in the test data., Conclusions: The developed radiomics classifier allows a noninvasive prediction of the intracranial BRAF V600E mutation status in patients with melanoma brain metastases with high diagnostic performance., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We investigated the value of O -(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastasis (BM) since contrast-enhanced MRI often remains inconclusive. Methods: We retrospectively identified 40 patients with 107 BMs secondary to melanoma ( n = 29 with 75 BMs) or non-small cell lung cancer ( n = 11 with 32 BMs) treated with ICI or TT who had 18 F-FET PET ( n = 60 scans) for treatment monitoring from 2015 to 2019. Most patients ( n = 37; 92.5%) had radiotherapy during the course of the disease. In 27 patients, 18 F-FET PET was used to differentiate treatment-related changes from BM relapse after ICI or TT. In 13 patients, 18 F-FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 mo). In all lesions, static and dynamic 18 F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios [TBR], time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathologic findings as a reference. Results: A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% ( P = 0.003). Metabolic responders to ICI or TT on 18 F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P = 0.004). Furthermore, at follow-up, time to peak in metabolic responders increased significantly ( P = 0.019). Conclusion: 18 F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Stereotactic radiosurgery (SRS) is widely accepted as a therapeutic option for meningiomas (M) and vestibular schwannomas (VS). However, data on outcome and toxicity in the elderly population have rarely been reported in detail., Methods: All patients aged ≥ 65 years with M or VS who underwent single fraction SRS were included. Patient data were analyzed in terms of clinical tumor control and incidence of early and late treatment related complications, which were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), RESULTS: We identified 245 patients with benign brain tumors (129 M and 116 VS, median tumor volume 2.9 ml, range 0.1-28). The median age was 71 years (range 65-86) and the mean follow-up times were 42 months (range 2-181). Tumors were irradiated with a median dose of 12.4 Gy. Actuarial clinical and radiological tumor control rates at 2, 5, and 10 years after SRS were 98%, 93%, and 88%, respectively. Recurrent tumors after previous treatment had a higher probability of post-radiosurgical progression (p < 0.001). Permanent toxicity (CTCAE I/II) were noted in 5.7%. No severe adverse events were observed during early and late follow up, although patients > 70 years had a slightly higher risk for toxicity (p = 0.027). The presence and extent of co-morbidities had no significant influence on local tumor control or toxicity., Conclusion: SRS provides favorable tumor control with low risk for treatment-related severe complications. Thus, SRS should always be considered as treatment option for benign intracranial tumors (meningiomas, schwannomas), especially in the group of elderly patients.

Background: Magnetic resonance imaging (MRI) and amino acid positron-emission tomography (PET) of the brain contain a vast amount of structural and functional information that can be analyzed by machine learning algorithms and radiomics for the use of radiotherapy in patients with malignant brain tumors., Methods: This study is based on comprehensive literature research on machine learning and radiomics analyses in neuroimaging and their potential application for radiotherapy in patients with malignant glioma or brain metastases., Results: Feature-based radiomics and deep learning-based machine learning methods can be used to improve brain tumor diagnostics and automate various steps of radiotherapy planning. In glioma patients, important applications are the determination of WHO grade and molecular markers for integrated diagnosis in patients not eligible for biopsy or resection, automatic image segmentation for target volume planning, prediction of the location of tumor recurrence, and differentiation of pseudoprogression from actual tumor progression. In patients with brain metastases, radiomics is applied for additional detection of smaller brain metastases, accurate segmentation of multiple larger metastases, prediction of local response after radiosurgery, and differentiation of radiation injury from local brain metastasis relapse. Importantly, high diagnostic accuracies of 80-90% can be achieved by most approaches, despite a large variety in terms of applied imaging techniques and computational methods., Conclusion: Clinical application of automated image analyses based on radiomics and artificial intelligence has a great potential for improving radiotherapy in patients with malignant brain tumors. However, a common problem associated with these techniques is the large variability and the lack of standardization of the methods applied.

Purpose: To provide detailed long-term data after initial observation for patients after histological confirmation of low grade (WHO II) gliomas according to molecular stratification., Methods: A series of 110 patients with watchful waiting strategy after initial surgery for LGG and re-surgery at tumor progression were analyzed. Progression-free survival, time to malignant transformation, post-recurrence survival, and overall survival were estimated with the Kaplan-Meier method. Prognostic factors were identified by the Log Rank test and Cox multivariate proportional hazards model., Results: The cohort comprised 18 IDH wild type (IDH wt ) and 53 IDH mutated (IDH mut ) astrocytomas, and 39 IDH mutated and 1p 19q co-deleted (IDH mut/codel ) patients. The median follow-up was 126 (95% CI 109-143) months. Surgery was gross total resection in 58, subtotal resection in 28, and biopsy in 24 patients. Progression-free survival rates at 5, 10 and 15 years was 38% 18% and 1%. The corresponding malignant transformation rates were 17%, 39% and 71%. The initial extent of resection influenced progression-free survival, time to malignant transformation and overall survival. Molecular subtype IDH mut/codel was the strongest prognostic factor for overall survival and for time to malignant transformation., Conclusion: The strongest determinant of the patients' course after initial watchful waiting was the molecular tumor status. Extensive resection may increase time to progression and malignant transformation. Observation may be justified in selected patients.

Objectives: We evaluated the feasibility, safety, and diagnostic yield of frame-based stereotactic biopsies (SB) in lesions located in deep-seated and midline structures of the brain to analyze these parameters in comparison to other brain areas., Patients and Methods: In a retrospective, tertiary care single-center analysis, we identified all patients who received SB for lesions localized in deep-seated and midline structures (corpus callosum, basal ganglia, pineal region, sella, thalamus, and brainstem) between January 1996 and June 2015. Study participants were between 1 and 82 years. We evaluated the feasibility, procedural complications (mortality, transient and permanent morbidity), and diagnostic yield. We further performed a risk analysis of factors influencing the latter parameters. Chi-square test, Student t test, and Mann-Whitney rank-sum test were used for statistical analysis., Results: Four hundred eighty-nine patients receiving 511 SB procedures (median age 48.5 years, range 1-82; median Karnofsky Performance Score 80%, range 50-100%, 43.8% female/56.2% male) were identified. Lesions were localized in the corpus callosum (29.5%), basal ganglia (17.0%), pineal region (11.5%), sella (7.8%), thalamus (4.3%), brainstem (28.8%), and others (1.1%). Procedure-related mortality was 0%, and permanent morbidity was 0.4%. Transient morbidity was 9.6%. Histological diagnosis was possible in 99.2% (low-grade gliomas 16.2%, high-grade gliomas 40.3%, other tumors in 27.8%, no neoplastic lesions 14.5%, no definitive histological diagnosis 0.8%). Only the pons location correlated significantly with transient morbidity (p < 0.001)., Conclusion: In experienced centers, frame-based stereotactic biopsy is a safe diagnostic tool with a high diagnostic yield also for deep-seated and midline lesions.

Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with SRS alone ( n = 13; 20 lesions) or in combination with anti-PD-1 therapy ( n = 13; 28 lesions) were analyzed. Lesion size was evaluated three and six months after SRS using a volumetric assessment based on cranial magnetic resonance imaging (cMRI) and acute toxicity after 12 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE). Local control after six months was comparable (86%, SRS + anti-PD-1, and 80%, SRS). All toxicities reported were less than or equal to grade 2. One metastasis (5%) in the SRS group and six (21%) in the SRS + anti-PD-1 group increased after three months, whereas four (14%) of the six regressed during further follow-ups. This was rated as pseudoprogression (PsP). Three patients (23%) in the SRS + anti-PD-1 group showed characteristics of PsP. Treatment with SRS and anti-PD-1 antibodies can be combined safely in melanoma patients with cerebral metastases. Early volumetric progression of lesions under simultaneous treatment may be related to PsP; thus, the evaluation of combined radioimmunotherapy remains challenging and requires experienced teams.

Mutations in the isocitrate dehydrogenase (IDH mut) gene have gained paramount importance for the prognosis of glioma patients. To date, reliable techniques for a preoperative evaluation of IDH genotype remain scarce. Therefore, we investigated the potential of O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) PET radiomics using textural features combined with static and dynamic parameters of FET uptake for noninvasive prediction of IDH genotype. Prior to surgery, 84 patients with newly diagnosed and untreated gliomas underwent FET PET using a standard scanner (15 of 56 patients with IDH mut) or a dedicated high-resolution hybrid PET/MR scanner (11 of 28 patients with IDH mut). Static, dynamic and textural parameters of FET uptake in the tumor area were evaluated. Diagnostic accuracy of the parameters was evaluated using the neuropathological result as reference. Additionally, FET PET and textural parameters were combined to further increase the diagnostic accuracy. The resulting models were validated using cross-validation. Independent of scanner type, the combination of standard PET parameters with textural features increased significantly diagnostic accuracy. The highest diagnostic accuracy of 93% for prediction of IDH genotype was achieved with the hybrid PET/MR scanner. Our findings suggest that the combination of conventional FET PET parameters with textural features provides important diagnostic information for the non-invasive prediction of the IDH genotype.

Background: The aim of this study was to investigate the potential of combined textural feature analysis of contrast-enhanced MRI (CE-MRI) and static O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation between local recurrent brain metastasis and radiation injury since CE-MRI often remains inconclusive., Methods: Fifty-two patients with new or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly stereotactic radiosurgery) of brain metastases were additionally investigated using FET PET. Based on histology ( n  = 19) or clinicoradiological follow-up ( n  = 33), local recurrent brain metastases were diagnosed in 21 patients (40%) and radiation injury in 31 patients (60%). Forty-two textural features were calculated on both unfiltered and filtered CE-MRI and summed FET PET images (20-40 min p.i.), using the software LIFEx. After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model., Results: For the differentiation between radiation injury and recurrence of brain metastasis, textural features extracted from CE-MRI had a diagnostic accuracy of 81% (sensitivity, 67%; specificity, 90%). FET PET textural features revealed a slightly higher diagnostic accuracy of 83% (sensitivity, 88%; specificity, 75%). However, the highest diagnostic accuracy was obtained when combining CE-MRI and FET PET features (accuracy, 89%; sensitivity, 85%; specificity, 96%)., Conclusions: Our findings suggest that combined FET PET/CE-MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases.

Background: As irradiated brain volume at 12 Gy (V12) is a predictor for radionecrosis, the purpose of the study was to develop a model for Cyberknife (CK) plans that is able to predict the lowest achievable V12 at a given tumor size and prescription dose (PD), and to suggest a new quality index regarding V12 for optimizing the treatment planning of brain metastases., Method: In our model V12 was approximated as a spherical shell around the tumor volume. The radial distance between tumor surface and the 12 Gy isodose line was calculated using an approximation of the mean dose gradient in that area. Assuming a radially symmetrical irradiation from the upper half space, the dose distribution is given by the superposition of single fields. The dose profiles of a single field were derived by the measured off-center ratios (OCR) of the CK system. Using the calculated gradients of the sum dose profiles, minimal-V12 was estimated for different tumor sizes. The model calculation was tested using a phantom dataset and retrospectively applied on clinical cases., Results: Our model allows the prediction of a best-case scenario for V12 at a given tumor size and PD which was confirmed by the results of the isocentric phantom plans. The results of the non-isocentric phantom plans showed that an optimization of coverage caused an increase in V12. This was in accordance with the results of the retrospective analysis. V12 s of the clinical cases were on average twice that of the predicted model calculation. A good agreement was achieved for plans with an optimal conformity index (nCI). Re-planning of cases with high V12 showed that lower values could be reached by selecting smaller collimators and by allowing a larger number of total MU and more MU per beam., Conclusions: V12 is a main parameter for assessing plan quality in terms of radiotoxicity. The index f12 defined as the ratio of V12 from the actual plan with the evaluated V12 from our model describes the conformity of an optimally possible V12 and thus can be used as a new quality index for optimizing treatment plans.

Objective: To evaluate the impact of surgical resection and adjuvant treatment on the course of patients after malignant progression of previously treated isocitrate dehydrogenase 1 (IDH1)-mutated World Health Organization (WHO) grade II astrocytoma., Methods: This retrospective study explored 56 patients undergoing tumor resection for malignant progression after previously treated IDH1-mutated WHO grade II astrocytoma. We analyzed survival after malignant progression, analyzed overall survival (OS), and identified prognostic factors using Kaplan-Meier estimates and log-rank test., Results: By the time of malignant transformation, median age was 44 years, and median Karnofsky Performance Status (KPS) score was 90. Complete resection of contrast-enhancing tissue was achieved in 18 (32.1%) patients. Median survival after re-resection was 33 months (95% confidence interval [CI], 20-46); median OS was 123 months (95% CI, 77-170). Gross total tumor resection, postoperative KPS score ≥80, adjuvant radiochemotherapy, and prior radiotherapy significantly correlated with post-malignant progression survival., Conclusions: Patients in good clinical condition with malignant progression of previously treated low-grade gliomas should receive aggressive treatment, including re-resection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective To evaluate the feasibility, safety, and diagnostic yield of stereotactic biopsy (SB) in children and adolescents with cerebral lesions. Methods We performed a systematic review of the literature and a retrospective analysis of all pediatric and adolescent patients who underwent SB for unclear brain lesions at our center. We collected patient and lesion-associated parameters, analysed the rate of procedural complications and diagnostic yield. Results Our institutional series consisted of 285 SBs in 269 children and young adults between 1989 and 2016 (median age, 9 (range 1-18) years). There was no procedure-related mortality. Permanent and transient morbidity was 0.7% and 5.8%, respectively. Lesions were located in brain lobes (26.3%) and in midline structures (73.7%). The diagnostic yield was 97.5% and histology consisted low-grade gliomas (44.2%), high-grade gliomas (15.1%), non-glial tumors (22.8%), and non-neoplastic disease (15.4%). Morbidity was not associated with tumor location, age, histology or intraoperative position of the patient. In order to compare our findings with previous reports, we reviewed 25 studies with 1 109 children and young adults which had underwent SB. The diagnostic yield ranged between 83% and 100%. The reported morbidity and mortality rates range from 0-27% and 0-3.3%, respectively. Conclusions SB in this particular patient population is a safe and a high-yield diagnostic procedure and indicates therefore its importance in the light of personalized medicine with the development of individual molecular treatment strategies., Competing Interests: Conflict of Interest: The authors have no conflict of interest to disclose., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The aim of this study was to investigate the potential of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive., Methods: Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of 18F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test., Results: TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001)., Conclusions: The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of 18F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

The irradiation of tumors in the brain is challenging due to the proximity of radiation sensitive critical structures and the tumors to be treated. In addition, irradiation above a certain level can cause irreversible damage to nerve tissue. The irradiation of benign and malignant brain tumors requires precise techniques to preserve critical structures while simultaneously administering a high radiation dose for maximum effectiveness. Therefore, stereotaxy, as a subspecialty of neurosurgery, has developed various irradiation techniques, e. g., intracerebral application of interstitial brachytherapy (SBT; stereotactic brachytherapy) and stereotactic radiosurgery (SRS). Due to the development of computer-controlled radiation techniques (e. g., Cyberknife) over the last 20 years, SRS has gained increasing importance.

Purpose: The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood-brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma., Methods: A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with (18)F-FET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) were determined. (18)F-FET uptake kinetic parameters (i.e. patterns of time-activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS)., Results: PsP was confirmed in 11 of the 22 patients. In patients with PsP, (18)F-FET uptake was significantly lower than in patients with EP (TBRmax 1.9 ± 0.4 vs. 2.8 ± 0.5, TBRmean 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal (18)F-FET TBRmax cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBRmax <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046)., Conclusion: (18)F-FET PET may facilitate the diagnosis of PsP following radiochemotherapy of glioblastoma.

Treatment options for inoperable glioblastoma are limited. Low-dose-rate stereotactic iodine-125 brachytherapy (SBT) has been reported as an effective and low-risk treatment option for circumscribed low-grade gliomas and brain metastases. The present study evaluates this treatment approach for patients with inoperable glioblastoma. Between 1990 and 2012, 201 patients with histologically proven glioblastoma were treated with SBT (iodine-125 seeds; median cumulative surface dose, 60 Gy; median dose-rate, 6 cGy/h; median gross-tumor-volume, 17 ml) either as primary treatment (n = 103) or at recurrence (n = 98). In addition to SBT, 90.3 % of patients in the primary treatment group received external boost radiotherapy (median dose, 25.2 Gy). Adjuvant chemotherapy was added for 30.8 % of patients following SBT and consisted of temozolomide for the majority of cases (88.7 %). Procedure-related complications, clinical outcome, progression-free and overall survival (PFS, OS) were evaluated. Median follow-up was 9.8 months. The procedure-related mortality was zero. During follow-up, transient and permanent procedure-related morbidity was observed in 7.5 and 2.0 %, respectively. Calculated from the time of SBT, median OS and PFS rates were 10.5 and 6.2 months, with no significant differences among primary and recurrent tumors (11.1 vs.10.4 months for OS and 6.2 vs. 5.9 months for PFS). For OS, multivariate analysis revealed Karnofsky performance score, age, and adjuvant chemotherapy as independent prognostic factors (all p < 0.01). Low-dose-rate SBT is a relatively safe and potentially effective local treatment option for patients with circumscribed inoperable glioblastoma initially or at recurrence. It deserves prospective validation since it may improve the outcome for a subset of patients with inoperable GBM.

Background: Resection of gliomas located in eloquent brain areas remains a neurosurgical challenge. The reported incidence of transient or permanent neurological deficits after microsurgery in eloquent brain ranges 20%-100%, or 0%-47% among contemporary neurosurgical series. The aim of this study was to assess the feasibility of stereotactic brachytherapy (SBT) as a local treatment alternative to microsurgical resection for patients with gliomas in highly eloquent areas, located in the central sulcus region (CSR)., Method: Between 1997 and 2010, 60 patients with World Health Organization (WHO) grades II and III gliomas located in the CSR were treated with SBT (iodine-125 seeds; cumulative therapeutic dose, 50-65 Gy). Following SBT, WHO grade III glioma patients additionally received percutaneous radiotherapy (median boost dose, 25.2 Gy). We evaluated procedure-related complications, clinical outcome, and progression-free survival., Results: Procedure-related mortality was zero. Within 30 days of SBT, 3 patients (5%) had transient neurological deficits, and 8 patients (13%) had temporarily increased seizure activity. One patient (1.6%) deteriorated permanently. Space-occupying cysts (6 patients) and radiation necrosis (1 patient) developed after a median of 38 months and required surgical intervention. Seizure activity, rated 12 months following SBT, decreased in 82% of patients (Engel classes I-III). Median progression-free survivals were 62.2 ± 19.7 months (grade II gliomas) and 26.1 ± 17.9 months (grade III gliomas)., Conclusions: Compared with microsurgical resection, SBT harbors a low risk of procedural complications, is minimally invasive, and seems to be an effective local treatment option for patients with inoperable, eloquent WHO grade II and III gliomas in the CSR. However, the value of SBT for treating gliomas still needs to be determined in prospective, randomized studies.

Background: Structural follow-up magnetic resonance imaging (MRI) after stereotactic radiosurgery (SRS) for brain metastases frequently displays local changes in the area of applied irradiation, which are often difficult to interpret (e.g., local tumor recurrence, radiation-induced changes). The use of stereotactic biopsy for histological assessment of these changes has a high diagnostic accuracy and can be considered as method of choice. In order to solve this relevant clinical problem non-invasively, advanced MRI techniques and amino acid positron-emission-tomography (PET) are increasingly used., Case Presentation: We report the long-term follow-up of a patient who had been treated with linear accelerator based SRS for cerebral metastases of a lung cancer. Fifty-eight months after SRS, the differentiation of local recurrent brain metastasis from radiation-induced changes using structural MRI was difficult. For further differentiation, perfusion-weighted MRI (PWI), proton magnetic resonance spectroscopy (MRS), and (11)C-methyl-L-methionine (MET) PET was performed. Due to artifacts and technical limitations, PWI MRI and MRS findings were not conclusive. In contrast, MET PET findings were suggestive for radiation-induced changes. Finally, a stereotactic biopsy for histological assessment of these changes demonstrated clearly a radiation-induced necrosis and the absence of vital tumor., Conclusion: The use of stereotactic biopsy for histological assessment of indistinguishable lesions on structural MRI after SRS for treatment of brain metastasis represents a highly reliable method to differentiate local tumor recurrence from radiation-induced changes. In this field, results of studies with both advanced MRI techniques and amino acid PET suggest encouraging results. However, artifacts and technical limitations (e.g., lesion size) are still a problem and comparative studies are needed to investigate the relationship, diagnostic performance, and complementary character of advanced MRI techniques and amino acid PET.

Unlabelled: The aim of this study was to investigate the potential of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET for differentiating local recurrent brain metastasis from radiation necrosis after radiation therapy because the use of contrast-enhanced MRI for this issue is often difficult., Methods: Thirty-one patients (mean age ± SD, 53 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 40) on MRI after radiation therapy of brain metastases were investigated with dynamic (18)F-FET PET. Maximum and mean tumor-to-brain ratios (TBR(max) and TBR(mean), respectively; 20-40 min after injection) of (18)F-FET uptake were determined. Time-activity curves were generated, and the time to peak (TTP) was calculated. Furthermore, time-activity curves of each lesion were assigned to one of the following curve patterns: (I) constantly increasing (18)F-FET uptake, (II) (18)F-FET uptake peaking early (TTP ≤ 20 min) followed by a plateau, and (III) (18)F-FET uptake peaking early (TTP ≤ 20 min) followed by a constant descent. The diagnostic accuracy of the TBR(max) and TBR(mean) of (18)F-FET uptake and the curve patterns for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or Fisher exact test for 2 × 2 contingency tables using subsequent histologic analysis (11 lesions in 11 patients) or clinical course and MRI findings (29 lesions in 20 patients) as reference., Results: Both TBR(max) and TBR(mean) were significantly higher in patients with recurrent metastasis (n = 19) than in patients with radiation necrosis (n = 21) (TBR(max), 3.2 ± 0.9 vs. 2.3 ± 0.5, P < 0.001; TBR(mean), 2.1 ± 0.4 vs. 1.8 ± 0.2, P < 0.001). The diagnostic accuracy of (18)F-FET PET for the correct identification of recurrent brain metastases reached 78% using TBR(max) (area under the ROC curve [AUC], 0.822 ± 0.07; sensitivity, 79%; specificity, 76%; cutoff, 2.55; P = 0.001), 83% using TBR(mean) (AUC, 0.851 ± 0.07; sensitivity, 74%; specificity, 90%; cutoff, 1.95; P < 0.001), and 92% for curve patterns II and III versus curve pattern I (sensitivity, 84%; specificity, 100%; P < 0.0001). The highest accuracy (93%) to diagnose local recurrent metastasis was obtained when both a TBR(mean) greater than 1.9 and curve pattern II or III were present (AUC, 0.959 ± 0.03; sensitivity, 95%; specificity, 91%; P < 0.001)., Conclusion: Our findings suggest that the combined evaluation of the TBR(mean) of (18)F-FET uptake and the pattern of the time-activity curve can differentiate local brain metastasis recurrence from radionecrosis with high accuracy. (18)F-FET PET may thus contribute significantly to the management of patients with brain metastases.

Stereotactic brachytherapy (SBT) has been described in several publications as an effective, minimal invasive and safe highly focal treatment option in selected patients with well circumscribed brain tumors <4 cm. However, a still ongoing discussion about indications and technique is hindering the definition of a clear legitimation of SBT in modern brain tumor treatment. These controversies encompass the question of how intense the irradiation should be delivered into the target volume (dose rate). For instance, reports about the use of high does rate (HDR) implantation schemes (>40 cGy/h) in combination with adjuvant external beam radiation and/or chemotherapy for the treatment of malignant gliomas and metastases resulted in increased rates of radiation induced adverse tissue changes requiring surgical intervention. Vice versa, such effects have been only minimally observed in numerous studies applying low dose rate (LDR) regiments (3-8 cGy/h) for low grade gliomas, metastases and other rare indications. Besides these observations, there are, however, no data available directly comparing the long term incidences of tissue changes after HDR and LDR and there is, furthermore, no evidence regarding a difference between temporary or permanent LDR implantation schemes. Thus, recommendations for effective and safe implantation schemes have to be investigated and compared in future studies.

Purpose: Resection is generally considered the gold standard for treatment of low-grade (WHO grades I and II) gliomas (LGGs) in childhood. However, approximately 30% to 50% of these tumors are inoperable because of their localization in highly eloquent brain areas. A few reports have suggested stereotactic brachytherapy (SBT) with implantation of iodine-125 ((125)I) seeds as a safe and effective local treatment alternative. This single-center study provides a summary of the long-term outcome after SBT in one of the largest reported patient series., Patients and Methods: All pediatric patients treated with SBT ((125)I seeds; cumulative therapeutic dose 50-65 Gy within 9 months) by our group for LGG with follow-up of more than 6 months were included. Clinical and radiologic outcome, time to progression, and overall survival were evaluated. Prognostic factors (age, sex, Karnofsky performance score, tumor volume, and histology) for survival and disease progression were investigated., Results: In all, 147 of 160 pediatric patients treated with SBT (from 1982 through 2009) were analyzed in detail. Procedure-related mortality was zero, and the 30-day morbidity was transient and low (5.4%). Survival rates at 5 and 10 years were 93%, and 82%, respectively, with no significant difference between WHO grades I and II tumors (median follow-up, 67.1 ± 57.7 months). Twenty-one (14.8%) of 147 patients presented with tumor relapse. The remaining 126 patients revealed complete response in 24.6%, partial response in 31.0%, and stable disease in 29.6%. Neurologic status improved (57.8%) or remained stable (23.0%). None of the evaluated factors had significant impact on the study's end points except tumor volume more than 15 mL, which caused significantly higher rates of tumor recurrence (P < .05)., Conclusion: We demonstrate that SBT represents a safe, minimally invasive, and highly effective local treatment option for pediatric patients with inoperable LGG WHO grades I and II.

This paper reports on stereotactic biopsy combined with stereotactic (125)iodine brachytherapy (SBT) for locally recurrent, previously irradiated cerebral metastases, focusing on feasibility, complications, cerebral disease control, and survival. All patients with suspected locally recurrent metastases detected by MRI were selected for this combined procedure. After stereotactic biopsy, all patients with a verified vital tumor underwent SBT (50 Gy surface dose applied for 42 days) during the same surgical procedure. Histological results of biopsy, complications, treatment response, local and distant disease control, and survival were evaluated. Thirty patients underwent stereotactic biopsy, and 27 were treated with SBT for histologically proved tumor recurrence. There was no treatment-related mortality, and morbidity was transient and low (6.6%). Median survival was 14.8 months. After one year the actuarial incidence of local and distant relapse was 6.7 and 45.5%, respectively. There was no grade 3 or 4 CNS toxicity, even among the 18.5% of patients with tumors >30 mm. For these patients stereotactic biopsy seems to be a safe and valuable means of differentiating between radiation-induced tissue changes and tumor recurrence/progression. SBT is a safe, minimally invasive, and highly effective treatment option for cerebral disease control and survival. Furthermore, it can be performed during the same stereotactic operation.

Background: Brain metastases represent the most common intracranial tumors and are associated with very poor prognosis., Objective: To investigate the feasibility, survival, and cerebral disease control of patients with singular brain metastases treated with stereotactic 125iodine brachytherapy (SBT), to identify prognostic factors, and to compare results with other local treatment methods., Methods: Complications, survival (overall and separated by recursive partitioning analysis [RPA] classes), and local and distant disease control were evaluated retrospectively in 90 patients. Prognostic factors were identified by forming subgroups of patients based on age, Karnofsky Performance Status, status of extracranial disease, interval since initial diagnosis, absence/presence of prior whole-brain radiation therapy, localization, morphology, and tumor volume., Results: There was no treatment-related mortality, and morbidity was transient and low (3.3%). Median survival was 8.5 months overall and 18.1 months for RPA class 1 patients. After 1 year, the actuarial incidence of local and distant cerebral relapse was 5.4% and 46.4%, respectively. Karnofsky Performance Status ≥ 70 (P < .002), stable systemic disease (P < .02), RPA class 1 (P < .02), and a prolonged (> 12 month) interval between initial diagnosis and SBT (P < .05) significantly improved survival. No significant influence of previous whole-brain radiation therapy on survival or cerebral disease relapse was found., Conclusion: SBT represents a safe, minimally invasive, and, compared with SRS and microsurgery, a similarly effective local treatment option in terms of survival and cerebral disease control. It allows histological (re-)evaluation and treatment within 1 stereotactic operation. Because it is less restricted by tumor localization or size, it greatly advances local treatment options, and on the basis of its favorable biological irradiation effect, SBT does not limit additional irradiation treatment in the event of disease relapse.

Purpose: To compare stereotactic brachytherapy (SBT) with stereotactic radiosurgery (SRS) for treating singular cerebral metastases, regarding feasibility, complications, cerebral disease control, and survival., Patients and Methods: For this retrospective, single-center study, all patients treated for newly diagnosed, untreated singular cerebral metastasis with SBT using (125)iodine seeds (cumulative tumor surface dose 50 Gy, applied for 42 days) were compared with patients receiving LINAC-based SRS for the same indication. Survival and actuarial local and distant disease control were evaluated using univariate Kaplan-Meier estimates and Cox regression. Results were compared using Student's t test and the χ2 test., Results: A total of 142 patients treated with SRS were compared with 77 patients undergoing SBT. No significant differences were observed between epidemiological and disease-related features (p > 0.05), except a lower KPS (p < 0.007) and a larger tumor volume (p < 0.001) in the SBT group. Neither median survival (LINAC-SRS vs. SBT = 8.1 vs. 8.0 months, respectively) nor actuarial local/distant cerebral disease control after 12 months showed significant differences (93.6% vs. 96.7% / 42.4% vs. 46.4%). There was no treatment-related mortality and no permanent grade 3 or 4 CNS toxicity (RTOG/EORTC CNS toxicity criteria)., Conclusion: For the treatment of singular cerebral metastasis, SBT represents a safe, minimally invasive, and effective local treatment option with results comparable to SRS regarding survival and cerebral disease control. Its advantage is that it allows histological (re-)evaluation and treatment within one stereotactic procedure and, compared to microneurosurgery, is almost unrestricted regarding tumor localization. Furthermore, larger metastases can be treated than with SRS. SBT, therefore, represents an alternative local treatment in selected cases.

Functional magnetic resonance imaging (fMRI) in pediatric patients presents a unique set of problems due to the need for patient compliance, the frequent need for sedation and an early developmental status. A new method for using fMRI in sedated infants and young children is presented using passive stimuli focused on visual, sensorimotor and language functions. All of these stimuli are presented such that no patient interaction is required. Eight sedated children undergoing diagnostic MRI scans of the brain participated in these passive fMRI procedures. Cortical regions were identified using standard techniques applied to the blood-oxygen-level-dependent signal which is the basis for fMRI. The results support the feasibility of brain mapping in sedated children with passive fMRI techniques.