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Background The normal tissue objective (NTO) is an inverse planning approach in radiosurgery, also available for the CyberKnife system. By employing a model function, it aims to achieve precise control over the global dose fall‐off in healthy tissue. As a novel technique, NTO can serve as an alternative to the established method, which utilizes layered contours around the target to shape dose gradients and enhance conformity, referred to as Auto‐shells in CyberKnife systems. Purpose This study compares the dose distribution achieved with NTO and Auto‐shells to evaluate their respective advantages in CyberKnife treatment planning. Methods A total of 45 patients with brain tumors—including 15 vestibular schwannomas, 15 meningiomas, and 15 metastases, all of whom had previously been treated using an Auto‐shells‐generated plan, were analyzed. For each case, an alternative NTO‐based plan was generated and compared with its Auto‐shells counterpart. Key treatment parameters—including nodes, beams, total monitor units (MU), treatment time, new conformity index (nCI), gradient index (GI), and dose exposure volumes to healthy brain tissue (V12Gy and V5Gy)—were evaluated. Results Both methods resulted in comparable plans across many indices. Significant differences were particularly in terms of healthy brain tissue dose exposure. With the NTO method, V12Gy and V5Gy were reduced by up to 14%, and in the case of meningiomas and metastases, the GI was reduced by up to 7%. The conformity, described by the nCI, was within 2%. No significant difference was observed in MU. Conclusion NTO optimization presents a viable option to the Auto‐shells method for CyberKnife treatment of brain tumors. By reducing healthy brain tissue exposure without increasing monitor units, it enhances dose‐sparing efficiency. However, maintaining optimal conformity remains an important issue, highlighting the trade‐offs between precision and tissue preservation.

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.

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.

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.

Abstract BACKGROUND: The feasibility and safety of stereotactic biopsy for brainstem tumors (BSTs) are controversial. Although magnetic resonance imaging (MRI) has been reported as the preferred diagnostic tool, histopathological analysis is frequently necessary to establish a definitive diagnosis. Recent advances in molecular characterization of brainstem gliomas—accounting for the majority of BSTs—have revealed several potential targets for molecular-based therapies. Hence, a molecular stereotactic biopsy that combines histopathological diagnosis with molecular-genetic analysis will become increasingly important for patients with BSTs. OBJECTIVE: We conducted a systemic review and meta-analysis to determine the risks and benefits of stereotactic biopsy for BSTs. METHODS: A systematic search in PubMed, Embase, and the Web of Science yielded 3766 potentially eligible abstracts. Meta-analysis was conducted on 38 studies describing 1480 biopsy procedures for BSTs. Primary outcome measures were diagnostic success and procedure-related complications. Data were analyzed according to standard meta-analytic techniques. RESULTS: The weighted average proportions across the analyzed studies were: 96.2% (95% confidence interval [CI]: 94.5%-97.6%) for diagnostic success, 7.8% (95% CI: 5.6%-10.2%) for overall morbidity, 1.7% (95% CI: 0.9%-2.7%) for permanent morbidity, and 0.9% (95% CI: 0.5%-1.4%) for mortality. Meta-regression revealed a significant correlation between diagnostic success rates and the number of biopsy procedures performed annually in each center (P = .011). Other factors did not affect the outcome measures. CONCLUSION: Stereotactic biopsy of BSTs is safe. It allows exact histopathological diagnosis as a prerequisite for adequate treatment and opens new perspectives for the molecular characterization of these tumors as a crucial first step toward more individualized treatment concepts.

Self-injurious behavior (SIB) is associated with diverse psychiatric conditions. Sometimes, (e.g., in patients with autism spectrum disorder or acquired brain injuries) SIB is the most dominant symptom, severely restricting the psychosocial functioning and quality of life of the patients and inhibiting appropriate patient care. In severe cases, it can lead to permanent physical injuries or even death. Primary therapy consists of medical treatment and if implementable, behavioral therapy. For patients with severe SIB refractory to conventional therapy neuromodulation can be considered as a last recourse. In scientific literature, several successful lesioning and deep brain stimulation targets have been described that can indicate a common underlying neuronal pathway. The objectives of this study were to evaluate the short- and long-term clinical outcome of patients with severe, therapy refractory SIB who underwent DBS with diverse underlying psychiatric disorders and to correlate these outcomes with the activated connectivity networks. We retrospectively analyzed ten patients with SIB who underwent DBS surgery with diverse psychiatric conditions including autism spectrum disorder, organic personality disorder after hypoxic or traumatic brain injury or Tourette syndrome. DBS targets were chosen according to the underlying disorder, patients were either stimulated in the nucleus accumbens, amygdala, posterior hypothalamus, medial thalamus or ventrolateral thalamus. Clinical outcome was measured six months after surgery and at long-term follow-up after ten or more years using the Early Rehabilitation Barthel index (ERBI) and time of restraint. Connectivity patterns were analyzed using normative connectome. Based on previous literature the orbitofrontal cortex, superior frontal gyrus, the amygdala and the hippocampus were chosen as regions of interest. This analysis showed a significant improvement in the functionality of the patients with DBS in the short- and long-term follow-up. Good clinical outcome correlated with higher connectivity to the amygdala and hippocampus. These findings may suggest a common pathway, which can be relevant when planning a surgical procedure in patients with SIB.

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 (TBR max , TBR mean ) 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 (TBR max 1.9 ± 0.4 vs. 2.8 ± 0.5, TBR mean 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 TBR max 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 TBR max <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.

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.

(1) Background: Transient increase in volume of vestibular schwannomas (VS) after stereotactic radiosurgery (SRS) is common and complicates differentiation between treatment-related changes (pseudoprogression, PP) and tumor recurrence (progressive disease, PD). (2) Methods: Patients with unilateral VS (n = 63) underwent single fraction robotic-guided SRS. Volume changes were classified according to existing RANO criteria. A new response type, PP, with a >20% transient increase in volume was defined and divided into early (within the first 12 months) and late (>12 months) occurrence. (3) Results: The median age was 56 (range: 20–82) years, the median initial tumor volume was 1.5 (range: 0.1–8.6) cm3. The median radiological and clinical follow-up time was 66 (range: 24–103) months. Partial response was observed in 36% (n = 23), stable disease in 35% (n = 22) and PP in 29% (n = 18) of patients. The latter occurred early (16%, n = 10) or late (13%, n = 8). Using these criteria, no case of PD was observed. (4) Conclusion: Any volume increase after SRS for vs. assumed to be PD turned out to be early or late PP. Therefore, we propose modifying RANO criteria for SRS of VS, which may affect the management of vs. during follow-up in favor of further observation.

The aim of this study was to investigate the potential of O-(2-18F-fluoroethyl)-L-tyrosine (18F-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 contrastenhancing brain lesions (n = 40) on MRI after radiation therapy of brain metastases were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively; 20-40 min after injection) of 18F-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 18F-FET uptake, (II) 18F-FET uptake peaking early (TTP # 20 min) followed by a plateau, and (III) 18F-FET uptake peaking early (TTP # 20 min) followed by a constant descent. The diagnostic accuracy of the TBRmax and TBRmean of 18F-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 x 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 TBRmax and TBRmean were significantly higher in patients with recurrent metastasis (n = 19) than in patients with radiation necrosis (n = 21) (TBRmax, 3.2 ± 0.9 vs. 2.3 ± 0.5, < 0.001; TBRmean, 2.1 ± 0.4 vs. 1.8 ± 0.2, < 0.001). The diagnostic accuracy of 18F-FET PET for the correct identification of recurrent brain metastases reached 78% using TBRmax (area under the ROC curve [AUC], 0.822 ± 0.07; sensitivity, 79%; specificity, 76%; cutoff, 2.55; P = 0.001), 83% using TBRmean (AUC, 0.851 ± 0.07; sensitivity, 74%; specificity, 90%; cutoff, 1.95; < 0.001), and 92% for curve patterns II and III versus curve pattern I (sensitivity, 84%; specificity, 100%; < 0.0001). The highest accuracy (93%) to diagnose local recurrent metastasis was obtained when both a TBRmean greater than 1.9 and curve pattern II or III were present (AUC, 0.959 ± 0.03; sensitivity, 95%; specificity, 91%; < 0.001). Conclusion: Our findings suggest that the combined evaluation of the TBRmean of 18F-FET uptake and the pattern of the time-activity curve can differentiate local brain metastasis recurrence from radionecrosis with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases. [PUBLICATION ABSTRACT]