Amyloid-ß levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy.

Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-ß42 (Aß42) and Aß42/Aß40 ratio (A) into A+T+N±, A+T-N±, A-T+N±, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N± compared to A-T+N±, whereas there was no difference between A-T+N± and A-T-N-. Furthermore, there was no significant difference between A-T+N± and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N± and A-T-N- could be distinguished based on their Aß42 and Aß40 levels. Both Aß40 and Aß42 levels were significantly increased in A-T+N± compared to controls. Long term follow-up of A-T+N± individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with Aß in the A-T+N± group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and Aß surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and Aß might provide a deeper insight into the process under which Aß becomes pathological.

Magnetic resonance imaging for brain stereotactic radiotherapy : A review of requirements and pitfalls.

Due to its superior soft tissue contrast, magnetic resonance imaging (MRI) is essential for many radiotherapy treatment indications. This is especially true for treatment planning in intracranial tumors, where MRI has a long-standing history for target delineation in clinical practice. Despite its routine use, care has to be taken when selecting and acquiring MRI studies for the purpose of radiotherapy treatment planning. Requirements on MRI are particularly demanding for intracranial stereotactic radiotherapy, where accurate imaging has a critical role in treatment success. However, MR images acquired for routine radiological assessment are frequently unsuitable for high-precision stereotactic radiotherapy as the requirements for imaging are significantly different for radiotherapy planning and diagnostic radiology. To assure that optimal imaging is used for treatment planning, the radiation oncologist needs proper knowledge of the most important requirements concerning the use of MRI in brain stereotactic radiotherapy. In the present review, we summarize and discuss the most relevant issues when using MR images for target volume delineation in intracranial stereotactic radiotherapy.

Evidence for improved survival with bevacizumab treatment in recurrent high-grade gliomas: a retrospective study with ("pseudo-randomized") treatment allocation by the health insurance provider.

INTRODUCTION: Despite a large number of trials, the role of bevacizumab (BEV) in the treatment of recurrent high-grade gliomas is still controversial. Evidence regarding an effect on overall survival in this context is ultimately inconclusive. At the Department of Radiation Oncology at Erlangen, Germany we treated a large cohort of patients with recurrent gliomas where bevacizumab use was determined exclusively by the health care provider's approval of reimbursement. METHODS: 61 patients (between 06/2008 and 01/2014) with recurrent high-grade gliomas had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without bevacizumab (non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider. RESULTS: Median overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, logrank p = 0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p = 0.578) (second or higher order of recurrence, 9.9 vs. 2.6 months, p = 0.010). On multivariate analysis for overall survival the prognostic impact of bevacizumab (HR = 0.43, p = 0.034) remained significant. CONCLUSION: Our results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas with BEV benefit being greatest in case of second or later recurrence.

Accuracy of Dose-Saving Artificial-Intelligence-Based 3D Angiography (3DA) for Grading of Intracranial Artery Stenoses: Preliminary Findings.

BACKGROUND AND PURPOSE: Based on artificial intelligence (AI), 3D angiography (3DA) is a novel postprocessing algorithm for "DSA-like" 3D imaging of cerebral vasculature. Because 3DA requires neither mask runs nor digital subtraction as the current standard 3D-DSA does, it has the potential to cut the patient dose by 50%. The object was to evaluate 3DA's diagnostic value for visualization of intracranial artery stenoses (IAS) compared to 3D-DSA. MATERIALS AND METHODS: 3D-DSA datasets of IAS (nIAS = 10) were postprocessed using conventional and prototype software (Siemens Healthineers AG, Erlangen, Germany). Matching reconstructions were assessed by two experienced neuroradiologists in consensus reading, considering image quality (IQ), vessel diameters (VD1/2), vessel-geometry index (VGI = VD1/VD2), and specific qualitative/quantitative parameters of IAS (e.g., location, visual IAS grading [low-/medium-/high-grade] and intra-/poststenotic diameters [dintra-/poststenotic in mm]). Using the NASCET criteria, the percentual degree of luminal restriction was calculated. RESULTS: In total, 20 angiographic 3D volumes (n3DA = 10; n3D-DSA = 10) were successfully reconstructed with equivalent IQ. Assessment of the vessel geometry in 3DA datasets did not differ significantly from 3D-DSA (VD1: r = 0.994, p = 0.0001; VD2:r = 0.994, p = 0.0001; VGI: r = 0.899, p = 0.0001). Qualitative analysis of IAS location (3DA/3D-DSA:nICA/C4 = 1, nICA/C7 = 1, nMCA/M1 = 4, nVA/V4 = 2, nBA = 2) and the visual IAS grading (3DA/3D-DSA:nlow-grade = 3, nmedium-grade = 5, nhigh-grade = 2) revealed identical results for 3DA and 3D-DSA, respectively. Quantitative IAS assessment showed a strong correlation regarding intra-/poststenotic diameters (rdintrastenotic = 0.995, pdintrastenotic = 0.0001; rdpoststenotic = 0.995, pdpoststenotic = 0.0001) and the percentual degree of luminal restriction (rNASCET 3DA = 0.981; pNASCET 3DA = 0.0001). CONCLUSIONS: The AI-based 3DA is a resilient algorithm for the visualization of IAS and shows comparable results to 3D-DSA. Hence, 3DA is a promising new method that allows a considerable patient-dose reduction, and its clinical implementation would be highly desirable.

Can Perfusion-Based Brain Tissue Oxygenation MRI Support the Understanding of Cerebral Abscesses In Vivo?

PURPOSE: The clinical condition of a brain abscess is a potentially life-threatening disease. The combination of MRI-based imaging, surgical therapy and microbiological analysis is critical for the treatment and convalescence of the individual patient. The aim of this study was to evaluate brain tissue oxygenation measured with dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI) in patients with brain abscess and its potential benefit for a better understanding of the environment in and around brain abscesses. METHODS: Using a local database, 34 patients (with 45 abscesses) with brain abscesses treated between January 2013 and March 2021 were retrospectively included in this study. DSC-PWI imaging and microbiological work-up were key inclusion criteria. These data were analysed regarding a correlation between DSC-PWI and microbiological result by quantifying brain tissue oxygenation in the abscess itself, the abscess capsula and the surrounding oedema and by using six different parameters (CBF, CBV, CMRO2, COV, CTH and OEF). RESULTS: Relative cerebral blood flow (0.335 [0.18-0.613] vs. 0.81 [0.49-1.08], p = 0.015), relative cerebral blood volume (0.44 [0.203-0.72] vs. 0.87 [0.67-1.2], p = 0.018) and regional cerebral metabolic rate for oxygen (0.37 [0.208-0.695] vs. 0.82 [0.55-1.19], p = 0.022) were significantly lower in the oedema around abscesses without microbiological evidence of a specific bacteria in comparison with microbiological positive lesions. CONCLUSIONS: The results of this study indicate a relationship between brain tissue oxygenation status in DSC-PWI and microbiological/inflammatory status. These results may help to better understand the in vivo environment of brain abscesses and support future therapeutic decisions.

PASSED: Brain atrophy in non-demented individuals in a long-term longitudinal study from two independent cohorts.

Introduction: Alzheimer's disease (AD) is indicated by a decrease in amyloid beta 42 (Aß42) level or the Aß42/Aß40 ratio, and by increased levels of Tau with phosphorylated threonine at position 181 (pTau181) in cerebrospinal fluid (CSF) years before the onset of clinical symptoms. However, once only pTau181 is increased, cognitive decline in individuals with subjective or mild cognitive impairment is slowed compared to individuals with AD. Instead of a decrease in Aß42 levels, an increase in Aß42 was observed in these individuals, leading to the proposal to refer to them as nondemented subjects with increased pTau-levels and Aß surge with subtle cognitive deterioration (PASSED). In this study, we determined the longitudinal atrophy rates of AD, PASSED, and Biomarker-negative nondemented individuals of two independent cohorts to determine whether these groups can be distinguished by their longitudinal atrophy patterns or rates. Methods: Depending on their CSF-levels of pTau 181 (T), total Tau (tTau, N), Aß42 or ratio of Aß42/Aß40 (A), 185 non-demented subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 62 non-demented subjects from Erlangen AD cohort were assigned to an ATN group (A-T-N-, A-T+N±, A+T-N±and A+T+N±) and underwent T1-weighted structural magnetic resonance imaging (sMRI). Longitudinal grey matter (GM) atrophy patterns were assessed with voxel-based morphometry (VBM) using the cat12 toolbox on spm12 (statistical parametric mapping) of MRI scans from individuals in the ADNI cohort with a mean follow-up of 2 and 5 years, respectively. The annualized atrophy rate for individuals in the Erlangen cohort was determined using region of interest analysis (ROI) in terms of a confirmatory analysis. Results: In the A-T+N± group, VBM did not identify any brain region that showed greater longitudinal atrophy than the A+T+N±, A+T+N± or biomarker negative control group. In contrast, marked longitudinal atrophy in the temporal lobe was evident in the A+T-N± group compared with A+T-N± and biomarker-negative subjects. The ROI in the angular gyrus identified by VBM analysis of the ADNI cohort did not discriminate better than the hippocampal volume and atrophy rate between AD and PASSED in the confirmatory analysis. Discussion: In this study, nondemented subjects with PASSED did not show a unique longitudinal atrophy pattern in comparison to nondemented subjects with AD. The nonsignificant atrophy rate compared with controls suggests that increased pTau181-levels without concomitant amyloidopathy did not indicate a neurodegenerative disorder.

Cerebrospinal fluid biomarkers for cerebral amyloid angiopathy.

Integrating cerebrospinal fluid-biomarkers into diagnostic workup of patients with sporadic cerebral amyloid angiopathy may support early and correct identification. We aimed to identify and validate clinical- and cerebrospinal fluid-biomarkers for in vivo diagnosis of cerebral amyloid angiopathy. This observational cohort study screened 2795 consecutive patients admitted for cognitive complaints to the academic departments of neurology and psychiatry over a 10-year period (2009-2018). We included 372 patients with available hemosiderin-sensitive MR imaging and cerebrospinal fluid-based neurochemical dementia diagnostics, i.e. Aß40, Aß42, t-tau, p-tau. We investigated the association of clinical- and cerebrospinal fluid-biomarkers with the MRI-based diagnosis of cerebral amyloid angiopathy, applying confounder-adjusted modelling, receiver operating characteristic and unsupervised cluster analyses. We identified 67 patients with cerebral amyloid angiopathy, 76 patients with Alzheimer's disease, 75 patients with mild cognitive impairment due to Alzheimer's disease, 76 patients with mild cognitive impairment with unlikely Alzheimer's disease and 78 healthy controls. Patients with cerebral amyloid angiopathy showed a specific cerebrospinal fluid pattern: average concentration of Aß40 [13 792 pg/ml (10 081-18 063)] was decreased compared to all controls (P < 0.05); Aß42 [634 pg/ml (492-834)] was comparable to Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease (P = 0.10, P = 0.93) but decreased compared to mild cognitive impairment and healthy controls (both P < 0.001); p-tau [67.3 pg/ml (42.9-91.9)] and t-tau [468 pg/ml (275-698)] were decreased compared to Alzheimer's disease (P < 0.001, P = 0.001) and mild cognitive impairment due to Alzheimer's disease (P = 0.001, P = 0.07), but elevated compared to mild cognitive impairment and healthy controls (both P < 0.001). Multivariate modelling validated independent clinical association of cerebral amyloid angiopathy with older age [odds-ratio: 1.06, 95% confidence interval (1.02-1.10), P < 0.01], prior lobar intracerebral haemorrhage [14.00 (2.64-74.19), P < 0.01], prior ischaemic stroke [3.36 (1.58-7.11), P < 0.01], transient focal neurologic episodes (TFNEs) [4.19 (1.06-16.64), P = 0.04] and gait disturbance [2.82 (1.11-7.15), P = 0.03]. For cerebrospinal fluid-biomarkers per 1 pg/ml, both lower Aß40 [0.9999 (0.9998-1.0000), P < 0.01] and lower Aß42 levels [0.9989 (0.9980-0.9998), P = 0.01] provided an independent association with cerebral amyloid angiopathy controlled for all aforementioned clinical confounders. Both amyloid biomarkers showed good discrimination for diagnosis of cerebral amyloid angiopathy among adjusted receiver operating characteristic analyses (area under the receiver operating characteristic curves, Aß40: 0.80 (0.73-0.86), P < 0.001; Aß42: 0.81 (0.75-0.88), P < 0.001). Unsupervised Euclidian clustering of all cerebrospinal fluid-biomarker-profiles resulted in distinct segregation of cerebral amyloid angiopathy patients from all controls. Together, we demonstrate that a distinctive set of cerebrospinal fluid-biomarkers effectively differentiate cerebral amyloid angiopathy patients from patients with Alzheimer's disease, mild cognitive impairment with or without underlying Alzheimer's disease, and healthy controls. Integrating our findings into a multiparametric approach may facilitate diagnosing cerebral amyloid angiopathy, and may aid clinical decision-making, but warrants future prospective validation.

Improved Detection of Cavernous Sinus Invasion of Pituitary Macroadenomas with Ultra-High-Field 7 T MRI.

To compare 7 T magnetic resonance imaging (MRI) of pituitary macroadenomas (PMA) with standard MRI and intraoperative findings regarding tumor detection, localization, size, and extension. Patients with suspected pituitary adenoma underwent pre-operative 1.5 T or 3 T and 7 T MRI; 14 patients with a PMA were included. A qualitative (lesion detection, location, cavernous sinus infiltration) and quantitative (lesion size, depth of cavernous sinus infiltration) analysis of 1.5 T, 3 T and 7 T MRI was performed and compared with intraoperative findings. Both 1.5/3 T and 7 T MRI enabled the detection of all PMAs; lesion size determination was equal. 7 T MRI enables more precise assessments of cavernous sinus infiltration of PMA (ncorrect 7T = 78.6%, ncorrect 1.5/3T = 64.3%). Ultra-high-field MRI is a reliable imaging modality for evaluation of PMAs providing exact information on lesion location and size. 7 T MRI yielded more accurate information on cavernous sinus infiltration with better agreement with intraoperative findings than standard MRI.

Clinical Evaluation of an Innovative Metal-Artifact-Reduction Algorithm in FD-CT Angiography in Cerebral Aneurysms Treated by Endovascular Coiling or Surgical Clipping.

Treated cerebral aneurysms (IA) require follow-up imaging to ensure occlusion. Metal artifacts complicate radiologic assessment. Our aim was to evaluate an innovative metal-artifact-reduction (iMAR) algorithm for flat-detector computed tomography angiography (FD-CTA) regarding image quality (IQ) and detection of aneurysm residua/reperfusion in comparison to 2D digital subtraction angiography (DSA). Patients with IAs treated by endovascular coiling or clipping underwent both FD-CTA and DSA. FD-CTA datasets were postprocessed with/without iMAR algorithm (MAR+/MAR−). Evaluation of all FD-CTA and DSA datasets regarding qualitative (IQ, MAR) and quantitative (coil package diameter/CPD) parameters was performed. Aneurysm occlusion was assessed for each dataset and compared to DSA findings. In total, 40 IAs were analyzed (ncoiling = 24; nclipping = 16). All iMAR+ datasets demonstrated significantly better IQ (pIQ coiling < 0.0001; pIQ clipping < 0.0001). iMAR significantly reduced the metal-artifact burden but did not affect the CPD. iMAR significantly improved the detection of aneurysm residua/reperfusion with excellent agreement with DSA (naneurysm detection MAR+/MAR−/DSA = 22/1/26). The iMAR algorithm significantly improves IQ by effective reduction of metal artifacts in FD-CTA datasets. The proposed algorithm enables reliable detection of aneurysm residua/reperfusion with good agreement to DSA. Thus, iMAR can help to reduce the need for invasive follow-up in treated IAs.

Transient Enlargement in Meningiomas Treated with Stereotactic Radiotherapy.

To investigate the occurrence of pseudoprogression/transient enlargement in meningiomas after stereotactic radiotherapy (RT) and to evaluate recently proposed volumetric RANO meningioma criteria for response assessment in the context of RT. Sixty-nine meningiomas (benign: 90%, atypical: 10%) received stereotactic RT from January 2005-May 2018. A total of 468 MRI studies were segmented longitudinally during a median follow-up of 42.3 months. Best response and local control were evaluated according to recently proposed volumetric RANO criteria. Transient enlargement was defined as volumetric increase ≥20% followed by a subsequent regression ≥20%. The mean best volumetric response was -23% change from baseline (range, -86% to +19%). According to RANO, the best volumetric response was SD in 81% (56/69), MR in 13% (9/69) and PR in 6% (4/69). Transient enlargement occurred in only 6% (4/69) post RT but would have represented 60% (3/5) of cases with progressive disease if not accounted for. Transient enlargement was characterized by a mean maximum volumetric increase of +181% (range, +24% to +389 %) with all cases occurring in the first year post-RT (range, 4.1-10.3 months). Transient enlargement was significantly more frequent with SRS or hypofractionation than with conventional fractionation (25% vs. 2%, p = 0.015). Five-year volumetric control was 97.8% if transient enlargement was recognized but 92.9% if not accounted for. Transient enlargement/pseudoprogression in the first year following SRS and hypofractionated RT represents an important differential diagnosis, especially because of the high volumetric control achieved with stereotactic RT. Meningioma enlargement during subsequent post-RT follow-up and after conventional fractionation should raise suspicion for tumor progression.

Neurometabolic Dysfunction in SPG11 Hereditary Spastic Paraplegia.

BACKGROUND: Pathogenic variants in SPG11 cause the most common autosomal recessive complicated hereditary spastic paraplegia. Besides the prototypical combination of spastic paraplegia with a thin corpus callosum, obesity has increasingly been reported in this multisystem neurodegenerative disease. However, a detailed analysis of the metabolic state is lacking. METHODS: In order to characterize metabolic alterations, a cross-sectional analysis was performed comparing SPG11 patients (n = 16) and matched healthy controls (n = 16). We quantified anthropometric parameters, body composition as determined by bioimpedance spectroscopy, and serum metabolic biomarkers, and we measured hypothalamic volume by high-field MRI. RESULTS: Compared to healthy controls, SPG11 patients exhibited profound changes in body composition, characterized by increased fat tissue index, decreased lean tissue index, and decreased muscle mass. The presence of lymphedema correlated with increased extracellular fluid. The serum levels of the adipokines leptin, resistin, and progranulin were significantly altered in SPG11 while adiponectin and C1q/TNF-related protein 3 (CTRP-3) were unchanged. MRI volumetry revealed a decreased hypothalamic volume in SPG11 patients. CONCLUSIONS: Body composition, adipokine levels, and hypothalamic volume are altered in SPG11. Our data indicate a link between obesity and hypothalamic neurodegeneration in SPG11 and imply that specific metabolic interventions may prevent obesity despite severely impaired mobility in SPG11.

Standardized acquisition and post-processing of dynamic susceptibility contrast perfusion in patients with brain tumors, cerebrovascular disease and dementia: comparability of post-processing software.

OBJECTIVE: MR-perfusion post-processing still lacks standardization. This study evaluates the results of perfusion analysis with two established software solutions in a large series of patients with different diseases when a highly standardized processing workflow is ensured. METHODS: Multicenter data of 260 patients (80 with brain tumors, 124 with cerebrovascular disease and 56 with dementia examined with the same MR protocol) were analyzed. Raw data sets were processed with two software suites: Olea sphere and NordicICE. Group differences were analyzed with paired t-tests and one-way ANOVA. RESULTS: Perfusion metrics were significantly different for all examined diseases in the unaffected brain for both software suites [ratio cortex/white matter left hemisphere: mean transit time (MTT) 0.991 vs 0.847, p < 0.05; relative cerebral bloodflow (rBF) 3.23 vs 4.418, p < 0.001; relative cerebral bloodvolume (rBVc) 2.813 vs 3.884, p < 0.001; right hemisphere: MTT 1.079 vs 0.854, p < 0.05; rBF 3.262 vs 4.378, p < 0.001; rBVc 2.762 vs 3.935, p < 0.001)]. Perfusion results were also significantly different in patients with stroke (ratio cortex/white matter affected hemisphere: MTT 1.058 vs 0.784; p < 0.001), dementia (ratio cortex/white matter left hemisphere: rBVc 1.152 vs 1.795, p < 0.001; right hemisphere: rBVc 1.396 vs 1.662, p < 0.05) and brain tumors (ratio cortex/whole tumor rBVc: 0.778 vs 0.919, p < 0.001 and ratio cortex/tumor hotspot rBVc: 0.529 vs 0.512, p < 0.05). CONCLUSION: Despite a highly standardized workflow, parametric perfusion maps are depended on the chosen software. Radiologists should consider software related variances when using dynamic susceptibility contrast perfusion for clinical imaging and research. ADVANCES IN KNOWLEDGE: This multicenter study compared perfusion parameters calculated by two commercial dynamic susceptibility contrast perfusion post-processing software solutions in different central nervous system disorders with a large sample size and a highly standardized processing workflow. Despite, parametric perfusion maps are depended on the chosen software which impacts clinical imaging and research.

Volumetric Regression in Brain Metastases After Stereotactic Radiotherapy: Time Course, Predictors, and Significance.

BACKGROUND: There is insufficient understanding of the natural course of volumetric regression in brain metastases after stereotactic radiotherapy (SRT) and optimal volumetric criteria for the assessment of response and progression in radiotherapy clinical trials for brain metastases are currently unknown. METHODS: Volumetric analysis via whole-tumor segmentation in contrast-enhanced 1 mm³-isotropic T1-Mprage sequences before SRT and during follow-up. A total of 3,145 MRI studies of 419 brain metastases from 189 patients were segmented. Progression was defined using a volumetric extension of the RANO-BM criteria. A subset of 205 metastases without progression/radionecrosis during their entire follow-up of at least 3 months was used to study the natural course of volumetric regression after SRT. Predictors for volumetric regression were investigated. A second subset of 179 metastases was used to investigate the prognostic significance of volumetric response at 3 months (defined as ≥20% and ≥65% volume reduction, respectively) for subsequent local control. RESULTS: Median relative metastasis volume post-SRT was 66.9% at 6 weeks, 38.6% at 3 months, 17.7% at 6 months, 2.7% at 12 months and 0.0% at 24 months. Radioresistant histology and FSRT vs. SRS were associated with reduced tumor regression for all time points. In multivariate linear regression, radiosensitive histology (p=0.006) was the only significant predictor for metastasis regression at 3 months. Volumetric regression ≥20% at 3 months post-SRT was the only significant prognostic factor for subsequent control in multivariate analysis (HR 0.63, p=0.023), whereas regression ≥65% was no significant predictor. CONCLUSIONS: Volumetric regression post-SRT does not occur at a constant rate but is most pronounced in the first 6 weeks to 3 months. Despite decreasing over time, volumetric regression continues beyond 6 months post-radiotherapy and may lead to complete resolution of controlled lesions by 24 months. Radioresistant histology is associated with slower regression. We found that a cutoff of ≥20% regression for the volumetric definition of response at 3 months post-SRT was predictive for subsequent control whereas the currently proposed definition of ≥65% was not. These results have implications for standardized volumetric criteria in future radiotherapy trials for brain metastases.

FSRT vs. SRS in Brain Metastases-Differences in Local Control and Radiation Necrosis-A Volumetric Study.

Background: While the role of stereotactic radiotherapy for brain metastases is increasing, evidence on the comparative efficacy and safety of fractionated stereotactic radiotherapy (FSRT) and single-session radiosurgery (SRS) is scarce. Methods: Longitudinal volumetric analysis was performed in a consecutive cohort of 120 patients and 190 brain metastases (>0.065 cm3 in volume / > ~5 mm in diameter) treated exclusively with FSRT (n = 98) and SRS (n = 92), respectively. A total of 972 tumor segmentations was used, averaging 5.1 time points per metastasis. Progression was defined using a volumetric extension of the RANO-BM criteria. Local control and radionecrosis were compared for lesions treated with FSRT and SRS, respectively. Results: Metastases treated with FSRT were significantly larger at baseline (mean, 4.66 vs. 0.40 cm3, p < 0.001). Biologically effective dose (BED) for metastases (α/ß = 12, linear-quadratic-cubic model) was significantly associated with local control, whereas BED for normal brain (α/ß = 2, linear-quadratic model) was significantly associated with radionecrosis. Median time to local progression was 22.9 months in the FSRT group compared to 14.5 months in the SRS group (p = 0.022). Overall radionecrosis rate at 12 months was 3.4% for FSRT and 14.8% for SRS (p = 0.010). Radionecrosis °IV requiring resection with histologic proof of radiation necrosis also was significantly reduced in the FSRT group (FSRT 0.0% vs. SRS 3.9%, p = 0.041). In multivariate analysis, FSRT was associated with reduced risk of progression (HR 0.47, p = 0.015) and reduced risk of radionecrosis (HR 0.18, p = 0.045). Conclusions: This volumetric study provides initial evidence that the improvements in therapeutic ratio expected for FSRT in larger brain metastases, might equally extend into the domain of smaller metastases, traditionally less considered for fractionated treatment. FSRT might constitute an important tool to further increase local control and reduce radionecrosis risk in stereotactic radiotherapy for brain metastases, that should be assessed in randomized intervention trials.

Brain volume reduction after whole-brain radiotherapy: quantification and prognostic relevance.

Background: Recent studies have questioned the value of adding whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) for brain metastasis treatment. Neurotoxicity, including radiation-induced brain volume reduction, could be one reason why not all patients benefit from the addition of WBRT. In this study, we quantified brain volume reduction after WBRT and assessed its prognostic significance. Methods: Brain volumes of 91 patients with cerebral metastases were measured during a 150-day period after commencing WBRT and were compared with their pretreatment volumes. The average daily relative change in brain volume of each patient, referred to as the "brain volume reduction rate," was calculated. Univariate and multivariate Cox regression analyses were performed to assess the prognostic significance of the brain volume reduction rate, as well as of 3 treatment-related and 9 pretreatment factors. A one-way analysis of variance was used to compare the brain volume reduction rate across recursive partitioning analysis (RPA) classes. Results: On multivariate Cox regression analysis, the brain volume reduction rate was a significant predictor of overall survival after WBRT (P < 0.001), as well as the number of brain metastases (P = 0.002) and age (P = 0.008). Patients with a relatively favorable prognosis (RPA classes 1 and 2) experienced significantly less brain volume decrease after WBRT than patients with a poor prognosis (RPA class 3) (P = 0.001). There was no significant correlation between delivered radiation dose and brain volume reduction rate (P = 0.147). Conclusion: In this retrospective study, a smaller decrease in brain volume after WBRT was an independent predictor of longer overall survival.