Abstract Purpose To evaluate delayed imaging after single-dose (0.05 mmol/kg) and double-dose (0.1 mmol/kg) gadopiclenol (i.e. standard dose for other MR contrast agents) in the detection of brain metastases. Methods In this prospective single-center study, 156 subjects (73 female; mean age 63.8 ± 12.6 years) underwent MRI (3T, n = 152) prior to stereotactic radiosurgery. T1-weighted 3D SPACE sequences were used for all evaluations. All subjects had standard postcontrast acquisitions with the recommended dose of gadopiclenol (0.05 mmol/kg). Delayed imaging was additionally performed after roughly 13 minutes; half of subjects received an additional dose of gadopiclenol prior to the delayed imaging (delayed double dose [DDD], n = 81), while the remaining subjects did not (delayed single dose [DSD], n = 78). Three blinded neuroradiologists independently evaluated all scans across 4 sessions minimally 4 weeks apart. Lesion coordinates were spatially clustered and classified under strict (unanimous) and majority (2-of-3) reference standards. Signal intensity ratios were evaluated in a subset of lesions (normalized to normal-appearing white matter [NAWM]). Results A total of 1,035 consensus and 1,335 majority-detected lesions were identified; median consensus lesion diameter was 7 mm (IQR 4–15). Among consensus lesions, 41% were ≤5 mm. DDD imaging detected significantly more consensus lesions than standard non-delayed (255 vs. 215, p < 0.001), while DSD imaging did not (287 vs. 278, p = 0.48). The DDD upstaging-to-downstaging ratio was 2.9:1 versus 1.1:1 for DSD. The DDD detection advantage was predominantly driven by small lesions: 79% of additional majority-detected lesions on DDD scans were ≤5 mm. The lesion-to-NAWM ratio increased 18% on DDD scans (1.83 to 2.13, p < 0.001) but was unchanged with DSD (p = 0.70). The DDD benefit was uniform across all readers with no significant reader×dose interaction. Conclusion DDD gadopiclenol significantly improves detection of small brain metastases and enhances lesion-to-tissue contrast, supporting its use in pre-radiosurgery planning.

BACKGROUND:Glioblastoma (GBM) is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification. METHODS:We developed a highly reproducible, personalized prognostication, and clinical subgrouping system using machine learning (ML) on routine clinical data, magnetic resonance imaging (MRI), and molecular measures from 2838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, and III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]). RESULTS:The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95% CI: 1.43-1.84, P < .001) and 3.48 (95% CI: 2.94-4.11, P < .001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort. CONCLUSIONS:Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach to personalized patient management and clinical trial stratification in GBM.

Objectives Accurate detection of metastatic brain lesions (MBL) is critical due to advances in radiosurgery. We compared the results of three readers in detecting MBL using T1-weighted 2D spin echo (SE) and sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) sequences with whole-brain coverage at both 1.5 T and 3 T. Methods Fifty-six patients evaluated for MBL were included and underwent a standard protocol (1.5 T, n = 37; 3 T, n = 19), including postcontrast T1-weighted SE and SPACE. The rating was performed by three raters in two sessions > six weeks apart. The true number of MBL was determined using all available imaging including follow-up. Intraclass correlations for intra-rater and inter-rater agreement were calculated. Signal intensity ratios (SIR; enhancing lesion, white matter) were determined on a subset of 46 MBL > 4 mm. A paired t -test was used to evaluate postcontrast sequence order and SIR. Reader accuracy was evaluated by the coefficient of determination. Results A total of 135 MBL were identified (mean/subject 2.41, SD 6.4). The intra-rater agreement was excellent for all 3 raters (ICC = 0.97–0.992), as was the inter-rater agreement (ICC = 0.995 SE, 0.99 SPACE). Subjective qualitative ratings were lower for SE images; however, signal intensity ratios were higher in SE sequences. Accuracy was high in all readers for both SE ( R 2 0.95–0.96) and SPACE ( R 2 0.91–0.96) sequences. Conclusions Although SE sequences are superior to gradient echo sequences in the detection of small MBL, they have long acquisition times and frequent artifacts. We show that T1-weighted SPACE is not inferior to standard thin-slice SE sequences in the detection of MBL at both imaging fields. Critical relevance statement Our results show the suitability of 3D T1-weighted turbo spin echo (TSE) sequences (SPACE, CUBE, VISTA) in the detection of brain metastases at both 1.5 T and 3 T. Key points • Accurate detection of brain metastases is critical due to advances in radiosurgery. • T1-weighted SE sequences are superior to gradient echo in detecting small metastases. • T1-weighted 3D-TSE sequences may achieve high resolution and relative insensitivity to artifacts. • T1-weighted 3D-TSE sequences have been recommended in imaging brain metastases at 3 T. • We found T1-weighted 3D-TSE equivalent to thin-slice SE at 1.5 T and 3 T. Graphical Abstract

Abstract Gadolinium-based contrast agents (GBCA) were introduced with high expectations for favorable efficacy, low nephrotoxicity, and minimal allergic-like reactions. Nephrogenic systemic fibrosis and proven gadolinium retention in the body including the brain has led to the restriction of linear GBCAs and a more prudent approach regarding GBCA indication and dosing. In this review, we present the chemical, physical, and clinical aspects of this topic and aim to provide an equanimous and comprehensive summary of contemporary knowledge with a perspective of the future. In the first part of the review, we present various elements and compounds that may serve as MRI contrast agents. Several GBCAs are further discussed with consideration of their relaxivity, chelate structure, and stability. Gadolinium retention in the brain is explored including correlation with the presence of metalloprotein ferritin in the same regions where visible hyperintensity on unenhanced T1-weighted imaging occurs. Proven interaction between ferritin and gadolinium released from GBCAs is introduced and discussed, as well as the interaction of other elements with ferritin; and manganese in patients with impaired liver function or calcium in Fahr disease. We further present the concept that only high-molecular-weight forms of gadolinium can likely visibly change signal intensity on unenhanced T1-weighted imaging. Clinical data are also presented with respect to potential neurological manifestations originating from the deep-brain nuclei. Finally, new contrast agents with relatively high relaxivity and stability are introduced. Critical relevance statement GBCA may accumulate in the brain, especially in ferritin-rich areas; however, no adverse neurological manifestations have been detected in relation to gadolinium retention. Key Points Gadolinium currently serves as the basis for MRI contrast agents used clinically. No adverse neurological manifestations have been detected in relation to gadolinium retention. Future contrast agents must advance chelate stability and relativity, facilitating lower doses. Graphical Abstract

Abstract High grade glioma (HGG) is the most common primary brain tumour; we aimed to evaluate T2 relaxivity and diffusion tensor imaging (DTI) metrics in the prediction of progression-free survival. Seventy-two non-recurrent HGG subjects (IDH: MUT=10, Unknown=20) followed at our institution after surgery and combined chemo-radiotherapy were included. All data used were prior to progression as per RANO criteria; only the first 2 years of follow up was included in the analyses. T2 relaxation rates (1/T2) were calculated voxel-wise assuming mono-exponential decay. Diffusion data were corrected from two opposite phase encode acquisitions and DTI metrics evaluated included FA, MD, p, q, and L1. Whole- and half-brain (ipsilateral/contralateral) masks were generated by brain extraction and registration; data extracted from these masks were analyzed using python 3.8 with the exception of numerous histogram features extracted using fsl tools. Radiomics features were also extracted using the pyradiomics package. The lofo-importance package was used for feature selection. A multi-level approach was used to reduce the initial 32,000 MRI features to a final number of 443; from these, the 50 highest-ranked features were used further. Within-subject feature engineering was then performed including 1–4 step forward and backward lag, lag difference, as well as area, maximum, mean and cumulative sum. Non-MRI features included available demographic, histological and treatment-related data. A LightGBM classification model was used for the prediction of progression within 90 days; the data were grouped by subject, such that each subject was present only in training or testing datasets. Hyperparameters were tuned using randomized search cross validation, and the final model using 5-fold cross validation reached a mean ROC-AUC of 0.89. Our results show the potential of quantitative MRI features derived from qualitatively unremarkable images within the progress-free interval to identify subjects at risk of imminent progression.

Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role. We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method. Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95

Abstract BACKGROUND Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression by a multi-modal mechanism of action. TTFields therapy is FDA-approved for newly diagnosed glioblastoma (ndGBM) based on results from the randomized, phase 3 EF-14 study (NCT00916409). We assessed the overall survival (OS) benefit of adding TTFields therapy to standard of care (SOC) in ndGBM, as well as the relationship between OS and time using the device. METHODS A systematic literature review (PubMed, Embase, and Cochrane Library) identified single-cohort and comparative clinical studies that assessed survival in patients with ndGBM who received TTFields therapy. Inter-study heterogeneity was quantified using the Higgins I2 statistic and Cochran Q test. A distribution-free random-effects method was used to pool survival curves. RESULTS Nine studies were identified that evaluated survival with TTFields therapy in ndGBM. Of these, 7 studies (1430 patients) that compared TTFields therapy with SOC to SOC alone, were included in the pooled analysis for OS. The pooled data showed significantly longer OS with TTFields therapy/SOC versus SOC alone (HR: 0.63; 95% CI, 0.53-0.75; P<0.001). A sensitivity analysis indicated that the effect was robust and independent of any individual study. In post-approval studies, pooled median OS was 22.2 months (95% CI, 17.3-42.6) for TTFields therapy/SOC and 17.3 months (95% CI, 13.6-22.0) for SOC alone. Gross total resection was generally more prevalent in the real-world setting, irrespective of TTFields therapy use. Average recommended device usage of ≥75% was associated with prolonged OS vs <75% usage in 6 studies (pooled HR: 0.60; 95% CI, 0.48-0.73; P<0.001). CONCLUSIONS Pooled analysis of comparative TTFields therapy studies suggests a significant survival benefit with TTFields added to SOC for patients with ndGBM, and that a recommended 75% usage rate may be clinically meaningful in the real-world setting.

Introduction The prognosis of glioblastoma remains unfavorable. TTFields utilize low intensity electric fields (frequency 150–300 kHz) that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields are delivered via transducer arrays placed on the patients’ scalp. Methods: Between the years 2004 and 2022, 55 patients (20 female), aged 21.9–77.8 years (mean age 47.3±11.8 years; median 47.6 years) were treated with TTFields for newly-diagnosed GBM, and compared to 54 control patients (20 females), aged 27.0–76.7 years (mean age 51.4±12.2 years; median 51.7 years) (p=0.08). All patients underwent gross total or partial resection of GBM. One patient had biopsy only. When available, MGMT promoter methylation status and IDH mutation was detected. Results Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.64, p=0.031; and 0.61, p=0.028 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 19.75 months. Seven patients with TTFields usage ≤60% (23–60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 12.45 months. Median OS of TTF patients was 31.67 months compared to 24.80 months for controls. Discussion This is the most extensive study on newly-diagnosed GBM patients treated with TTFields, covering a period of 18 years at a single center and presenting not only data from clinical trials but also a group of 36 patients treated with TTFields as a part of routine clinical practice.

2059 Background: Tumor Treating Fields (TTFields) are electric fields that exert forces on cancer cells, disrupting processes critical for cancer cell viability and tumor progression. TTFields therapy became an FDA-approved treatment option for patients with newly diagnosed glioblastoma (GBM) in 2015 on the basis of the randomized controlled EF-14 study (NCT00916409). Subsequent approvals worldwide and increased adoption of TTFields has led to the question of whether or not a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role. Methods: A literature search was conducted using PubMed, Embase, and the Cochrane Library to identify clinical studies evaluating overall survival in adult patients with GBM treated with TTFields therapy. Comparative studies and single-cohort studies reporting on survival outcomes were included in the analysis. Inter-study heterogeneity was assessed using the Cochran Q test and quantified using the Higgins I 2 statistic. Survival curves were pooled using a distribution-free random-effects method. Results: Our review identified 8 studies evaluating the clinical efficacy of TTFields therapy in newly diagnosed GBM, with patients spanning diverse geographic regions. Of these 8, 6 studies (reporting on a total of 1378 patients) compared the addition of TTFields therapy to standard of care (SOC) vs SOC alone, and were included in a pooled analysis for overall survival. Meta-analysis of comparative studies indicated a significant improvement in overall survival for patients treated with TTFields therapy vs those not receiving treatment (hazard ratio [HR]: 0.62; 95% CI, 0.52–0.73; P < 0.001). Inter-study heterogeneity was examined, and a sensitivity analysis indicated the pooled effect was robust and not dependent on any individual study. Among post-approval studies, the pooled median overall survival was 22.2 months (95% CI, 17.3–42.6) for TTFields-treated patients and 17.3 months (95% CI, 13.6–22.0) for the non-TTFields group. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, among studies reporting data on TTFields device usage, an average device usage rate of 75% or higher was found to consistently associate with prolonged survival when compared to an average usage rate below 75% (pooled HR: 0.63; 95% CI, 0.48–0.83; P = 0.001). Conclusions: Meta-analysis of comparative studies suggests a significant survival benefit with TTFields therapy added to standard radiochemotherapy for patients with newly diagnosed GBM, and that a 75% usage rate may be meaningful in the real-world setting.

Introduction: We aimed to evaluate T2 relaxation times in the follow-up of patients with glioblastoma (GBM), the most common and aggressive primary brain tumor with nearly universal recurrence following standard therapy. Methods: In this partially retrospective study, 53 patients (mean age 45.05 years ± 12.6) with non-recurrent GBM followed at our department roughly every 2 months after surgery and combined chemo-radiotherapy were included (>180 days progression-free survival [PFS] as determined by RANO,1 ≥3 MRI examinations in the PFS interval [same scanner and protocol]). Thirty-six patients additionally received Tumor-Treating Fields (TTFields) therapy. All data used were prior to progression. T2 relaxation rates (1/T2) were calculated voxel-wise assuming mono-exponential decay. Whole-brain (WB) histogram values were extracted from 1/T2 maps including skewness, kurtosis, mean, median, 15 and 85 percentile values and variance. We additionally segmented 1/T2 maps using a 5 compartment Gaussian mixture model (Python v3.8.2), producing mean, variance and voxel percentage for each component. To evaluate predictive potential with respect to PFS, we used a deep recurrent neural network (long short-term memory [LSTM] model) in Tensorflow v2.3.1 (4 timesteps); the features used included the above metrics as well as TTFields treatment status and scanner. Twenty subjects were included in the predictive model, as inclusion criteria were stricter (progression, ≤120 days between all MRIs [mean 43.6 days], ≥4 PFS MRIs). Two models were tested: a regression model (days to progression) and a classification model (±18 months PFS; models differed in output layer). Both models were run 10 times; mean results are presented. Results: We found WB median 1/T2 correlated with PFS, as values decreased prior to progression. WB median 1/T2 linear regression slopes also differed in progression versus pseudo-progression, as values were relatively stable in pseudo-progression. The deep LSTM regression model achieved an R2 of 97%. The deep LSTM classification model achieved a mean macro precision of 86%, recall 85% and F1 accuracy of 85% in predicting progression within 18 months. Conclusions: We found very intriguing results with WB median 1/T2 measurements in distinguishing progression from pseudo-progression, and in suggesting progression despite otherwise unremarkable imaging. A more complex predictive model trained on pre-progression data, using a fully-automated segmentation method followed by deep learning, showed very promising results. The present results may find utility in the monitoring of GBM patients and may be advantageous to include in multimodal predictive models. Reference: 1. Wen PY et al. J Clin Oncol 2010;28:1963-1972. Citation Format: Aaron M. Rulseh, Josef Vymazal. Prediction of progression-free survival in patients with primary glioblastoma: MRI T2 relaxivity and deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4138.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumour; we aimed to evaluate T2 relaxivity in their follow. Fifty-one newly diagnosed GBM followed at our department after surgery and combined chemo-radiotherapy were included (&gt; 180 days progression-free survival [PFS] as determined by RANO, ≥ 3 MRI examinations in the PFS interval). All data used were prior to progression. T2 relaxation rates (1/T2f) were calculated voxel-wise assuming mono-exponential decay. Whole-brain (WB) values were extracted including skewness, kurtosis, mean, median, 15 and 85 percentile histogram values and variance. We additionally segmented the 1/T2f volumes using a 5 compartment Gaussian mixture model, producing mean, variance and percent per component. To evaluate predictive potential with respect to PFS, we used a deep long short-term memory (LSTM) model in tensorflow (4 timesteps). Twenty subjects were included in the predictive model, as inclusion criteria differed (progression, ≤ 120 days between all MRIs [mean 44.3 days], ≥ 4 PFS MRIs). Two models were tested: a regression model (days to progression) and a classification model (±18 months PFS; models differed in output layer). Both models were run 10 times; mean results are presented. We found WB median 1/T2f correlated with PFS, as values decreased prior to progression. WB median 1/T2f linear regression slopes also differed in progression vs. pseudo-progression. The deep LSTM regression model achieved an R2 of 86%. The deep LSTM classification model achieved a mean macro precision of 85%, recall 84% and F1 accuracy of 84% in classifying progression/no progression at an 18 month cutoff. We found very intriguing results with WB median 1/T2f measurements in distinguishing progression from pseudo-progression, and in suggesting progression despite otherwise unremarkable imaging. A more complex predictive model, using a fully-automated segmentation method followed by deep learning, was very promising. Our results may find utility in the monitoring of GBM patients.

Glioblastoma (GBM) is the most common and aggressive primary brain tumour; we aimed to evaluate T2 relaxivity in their follow. Fifty-one newly diagnosed GBM followed at our department after surgery and combined chemo-radiotherapy were included (> 180 days progression-free survival [PFS] as determined by RANO, ≥ 3 MRI examinations in the PFS interval). All data used were prior to progression. T2 relaxation rates (1/T2f) were calculated voxel-wise assuming mono-exponential decay. Whole-brain (WB) values were extracted including skewness, kurtosis, mean, median, 15 and 85 percentile histogram values and variance. We additionally segmented the 1/T2f volumes using a 5 compartment Gaussian mixture model, producing mean, variance and percent per component. To evaluate predictive potential with respect to PFS, we used a deep long short-term memory (LSTM) model in tensorflow (4 timesteps). Twenty subjects were included in the predictive model, as inclusion criteria differed (progression, ≤ 120 days between all MRIs [mean 44.3 days], ≥ 4 PFS MRIs). Two models were tested: a regression model (days to progression) and a classification model (±18 months PFS; models differed in output layer). Both models were run 10 times; mean results are presented. We found WB median 1/T2f correlated with PFS, as values decreased prior to progression. WB median 1/T2f linear regression slopes also differed in progression vs. pseudo-progression. The deep LSTM regression model achieved an R2 of 86%. The deep LSTM classification model achieved a mean macro precision of 85%, recall 84% and F1 accuracy of 84% in classifying progression/no progression at an 18 month cutoff. We found very intriguing results with WB median 1/T2f measurements in distinguishing progression from pseudo-progression, and in suggesting progression despite otherwise unremarkable imaging. A more complex predictive model, using a fully-automated segmentation method followed by deep learning, was very promising. Our results may find utility in the monitoring of GBM patients.

Despite considerable progress in the management of many malignant tumors, the prognosis of the most malignant primary brain tumor, GBM, remains unfavorable. TTFields utilize low intensity electric fields with intermediate frequency (100–500 kHz) that act as an antimitotic, selectively inhibiting growth of rapidly dividing tumor cells by disrupting multiple phases of the cell cycle (metaphase, anaphase, and telophase) resulting in cellular apoptosis. TTFields are delivered via arrays of transducers placed on the patients’ scalp. Between 2004 and August 2021, 54 patients (KPS ≥, 20 female), aged 21.85–77.77 years (mean age 47.41 ± 11.92 years; median 47.88 years) were treated with TTFields for ndGBM, and compared to 52 control patients (15 females); aged 27.03–76.67 years (mean age 51.38 ± 12.55 years; median 51.74 years. All patients from both groups underwent gross total or partial resection of GBM. When available, MGMT promoter methylation status was comparable in both groups. The most frequent AE from TTFields therapy was skin irritation at the array site that usually responded to local corticosteroid application. Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.55, p=0.006; and 0.61, p=0.027 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 18.16 months. Seven patients with TTFields usage ≤ 60% (23–60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 11.04 months. In conclusion, this is one of the most extensive studies of ndGBM patients treated with TTFields, covering a period of 18 years in a single center. We demonstrate positive effects of TTFields on both PFS and OS in patients with ndGBM.

Gadolinium deposition in the brain following administration of gadolinium-based contrast agents (GBCAs) has led to health concerns. We show that some clinical GBCAs form Gd3+-ferritin nanoparticles at (sub)nanomolar concentrations of Gd3+ under physiological conditions. We describe their structure at atomic resolution and discuss potential relevance for clinical MRI.

Introduction: Glioblastoma multiforme (GBM) is the most common malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Tumor treating fields (TTFields; Optune, Novocure, Haifa, Israel) therapy is a novel treatment technique that has recently shown significant prolonged survival in GBM patients. This therapy is approved for the treatment of newly diagnosed and recurrent GBM and is based on the principle that low intensity, intermediate frequency alternating electric fields (100 to 300 kHz) have an anti-mitotic effect in specific cell types. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest. We aimed to compare overall survival between patients treated with standard therapy and standard therapy plus TTFields at our institution. Materials and Methods: A total of 34 patients (22 male, 15 female) diagnosed with GBM and treated by standard therapy plus TTFields (STDTh-TTF) at our institution were included. Standard therapy (STDTh) consisted of surgical resection, followed by combined radiotherapy and chemotherapy (Temozolomide); in 2 cases biopsy was performed in place of resection. The date of resection or biopsy was considered the entry date and was used in calculating survival, and ranged from June 2015 to July 2019. A matching control group treated by STDTh alone at our institution was assembled from our database, based primarily on date of resection or biopsy, and secondarily by age (1 subject underwent biopsy in place of resection). When assembling the control group, the investigators were blinded to survival outcome. Results: Significantly greater overall survival was observed for the group treated by TTFields in addition to standard therapy (p = 0.005; Hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.11-0.69). The groups were identical with respect to sex, and no differences with respect to age (p=0.12; STDTh-TTF mean 50.54 years, SD 10.3; STDTh mean 54.39 years, SD 9.3) or inclusion date (p=0.3) were detected. Conclusions: Our initial results appear promising with respect to overall survival in patients undergoing TTFields treatment in addition to standard therapy. Citation Format: Aaron Rulseh, Adam Derner, Jan Sroubek, Jan Klener, Josef Vymazal. Overall survival of glioblastoma patients treated by standard therapy in comparison to standard therapy plus tumor treating fields [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2038.

Objective: The purpose of the present study was to investigate if participants in NANOK study (National Normative Study of Cognitive Determinants of Healthy Ageing) who show no cognitive decline throughout five years (successful healthy agers; SHA) will show less age-related differences in instrumental activities of daily living (IADL) based on Functional Activities Questionnaire in comparison to participants who show subtle cognitive decline (Decliners) over time. Method: We used two different classifications of SHA: Rogalski (N = 25 SHA and N = 15 Decliners) based on cross-sectional neuropsychology measures and linear mixed model (LMEM; 20 SHA and 20 Decliners) based on the Montreal Cognitive Assessment longitudinal 5-years follow-up. Whole-brain T1- and T2-weighted images were corrected for distortions and segmented using Freesurfer. Whole-brain volumetry was performed using FSL's voxel-based morphometry tool. Results: The cognitive decline after four years follow-up but not age predicts subtle impairment in IADL in healthy ageing participants. We found brain volumetric differences between SHA and Decliners based on Rogalski but not LMEM classification especially in bilateral insular cortices and ventrolateral frontal cortex. The logistic regression model achieved an accuracy of 75% for the Rogalski in comparison to 67.5% for the LMEM classification. Conclusions: Slight restrictions in IADL seem to be a useful tool for screening healthy ageing participants at risk of developing subtle cognitive decline over a period of five years and the cross-sectional Rogalski criteria based on standardized neuropsychological measures were superior for tapping age-related brain changes to longitudinal LMEM classification based on screening (Montreal Cognitive Assessment).

Glioblastoma (GBM) is the most common malignant primary brain tumor, and methods to improve the early detection of disease progression and evaluate treatment response are highly desirable. We therefore explored changes in whole-brain apparent diffusion coefficient (ADC) values with respect to survival (progression-free [PFS], overall [OS]) in a cohort of GBM patients followed at regular intervals until disease progression. A total of 43 subjects met inclusion criteria and were analyzed retrospectively. Histogram data were extracted from standardized whole-brain ADC maps including skewness, kurtosis, entropy, median, mode, 15th percentile (p15) and 85th percentile (p85) values, and linear regression slopes (metrics versus time) were fitted. Regression slope directionality (positive/negative) was subjected to univariate Cox regression. The final model was determined by aLASSO on metrics above threshold. Skewness, kurtosis, median, p15 and p85 were all below threshold for both PFS and OS and were analyzed further. Median regression slope directionality best modeled PFS (p = 0.001; HR 3.3; 95% CI 1.6–6.7), while p85 was selected for OS (p = 0.002; HR 0.29; 95% CI 0.13–0.64). Our data show tantalizing potential in the use of whole-brain ADC measurements in the follow up of GBM patients, specifically serial median ADC values which correlated with PFS, and serial p85 values which correlated with OS. Whole-brain ADC measurements are fast and easy to perform, and free of ROI-placement bias.

INTRODUCTION: Ectopia is the most common sporadically occurring thyroid heterotopy. We present three cases of ectopic thyroid tissue with compression of the upper aerodigestive tract. The first case involved ectopic thyroid tissue in the lingual area of a 60-year-old male with dysphagia, swelling at the base of the tongue, and stomatolalia. The second case was a 66-year-old female with papillary thyroid carcinoma (PTC) in a thyroglossal duct cyst. The third patient was a 50-year-old female with aberrant thyroid tissue in the right submandibular region, with a cribriform-morular variant of PTC (CMV-PTC). METHODS: After resecting the heterotopic tissue and verifying the presence of PTC, the second and third cases underwent total thyroidectomy, and the third patient also underwent radioactive iodine ablation (RAI). Postoperative athyreosis was compensated by permanent levothyroxine substitution. RESULTS: The diagnosis of ectopic thyroid tissue is challenging. Clinical examination together with imaging methods play a key role, especially postoperative histological examination along with scintigraphy and single photon emission computed tomography (SPECT). Ultrasonography should be used to exclude normally localized thyroid tissue and to distinguish other tumorous diseases. In the pre-operative examination, ultrasound-guided fine-needle aspiration biopsy (US-FNAB) often results in technically-difficult sampling and non-diagnostic cytology. CONCLUSION: Resection is the most suitable therapy for clinical symptoms of a foreign body in the upper aerodigestive tract and inflammatory complications; total thyroidectomy follows in case of malignant transformation. Thyroid heterotopy is a rare pathological condition, yet it should be taken into consideration during differential diagnosis of tumorous oropharyngeal and neck lesions. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

Journal of Magnetic Resonance ImagingVolume 51, Issue 6 p. 1912-1913 Letter to the EditorOpen Access Does serial administration of gadolinium-based contrast agents affect patient neurological and neuropsychological status? Fourteen-year follow-up of patients receiving more than fifty contrast administrations Josef Vymazal MD, DSc, Josef Vymazal MD, DSc Department of Radiology, Na Homolce Hospital, Prague, Czech RepublicSearch for more papers by this authorLenka Krámská PhD, Lenka Krámská PhD Department of Neurology, Clinical Psychology, Na Homolce Hospital, Prague, Czech RepublicSearch for more papers by this authorHana Brožová MD, PhD, Hana Brožová MD, PhD Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine, Prague, Czech RepublicSearch for more papers by this authorEvžen Růžička MD, DSc, Evžen Růžička MD, DSc Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine, Prague, Czech RepublicSearch for more papers by this authorAaron M. Rulseh MD, PhD, Corresponding Author Aaron M. Rulseh MD, PhD aarulseh@gmail.com orcid.org/0000-0002-8332-4419 Department of Radiology, Na Homolce Hospital, Prague, Czech Republic*Aaron Rulseh (aarulseh@gmail.com)Search for more papers by this author Josef Vymazal MD, DSc, Josef Vymazal MD, DSc Department of Radiology, Na Homolce Hospital, Prague, Czech RepublicSearch for more papers by this authorLenka Krámská PhD, Lenka Krámská PhD Department of Neurology, Clinical Psychology, Na Homolce Hospital, Prague, Czech RepublicSearch for more papers by this authorHana Brožová MD, PhD, Hana Brožová MD, PhD Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine, Prague, Czech RepublicSearch for more papers by this authorEvžen Růžička MD, DSc, Evžen Růžička MD, DSc Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine, Prague, Czech RepublicSearch for more papers by this authorAaron M. Rulseh MD, PhD, Corresponding Author Aaron M. Rulseh MD, PhD aarulseh@gmail.com orcid.org/0000-0002-8332-4419 Department of Radiology, Na Homolce Hospital, Prague, Czech Republic*Aaron Rulseh (aarulseh@gmail.com)Search for more papers by this author First published: 30 October 2019 https://doi.org/10.1002/jmri.26948Citations: 11 Level of Evidence: : 1 Technical Efficacy: : Stage 5 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor: Gadolinium-based contrast agents (GBCAs) have been in clinical use for ~30 years and have been considered relatively safe in terms of acute allergy-like and chemotoxic reactions.1 The demonstration of increased signal intensity (SI) in the brain, particularly in the deep brain nuclei (dentate nucleus [DN] and globus pallidus [GP]) on unenhanced T1-weighted images following cumulative GBCA dosing and evidence of the presence of gadolinium (Gd) in these nuclei (and elsewhere)2 has generated concern over potential long-term detrimental effects of these agents, potentially leading to severe neurological deficits. As yet, however, no clinical manifestations of Gd toxicity or adverse clinical outcomes related to brain Gd retention have been observed following the repeated administration of any GBCA. Nevertheless, all linear GBCAs have been suspended in Europe with the exception of two substituted linear agents (MultiHance, Bracco Diagnostics, Princeton, NJ; and Primovist, Bayer Healthcare, Berlin, Germany) that are uniquely specific for liver imaging. The rationale for the suspension has been stated as: "to prevent any risks that could potentially be associated with gadolinium brain deposition."3 The basal ganglia and DN are primarily involved in cognitive processing and motor control.4 Damage to the DN and GP may therefore be expected to result predominantly in movement disorder manifestations such as resting tremor, rigidity, bradykinesia, and gait abnormalities, as well as cognitive impairment, depression, and neurobehavioral deficits. We therefore aimed to assess the neurological and neuropsychological status of four patients who received exceptionally large cumulative doses of GBCAs over many years at our center for the diagnosis and follow-up of glioblastoma multiforme (GBM). Materials and Methods We performed neurological and neuropsychological evaluation on four patients diagnosed with GBM in 2004–2005, verified histologically at two independent laboratories, who subsequently received at least 50 GBCA administrations as part of routine follow-up (Table 1). The study was approved by the institutional Ethics Committee and all subjects provided signed, informed consent to participate. Early magnetic resonance imaging (MRI) examinations were performed almost exclusively with Omniscan (GE Healthcare, Milwaukee, WI) and Magnevist (Bayer Healthcare, Berlin, Germany) at monthly intervals. Thereafter, examinations were performed primarily with MultiHance and macrocyclic GBCAs at bimonthly intervals or longer. Patients received fixed GBCA volumes that varied based on GBCA relaxivity and the concentration of the formulation. The mean (±standard deviation) volume of the 0.5 M agents was 10.8 ± 2.3 mL, with overall higher volumes administered for dotarem due to its lower relaxivity. The mean administered volume of the 1 M agent gadovist was 7.3 ± 2.2 mL. Table 1. Summary of Gadolinium-Based Contrast Agent (GBCA) Administrations GBCA type GBCA Patient 1 Patient 2 Patient 3 Patient 4 No. of exams Total volume (mL) No. of exams Total volume (mL) No. of exams Total volume (mL) No. of exams Total volume (mL) Simple linear Omniscan 10 110 15 155 9 90 7 70 Magnevist 14 140 10 100 9 90 6 60 Substituted linear MultiHance 22 216 12 134 24 279 23 234 Macrocyclic Gadovist 10 (56) 112a 31 (248) 496a 11 (86) 172a 9 (52.5) 105a ProHance 2 19 — — 1 9 5 59 Dotarem 6 83 — — 5 96 1 14 Unknownb 2 20 3 30 — — 2 20 Total 66 700 71 915 59 736 53 562 a Volume based on equivalence for a 0.5 M formulation. b Highly likely to be simple linear GBCAs based on examination dates. Detailed neurological and neuropsychological evaluations were performed in 2018, ~12–14 years after initial diagnosis. Neurological assessment in 2018 was performed by a neurologist (H.B.) with 16 years of experience. Assessment was performed both descriptively and by means of the Natural History and Neuroprotection in Parkinson Plus Syndromes—Parkinson Plus Scale (NNIPPS-PPS).5 Cognitive performance and mood status were tested with a battery of standardized neuropsychological tests and were performed by a clinical neuropsychologist (L.K.) with 16 years of experience. As impairment of multiple cognitive domains has been reported in GBM patients,6 the comprehensive battery comprised a wide variety of methods to assess different domains including global intellectual functioning, premorbid intellect level, language, verbal, perceptual and spatial functions, emotional and mood status, attention, and executive functions. Results and Discussion The four patients evaluated were 51, 42, 32, and 31 years of age at initial diagnosis and presented with Karnofsky performance scores of 70%, 100%, 100%, and 90%, respectively. All four patients had survived until the time of this report (ie, August 2019; roughly 13–15 years), are in relatively good health, lead independent lives, and no longer receive any relevant treatment. Additional specific details regarding these patients have been published previously.7 As of January 2019, these patients received between 53 and 71 GBCA administrations, corresponding to 562–915 mL of a 0.5 M GBCA formulation. Increased native T1-weighted SI was evident in the DN and GP of all four patients. None of the patients demonstrated any neurological or neuropsychological effects that could be attributed to GBCA administration or to Gd retention in the extrapyramidal nuclei. Two patients demonstrated no or only mild cognitive impairment, while the remaining two patients demonstrated cognitive impairment that can be attributed entirely to their age, clinical condition, and premorbid intellectual capacity. Importantly, no patient exhibited signs of rigidity, hypokinesis, or resting (or other) tremor and no patient exhibited manifestations indicative of parkinsonism or related movement disorders. Neuropsychological testing revealed no progression of tracked signs or symptoms. Although we cannot exclude selection bias in this cohort, we have no reason to hypothesize that their clinical outcome (continued survival) is related Gd retention in the brain. Our findings agree with previous observations suggesting no effect of multiple GBCA administrations on the incidence of parkinsonism8 and are at variance with a recent study in patients with multiple sclerosis (MS) that looked to correlate T1-weighted SI increases ascribed to brain Gd retention with loss of verbal fluency.9 In agreement with our findings, a more recent study in patients with MS has similarly found no effect attributed to DN hyperintensity, suggestive of Gd retention, on clinical worsening as indicated by assessment of expanded disability status scale (EDSS) scores.10 In conclusion, multiple applications of both linear and macrocyclic GBCAs over a period of 13–15 years did not lead to clinical impairment related to Gd deposition in the DN and GP. Neurological and neuropsychological testing of our patients did not reveal any aberrant findings beyond those that could be ascribed to each patient's premorbid intellectual capacity, to the location and progression of GBM, and to the therapeutic regimens undertaken. References 1European Society of Urogenital Radiology (ESUR) guidelines on contrast agents, Version 10.0. [http://www.esur-cm.org/]. 2Kanda T, Fukusato T, Matsuda M, et al. Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: Evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology 2015; 276: 228– 232. 3European Medicines Agency: EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans. [https://www.ema.europa.eu/documents/referral/gadolinium-article-31-referral-emas-final-opinion-confirms-restrictions-use-linear-gadolinium-agents_en.pdf]. 4Gillies MJ, Hyam JA, Weiss AR, et al. The cognitive role of the globus pallidus interna: Insights from disease states. Exp Brain Res 2017; 235: 1455– 1465. 5Payan CA, Viallet F, Landwehrmeyer BG, et al. Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: Validation of the NNIPPS—Parkinson Plus Scale. PLoS One 2011; 6:e 22293. 6Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: A clinical review. JAMA 2013; 310: 1842– 1850. 7Rulseh AM, Keller J, Klener J, et al. Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields. World J Surg Oncol 2012; 10: 220. 8Welk B, McArthur E, Morrow SA, et al. Association between gadolinium contrast exposure and the risk of parkinsonism. JAMA 2016; 316: 96– 98. 9Forslin Y, Shams S, Hashim F, et al. Retention of gadolinium-based contrast agents in multiple sclerosis: Retrospective analysis of an 18-year longitudinal study. AJNR Am J Neuroradiol 2017; 38: 1311– 1316. 10Cocozza S, Pontillo G, Lanzillo R, et al. MRI features suggestive of gadolinium retention do not correlate with Expanded Disability Status Scale worsening in multiple sclerosis. Neuroradiology 2019; 61: 155– 162. Citing Literature Volume51, Issue6June 2020Pages 1912-1913 ReferencesRelatedInformation