Early MRI Predictors of Relapse in Primary Central Nervous System Lymphoma Treated with MATRix Immunochemotherapy.

Primary Central Nervous System Lymphoma (PCNSL) is a highly malignant brain tumour. We investigated dynamic changes in tumour volume and apparent diffusion coefficient (ADC) measurements for predicting outcome following treatment with MATRix chemotherapy in PCNSL. Patients treated with MATRix (n = 38) underwent T1 contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) before treatment, after two cycles and after four cycles of chemotherapy. Response was assessed using the International PCNSL Collaborative Group (IPCG) imaging criteria. ADC histogram parameters and T1CE tumour volumes were compared among response groups, using one-way ANOVA testing. Logistic regression was performed to examine those imaging parameters predictive of response. Response after two cycles of chemotherapy differed from response after four cycles; of the six patients with progressive disease (PD) after four cycles of treatment, two (33%) had demonstrated a partial response (PR) or complete response (CR) after two cycles. ADCmean at baseline, T1CE at baseline and T1CE percentage volume change differed between response groups (0.005 < p < 0.038) and were predictive of MATRix treatment response (area under the curve: 0.672-0.854). Baseline ADC and T1CE metrics are potential biomarkers for risk stratification of PCNSL patients early during remission induction therapy with MATRix. Standard interim response assessment (after two cycles) according to IPCG imaging criteria does not reliably predict early disease progression in the context of a conventional treatment approach.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.

Altered pituitary morphology as a sign of benign hereditary chorea caused by TITF1/NKX2.1 mutations.

Benign hereditary chorea (BHC) is a rare genetically heterogeneous movement disorder, in which conventional neuroimaging has been reported as normal in most cases. Cystic pituitary abnormalities and features of empty sella have been described in only 7 patients with BHC to date. We present 4 patients from 2 families with a BHC phenotype, 3 of whom underwent targeted pituitary MR imaging and genetic testing. All four patients in the two families displayed a classic BHC phenotype. The targeted pituitary MR imaging demonstrated abnormal pituitary sella morphology. Genetic testing was performed in three patients, and showed mutations causing BHC in three of the patients, as well as identifying a novel nonsense mutation of the TITF1/NKX2-1 gene in one of the patients. The presence of the abnormal pituitary sella in two affected members of the same family supports the hypothesis that this sign is a distinct feature of the BHC phenotype spectrum due to mutations in the TITF1 gene. Interestingly, these abnormalities seem to develop in adult life and are progressive. They occur in at least 26% of patients affected with Brain-lung-thyroid syndrome. As a part of the management of these patients we recommend to perform follow-up MRI brain with dedicated pituitary imaging also in adult life as the abnormality can occur years after the onset of chorea.

A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

Longitudinal structural and perfusion MRI enhanced by machine learning outperforms standalone modalities and radiological expertise in high-grade glioma surveillance.

PURPOSE: Surveillance of patients with high-grade glioma (HGG) and identification of disease progression remain a major challenge in neurooncology. This study aimed to develop a support vector machine (SVM) classifier, employing combined longitudinal structural and perfusion MRI studies, to classify between stable disease, pseudoprogression and progressive disease (3-class problem). METHODS: Study participants were separated into two groups: group I (total cohort: 64 patients) with a single DSC time point and group II (19 patients) with longitudinal DSC time points (2-3). We retrospectively analysed 269 structural MRI and 92 dynamic susceptibility contrast perfusion (DSC) MRI scans. The SVM classifier was trained using all available MRI studies for each group. Classification accuracy was assessed for different feature dataset and time point combinations and compared to radiologists' classifications. RESULTS: SVM classification based on combined perfusion and structural features outperformed radiologists' classification across all groups. For the identification of progressive disease, use of combined features and longitudinal DSC time points improved classification performance (lowest error rate 1.6%). Optimal performance was observed in group II (multiple time points) with SVM sensitivity/specificity/accuracy of 100/91.67/94.7% (first time point analysis) and 85.71/100/94.7% (longitudinal analysis), compared to 60/78/68% and 70/90/84.2% for the respective radiologist classifications. In group I (single time point), the SVM classifier also outperformed radiologists' classifications with sensitivity/specificity/accuracy of 86.49/75.00/81.53% (SVM) compared to 75.7/68.9/73.84% (radiologists). CONCLUSION: Our results indicate that utilisation of a machine learning (SVM) classifier based on analysis of longitudinal perfusion time points and combined structural and perfusion features significantly enhances classification outcome (p value= 0.0001).

From research to clinical practice: a European neuroradiological survey on quantitative advanced MRI implementation.

OBJECTIVE: Quantitative MRI (qMRI) methods provide versatile neuroradiological applications and are a hot topic in research. The degree of their clinical implementation is however barely known. This survey was created to illuminate which and how qMRI techniques are currently applied across Europe. METHODS: In total, 4753 neuroradiologists from 27 countries received an online questionnaire. Demographic and professional data, experience with qMRI techniques in the brain and head and neck, usage, reasons for/against application, and knowledge of the QIBA and EIBALL initiatives were assessed. RESULTS: Two hundred seventy-two responders in 23 countries used the following techniques clinically (mean values in %): DWI (82.0%, n = 223), DSC (67.3%, n = 183), MRS (64.3%, n = 175), DCE (43.4%, n = 118), BOLD-fMRI (42.6%, n = 116), ASL (37.5%, n = 102), fat quantification (25.0%, n = 68), T2 mapping (16.9%, n = 46), T1 mapping (15.1%, n = 41), PET-MRI (11.8%, n = 32), IVIM (5.5%, n = 15), APT-CEST (4.8%, n = 13), and DKI (3.3%, n = 9). The most frequent usage indications for any qMRI technique were tissue differentiation (82.4%, n = 224) and oncological monitoring (72.8%, n = 198). Usage differed between countries, e.g. ASL: Germany (n = 13/63; 20.6%) vs. France (n = 31/40; 77.5%). Neuroradiologists endorsed the use of qMRI because of an improved diagnostic accuracy (89.3%, n = 243), but 50.0% (n = 136) are in need of better technology, 34.9% (n = 95) wish for more communication, and 31.3% need help with result interpretation/generation (n = 85). QIBA and EIBALL were not well known (12.5%, n = 34, and 11.0%, n = 30). CONCLUSIONS: The clinical implementation of qMRI methods is highly variable. Beyond the aspect of readiness for clinical use, better availability of support and a wider dissemination of guidelines could catalyse a broader implementation. KEY POINTS: • Neuroradiologists endorse the use of qMRI techniques as they subjectively improve diagnostic accuracy. • Clinical implementation is highly variable between countries, techniques, and indications. • The use of advanced imaging could be promoted through an increase in technical support and training of both doctors and technicians.

Fifteen-minute consultation: The toddler's fracture.

The toddler's fracture is a distinct entity among tibial shaft fractures. It is defined as a minimally displaced or undisplaced spiral fracture, usually affecting the distal shaft of the tibia, with an intact fibula. They are often difficult to diagnose due to the absence of witnessed trauma and because initial radiographs may appear normal. Moreover, the presenting complaint (a non-weight bearing child) has a wide differential diagnosis. A detailed history and examination, together with additional imaging and other investigations, is crucial to diagnose a toddler's fracture. Analgesia and immobilisation are the mainstays of treatment, with follow-up in fracture clinic recommended. Inflicted injury (Note: this article will use the term inflicted injury which is also called non-accidental injury. In the field of safeguarding, there is a move away from using the term 'non-accidental injury' due to misinterpretation of the term as being less serious than 'abusive injury' and that in child protection reports the term can be easily misread or mistyped as 'accidental' injury) should always be considered when red flags for child abuse are present. In this article, we aim to cover the differential diagnoses for toddler's fracture including indicators that might suggest an inflicted injury.

A modality-adaptive method for segmenting brain tumors and organs-at-risk in radiation therapy planning.

In this paper we present a method for simultaneously segmenting brain tumors and an extensive set of organs-at-risk for radiation therapy planning of glioblastomas. The method combines a contrast-adaptive generative model for whole-brain segmentation with a new spatial regularization model of tumor shape using convolutional restricted Boltzmann machines. We demonstrate experimentally that the method is able to adapt to image acquisitions that differ substantially from any available training data, ensuring its applicability across treatment sites; that its tumor segmentation accuracy is comparable to that of the current state of the art; and that it captures most organs-at-risk sufficiently well for radiation therapy planning purposes. The proposed method may be a valuable step towards automating the delineation of brain tumors and organs-at-risk in glioblastoma patients undergoing radiation therapy.

Texture analysis- and support vector machine-assisted diffusional kurtosis imaging may allow in vivo gliomas grading and IDH-mutation status prediction: a preliminary study.

We sought to investigate, whether texture analysis of diffusional kurtosis imaging (DKI) enhanced by support vector machine (SVM) analysis may provide biomarkers for gliomas staging and detection of the IDH mutation. First-order statistics and texture feature extraction were performed in 37 patients on both conventional (FLAIR) and mean diffusional kurtosis (MDK) images and recursive feature elimination (RFE) methodology based on SVM was employed to select the most discriminative diagnostic biomarkers. The first-order statistics demonstrated significantly lower MDK values in the IDH-mutant tumors. This resulted in 81.1% accuracy (sensitivity = 0.96, specificity = 0.45, AUC 0.59) for IDH mutation diagnosis. There were non-significant differences in average MDK and skewness among the different tumour grades. When texture analysis and SVM were utilized, the grading accuracy achieved by DKI biomarkers was 78.1% (sensitivity 0.77, specificity 0.79, AUC 0.79); the prediction accuracy for IDH mutation reached 83.8% (sensitivity 0.96, specificity 0.55, AUC 0.87). For the IDH mutation task, DKI outperformed significantly the FLAIR imaging. When using selected biomarkers after RFE, the prediction accuracy achieved 83.8% (sensitivity 0.92, specificity 0.64, AUC 0.88). These findings demonstrate the superiority of DKI enhanced by texture analysis and SVM, compared to conventional imaging, for gliomas staging and prediction of IDH mutational status.

Impact of induction chemotherapy, hyperfractionated accelerated radiotherapy and high-dose thiotepa on brain volume loss and functional status of children with primitive neuroectodermal tumour.

BACKGROUND: The introduction of aggressive chemo-radiotherapy regimens has improved overall survival in children with primitive neuroectodermal tumours (PNET). However, these combinations may result in neurotoxicity. Previously reported magnetic resonance imaging abnormalities in children receiving intensive sequential chemotherapy, hyperfractionated accelerated radiotherapy (HART) and high-dose thiotepa prompted us to investigate the degree of brain volume loss and patients' functional status after therapy. METHODS: We retrospectively reviewed clinico-radiological data of children with PNET treated in this way at our centre. RESULTS: We studied 14 children treated between December 2009 and April 2013. Data were not complete for one child. Performance status was severely restricted in four children, and mildly to moderately impaired in 7 of the 13 children. Eleven of 13 children showed mild-to-severe generalised neuroparenchymal atrophy, in 7 of whom neuroparenchymal volume loss was moderate to severe. Of these seven, six had received high-dose thiotepa. There was no correlation between brain volume loss and Lansky performance status. However, unexpected neurotoxicities, such as symptoms of transverse myelitis, were observed. CONCLUSION: Measurement of brain volume loss in patients treated with HART and high-dose thiotepa may not be sufficient to predict function. However, correlation of brain volume loss due to late neurotoxicity with performance decline may be more obvious over longer period of follow-up. The combination of HART and myeloablative courses of thiotepa is associated with severe neurotoxicity and subsequent decline in performance status in a significant proportion of patients.

Advanced MRI Techniques in the Monitoring of Treatment of Gliomas.

OPINION STATEMENT: With advances in treatments and survival of patients with glioblastoma (GBM), it has become apparent that conventional imaging sequences have significant limitations both in terms of assessing response to treatment and monitoring disease progression. Both 'pseudoprogression' after chemoradiation for newly diagnosed GBM and 'pseudoresponse' after anti-angiogenesis treatment for relapsed GBM are well-recognised radiological entities. This in turn has led to revision of response criteria away from the standard MacDonald criteria, which depend on the two-dimensional measurement of contrast-enhancing tumour, and which have been the primary measure of radiological response for over three decades. A working party of experts published RANO (Response Assessment in Neuro-oncology Working Group) criteria in 2010 which take into account signal change on T2/FLAIR sequences as well as the contrast-enhancing component of the tumour. These have recently been modified for immune therapies, which are associated with specific issues related to the timing of radiological response. There has been increasing interest in quantification and validation of physiological and metabolic parameters in GBM over the last 10 years utilising the wide range of advanced imaging techniques available on standard MRI platforms. Previously, MRI would provide structural information only on the anatomical location of the tumour and the presence or absence of a disrupted blood-brain barrier. Advanced MRI sequences include proton magnetic resonance spectroscopy (MRS), vascular imaging (perfusion/permeability) and diffusion imaging (diffusion weighted imaging/diffusion tensor imaging) and are now routinely available. They provide biologically relevant functional, haemodynamic, cellular, metabolic and cytoarchitectural information and are being evaluated in clinical trials to determine whether they offer superior biomarkers of early treatment response than conventional imaging, when correlated with hard survival endpoints. Multiparametric imaging, incorporating different combinations of these modalities, improves accuracy over single imaging modalities but has not been widely adopted due to the amount of post-processing analysis required, lack of clinical trial data, lack of radiology training and wide variations in threshold values. New techniques including diffusion kurtosis and radiomics will offer a higher level of quantification but will require validation in clinical trial settings. Given all these considerations, it is clear that there is an urgent need to incorporate advanced techniques into clinical trial design to avoid the problems of under or over assessment of treatment response.

Neurocognitive Function and Neuroimaging Markers in Virologically Suppressed HIV-positive Patients Randomized to Ritonavir-boosted Protease Inhibitor Monotherapy or Standard Combination ART: A Cross-sectional Substudy From the PIVOT Trial.

BACKGROUND: To determine whether treatment with ritonavir-boosted protease inhibitor (PI) monotherapy is associated with detrimental effects on neurocognitive function or brain imaging markers compared to standard antiretroviral therapy (ART). METHODS: Neuropsychological assessment and brain magnetic resonance imaging were performed at the last study visit in a subset of participants randomized to PI monotherapy (PI-mono group) or ongoing triple ART (OT group) in the PIVOT trial. We calculated a global z-score (NPZ-7) from the average of the individual test z-scores and the proportion of participants with symptomatic neurocognitive impairment (score >1 standard deviation below normative means in ≥2 cognitive domains and neurocognitive symptoms). In a subgroup, white matter hyperintensities, bicaudate index, global cortical (GCA) and medial temporal lobe atrophy scores and single voxel (basal ganglia) N-acetylaspartate (NAA)/Choline, NAA/Creatine and myo-inositol/Creatine ratios were measured. RESULTS: 146 participants (75 PI-mono) had neurocognitive testing (median time after randomization 3.8 years), of whom 78 were imaged. We found no difference between arms in NPZ-7 score (median -0.4 (interquartile range [IQR] = -0.7; 0.1) vs -0.3 (IQR = -0.7; 0.3) for the PI-mono and OT groups respectively, P = .28), the proportion with symptomatic neurocognitive impairment (13% and 18% in the PI-mono and OT groups respectively; P = .41), or any of the neuroimaging variables (P > .05). Symptomatic neurocognitive impairment was associated with higher GCA score (OR = 6.2 per additional score; 95% confidence interval, 1.7-22.3 P = .005) but no other imaging variables. CONCLUSIONS: Based on a comprehensive neuropsychological assessment and brain imaging, PI monotherapy does not increase the risk of neurocognitive impairment in stable human immunodeficiency virus-positive patients.

A Novel MAPT Mutation Causing Corticobasal Syndrome Led by Progressive Apraxia of Speech.

The authors describe a case of corticobasal syndrome led by progressive apraxia of speech, associated with a novel mutation in exon 10 of the MAPT gene. Genetic bases for progressive apraxia of speech and corticobasal syndrome are only rarely described, and have not been described in conjunction.

Hybrid segmentation and virtual bronchoscopy based on CT images.

RATIONALE AND OBJECTIVES: Introduction of combination of the segmentation tool SegoMeTex and the virtual endoscopy system VIVENDI to perform virtual endoscopic inspections of the human lung. This virtual bronchoscopy system enables visualization of the tracheobronchial tree down to seventh generation. Furthermore, the modified virtual system visualizes hidden structures such as segmented vascular system or tumors. MATERIALS AND METHODS: The segmentation is based on image data acquired by a multislice computed tomography scanner. SegoMeTex is used to segment the tracheobronchial tree by a hybrid system with minimal user action. Similarly, the complementary pulmonary arterial can be segmented, whereas additional structures such as tumors are marked manually. On this dataset, subsequently, data structures of the inner surface for virtual endoscopy are generated. Finally, the dataset can be explored by a virtual bronchoscopy procedure using the VIVENDI system. RESULTS: The segmentation method was successfully tested on 22 patients. The hybrid segmentation system identified bronchi up to the sixth generation with a sensitivity of more than 58%, and a positive predictive value of more than 90%. After the segmentation, the datasets are explored interactively (>30 fps on a standard personal computer platform in real-time rendering) using the virtual endoscopy software. The exploration exposed a high-quality reconstruction, even of small structures throughout the dataset. CONCLUSION: Virtual bronchoscopy in combining with a highly sensitive segmentation is a valuable tool for the localization and measurement of stenosis for resection planning.