Explanation and Elaboration with Examples for CLEAR (CLEAR-E3): an EuSoMII Radiomics Auditing Group Initiative.

Overall quality of radiomics research has been reported as low in literature, which constitutes a major challenge to improve. Consistent, transparent, and accurate reporting is critical, which can be accomplished with systematic use of reporting guidelines. The CheckList for EvaluAtion of Radiomics research (CLEAR) was previously developed to assist authors in reporting their radiomic research and to assist reviewers in their evaluation. To take full advantage of CLEAR, further explanation and elaboration of each item, as well as literature examples, may be useful. The main goal of this work, Explanation and Elaboration with Examples for CLEAR (CLEAR-E3), is to improve CLEAR's usability and dissemination. In this international collaborative effort, members of the European Society of Medical Imaging Informatics-Radiomics Auditing Group searched radiomics literature to identify representative reporting examples for each CLEAR item. At least two examples, demonstrating optimal reporting, were presented for each item. All examples were selected from open-access articles, allowing users to easily consult the corresponding full-text articles. In addition to these, each CLEAR item's explanation was further expanded and elaborated. For easier access, the resulting document is available at https://radiomic.github.io/CLEAR-E3/ . As a complementary effort to CLEAR, we anticipate that this initiative will assist authors in reporting their radiomics research with greater ease and transparency, as well as editors and reviewers in reviewing manuscripts.Relevance statement Along with the original CLEAR checklist, CLEAR-E3 is expected to provide a more in-depth understanding of the CLEAR items, as well as concrete examples for reporting and evaluating radiomic research.Key points• As a complementary effort to CLEAR, this international collaborative effort aims to assist authors in reporting their radiomics research, as well as editors and reviewers in reviewing radiomics manuscripts.• Based on positive examples from the literature selected by the EuSoMII Radiomics Auditing Group, each CLEAR item explanation was further elaborated in CLEAR-E3.• The resulting explanation and elaboration document with examples can be accessed at  https://radiomic.github.io/CLEAR-E3/ .

Quality assessment of the MRI-radiomics studies for MGMT promoter methylation prediction in glioma: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the methodological quality and diagnostic accuracy of MRI-based radiomic studies predicting O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in gliomas. METHODS: PubMed Medline, EMBASE, and Web of Science were searched to identify MRI-based radiomic studies on MGMT methylation in gliomas published until December 31, 2022. Three raters evaluated the study methodological quality with Radiomics Quality Score (RQS, 16 components) and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis Or Diagnosis (TRIPOD, 22 items) scales. Risk of bias and applicability concerns were assessed with QUADAS-2 tool. A meta-analysis was performed to estimate the pooled area under the curve (AUC) and to assess inter-study heterogeneity. RESULTS: We included 26 studies, published from 2016. The median RQS total score was 8 out of 36 (22%, range 8-44%). Thirteen studies performed external validation. All studies reported AUC or accuracy, but only 4 (15%) performed calibration and decision curve analysis. No studies performed phantom analysis, cost-effectiveness analysis, and prospective validation. The overall TRIPOD adherence score was between 50% and 70% in 16 studies and below 50% in 10 studies. The pooled AUC was 0.78 (95% CI, 0.73-0.83, I2 = 94.1%) with a high inter-study heterogeneity. Studies with external validation and including only WHO-grade IV gliomas had significantly lower AUC values (0.65; 95% CI, 0.57-0.73, p < 0.01). CONCLUSIONS: Study RQS and adherence to TRIPOD guidelines was generally low. Radiomic prediction of MGMT methylation status showed great heterogeneity of results and lower performances in grade IV gliomas, which hinders its current implementation in clinical practice. CLINICAL RELEVANCE STATEMENT: MGMT promoter methylation status appears to be variably correlated with MRI radiomic features; radiomic models are not sufficiently robust to be integrated into clinical practice to accurately predict MGMT promoter methylation status in patients with glioma before surgery. KEY POINTS: • Adherence to the indications of TRIPOD guidelines was generally low, as was RQS total score. • MGMT promoter methylation status prediction with MRI radiomic features provided heterogeneous diagnostic accuracy results across studies. • Studies that included grade IV glioma only and performed external validation had significantly lower diagnostic accuracy than others.

Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations.

The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.

Use of gadolinium-based contrast agents in multiple sclerosis: a review by the ESMRMB-GREC and ESNR Multiple Sclerosis Working Group.

Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: • Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. • The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. • Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice.

Interval between contrast administration and T1-weighted MRI for cerebral adrenoleukodystrophy: a single-case observation.

In adrenoleukodystrophy (ALD), contrast enhancement (CE) is a disease activity marker, but there is uncertainty about the optimal delay, if any, between contrast injection and magnetic resonance imaging (MRI) acquisition to avoid false-negative results. We acquired axial two-dimensional (2D) and three-dimensional (3D) T1-weighted gradient-echo every 6 min from 0 to 36 min after contrast administration (gadobutrol 0.1 mmol/kg) in an ALD patient with enlarging white matter lesions and progressive neuropsychological symptoms, using a 3-T magnet. The image signal over time was qualitatively assessed and measured in two regions of interest. On 3D sequences, no definite CE was appreciated, whereas on 2D sequences, CE was noticed after 6 min and definitely evident after 12 min, when 73% of the maximum signal intensity was measured. In ALD subjects, contrast-enhanced 2D T1-weighted gradient-echo sequences acquired at least 10 min after contrast injection may be considered to reduce false negative results.Relevance statementOur report is the first attempt to find an optimal delay between contrast administration and T1-weighted acquisition in cALD patients in order to correctly detect disease activity and avoid false negative results.Key points• The optimal time between contrast injection and image acquisition for MRI of adrenoleukodystrophy is unknown.• Contrast enhancement predicts adrenoleukodystrophy progression and could help patient's selection for the therapy.• We acquired two post-contrast T1-GRE-2D/3D sequences several times to find the best injection-time.• T1-weighted 2D GRE resulted more sensitive than T1-weighted 3D GRE even after long intervals from injection.• A delay of about 10 min may minimize false negatives.

Distinctive electro-clinical, neuroimaging and histopathological features of temporal encephaloceles associated to epilepsy.

OBJECTIVE: Encephaloceles (ENCs) may cause clinical complications, including drug-resistant epilepsy that can be cured with epilepsy surgery. METHODS: We describe clinical, diagnostic, and neuropathological findings of 12 patients with temporal ENC and epilepsy evaluated for surgery and compare them with a control group of 26 temporal lobe epilepsy (TLE) patients. RESULTS: Six patients had unilateral and 6 bilateral temporal ENCs. Compared to TLEs, ENCs showed i) later epilepsy onset, ii) higher prevalence of psychiatric comorbidities, iii) no history of febrile convulsions, and iv) ictal semiology differences. Seven patients had MRI signs of gliosis, and 9 of intracranial hypertension. Interictal EEG analysis in ENCs demonstrated significant differences with controls: prominent activity in the beta/gamma frequency bands in frontal regions, interictal short sequences of low-voltage fast activity, and less frequent and more localized interictal epileptiform discharges. Ictal EEG patterns analyzed in 9 ENCs showed delayed and slower contralateral spread compared to TLEs. All ENCs that underwent surgery (7 lobectomies and 1 lesionectomy) are in Engel class I. Neuropathological examination revealed 4 patterns: herniated brain fragments, focal layer I distortion, white matter septa extending into the cortex, and altered gyral profile. CONCLUSIONS AND SIGNIFICANCE: The described peculiarities might help clinicians to suspect the presence of largely underdiagnosed ENCs.

Magnetic resonance imaging characteristics of pediatric pilocytic astrocytoma.

PURPOSE: MRI has an important role in diagnosing pilocytic astrocytoma and post-surgical follow-up since the surgical approach has a leading role in its treatment. The purpose of our study is to provide an overview of the typical and atypical MRI findings in a series of pediatric patients with isolated-not NF1-related-pilocytic astrocytomas and to correlate specific MRI patterns with clinical variables. METHODS: This is a cross-sectional retrospective study providing the analysis of several clinical and neuroradiological findings from a cohort of pediatric pilocytic astrocytoma, starting from the data collected in the Fondazione IRCCS Istituto Neurologico Carlo Besta (FINCB) internal Cancer Registry during an 11-year time period (January 2008-January 2019). RESULTS: Fifty-six patients were included in the study. Median age at diagnosis was 9.4 years; a slight female prevalence was noticed (m/f ratio 44.6%/55.4%). The majority of pPAs had well-defined contours: 51 (91.1%), 47 (88.7%) were hypointense on T1-wi, all of them were hyperintense on T2-wi, 46 (90.2%) were hyperintense on FLAIR, and 48 (85.7%) were heterogeneous on T1-wi and T2-wi sequences. We found positive correlation between pPAs location and age (r = 0.017), and small degree of connection between pPAs location and gender (Cramer's V = 0.268). CONCLUSIONS: We presented typical and atypical pPAs MRI findings. Age and tumor location were positevely correlated, while degree of connection between gender and pPAs location was small. All of this may aid clinicians, most of all neuroradiologists, neurosurgeons, and neurologists in proper diagnoses and follow-up of these specific patient population.

Development of A Radiomic Model for MGMT Promoter Methylation Detection in Glioblastoma Using Conventional MRI.

The methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is a molecular marker associated with a better response to chemotherapy in patients with glioblastoma (GB). Standard pre-operative magnetic resonance imaging (MRI) analysis is not adequate to detect MGMT promoter methylation. This study aims to evaluate whether the radiomic features extracted from multiple tumor subregions using multiparametric MRI can predict MGMT promoter methylation status in GB patients. This retrospective single-institution study included a cohort of 277 GB patients whose 3D post-contrast T1-weighted images and 3D fluid-attenuated inversion recovery (FLAIR) images were acquired using two MRI scanners. Three separate regions of interest (ROIs) showing tumor enhancement, necrosis, and FLAIR hyperintensities were manually segmented for each patient. Two machine learning algorithms (support vector machine (SVM) and random forest) were built for MGMT promoter methylation prediction from a training cohort (196 patients) and tested on a separate validation cohort (81 patients), based on a set of automatically selected radiomic features, with and without demographic variables (i.e., patients' age and sex). In the training set, SVM based on the selected radiomic features of the three separate ROIs achieved the best performances, with an average of 83.0% (standard deviation: 5.7%) for accuracy and 0.894 (0.056) for the area under the curve (AUC) computed through cross-validation. In the test set, all classification performances dropped: the best was obtained by SVM based on the selected features extracted from the whole tumor lesion constructed by merging the three ROIs, with 64.2% (95% confidence interval: 52.8-74.6%) accuracy and 0.572 (0.439-0.705) for AUC. The performances did not change when the patients' age and sex were included with the radiomic features into the models. Our study confirms the presence of a subtle association between imaging characteristics and MGMT promoter methylation status. However, further verification of the strength of this association is needed, as the low diagnostic performance obtained in this validation cohort is not sufficiently robust to allow clinically meaningful predictions.

Neurophysiology-Guided Laser Interstitial Thermal Therapy: A Synergistic Approach For Motor Function Preservation. Technical Note.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive ablative technique with specific indications for neuro-oncology, especially in the case of lesions in eloquent areas. Even being performed through a small catheter under stereotactic conditions, the risk of damaging vital structures such as white matter tracts or cortical eloquent areas is not negligible. The mechanism of damage can be related to catheter insertion or to excessive laser ablation. An accurate preoperative workup, aimed at locating the eloquent structures, can be combined with a real-time intraoperative neurophysiologic monitoring to reduce surgical morbidity while maximizing the efficacy of LITT. METHODS: We developed a synergistic approach for neurophysiology-guided LITT based on state-of-the-art technologies, namely, magnetoencephalography, diffusion tensor imaging, and intraoperative neurophysiologic monitoring. RESULTS: As a result, we improved the planning phase thanks to a more precise representation of functional structures that allows the simulation of different trajectories and the identification of the most suitable trajectory to treat the lesion while respecting the functional boundaries. Catheter insertion is conducted under continuous neurophysiologic feedback and the ablation phase is modeled on the functional boundaries identified by stimulation, allowing it to be extremely accurate. CONCLUSIONS: An integrated approached guided by neurophysiology is able to reduce the surgical morbidity even in a relatively accurate technique such as LITT. To the best of our knowledge, this represents the first report on this synergistic approach which could really impact the treatment of tumors in eloquent areas. Future studies are needed in the effort to implement this approach in functional or epilepsy neurosurgery as well.

Interhemispheric Pediatric Meningioma, YAP1 Fusion-Positive.

Meningiomas are uncommon in children and usually arise in the context of tumor-predisposing syndromes. Recently, YAP1-fusions have been identified for the first time as potential NF2-independent oncogenic drivers in the development of meningiomas in pediatric patients. We report a case of a YAP1-fusion-positive atypical meningioma in a young child and compare it with the previous ones reported. Extending the clinico-pathological features of YAP1-fused meningiomas, we suggest additional clues for diagnosis and emphasize the urgent need for an integrated multilayered diagnostic approach, combining data from histological and molecular analyses, neuroradiology, and clinical findings.

A Critical Appraisal of the Quality of Vertigo Practice Guidelines Using the AGREE II Tool: A EuroAIM Initiative.

OBJECTIVES: The aim of this review is to assess the methodological quality of guidelines for the management of vertigo and dizziness and to compare their recommendations, with specific focus on neuroimaging. DATABASES REVIEWED: MEDLINE, EMBASE, National Guideline Clearinghouse, and National Institute for Health and Clinical Excellence database. METHODS: In March 2022, a systematic search was performed to find practice guidelines of management of vertigo and dizziness. The evaluation of guidelines quality was performed independently by four authors using the AGREE II tool. We excluded from the results those guidelines that were not primarily focused on vertigo and dizziness, such as national/international guidelines in which vertigo and dizziness were only briefly mentioned. RESULTS: Our strategy of literature search identified 161 studies, and 18 guidelines were selected for the appraisal. Only five guidelines reached the acceptance level in the overall result (at least 60%), with three of them reaching the highest scores (at least 80%). The highest scores were found in Domain 6 "Editorial Independence," Domain 1 "Scope and purpose," and Domain 4 "Clarity of presentation" (median value = 66%, 62%, and 61%, respectively). The remaining domains showed a low level of quality: Domain 2 "Stakeholder Involvement," Domain 3 "Rigor of development," and Domain 5 "Applicability" had median values of 27%, 27%, and 22%, respectively. The quality of these guidelines was very low, because of low involvement of multidisciplinary teams in writing guidelines recommendations. CONCLUSION: Considering all guidelines, only three had a "high" overall score, whereas 13 of 18 (72%) of them were rated as of "low" quality. Future guidelines might take this into account to improve clinical applicability.

Multiparametric Intraoperative Ultrasound in Oncological Neurosurgery: A Pictorial Essay.

Intraoperative ultrasound (ioUS) is increasingly used in current neurosurgical practice. This is mainly explained by its affordability, handiness, multimodal real-time nature, and overall by its image spatial and temporal resolution. Identification of lesion and potential residue, analysis of the vascularization pattern, and characterization of the nature of the mass are only some of the advantages that ioUS offers to guide safe and efficient tumor resection. Technological advances in ioUS allow to achieve both structural and functional imaging. B-mode provides high-resolution visualization of the lesion and of its boundaries and relationships. Pioneering modes, such as contrast-enhanced ultrasound (CEUS), ultrasensitive Doppler, and elastosonography, are tools with great potential in characterizing different functional aspects of the lesion in a qualitative and quantitative manner. As already happening for many organs and pathologies, the combined use of different US modalities offers new insights in a multiparametric fashion. In this study, we present the potential of our multiparametric approach for ioUS during neuro-oncological surgery. In this effort, we provide a pictorial essay focusing on the most frequent pathologies: low- and high-grade gliomas, meningiomas, and brain metastases.

MRI in Late-Onset Rasmussen Encephalitis: A Long-Term Follow-Up Study.

Late-onset Rasmussen encephalitis (LoRE) is a rare unihemispheric progressive inflammatory disorder causing neurological deficits and epilepsy. The long-term radiological evolution has never been fully described. We retrospectively analyzed the MR images of 13 LoRE patients from a total of 136 studies, and searched for focal areas of volume loss or signal intensity abnormality in grey matter or white matter. Each subject had a median of nine MRI studies (IQR 7-13). Frontal and temporal lobes were the most affected regions (13/13 and 8/13, respectively) and showed the greatest worsening over time in terms of atrophic changes (9/13 and 5/8, respectively). A milder cortical atrophy was found in the insular and parietal lobes. The caudate nucleus was affected in seven patients. Hyperintensities of grey matter and white matter on T2-WI and FLAIR images were observed in all patients, and transiently in eight patients. In two cases out of the latter patients, these transient alterations evolved into atrophy of the same region. Disease duration was significantly associated with signal abnormalities in the grey matter at last follow-up. LoRE MRI alterations are milder, and their progression is markedly slower compared to radiological findings described in the childhood form.

Carcinomatosis under control by osimertinib in EGFR and TP53 mutated lung adenocarcinoma.

INTRODUCTION: Approximately 25%-30% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases during the course of the disease; this percentage is higher in patients with epidermal growth factor receptor (EGFR) mutations. Leptomeningeal metastases, infrequent in the advanced setting, have a particularly dismal prognosis. Osimertinib, a third-generation EGFR inhibitor, can provide effective and durable response in this setting. CASE DESCRIPTION: We present a 62-year-old man with progressive vomiting, headache, short-term memory impairment, and left lower limb hyposthenia. Computed tomography (CT) showed bilateral lung nodules, multiple lymphadenopathies, liver and bone metastases, and CNS and leptomeningeal dissemination, including multiple parenchymal nodules located at supra- and infratentorial brain. Bone needle biopsy documented TTF1+ lung adenocarcinoma. Whole brain radiotherapy (WBRT) and symptomatic treatments were started. Next-generation sequencing reported deletion of exon 19 of EGFR and mutation 8 of TP53. Osimertinib 80 mg was promptly started and WBRT interrupted. Some days after the patient experienced repetitive seizures and neurologic worsening, antiepileptic drugs and dexamethasone were implemented, with gradual improvement. Radiologic evaluation, including brain MRI and thorax-abdominal CT, showed partial response on CNS as well as extracranial sites, which was sustained. CONCLUSIONS: First-line treatment with osimertinib can be safe and effective in EGFR-mutated NSCLC even in presence of multiple negative predictive factors (poor Performance Status, diffuse leptomeningeal involvement, TP53 comutation), suggesting that deferring local treatments can be feasible in this setting, allowing the patient to maintain a good quality of life.

Subtype Diagnosis of Sporadic Creutzfeldt-Jakob Disease with Diffusion Magnetic Resonance Imaging.

OBJECTIVE: Sporadic Creutzfeldt-Jakob disease (sCJD) comprises several subtypes as defined by genetic and prion protein characteristics, which are associated with distinct clinical and pathological phenotypes. To date, no clinical test can reliably diagnose the subtype. We established two procedures for the antemortem diagnosis of sCJD subtype using diffusion magnetic resonance imaging (MRI). METHODS: MRI of 1,458 patients referred to the National Prion Disease Pathology Surveillance Center were collected through its consultation service. One neuroradiologist blind to the diagnosis scored 12 brain regions and generated a lesion profile for each MRI scan. We selected 487 patients with autopsy-confirmed diagnosis of "pure" sCJD subtype and at least one positive diffusion MRI examination. We designed and tested two data-driven procedures for subtype diagnosis: the first procedure-prion subtype classification algorithm with MRI (PriSCA_MRI)-uses only MRI examinations; the second-PriSCA_MRI + Gen-includes knowledge of the prion protein codon 129 genotype, a major determinant of sCJD subtypes. Both procedures were tested on the first MRI and the last MRI follow-up. RESULTS: PriSCA_MRI classified the 3 most prevalent subtypes with 82% accuracy. PriSCA_MRI + Gen raised the accuracy to 89% and identified all subtypes. Individually, the 2 most prevalent sCJD subtypes, MM1 and VV2, were diagnosed with sensitivities up to 95 and 97%, respectively. The performances of both procedures did not change in 168 patients with longitudinal MRI studies when the last examination was used. INTERPRETATION: This study provides the first practical algorithms for antemortem diagnosis of sCJD subtypes. MRI diagnosis of subtype is likely to be attainable at early disease stages to prognosticate clinical course and design future therapeutic trials. ANN NEUROL 2021;89:560-572.