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.

scMuffin: an R package to disentangle solid tumor heterogeneity by single-cell gene expression analysis.

INTRODUCTION: Single-cell (SC) gene expression analysis is crucial to dissect the complex cellular heterogeneity of solid tumors, which is one of the main obstacles for the development of effective cancer treatments. Such tumors typically contain a mixture of cells with aberrant genomic and transcriptomic profiles affecting specific sub-populations that might have a pivotal role in cancer progression, whose identification eludes bulk RNA-sequencing approaches. We present scMuffin, an R package that enables the characterization of cell identity in solid tumors on the basis of a various and complementary analyses on SC gene expression data. RESULTS: scMuffin provides a series of functions to calculate qualitative and quantitative scores, such as: expression of marker sets for normal and tumor conditions, pathway activity, cell state trajectories, Copy Number Variations, transcriptional complexity and proliferation state. Thus, scMuffin facilitates the combination of various evidences that can be used to distinguish normal and tumoral cells, define cell identities, cluster cells in different ways, link genomic aberrations to phenotypes and identify subtle differences between cell subtypes or cell states. We analysed public SC expression datasets of human high-grade gliomas as a proof-of-concept to show the value of scMuffin and illustrate its user interface. Nevertheless, these analyses lead to interesting findings, which suggest that some chromosomal amplifications might underlie the invasive tumor phenotype and the presence of cells that possess tumor initiating cells characteristics. CONCLUSIONS: The analyses offered by scMuffin and the results achieved in the case study show that our tool helps addressing the main challenges in the bioinformatics analysis of SC expression data from solid tumors.

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.

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.

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3-Related Syndrome.

Background and Objectives: Heterozygous mutations or deletions of the EBF3 gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of EBF3-related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking. Methods: We report on 6 patients (2 females and 4 males, age range 2-12 years), of whom 4 carrying a heterozygous point mutation of the EBF3 gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy. Clinical evaluation was performed by a pediatric neurologist and pediatric dysmorphologist; ataxia severity was rated by Scale for the Assessment and Rating of Ataxia (SARA); brain MRIs were reviewed by expert neuroradiologists; general quotient levels were obtained through standardized Griffiths Mental Development Scales. Patients carrying a 10q26.3 deletion were diagnosed by array-CGH, whereas EBF3 variants were detected by whole exome sequencing. Results: Phenotype was consistent in all patients, but with wide variability in severity. Developmental milestones were invariably delayed and resulted in an extremely variable cognitive impairment. All patients showed ataxic signs, as confirmed by SARA scores, often associated with hypotonia. Brain MRI revealed in all children a cerebellar malformation with vermis hypoplasia and a peculiar foliation anomaly characterized by a radial disposition of cerebellar folia (dandelion sign). Neurophysiologic examinations were unremarkable. Discussion: EBF3-related syndrome has been so far described as a neurodevelopmental condition with dysmorphic traits, with limited emphasis on the neurologic features; we highlight the predominant neurologic involvement of these patients, which can be explained at least in part by the underlying cerebellar malformation. We therefore propose that EBF3-related syndrome should be classified and treated as a congenital, nonprogressive ataxia.

Clinical Consequences of Incidental Durotomy during Full-Endoscopic Lumbar Decompression Surgery in Relation to Intraoperative Epidural Pressure Measurements.

Background: Seizures, neurological deficits, bradycardia, and, in the worst cases, cardiac arrest may occur following incidental durotomy during routine lumbar endoscopy. Therefore, we set out to measure the intraoperative epidural pressure during lumbar endoscopic decompression surgery. Methods: We conducted a retrospective observational cohort study to obtain intraoperative epidural measurements with an epidural catheter-pressure transducer assembly through the spinal endoscope on 15 patients who underwent lumbar endoscopic decompression of symptomatic lumbar herniated discs and spinal stenosis. The endoscopic interlaminar technique was employed. Results: There were six (40.0%) female and nine (60.0%) male patients aged 49.0667 ± 11.31034, ranging from 36 to 72 years, with an average follow-up of 35.15 ± 12.48 months. Three of the fifteen patients had seizures with durotomy and one of these three had intracranial air on their postoperative brain CT. Another patient developed spinal headaches and diplopia on postoperative day one when her deteriorating neurological function was investigated with a brain computed tomography (CT) scan, showing an intraventricular hemorrhage consistent with a Fisher Grade IV subarachnoid hemorrhage. A CT angiogram did not show any abnormalities. Pressure recordings in the epidural space in nine patients ranged from 20 to 29 mm Hg with a mean of 24.33 mm Hg. Conclusion: Most incidental durotomies encountered during lumbar interlaminar endoscopy can be managed without formal repair and supportive care measures. The intradural spread of irrigation fluid and intraoperatively used drugs and air entrapment through an unrecognized durotomy should be suspected if patients deteriorate in the recovery room. Ascending paralysis may cause nausea, vomiting, upper and lower motor neuron symptoms, cranial nerve palsies, hypotension, bradycardia, and respiratory and cardiac arrest. The recovery team should be prepared to manage these complications.

Identification of the Magna Radicular Artery Entry Foramen and Adamkiewicz System: Patient Selection for Open versus Full-Endoscopic Thoracic Spinal Decompression Surgery.

BACKGROUND: Casually cauterizing the radicular magna during routine thoracic discectomy may have dire consequences. METHODS: We performed a retrospective observational cohort study on patients scheduled for decompression of symptomatic thoracic herniated discs and spinal stenosis who underwent a preoperative computed tomography angiography (CTA) to assess the surgical risks by anatomically defining the foraminal entry level of the magna radicularis artery into the thoracic spinal cord and its relationship to the surgical level. RESULTS: Fifteen patients aged 58.53 ± 19.57, ranging from 31 to 89 years, with an average follow-up of 30.13 ± 13.42 months, were enrolled in this observational cohort study. The mean preoperative VAS for axial back pain was VAS of 8.53 ± 2.06 and reduced to a postoperative VAS of 1.60 ± 0.92 (p < 0.0001) at the final follow-up. The Adamkiewicz was most frequently found at T10/11 (15.4%), T11/12 (23.1%), and T9/10 (30.8%). There were eight patients where the painful pathology was found far from the AKA foraminal entry-level (type 1), three patients with near location (type 2), and another four patients needing decompression at the foraminal (type 3) entry-level. In five of the fifteen patients, the magna radicularis entered the spinal canal on the ventral surface of the exiting nerve root through the neuroforamen at the surgical level requiring a change of surgical strategy to prevent injury to this important contributor to the spinal cord's blood supply. CONCLUSIONS: The authors recommend stratifying patients according to the proximity of the magna radicularis artery to the compressive pathology with CTA to assess the surgical risk with targeted thoracic discectomy methods.

A discriminative event-based model for subtype diagnosis of sporadic Creutzfeldt-Jakob disease using brain MRI.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) comprises multiple subtypes (MM1, MM2, MV1, MV2C, MV2K, VV1, and VV2) with distinct disease durations and spatiotemporal cascades of brain lesions. Our goal was to establish the ante mortem diagnosis of sCJD subtype, based on patient-specific estimates of the spatiotemporal cascade of lesions detected by diffusion-weighted magnetic resonance imaging (DWI). METHODS: We included 488 patients with autopsy-confirmed diagnosis of sCJD subtype and 50 patients with exclusion of prion disease. We applied a discriminative event-based model (DEBM) to infer the spatiotemporal cascades of lesions, derived from the DWI scores of 12 brain regions assigned by three neuroradiologists. Based on the DEBM cascades and the prion protein genotype at codon 129, we developed and validated a novel algorithm for the diagnosis of the sCJD subtype. RESULTS: Cascades of MM1, MM2, MV1, MV2C, and VV1 originated in the parietal cortex and, following subtype-specific orderings of propagation, went toward the striatum, thalamus, and cerebellum; conversely, VV2 and MV2K cascades showed a striatum-to-cortex propagation. The proposed algorithm achieved 76.5% balanced accuracy for the sCJD subtype diagnosis, with low rater dependency (differences in accuracy of ± 1% among neuroradiologists). DISCUSSION: Ante mortem diagnosis of sCJD subtype is feasible with this novel data-driven approach, and it may be valuable for patient prognostication, stratification in targeted clinical trials, and future therapeutics. HIGHLIGHTS: Subtype diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is achievable with diffusion MRI. Cascades of diffusion MRI abnormalities in the brain are subtype-specific in sCJD. We proposed a diagnostic algorithm based on cascades of diffusion MRI abnormalities and demonstrated that it is accurate. Our method may aid early diagnosis, prognosis, stratification in clinical trials, and future therapeutics. The present approach is applicable to other neurodegenerative diseases, enhancing the differential diagnoses.

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.

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.

Severe Epilepsy and Movement Disorder May Be Early Symptoms of TMEM106B-Related Hypomyelinating Leukodystrophy.

Objective: To report the clinical presentation of the first Italian child affected by hypomyelinating leukodystrophy (HLD) associated with the recurrent variant p.Asp252Asn in the TMEM106B gene. Methods: The methods included clinical case description, neurophysiologic assessment, brain MRI, and whole-exome sequencing (WES). Results: The child presented soon after birth with nystagmus and hyperkinetic movement disorder. Focal seizures appeared from 2 months of age and recurred at high frequency, despite several antiseizure medications, and focal epileptic status frequently required IV phenytoin. Control of seizures was achieved at the age of 8 months by the association of high doses of sodium blockers. Clinical picture worsened over time and was characterized by axial hypotonia, failure to thrive requiring gastrostomy, pyramidal sings, and severe secondary microcephaly. MRI performed at ages 2, 6, and 20 months showed diffuse supratentorial and subtentorial hypomyelination; multimodal evoked potentials showed increased latency. WES performed at 6 months of age identified the p.Asp252Asn de novo variant in the TMEM106B gene. Discussion: Hyperkinetic movement disorders and seizures may be early symptoms of TMEM106B-HLD. Our observation, supported by video EEG recordings, emphasizes that seizures may be difficult to recognize from movement disorders and that epilepsy may be a severe and prominent symptom of the disease. TMEM106B-HLD should be considered in the genetic screening of infants with early-onset seizures and movement disorders.

Characterization of 22q12 Microdeletions Causing Position Effect in Rare NF2 Patients with Complex Phenotypes.

Neurofibromatosis type 2 is an autosomal dominant tumor-prone disorder mainly caused by NF2 point mutations or intragenic deletions. Few individuals with a complex phenotype and 22q12 microdeletions have been described. The 22q12 microdeletions' pathogenic effects at the genetic and epigenetic levels are currently unknown. We here report on 22q12 microdeletions' characterization in three NF2 patients with different phenotype complexities. A possible effect of the position was investigated by in silico analysis of 22q12 topologically associated domains (TADs) and regulatory elements, and by expression analysis of 12 genes flanking patients' deletions. A 147 Kb microdeletion was identified in the patient with the mildest phenotype, while two large deletions of 561 Kb and 1.8 Mb were found in the other two patients, showing a more severe symptomatology. The last two patients displayed intellectual disability, possibly related to AP1B1 gene deletion. The microdeletions change from one to five TADs, and the 22q12 chromatin regulatory landscape, according to the altered expression levels of four deletion-flanking genes, including PIK3IP1, are likely associated with an early ischemic event occurring in the patient with the largest deletion. Our results suggest that the identification of the deletion extent can provide prognostic markers, predictive of NF2 phenotypes, and potential therapeutic targets, thus overall improving patient management.

Muscle quantitative MRI in adult SMA patients on nusinersen treatment: a longitudinal study.

The recent approval of disease-modifying therapies for spinal muscular atrophy (SMA) raised the need of alternative outcome measures to evaluate treatment efficacy. In this study, we investigated the potential of muscle quantitative MRI (qMRI) as a biomarker of disease progression in adult SMA3 patients during nusinersen treatment. Six adult SMA3 patients (age ranging from 19 to 65 years) underwent 2-point Dixon muscle qMRI at beginning of nusinersen treatment (T0) and after 14 months (T14) to evaluate the muscle fat fraction (FF) at thigh and leg levels; patients were clinically assessed at T0 and T14 with the Hammersmith Functional Rating Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM) and the 6-minute walk test (6MWT). At T0, vastus lateralis muscle displayed the highest mean FF (67.5%), while tibialis anterior was the most preserved one (mean FF = 35.2%). At T0, a slightly significant correlation of FF with HFMSE (p = 0.042) and disease duration (p = 0.042) at thigh level and only with HFMSE (p = 0.042) at leg level was found. At T14, no significant change of mean FF values at thigh and leg muscles was found compared to T0. Conversely, a statistically significant (p = 0.042) improvement of HFMSE was reported at T14. We observed no significant change of FF in thigh and leg muscles after 14 months of nusinersen therapy despite a significant clinical improvement of HFMSE. Further studies with longer follow-up and larger cohorts are needed to better investigate the role of qMRI as marker of disease progression in SMA patients.