Extent of Resection Thresholds in Molecular Subgroups of Newly Diagnosed Isocitrate Dehydrogenase-Wildtype Glioblastoma.

BACKGROUND AND OBJECTIVES: Maximizing the extent of resection (EOR) improves outcomes in glioblastoma (GBM). However, previous GBM studies have not addressed the EOR impact in molecular subgroups beyond IDH1/IDH2 status. In the current article, we evaluate whether EOR confers a benefit in all GBM subtypes or only in particular molecular subgroups. METHODS: A retrospective cohort of newly diagnosed GBM isocitrate dehydrogenase (IDH)-wildtype undergoing resection were prospectively included in a database (n = 138). EOR and residual tumor volume (RTV) were quantified with semiautomated software. Formalin-fixed paraffin-embedded tumor tissues were analyzed by targeted next-generation sequencing. The association between recurrent genomic alterations and EOR/RTV was evaluated using a recursive partitioning analysis to identify thresholds of EOR or RTV that may predict survival. The Kaplan-Meier methods and multivariable Cox proportional hazards regression methods were applied for survival analysis. RESULTS: Patients with EOR ≥88% experienced 44% prolonged overall survival (OS) in multivariable analysis (hazard ratio: 0.56, P = .030). Patients with alterations in the TP53 pathway and EOR <89% showed reduced OS compared to TP53 pathway altered patients with EOR>89% (10.5 vs 18.8 months; HR: 2.78, P = .013); however, EOR/RTV was not associated with OS in patients without alterations in the TP53 pathway. Meanwhile, in all patients with EOR <88%, PTEN-altered had significantly worse OS than PTEN-wildtype (9.5 vs 15.4 months; HR: 4.53, P < .001). CONCLUSION: Our results suggest that a subset of molecularly defined GBM IDH-wildtype may benefit more from aggressive resections. Re-resections to optimize EOR might be beneficial in a subset of molecularly defined GBMs. Molecular alterations should be taken into consideration for surgical treatment decisions in GBM IDH-wildtype.

Imaging predictors of 4q12 amplified and RB1 mutated glioblastoma IDH-wildtype.

INTRODUCTION: Recent studies have identified that glioblastoma IDH-wildtype consists of different molecular subgroups with distinct prognoses. In order to accurately describe and classify gliomas, the Visually AcceSAble Rembrandt Images (VASARI) system was developed. The goal of this study was to evaluate the VASARI characteristics in molecular subgroups of IDH-wildtype glioblastoma. METHODS: A retrospective analysis of glioblastoma IDH- wildtype with comprehensive next-generation sequencing and pre-operative and post-operative MRI was performed. VASARI characteristics and 205 genes were evaluated. Multiple comparison adjustment by the Bejamin-Hochberg false discovery rate (BH-FDR) was performed. A 1:3 propensity score match (PSM) with a Caliper of 0.2 was done. RESULTS: 178 patients with GBM IDH-WT met the inclusion criteria. 4q12 amplified patients (n = 20) were associated with cyst presence (30% vs. 12%, p = 0.042), decreased hemorrhage (35% vs. 62%, p = 0.028), and non-restricting/mixed (35%/60%) rather than restricting diffusion pattern (5%), meanwhile, 4q12 non-amplified patients had mostly restricting (47.4%) rather than a non-restricting/mixed diffusion pattern (28.4%/23.4%). This remained statistically significant after BH-FDR adjustment (p = 0.002). PSM by 4q12 amplification showed that diffusion characteristics continued to be significantly different. Among RB1-mutant patients, 96% had well-defined enhancing margins vs. 70.6% of RB1-WT (p = 0.018), however, this was not significant after BH-FDR or PSM. CONCLUSIONS: Patients with glioblastoma IDH-wildtype harboring 4q12 amplification rarely have restricting DWI patterns compared to their wildtype counterparts, in which this DWI pattern is present in ~ 50% of patients. This suggests that some phenotypic imaging characteristics can be identified among molecular subtypes of IDH-wildtype glioblastoma.

Rapid detection of mutations in CSF-cfTNA with the Genexus Integrated Sequencer.

PURPOSE: Genomic alterations are fundamental for molecular-guided therapy in patients with breast and lung cancer. However, the turn-around time of standard next-generation sequencing assays is a limiting factor in the timely delivery of genomic information for clinical decision-making. METHODS: In this study, we evaluated genomic alterations in 54 cerebrospinal fluid samples from 33 patients with metastatic lung cancer and metastatic breast cancer to the brain using the Oncomine Precision Assay on the Genexus sequencer. There were nine patients with samples collected at multiple time points. RESULTS: Cell-free total nucleic acids (cfTNA) were extracted from CSF (0.1-11.2 ng/µl). Median base coverage was 31,963× with cfDNA input ranging from 2 to 20 ng. Mutations were detected in 30/54 CSF samples. Nineteen (19/24) samples with no mutations detected had suboptimal DNA input (< 20 ng). The EGFR exon-19 deletion and PIK3CA mutations were detected in two patients with increasing mutant allele fraction over time, highlighting the potential of CSF-cfTNA analysis for monitoring patients. Moreover, the EGFR T790M mutation was detected in one patient with prior EGFR inhibitor treatment. Additionally, ESR1 D538G and ESR1::CCDC170 alterations, associated with endocrine therapy resistance, were detected in 2 mBC patients. The average TAT from cfTNA-to-results was < 24 h. CONCLUSION: In summary, our results indicate that CSF-cfTNA analysis with the Genexus-OPA can provide clinically relevant information in patients with brain metastases with short TAT.

Impacts of spaceflight experience on human brain structure.

Spaceflight induces widespread changes in human brain morphology. It is unclear if these brain changes differ with varying mission duration or spaceflight experience history (i.e., novice or experienced, number of prior missions, time between missions). Here we addressed this issue by quantifying regional voxelwise changes in brain gray matter volume, white matter microstructure, extracellular free water (FW) distribution, and ventricular volume from pre- to post-flight in a sample of 30 astronauts. We found that longer missions were associated with greater expansion of the right lateral and third ventricles, with the majority of expansion occurring during the first 6 months in space then appearing to taper off for longer missions. Longer inter-mission intervals were associated with greater expansion of the ventricles following flight; crew with less than 3 years of time to recover between successive flights showed little to no enlargement of the lateral and third ventricles. These findings demonstrate that ventricle expansion continues with spaceflight with increasing mission duration, and inter-mission intervals less than 3 years may not allow sufficient time for the ventricles to fully recover their compensatory capacity. These findings illustrate some potential plateaus in and boundaries of human brain changes with spaceflight.

Imaging of Common and Infrequent Extradural Tumors.

Spinal extradural tumors, although uncommon, have high morbidity and mortality rates. Radiographs and computed tomography scans are typically used to assess and determine the characteristics of these tumors. However, MR imaging is the preferred method for the evaluation of complications that can increase morbidity, such as spinal cord and nerve compression. Imaging features, such as type of matrix, cortical involvement, and margins, aid in determining the diagnosis. This article discusses common and infrequent extradural spinal tumors, their imaging characteristics, and how age, location, and clinical presentation help in diagnosing these neoplasms.

The Cortico-Limbo-Thalamo-Cortical Circuits: An Update to the Original Papez Circuit of the Human Limbic System.

The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity of the limbic circuits based on the published literature as an update to the original Papez circuit.

Vascular Injuries in Head and Neck Trauma.

Blunt and penetrating vascular injuries of the head and neck can represent life-threatening emergencies that require accurate detection to prevent devastating and long-lasting consequences. Implementing appropriate screening criteria to indicate imaging studies is crucial as there is a variable latent time before the onset of clinical manifestations. Computed tomography angiography, MR imaging, and digital subtraction angiography represent the imaging modalities of choice to evaluate vascular injuries. The aim of this review is to provide a description of the different types of vascular injuries, describe the importance of each imaging modality, and recognize the imaging appearance of traumatic vessel injury.

Introducing the "Temporal Thumb Sign" in Pediatric Patients With New-Onset Idiopathic Seizures With and Without Elevated Cerebrospinal Fluid Opening Pressure.

BACKGROUND: Temporal lobe changes, such as anterior temporal lobe meningoceles or encephaloceles, have been documented as possible epileptogenic foci in a subset of pediatric patients with seizures. In our study, we aim to analyze a different structural change in the temporal lobe, remodeling of the posterior temporal skull base by the inferior temporal gyrus called the "temporal thumb sign" (TTS), in pediatric patients presenting with new-onset seizures with or without elevated opening pressure (OP), patients presenting with confirmed diagnosis of idiopathic intracranial hypertension (IIH) without seizure presentation, and healthy controls. METHODS: Magnetic resonance imaging scans of 163 pediatric patients were studied retrospectively for the presence of TTS. We analyzed the scans of 43 patients with elevated OP and confirmed IIH, 40 patients with elevated OP and new-onset idiopathic seizures, 40 patients with normal OP and new-onset idiopathic seizures, and 40 age- and sex-matched healthy controls. RESULTS: The TTS was detected most frequently in patients with elevated OP and seizures at 72.5% compared with patients with IIH with no seizures and patients with normal OP and seizures (32.6% and 27.5%, respectively). The TTS had a frequency of 12.5% in the control group. The TTS had the highest combination of specificity and sensitivity (72.5% and 72.5%) in patients with seizures and elevated OP compared with patients with seizures and normal OP (P value < 0.001). CONCLUSIONS: Our results suggest the Kamali "temporal thumb sign" is a novel imaging feature that may be used as a sensitive and specific imaging finding associated with seizures and elevated OP in the pediatric population.

Changes in working memory brain activity and task-based connectivity after long-duration spaceflight.

We studied the longitudinal effects of approximately 6 months of spaceflight on brain activity and task-based connectivity during a spatial working memory (SWM) task. We further investigated whether any brain changes correlated with changes in SWM performance from pre- to post-flight. Brain activity was measured using functional magnetic resonance imaging while astronauts (n = 15) performed a SWM task. Data were collected twice pre-flight and 4 times post-flight. No significant effects on SWM performance or brain activity were found due to spaceflight; however, significant pre- to post-flight changes in brain connectivity were evident. Superior occipital gyrus showed pre- to post-flight reductions in task-based connectivity with the rest of the brain. There was also decreased connectivity between the left middle occipital gyrus and the left parahippocampal gyrus, left cerebellum, and left lateral occipital cortex during SWM performance. These results may reflect increased visual network modularity with spaceflight. Further, increased visual and visuomotor connectivity were correlated with improved SWM performance from pre- to post-flight, while decreased visual and visual-frontal cortical connectivity were associated with poorer performance post-flight. These results suggest that while SWM performance remains consistent from pre- to post-flight, underlying changes in connectivity among supporting networks suggest both disruptive and compensatory alterations due to spaceflight.

Characterization of acute American football spinal injuries in a multi-center healthcare system.

PURPOSE: American football is considered one of the more injury-prone sports given its high-speed and high-impact nature. While much attention has been focused on chronic traumatic encephalopathy, spinal injuries represent the most common catastrophic injury incurred in football. The goal of this investigation is to describe the most common football-associated spinal lesions in a multi-center health system. METHODS: This is a retrospective analysis of patients with imaging evidence of spinal injuries related to American football during a 10-year period. Injuries were classified based on the anatomic level, type injury, spinal cord compromise, and therapeutic management. Chi-squared and Fisher's exact test were used for statistical analysis of categorial variables, and simple logistic regression was used to determine individual odds ratios. RESULTS: A total of 71 patients were included, with a median age of 17 (IQR, 15-22) years. The cervical spine was the most frequently affected segment (46%), followed by lumbar spine injuries (45%), and thoracic spine injuries (10%). Discogenic injuries were identified in 45 patients (63%). Spinal cord injury was documented in 7 subjects (10%), while cauda equina compression was reported in 1 patient (1%). CONCLUSIONS: Acute spinal injuries continue to represent a significant cause of morbidity among American football players. Compared to national statistics, we found a similar distribution of spinal injuries in terms of anatomic location and an alarmingly high proportion of SCI. This investigation represents the largest single-center study addressing spinal injuries among football players.

The Role of Apparent Diffusion Coefficient Values in Glioblastoma: Differentiating Tumor Progression Versus Treatment-Related Changes.

OBJECTIVE: Glioblastoma represents the most common primary brain malignancy with a median survival of 15 months. Follow-up examinations are crucial to establish the presence of tumor recurrence, as well as treatment-associated changes such as ischemic infarction and radiation effects. Even though magnetic resonance imaging is a valuable tool, a histopathological diagnosis is often required because of imaging overlap between tumor recurrence and treatment associated changes. We set out to measure the apparent diffusion coefficient (ADC) values of the lesions in magnetic resonance imaging scans of treated glioblastoma patients to investigate if ADC values could accurately differentiate between tumor progression, radiation-related changes, and ischemic infarctions. METHODS: We evaluated ADC values among 3 groups, patients with tumor progression, radiation necrosis, and ischemic infarctions. The regions of interest were placed in the areas of greatest hypointensity among solid lesions using the ADC maps, excluding areas with necrotic, cystic, or hemorrhagic changes. The ADC values of the contralateral normal appearing white matter were also measured as the reference value for each patient. The relative ADC (rADC) values were measured for all 3 groups. Comparison between lesions and normal white matter was evaluated by Wilcoxon signed test. RESULTS: A total of 157 patients were included in the study; 49 patients classified as tumor progression, 58 patients as radiation necrosis, and 50 patients as ischemic infarctions. The mean ± SD ADC value was 752.8 ± 132.5 for tumor progression, 479.0 ± 105.2 for radiation-related changes, and 250.1 ± 57.2 for ischemic infarctions. The mean ± SD rADC value was 1.07 ± 0.22 for tumor progression, 0.66 ± 0.14 for radiation necrosis, and 0.34 ± 0.08 for ischemic infarctions. The mean rADC values were significantly higher in tumor progression, compared with both radiation necrosis and ischemic changes ( P < 0.001). CONCLUSIONS: The present study demonstrates that ADC values are a helpful tool to differentiate between tumor progression, radiation necrosis, and posttreatment ischemic changes.

IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas.

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas. METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images. RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas. CONCLUSION: Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.

Traumatic spondylolisthesis of axis: clinical and imaging experience at a level one trauma center.

PURPOSE: Traumatic spondylolisthesis of the axis (TSA) with bilateral pars interarticularis fracture (a pattern also known as Hangman's fractures) accounts for 4-5% of all cervical fractures. Various classification systems have been described to assist therapeutic decision-making. The goal is to reassess the utility of these classifications for treatment strategy and evaluate additional imaging associations. METHODS: This is an IRB approved, retrospective analysis of patients with imaging diagnosis of TSA from 2016 to 2019. Consensus reads were performed classifying TSA into various Levine and Edwards subtypes and typical vs. atypical fractures. Other imaging findings such as additional cervical fractures, traumatic brain injury, spinal cord injury, and vertebral artery injury were recorded. Treatment strategy and outcome were reviewed from clinical charts. Fisher exact test was used for statistical analysis. RESULTS: A total of 58 patients were included, with a mean age of 62.7 ± 25 years, and male to female ratio of 1:1.2. Motor vehicle collision was the most common cause of TSA. Type I and III injuries were the most and the least common injuries, respectively. Patients with type I injuries were found to have good healing rates with conservative management (p < 0.001) while type IIa and III injuries were managed with surgical stabilization (p = 0.04 and p = 0.01, respectively). No statistical difference was observed in the treatment strategy for type II fractures (p = 0.12) and its prediction of the associated injuries. Atypical fractures were not found to have a higher incidence of SCI (p = 0.31). A further analysis revealed significantly higher-grade vertebral artery injuries (grades III and IV according to Biffl grading) in patients with type IIa and III injuries (p = 0.001) and an 11-fold increased risk of TBI compared to type I and type II fractures (p = 0.013). CONCLUSION: TSA fracture types were not associated with any clinical outcome. Levine and Edwards type II classification itself is not enough to guide the treatment plan and does not account for associated injuries. Additional imaging markers may be needed.

Longitudinal MRI-visible perivascular space (PVS) changes with long-duration spaceflight.

Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T1-weighted 3 T MRI scans, twice prior to launch and four times following their return to Earth after ~ 6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established, automated segmentation algorithm. We validated our automated segmentation algorithm by comparing algorithm PVS counts with those identified by two trained raters in 50 randomly selected slices from this cohort; the automated algorithm performed similarly to visual ratings (r(48) = 0.77, p < 0.001). In addition, we found high reliability for four of five PVS metrics across the two pre-flight time points and across the four control time points (ICC(3,k) > 0.50). Among the astronaut cohort, we found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (p = 0.020), suggesting that experienced astronauts may exhibit holdover effects from prior spaceflight(s). Greater pre-flight PVS load was associated with more prior flight experience (r = 0.60-0.71), though these relationships did not reach statistical significance (p > 0.05). Pre- to post-flight changes in ventricular volume were not significantly associated with changes in PVS characteristics, and the presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that PVSs can be consistently identified on T1-weighted MRI scans, and that spaceflight is associated with PVS changes. Specifically, prior spaceflight experience may be an important factor in determining PVS characteristics.

Accuracy of CT Perfusion-Based Core Estimation of Follow-up Infarction: Effects of Time Since Last Known Well.

BACKGROUND AND OBJECTIVES: To assess the accuracy of baseline CT perfusion (CTP) ischemic core estimates. METHODS: From SELECT (Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke), a prospective multicenter cohort study of imaging selection, patients undergoing endovascular thrombectomy who achieved complete reperfusion (modified Thrombolysis In Cerebral Ischemia score 3) and had follow-up diffusion-weighted imaging (DWI) available were evaluated. Follow-up DWI lesions were coregistered to baseline CTP. The difference between baseline CTP core (relative cerebral blood flow [rCBF] <30%) volume and follow-up infarct volume was classified as overestimation (core ≥10 mL larger than infarct), adequate, or underestimation (core ≥25 mL smaller than infarct) and spatial overlap was evaluated. RESULTS: Of 101 included patients, median time from last known well (LKW) to imaging acquisition was 138 (82-244) minutes. The median baseline ischemic core estimate was 9 (0-31.9) mL and median follow-up infarct volume was 18.4 (5.3-68.7) mL. All 6/101 (6%) patients with overestimation of the subsequent infarct volume were imaged within 90 minutes of LKW and achieved rapid reperfusion (within 120 minutes of CTP). Using rCBF <20% threshold to estimate ischemic core in patients presenting within 90 minutes eliminated overestimation. Volumetric correlation between the ischemic core estimate and follow-up imaging improved as LKW time to imaging acquisition increased: Spearman ρ <90 minutes 0.33 (p = 0.049), 90-270 minutes 0.63 (p < 0.0001), >270 minutes 0.86 (p < 0.0001). Assessment of the spatial overlap between baseline CTP ischemic core lesion and follow-up infarct demonstrated that a median of 3.2 (0.0-9.0) mL of estimated core fell outside the subsequent infarct. These regions were predominantly in white matter. DISCUSSION: Significant overestimation of irreversibly injured ischemic core volume was rare, was only observed in patients who presented within 90 minutes of LKW and achieved reperfusion within 120 minutes of CTP acquisition, and occurred primarily in white matter. Use of a more conservative (rCBF <20%) threshold for estimating ischemic core in patients presenting within 90 minutes eliminated all significant overestimation cases. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03876457.

Neuroimaging Features of Intracranial Hypertension in Pediatric Patients With New-Onset Idiopathic Seizures, a Comparison With Patients with Confirmed Diagnosis of Idiopathic Intracranial Hypertension: A Preliminary Study.

CONCLUSION: A cutoff value of 6.0 mm for optic nerve sheath dilation may be used as a screening imaging marker to suspect elevated opening pressure with specificity of 88% in pediatric patients with new-onset idiopathic seizures.

Leveraging Spatial Information in Radiology Reports for Ischemic Stroke Phenotyping.

Classifying fine-grained ischemic stroke phenotypes relies on identifying important clinical information. Radiology reports provide relevant information with context to determine such phenotype information. We focus on stroke phenotypes with location-specific information: brain region affected, laterality, stroke stage, and lacunarity. We use an existing fine-grained spatial information extraction system-Rad-SpatialNet-to identify clinically important information and apply simple domain rules on the extracted information to classify phenotypes. The performance of our proposed approach is promising (recall of 89.62% for classifying brain region and 74.11% for classifying brain region, side, and stroke stage together). Our work demonstrates that an information extraction system based on a fine-grained schema can be utilized to determine complex phenotypes with the inclusion of simple domain rules. These phenotypes have the potential to facilitate stroke research focusing on post-stroke outcome and treatment planning based on the stroke location.