KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.

Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.

Systemic inflammation induced from remote extremity trauma is a critical driver of secondary brain injury.

Blast exposure, commonly experienced by military personnel, can cause devastating life-threatening polysystem trauma. Despite considerable research efforts, the impact of the systemic inflammatory response after major trauma on secondary brain injury-inflammation is largely unknown. The aim of this study was to identify markers underlying the susceptibility and early onset of neuroinflammation in three rat trauma models: (1) blast overpressure exposure (BOP), (2) complex extremity trauma (CET) involving femur fracture, crush injury, tourniquet-induced ischemia, and transfemoral amputation through the fracture site, and (3) BOP+CET. Six hours post-injury, intact brains were harvested and dissected to obtain biopsies from the prefrontal cortex, striatum, neocortex, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum. Custom low-density microarray datasets were used to identify, interpret and visualize genes significant (p < 0.05 for differential expression [DEGs]; 86 neuroinflammation-associated) using a custom python-based computer program, principal component analysis, heatmaps and volcano plots. Gene set and pathway enrichment analyses of the DEGs was performed using R and STRING for protein-protein interaction (PPI) to identify and explore key genes and signaling networks. Transcript profiles were similar across all regions in naïve brains with similar expression levels involving neurotransmission and transcription functions and undetectable to low-levels of inflammation-related mediators. Trauma-induced neuroinflammation across all anatomical brain regions correlated with injury severity (BOP+CET > CET > BOP). The most pronounced differences in neuroinflammatory-neurodegenerative gene regulation were between blast-associated trauma (BOP, BOP+CET) and CET. Following BOP, there were few DEGs detected amongst all 8 brain regions, most were related to cytokines/chemokines and chemokine receptors, where PPI analysis revealed Il1b as a potential central hub gene. In contrast, CET led to a more excessive and diverse pro-neuroinflammatory reaction in which Il6 was identified as the central hub gene. Analysis of the of the BOP+CET dataset, revealed a more global heightened response (Cxcr2, Il1b, and Il6) as well as the expression of additional functional regulatory networks/hub genes (Ccl2, Ccl3, and Ccl4) which are known to play a critical role in the rapid recruitment and activation of immune cells via chemokine/cytokine signaling. These findings provide a foundation for discerning pathophysiological consequences of acute extremity injury and systemic inflammation following various forms of trauma in the brain.

Venetoclax in combination with chemotherapy as treatment for pediatric advanced hematologic malignancies.

BACKGROUND: Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. PROCEDURE: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Children's Hospitals from 2016 to 2022. RESULTS: We identified 13 patients (acute myeloid leukemia, n = 8; B-acute lymphoblastic leukemia, n = 3; myelodysplastic syndrome, n = 2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0-5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5-52 months) and 3 months (range 2 weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses. CONCLUSIONS: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population.

Inhibition of the Sec61 translocon overcomes cytokine-induced glucocorticoid resistance in T-cell acute lymphoblastic leukaemia.

Glucocorticoid (GC) resistance is a poor prognostic factor in T-cell acute lymphoblastic leukaemia (T-ALL). Interleukin-7 (IL-7) mediates GC resistance via GC-induced upregulation of IL-7 receptor (IL-7R) expression, leading to increased pro-survival signalling. IL-7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL-7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR-445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)-induced increase in cell surface IL-7R and overcomes IL-7-induced DEX resistance.

Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice.

Oncogenic RAS mutations pose substantial challenges for rational drug discovery. Sequence variations within the hypervariable region of Ras isoforms underlie differential posttranslational modification and subcellular trafficking, potentially resulting in selective vulnerabilities. Specifically, inhibiting the palmitoylation/depalmitoylation cycle is an appealing strategy for treating NRAS mutant cancers, particularly as normal tissues would retain K-Ras4b function for physiologic signaling. The role of endogenous N-RasG12D palmitoylation in signal transduction, hematopoietic differentiation, and myeloid transformation is unknown, and addressing these key questions will inform efforts to develop mechanism-based therapies. To evaluate the palmitoylation/depalmitoylation cycle as a candidate drug target in an in vivo disease-relevant model system, we introduced a C181S mutation into a conditional NrasG12D "knock-in" allele. The C181S second-site amino acid substitution abrogated myeloid transformation by NrasG12D, which was associated with mislocalization of the nonpalmitoylated N-Ras mutant protein, reduced Raf/MEK/ERK signaling, and alterations in hematopoietic stem and progenitor populations. Furthermore, hematologic malignancies arising in NrasG12D/G12D,C181S compound heterozygous mice invariably acquired revertant mutations that restored cysteine 181. Together, these studies validate the palmitoylation cycle as a promising therapeutic target in NRAS mutant cancers.

Mortality Trends of Oncology and Hematopoietic Stem Cell Transplant Patients Supported on Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.

BACKGROUND: There is an increasing frequency of oncology and hematopoietic stem cell transplant (HSCT) patients seen in the intensive care unit and requiring extracorporeal membrane oxygenation (ECMO), however, prognosis of this population over time is unclear. METHODS: MEDLINE, EMBASE, Cochrane and Web of Science were searched from earliest publication until April 10, 2020 for studies to determine the mortality trend over time in oncology and HSCT patients requiring ECMO. Primary outcome was hospital mortality. Random-effects meta-analysis model was used to obtain pooled estimates of mortality and 95% confidence intervals. A priori subgroup metanalysis compared adult versus pediatric, oncology versus HSCT, hematological malignancy versus solid tumor, allogeneic versus autologous HSCT, and veno-arterial versus veno-venous ECMO populations. Multivariable meta-regression was also performed for hospital mortality to account for year of study and HSCT population. RESULTS: 17 eligible observational studies (n = 1109 patients) were included. Overall pooled hospital mortality was 72% (95% CI: 65, 78). In the subgroup analysis, only HSCT was associated with a higher hospital mortality compared to oncology subgroup [84% (95% CI: 70, 93) vs. 66% (95% CI: 56, 74); P = 0.021]. Meta-regression showed that HSCT was associated with increased mortality [adjusted odds ratio (aOR) 3.84 (95% CI 1.77, 8.31)], however, mortality improved with time [aOR 0.92 (95% CI: 0.85, 0.99) with each advancing year]. CONCLUSION: This study reports a high overall hospital mortality in oncology and HSCT patients on ECMO which improved over time. The presence of HSCT portends almost a 4-fold increased risk of mortality and this finding may need to be taken into consideration during patient selection for ECMO.

Convergent genetic aberrations in murine and human T lineage acute lymphoblastic leukemias.

The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance.

Development and Validation of a Test to Monitor Endoscopic Activity in Patients With Crohn's Disease Based on Serum Levels of Proteins.

BACKGROUND & AIMS: Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS: The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS: We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD.

Long-term Efficacy of Single-agent Vemurafenib for Pleomorphic Xanthoastrocytoma.

Pleomorphic xanthoastrocytoma is a malignant brain tumor that has a good prognosis with complete resection but does not respond well to chemotherapy if there is residual tumor. BRAF V600E mutations are common in pleomorphic xanthoastrocytomas and provide an additional means for treatment when excision is not possible. Monotherapy with the BRAF V600E inhibitor vemurafenib has only been reported in a small number of cases and mostly in adults. We present the case of a 16-year-old male who responded to vemurafenib monotherapy initially and had an additional response to vemurafenib following progression after a brief time off the medication.

Outcomes among Patients Treated with Renal Replacement Therapy during Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are modalities used in critically ill patients suffering organ failure and metabolic derangements. Although the effects of CRRT have been extensively studied, the impact of simultaneous CRRT and ECMO is less well described. The purpose of this study is to evaluate the incidence and the impact of CRRT on outcomes of patients receiving ECMO. METHODS: A single center, retrospective chart review was conducted for patients receiving ECMO therapy over a 6-year period. Patients who underwent combined ECMO and CRRT were compared to those who underwent ECMO alone. Intergroup -statistical comparisons were performed using Wilcoxon/Kruskal-Wallis and chi-square tests. Logistic regression was performed to identify independent risk factors for mortality. RESULTS: The demographic and clinical data of 92 patients who underwent ECMO at our center were reviewed including primary diagnosis, indications for and mode of ECMO support, illness severity, oxygenation index, vasopressor requirement, and presence of acute kidney injury. In those patients that required ECMO with CRRT, we reviewed urine output prior to initiation, modality used, prescribed dose, net fluid balance after 72 h, requirement of renal replacement therapy (RRT) at discharge, and use of diuretics prior to RRT initiation. Our primary endpoint was survival to hospital discharge. During the study period, 48 patients required the combination of ECMO with CRRT. Twenty-nine of these patients survived to hospital discharge. Of the 29 survivors, 6 were dialysis dependent at hospital discharge. The mortality rate was 39.5% with combined ECMO/CRRT compared to 31.4% among those receiving ECMO alone (p = 0.074). Of those receiving combined therapy, nonsurvivors were more likely to have a significantly positive net fluid balance at 72 h (p = 0.001). A multivariate linear regression analysis showed net positive fluid balance and increased age were independently associated with mortality. CONCLUSIONS: Use of CRRT is prevalent among patients undergoing ECMO, with over 50% of our patient population receiving combination therapy. Fluid balance appears to be an important variable associated with outcomes in this cohort. Rates of renal recovery and overall survival were higher compared to previously published reports among those requiring combined ECMO/CRRT.

MRI surveillance following concurrent cochlear implantation in cases of vestibular schwannoma resection.

OBJECTIVE: Cochlear nerve preserving translabyrinthine vestibular schwannoma (VS) resection enables concurrent cochlear implantation. Implantation in patients with VS raises important concerns including the ability to undergo postoperative magnetic resonance imaging (MRI) monitoring of residual tumor growth or tumor recurrence, specifically with a retained magnet. We aim to assess the feasibility of MRI monitoring and the impact on image quality with retained cochlear implant (CI) magnets. METHODS: Retrospective review of post-operative head MRI scans in CI recipients with a retained CI magnet, after cochlear nerve preserving translabyrinthine excision of VS. The ability to visualize the ipsilateral and contralateral internal auditory canal (IAC) and cerebellopontine angle (CPA) were assessed. RESULTS: A total of eight surveillance head MRI were performed in six patients. In one case, in which the receiver was positioned lower, the view of the ipsilateral IAC and CPA was distorted. In all other cases, the views of both the ipsilateral and contralateral IAC and CPA were overall unimpaired. DISCUSSION: Imaging artifact only very rarely impedes adequate visualization of the ipsilateral IAC or CPA in CI recipients. In anticipation of the need for further IAC and CPA imaging, it would be advisable to place the receiver in an exaggerated superior-posterior position to further decrease obscuring artifact. Thus, serial monitoring of VS tumors can be performed safely with preservation of image quality with a retained receiver magnet. CONCLUSIONS: When placing the CI receiver-stimulator farther posterior-superiorly, excellent visualization of the IAC and CPA can be accomplished without significantly impairing the image quality.

Anatomic factors affecting the use of ultrasound to predict vocal fold motion: A pilot study.

PURPOSE: Ultrasonography is a well-established modality for visualization of head and neck anatomy. Using ultrasound to detect vocal fold mobility has been described before, but no study has evaluated factors affecting the exam reliability. The aim of the study is to determine anatomic factors influencing the reliability of ultrasound to detect vocal fold motion. Methods and materials Patients underwent ultrasound evaluation and flexible laryngoscopy to assess vocal fold motion from August 2015 to March 2016. Length, accuracy, and clarity of ultrasound examination were assessed, compared to flexible laryngoscopy. For patients with prior neck CT scan imaging, laryngeal anatomy was independently assessed by a blinded neuroradiologist. RESULTS: A total of 23 patients, 21 with bilateral vocal fold motion and two with unilateral paralysis, were enrolled. Vocal folds were visible in 19 patients (82%). Eight patients (42%) had good/excellent view and 11 patients (58%) had fair/difficult view. The ultrasound correctly detected absent movement of the vocal fold in the two patients with unilateral paralysis. A total of 19 patients had CT scans, and a linear correlation (r2 = 0.65) was noted between the anterior thyroid cartilage angle measured on CT and the grade of view on ultrasound. CONCLUSION: Ultrasound was able to detect vocal fold motion in 82% of randomly screened patients. Ease of detection of vocal fold motion correlated with the anterior thyroid angle. Further studies are warranted to investigate the reproducibility of our results and how this might impact use of ultrasound for detection of vocal fold motion in the operative setting.

Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation.

OBJECTIVE: Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation. METHODS: Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy. The surgical specimens were histologically processed with sectioning matched to the ultrasound imaging plane. Three radiologists, blinded to histology, evaluated parametric images of ARFI-induced peak displacement to identify plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), calcium (CAL), and fibrous cap (FC) thickness. Reader performance was measured against the histologic standard using receiver operating characteristic curve analysis, linear regression, Spearman correlation (ρ), and Bland-Altman analysis. RESULTS: ARFI peak displacement was two-to-four-times larger in regions of NC and IPH relative to regions of COL or CAL. Readers detected soft plaque features (NC/IPH) with a median area under the curve of 0.887 (range, 0.867-0.924) and stiff plaque features (COL/CAL) with median area under the curve of 0.859 (range, 0.771-0.929). FC thickness measurements of two of the three readers correlated with histology (reader 1: R2 = 0.64, ρ = 0.81; reader 2: R2 = 0.89, ρ = 0.75). CONCLUSIONS: This study suggests that ARFI is capable of distinguishing soft from stiff atherosclerotic plaque components and delineating FC thickness.

The Relationship Between Cochleovestibular Orientation, Age, and Sensorineural Hearing Loss: Implications for Cochlear Implantation.

OBJECTIVES: To determine if spatial orientation of the cochlea within the temporal bone is related to age or sensorineural hearing loss (SNHL) and describe the implications for cochlear implantation. METHODS: Five angles of cochlear orientation were determined from computed tomography (CT) imaging of the temporal bones in adults with (n = 55) and without (n = 27) sensorineural hearing loss (SNHL) and children with (n = 45) and without (n = 12) SNHL: facial recess versus basal turn, posterior semicircular canal versus basal turn, round window versus basal turn (axial view), round window versus basal turn (coronal view), and the cochlear axis versus the mastoid facial nerve. RESULTS: All angles showed substantial variation between subjects and between ears. The angles between the round window and basal turn (coronal view) and the posterior semicircular canal and basal turn were significantly correlated with age for all subjects with SNHL (r = 0.22, P = .002 and r = 0.15, P = .03, respectively). Patients with SNHL had significantly more acute angles (46.6° vs 55.8°) between the round window versus basal turn (axial orientation) compared to controls (P < .001). CONCLUSIONS: Cochlear orientation within the temporal bone changes with age and the degree of SNHL. These results suggest that the approach to the round window for electrode insertion might differ between children and adults.

Postoperative radiotherapy for diffuse pigmented villonodular synovitis of the temporomandibular joint.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare/benign condition of the synovial joint lining. It most commonly presents in the knee but has also been reported to occur in the temporomandibular joint (TMJ). Although there are several series reporting the use of postoperative radiotherapy (PORT) for extremity PVNS, there is scant literature on the use of PORT for PVNS of the TMJ. METHODS: We conducted a literature review for case reports related to PVNS of the TMJ and discuss two additional cases treated with surgery and PORT. RESULTS: 71 cases were found in the literature. 89% were the diffuse subtype. 92% had primary surgery and 7% had PORT. 68% were locally controlled. Both patients treated at our institution are locally controlled. CONCLUSIONS: PVNS of the TMJ is a rare entity. Surgery is the mainstay of treatment but PORT may be useful for local control of extensive tumors or positive margins.

Targeting Hyperactive Ras Signaling in Pediatric Cancer.

Somatic RAS mutations are among the most frequent drivers in pediatric and adult cancers. Somatic KRAS, NRAS, and HRAS mutations exhibit distinct tissue-specific predilections. Germline NF1 and RAS mutations in children with neurofibromatosis type 1 and other RASopathy developmental disorders have provided new insights into Ras biology. In many cases, these germline mutations are associated with increased cancer risk. Promising targeted therapeutic strategies for pediatric cancers and neoplasms with NF1 or RAS mutations include inhibition of downstream Ras effector pathways, directly inhibiting the signal output of oncogenic Ras proteins and associated pathway members, and therapeutically targeting Ras posttranslational modifications and intracellular trafficking. Acquired drug resistance to targeted drugs remains a significant challenge but, increasingly, rational drug combination approaches have shown promise in overcoming resistance. Developing predictive preclinical models of childhood cancers for drug testing is a high priority for the field of pediatric oncology.

Cross-Frequency Coupling as a Biomarker for Early Stroke Recovery.

BACKGROUND: The application of neuroimaging-based biomarkers in stroke has enriched our understanding of post-stroke recovery mechanisms, including alterations in functional connectivity based on synchronous oscillatory activity across various cortical regions. Phase-amplitude coupling, a type of cross-frequency coupling, may provide additional mechanistic insight. OBJECTIVE: To determine how the phase of prefrontal cortex delta (1-3 Hz) oscillatory activity mediates the amplitude of motor cortex beta (13-20 Hz) oscillations in individual's early post-stroke. METHODS: Participants admitted to an inpatient rehabilitation facility completed resting and task-based EEG recordings and motor assessments around the time of admission and discharge along with structural neuroimaging. Unimpaired controls completed EEG procedures during a single visit. Mixed-effects linear models were performed to assess within- and between-group differences in delta-beta prefrontomotor coupling. Associations between coupling and motor status and injury were also determined. RESULTS: Thirty individuals with stroke and 17 unimpaired controls participated. Coupling was greater during task versus rest conditions for all participants. Though coupling during affected extremity task performance decreased during hospitalization, coupling remained elevated at discharge compared to controls. Greater baseline coupling was associated with better motor status at admission and discharge and positively related to motor recovery. Coupling demonstrated both positive and negative associations with injury involving measures of lesion volume and overlap injury to anterior thalamic radiation, respectively. CONCLUSIONS: This work highlights the utility of prefrontomotor cross-frequency coupling as a potential motor status and recovery biomarker in stroke. The frequency- and region-specific neurocircuitry featured in this work may also facilitate novel treatment strategies in stroke.

Does CISS MRI Reliably Depict the Endolymphatic Duct in Children with and without Vestibular Aqueduct Enlargement?

BACKGROUND AND PURPOSE: High-resolution CT is the mainstay for diagnosing an enlarged vestibular aqueduct (EVA), but MR imaging may be an appealing alternative, given its lack of ionizing radiation exposure. The purpose of this study was to determine how reliably MR imaging demonstrates the endolymphatic duct and endolymphatic duct enlargement in hearing-impaired children. MATERIALS AND METHODS: We performed a retrospective review of temporal bone high-resolution CT and MR imaging of hearing-impaired children evaluated between 2017 and 2020. Vestibular aqueduct diameter was measured on high-resolution CT. The vestibular aqueducts were categorized as being enlarged (EVA+) or nonenlarged (EVA-) using the Cincinnati criteria. The endolymphatic ducts were assessed on axial high-resolution CISS MR imaging. We categorized endolymphatic duct visibility into the following: type 1 (not visible), type 2 (faintly visible), and type 3 (easily visible). Mixed-effect logistic regression was used to identify associations between endolymphatic duct visibility and EVA. Interreader agreement for the endolymphatic duct among 3 independent readers was assessed using the Fleiss κ statistic. RESULTS: In 196 ears from 98 children, endolymphatic duct visibility on MR imaging was type 1 in 74.0%, type 2 in 14.8%, and type 3 in 11.2%; 20.4% of ears were EVA+ on high-resolution CT. There was a significant association between EVA+ status and endolymphatic duct visibility (P < .01). Endolymphatic duct visibility was type 1 in 87.1%, type 2 in 12.8%, and type 3 in 0% of EVA- ears and type 1 in 22.5%, type 2 in 22.5%, and type 3 in 55.0% of EVA+ ears. The predicted probability of a type 3 endolymphatic duct being EVA+ was 0.997. There was almost perfect agreement among the 3 readers for distinguishing type 3 from type 1 or 2 endolymphatic ducts. CONCLUSIONS: CISS MR imaging substantially underdiagnoses EVA; however, when a type 3 endolymphatic duct is evident, there is a >99% likelihood of an EVA.