Utility of Motor and Somatosensory Evoked Potentials for Neural Thermoprotection in Ablations of Musculoskeletal Tumors.

PURPOSE: To characterize the utility of monitoring transcranial electrical motor evoked potentials (TCeMEPs) and somatosensory evoked potentials (SSEPs) for neural thermoprotection during musculoskeletal tumor ablations. MATERIALS AND METHODS: Retrospective review of 29 patients (16 male; median age, 46 y; range, 7-77 y) who underwent musculoskeletal tumor radiofrequency ablation (n = 8) or cryoablation (n = 22) with intraprocedural TCeMEP and SSEP monitoring was performed. The most common tumor histologies were osteoid osteoma (n = 6), venous malformation (n = 5), sarcoma (n = 5), renal cell carcinoma (n = 4), and non-small-cell lung cancer (n = 3). The most common tumor sites were spine (n = 22) and lower extremities (n = 4). Abnormal TCeMEP change was defined by 100-V increase above baseline threshold activation for a given myotome; abnormal SSEP change was defined by 60% reduction in baseline amplitude and/or 10% increase in latency. RESULTS: Abnormal changes in TCeMEP (n = 9; 30%) and/or SSEP (n = 5; 17%) occurred in 12 procedures (40%) and did not recover in 5 patients. Patients with unchanged TCeMEP/SSEP activities throughout the procedure (n = 18) did not have motor or sensory symptoms after the procedure; 3 (60%) with unrecovered activity changes and 2 (29%) with transient activity changes had new motor (n = 1) or sensory (n = 4) symptoms. Relative risk for neurologic sequelae for patients with unrecovered TCeMEP/SSEP changes vs those with transient or no changes was 7.50 (95% confidence interval, 1.66-33.9; P = .009). CONCLUSIONS: Abnormal activity changes of TCeMEP or SSEP during percutaneous ablative procedures correlate with postprocedural neurologic sequelae.

Utility of Transthoracic Echocardiography in Diagnostic Evaluation of Ischemic Stroke.

Objective: Transthoracic echocardiography (TTE) is routinely performed as part of standard acute ischemic stroke (AIS) workup. However, the overall yield of TTE is unclear and many patients may undergo unnecessary investigations. This study aims to investigate the utility of TTE as part of AIS workup. Methods: We collected data on consecutive patients with AIS who were admitted to our institution between 07/01/2016 and 09/30/2017. Patients were included based on neuroimaging-documented AIS, age >18 and neuroimaging studies. Primary endpoint was the proportion of cases in which TTE yielded relevant finding, defined as Atrial Septa Defect or Patent Foramen Ovale, left atrial enlargement, left ventricular thrombus or ejection fraction of <35%. Secondary endpoint was the proportion of patients who had a TTE-drive change in management. Results: Among 548 AIS patients (median age 71 [59-81] years, 50% female), 482 (87%) underwent TTE. Clinically relevant findings were observed in 183 (38%) patients, leading to additional workup in 41 (8.5%). Further workup was associated with younger median age (58 [50-65] vs. 72 [62-81], p < 0.0001, and was less likely in suspected large vessel etiology (p = 0.02). Abnormal TTE lead to treatment change in 24 (5%) patients; 22/24 were started on anticoagulation. TTE results were less likely to influence treatment changes in older patients (71 [60-80] vs. 58 [49-69] years, p = 0.02) with known atrial fibrillation (p = 0.01). Conclusion: Our findings suggest that despite widespread use, the overall yield of TTE in AIS is low. Stratifying patients according to their likelihood of benefitting from it will be important toward better resource utilization.

Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with 89Zr in Human Lymphoma Xenografts.

Radioimmunotherapies with monoclonal antibodies to the B-lymphocyte antigen 20 (CD20) are effective treatments for B-cell lymphomas, but U.S. Food and Drug Administration-approved radioimmunotherapies exclusively use radiolabeled murine antibodies, potentially limiting redosing. The Food and Drug Administration recently approved 2 unlabeled anti-CD20 monoclonal antibodies, obinutuzumab and ofatumumab, termed next generation as they are humanized (obinutuzumab) or fully human (ofatumumab), thus potentially allowing a greater potential for redosing than with previous-generation anti-CD20 antibodies, including rituximab (chimeric) and tositumomab (murine), which contain more murine peptide sequences. We prepared 89Zr-ofatumumab and 89Zr-obinituzumab and assessed their tumor targeting by PET/CT imaging and their biodistribution in a preclinical mouse model with CD20 xenografts to determine whether these antibodies have potential as theranostics or for radioimmunotherapy. Methods: Obinutuzumab, ofatumumab, rituximab, tositumomab, and human IgG (as control) were radiolabeled with 89Zr. Raji Burkitt lymphoma xenografts were established in severe combined immunodeficient mice. Mice with palpable tumors (n = 4-9) were injected with 89Zr-obinutuzumab, 89Zr-ofatumumab, 89Zr-rituximab, 89Zr-tositumomab, or 89Zr-IgG, with small-animal PET/CT images acquired at 1, 3, and 7 d after injection, and then sacrificed for biodistribution analyses. Results: At 1, 3, and 7 d after injection, all anti-CD20 antibodies showed clear tumor uptake on PET/CT, with minimal tumor uptake of IgG. Biodistribution data showed significantly (P < 0.005) higher tumor uptake for obinutuzumab (41.4 ± 7.6 percentage injected dose [%ID]/g), ofatumumab (32.6 ± 17.5 %ID/g), rituximab (28.6 ± 7.6 %ID/g), and tositumomab (28.0 ± 6.5 %ID/g) than IgG (7.2 ± 1.2 %ID/g). Tositumomab had much higher splenic uptake (186.4 ± 49.7 %ID/g, P < 0.001) than the other antibodies. Conclusion:89Zr-labeled obinutuzumab and ofatumumab localized to tumor as well as or better than labeled rituximab and tositumomab, 2 monoclonal antibodies that have been used previously in B-cell lymphoma radioimmunotherapy, and both obinutuzumab and ofatumumab have the potential for repeated dosing.

The Radiologist's Primer to Imaging the Noncuff, Nonlabral Postoperative Shoulder.

Many radiologists are familiar with the preoperative imaging assessment of patients with labral tears, rotator cuff abnormalities, and end-stage arthritis, as well as the subsequent primary reconstructions and repairs commonly encountered in routine clinical management. However, the second-line surgical procedures and augmentation procedures performed for refractory or recurrent shoulder instability and the extra-articular surgical procedures of the shoulder girdle may challenge even the most experienced musculoskeletal radiologist. Knowledge of the indications, surgical techniques, expected postoperative imaging appearance, and complications of these uncommon shoulder girdle reconstructions and repairs will aid the radiologist in both the pre- and postoperative assessment of the injured shoulder. This article is divided into two parts. In the first part, procedures performed for shoulder instability are addressed, including capsular shift, Bristow-Latarjet coracoid transfer, remplissage, and humeral head allografts. In the second part, the imaging findings of extra-articular procedures of the shoulder girdle are reviewed, including biceps tenodesis, os acromiale fixation, and coracoclavicular ligament reconstruction. ©RSNA, 2017.

A Forward Genetic Screen for Molecules Involved in Pheromone-Induced Dauer Formation in Caenorhabditis elegans.

Animals must constantly assess their surroundings and integrate sensory cues to make appropriate behavioral and developmental decisions. Pheromones produced by conspecific individuals provide critical information regarding environmental conditions. Ascaroside pheromone concentration and composition are instructive in the decision of Caenorhabditis elegans to either develop into a reproductive adult or enter into the stress-resistant alternate dauer developmental stage. Pheromones are sensed by a small set of sensory neurons, and integrated with additional environmental cues, to regulate neuroendocrine signaling and dauer formation. To identify molecules required for pheromone-induced dauer formation, we performed an unbiased forward genetic screen and identified phd (pheromone response-defective dauer) mutants. Here, we describe new roles in dauer formation for previously identified neuronal molecules such as the WD40 domain protein QUI-1 and MACO-1 Macoilin, report new roles for nociceptive neurons in modulating pheromone-induced dauer formation, and identify tau tubulin kinases as new genes involved in dauer formation. Thus, phd mutants define loci required for the detection, transmission, or integration of pheromone signals in the regulation of dauer formation.

Diverse cell type-specific mechanisms localize G protein-coupled receptors to Caenorhabditis elegans sensory cilia.

The localization of signaling molecules such as G protein-coupled receptors (GPCRs) to primary cilia is essential for correct signal transduction. Detailed studies over the past decade have begun to elucidate the diverse sequences and trafficking mechanisms that sort and transport GPCRs to the ciliary compartment. However, a systematic analysis of the pathways required for ciliary targeting of multiple GPCRs in different cell types in vivo has not been reported. Here we describe the sequences and proteins required to localize GPCRs to the cilia of the AWB and ASK sensory neuron types in Caenorhabditis elegans. We find that GPCRs expressed in AWB or ASK utilize conserved and novel sequences for ciliary localization, and that the requirement for a ciliary targeting sequence in a given GPCR is different in different neuron types. Consistent with the presence of multiple ciliary targeting sequences, we identify diverse proteins required for ciliary localization of individual GPCRs in AWB and ASK. In particular, we show that the TUB-1 Tubby protein is required for ciliary localization of a subset of GPCRs, implying that defects in GPCR localization may be causal to the metabolic phenotypes of tub-1 mutants. Together, our results describe a remarkable complexity of mechanisms that act in a protein- and cell-specific manner to localize GPCRs to cilia, and suggest that this diversity allows for precise regulation of GPCR-mediated signaling as a function of external and internal context.

STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADalpha normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADalpha expression. STRADalpha-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADalpha in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADalpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.