Citations

AbstractPrimary aneurysmal bone cyst (ABC) is a benign multiloculated cystic lesion of bone that is defined cytogenetically by USP6 gene rearrangements. Rearrangements involving USP6 are promoter swaps, usually generated by fusion of the noncoding upstream exons of different partner genes with exon 1 or 2 of USP6, thus leading to transcriptional upregulation of full‐length USP6 coding sequence. Testing for USP6 rearrangements is used diagnostically to distinguish it from secondary ABC and other giant cell‐rich primary bone tumors. In this report, we present a case of a 16‐year‐old male with a primary ABC of the left distal femur. USP6 break apart fluorescence in situ hybridization was positive for a rearrangement and conventional chromosome analysis identified a reciprocal X;17 translocation. In order to identify the putative USP6 fusion partner, we performed RNA sequencing and uncovered a novel USP9X‐USP6 promoter swap fusion. This result was confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) and by mate pair sequencing thus showing the utility of these alternative methodologies in identifying novel fusion candidates. Ubiquitin‐specific protease 9X (USP9X), like USP6, encodes a highly conserved substrate‐specific deubiquitylating enzyme. USP9X is highly expressed in a number of tissue types and acts as both an oncogene and tumor suppressor in several human cancers. We conclude that oncogenic activation of USP6 via USP9X promoter exchange represents a novel driver of primary ABC formation.

Abstract Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

AbstractBackgroundThe purpose of this study was to evaluate the measurement properties of the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index‐Daily Diary, a patient‐reported outcome instrument developed to meet US FDA recommendations for a symptom‐based clinical trial endpoint in gastroparesis. The ANMS GCSI‐DD assesses nausea, early satiety, postprandial fullness, and upper abdominal pain on a severity score from none (0) to very severe (4) and number of vomiting episodes during the past 24 hours. The composite score includes the first four symptoms, the core symptom score includes all five symptoms.MethodsSeventy‐one patients diagnosed with idiopathic or diabetic gastroparesis were recruited for a four‐week observational study. Patients completed the ANMS GCSI‐DD at home between Baseline and Week 4. Statistical analyses included confirmatory factor analysis, item response theory analysis, internal consistency, test‐retest reliability, and construct and known‐groups validity.Key ResultsUnidimensionality for the composite and core symptom scores was supported, and items exhibited good fit. Internal consistency (Cronbach's alpha =0.85 and 0.83) and test‐retest reliability were 0.89 and 0.88, for composite and core symptom scores, respectively. Convergent validity was supported by strong correlations with patient‐reported and clinician measures. Baseline and Week 4 scores differed for three measures used to define disease severity status (P < 0.0001), supporting known‐groups validity.Conclusions & InferencesThe ANMS GCSI‐DD has excellent reliability and validity, supporting its use to assess symptom‐based endpoints in gastroparesis clinical studies. Further analyses will be conducted using clinical trial data to ascertain treatment responsiveness and define a responder.

Manually delivered intermittent bolus (MIB) and programmable intermittent bolus (PIB), alternatives to continuous infusion (CI), involve administering a set volume of solution at a set interval of time. The benefits of intermittent bolus techniques in truncal and peripheral nerve blockade (TPNB) are unclear, and studies have largely demonstrated conflicting results. Using MEDLINE, Embase, Google Scholar, and the Cochrane Library, we conducted an evidenced-based review of published randomized controlled trials comparing intermittent bolus and CI methods in TPNB. In total, 13 randomized controlled trials were identified and evaluated. Outcomes data addressed in these studies included assessments of pain, opioid and local anesthetic consumption, patient satisfaction, adverse events, and physical therapy metrics. The overall quality of current evidence was found to be low given the small sample sizes, heterogeneity of data, and the variations in intermittent bolus techniques between studies. At this time, we found limited supportive data to endorse MIB or PIB over CI in TPNB. While unable to provide data-driven conclusions for local anesthetic delivery methods at this time, we propose that future studies and quantitative analysis between techniques should be on an anatomic, site-specific basis, with greater focus on evaluation of opioid use, adverse events, patient satisfaction, and rehabilitative metrics.

Introduction: Cerebral small-vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate if chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods: Consecutive patients with MCA±ICA occlusion presenting within 6 hours after stroke symptoms onset from 2012- 2016 were included. Primary outcome was collateral flow, which was assessed on baseline CT-angiogram (poor ≤50% filling, good >50% filling). Markers of chronic SVD on brain MRI were rated for the presence of WMH (Fazekas scale 2-3), enlarged perivascular spaces (EPVS), chronic lacunae, and any cerebral microbleeds (CMB) using the STRIVE criteria. Severity of SVD was quantified by adding the presence of each SVD feature to a maximum score of 4. Multivariable logistic regression models were performed to evaluate the relationships between SVD and poor collaterals. Results: Of the 100 patients, the mean age was 65±16, median NIHSS was 15, and 68% had SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals (aOR 1.9; 95%CI 1.1-3.2) than patients without SVD. Of the SVD types, poor collaterals were associated with WMH (aOR 2.9 per Fazekas increment; 95%CI 1.6-5.3) but not EPVS (aOR 1.3; 0.4-4.0), lacunae (aOR 2.1; 0.6-7.1), or CMB (aOR 2.1; 0.6-7.8). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend p<.001; adjusted p=.056). There was a dose-dependent relationship between WMH burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1-3 (trends P=.015, Table). No patient with SVD score of 4 had good collaterals. Conclusions: Chronic cerebral small-vessel disease is associated with poor recruitment of collaterals in large-vessel occlusive stroke. A prospective study to elucidate the mechanism of how SVD may impair the recruitment of collaterals is ongoing.

Introduction: Shared decision making (SDM) incorporates patient and physician values and preferences into treatment selection. While multiple therapeutic options are available for stroke prevention in atrial fibrillation (AF), few studies have examined factors associated with SDM regarding choice of antithrombotic strategy. Methods: We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 sites participating in a substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II), an outpatient AF registry in the US. Patients were asked: “When choosing your blood thinner(s), who made this treatment decision?”, and SDM was defined as a response of “equally me and my healthcare provider (HCP)”, “mostly me” or “entirely me”, while no SDM was defined as a response of “mostly my HCP” or “entirely my HCP”. Multivariable logistic regression models evaluated associations between 13 patient-level factors, self-reported understanding of treatment options, and SDM for antithrombotic therapy. Results: Most patients allowed their HCP to make the therapeutic decisions on antithrombotic strategy, with 246 (24.5%) reporting SDM. Patients reporting SDM were more often female (47.2% vs. 40.5%) and were more frequently insured by Medicare (40.2% vs. 34.5%) than patients reporting no SDM. Among patients taking warfarin, median time in therapeutic range was higher among patients reporting SDM than among those not reporting SDM. In multivariable models, chronic obstructive pulmonary disease was associated with lower odds of SDM while self-reported understanding of blood thinner options was associated with higher odds of SDM (Table). Conclusion: One in four patients in an outpatient AF registry reported that their current antithrombotic strategy was the result of a shared decision making process. Additional work is need to determine whether patient-reported SDM is associated with medication adherence and outcomes of therapy.

Introduction: Robust leptomeningeal collaterals protect brain from ischemia, yet the determinants of poor collaterals remains unclear. We aimed to identify predictors of poor collaterals in patients with large-vessel occlusive stroke. Methods: We analyzed 112 consecutive patients with middle cerebral artery ± internal carotid artery occlusion from 2012-2016 who presented within 6 hours after stroke symptoms onset. Collaterals on baseline CT-angiogram (poor collaterals ≤50% filling, good collaterals >50% filling) were reviewed blinded to clinical data. Pre-specified predictors of poor collaterals were analyzed with adjusted logistic regression models: including known predictors (age, vascular risk factors and metabolic derangements) and hypothesized predictors (low cardiac output, elevated inflammatory markers, and imaging evidence for chronic cerebral small-vessel disease and chronic steno-occlusive arterial disease). Results: The mean age was 67± 16 years, there were 48% women, 57% white, and median NIHSS was 15 (IQR 11-20). Poor collaterals at baseline were detected in 48%. Multivariable modeling identified that age (aOR 1.8 per 10 years; 95% CI 1.3-2.6; p<0.001), black race (aOR 2.1; 95% CI 1.0-4.5; p=0.043), high blood glucose level (aOR 2.4 per 100 mg/dl; 95% CI 1.1-5.1; p=0.029), and high WMH burden (aOR 6.1; 95%CI 1.8-20.4; p=0.003) were independent predictors of poor collaterals. Associations between low cardiac output, elevated inflammatory markers, intracranial atherosclerosis and poor collaterals did not reach statistical significance (Table). Conclusions: We have identified that advanced age, black race, hyperglycemia, and white matter hyperintensities are predictors of poor collaterals. Independent replication study at another institution is ongoing to further explore the hypothesized predictors.