Citations

Abstract Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

Background: Most women will experience uterine fibroids by the age of 50, yet few data exist describing the overall patient experience with fibroids. The objective of this population-based survey was to characterize symptom burden, patient awareness, and treatment decision-making for fibroids, including a comparison among women of varying backgrounds. Materials and Methods: Women (≥18 years) were recruited via email from GfK KnowledgePanel ® , a representative panel of US households, or identified with opt-in consumer panels. The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QOL) questionnaire and Aberdeen Menorrhagia Severity Scale (AMSS) were included. Results: Eligible women were grouped into three cohorts: “at-risk” (symptoms suggestive of fibroids without clinical diagnosis, n = 300), “diagnosed” ( n = 871), and fibroid-related “hysterectomy” ( n = 272). Cohort and intracohort race/ethnicity and income analyses revealed differences in symptom burden, awareness/perception, and treatment history. Based on UFS-QOL scores, at-risk women reported significantly greater symptom severity and decreased health-related QOL versus diagnosed women; Hispanic women reported greater symptom severity versus white and black women. At-risk women also reported heavy menstrual bleeding and significant impact on work productivity. Among diagnosed women, 71% used pharmacologic therapy for symptom relief, and 30% underwent surgical or procedural treatment. Initial discussions with healthcare providers significantly impacted treatment outcomes; the hysterectomy cohort was most likely to first discuss hysterectomy. Conclusions: Women with fibroids or symptoms suggestive of fibroids experience significant distress that reduces QOL, particularly racial minorities and women in lower income brackets. Survey results suggest that many women are likely undiagnosed, underscoring the need for improved awareness and education.

Objectives/HypothesisVocal fold (VF) paralysis by sectioning the recurrent laryngeal nerve dramatically impacts the life of thyroidectomy patients. Volume‐expanding materials can temporarily restore VF medialization. To prolong this benefit, adipose mesenchymal stem cells (ADSCs) and micronized acellular dermis (MACD) were co‐injected in a rabbit model of injection medialization laryngoplasty. Biomarkers of in situ proliferation were identified by mass spectrometry proteomics and pathway analysis to guide future efforts to increase the length of benefit.MethodsADSCs were expanded and/or differentiated into chondrocytes (CHON) as collagen microspheres. After VF paralysis rabbits received MACD, MACD + undifferentiated ADSC, or MACD+CHON, ADSCs differentiated into chondrocytes. After 12 weeks, animals were sacrificed and 5‐µm paraffin‐embedded cryosections were prepared from larynges for hematoxylin and eosin visualization and nanoflow liquid chromatography electrospray‐ionization tandem‐mass spectrometry analysis of tissue collections. Validated proteins were processed by Venn subtraction and gene ontology (GO) overrepresentation analysis to identify unique pathways and biomarkers.ResultsConfirmed proteins numbered 147 (MACD), 1,243 (MACD+ADSC), and 1,033 (MACD+CHON). Totally, 333 proteins were uniquely found in the MACD+ADSC group, including mesenchymal surface markers CD9, CD44, fibronectin, and vimentin. Over 70% of proteins belonged to catalytic activity and binding GO categories, with the histone (H) family being overrepresented (P < 0.05). Histone variants H3.3, H2A.V, and H2A.Z (associated with open chromatin states) were overrepresented in the MACD+ADSC group, whereas structural histones H2A, H2B, and H4 were not.ConclusionBiomarkers, including atypical histones, are associated with in vivo proliferation of ADSCs and an expanded VF medialization volume.Level of EvidenceNA Laryngoscope, 128:E402–E408, 2018

Objective: Vocal cord dysfunction (VCD) is characterized by paradoxical vocal fold movement (PVFM) during inspiration. The aim of this study was to determine whether ultrasound could accurately differentiate between normal and PVFM during respirations in a resting state. Design: Prospective, single-subject design. Setting: Academic medical center. Patients: A speech-language pathologist who was able to volitionally alternate between normal and PVFM when breathing at rest was recruited to participate in the study. Interventions: The subject was instructed to randomly alternate between normal and PVFM 20 times (10 times each). A single investigator imaged the vocal folds using ultrasound and reported when the subject alternated between the 2 respiratory states. Main Outcome Measures: The subject recorded when they changed between the 2 respiratory states, whether the investigator identified with the change occurred, and if the correct respiratory state was identified. Results: The investigator recognized when the subject changed respiratory states and correctly identified the new respiratory state 100% of the time. Conclusions: The findings of the current study were promising and suggest that ultrasound may have utility in the diagnosis of VCD. However, because of the preliminary nature of these results, further research is required before recommending its clinical implementation.

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P &lt; 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P &lt; 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Introduction. Idiopathic subglottic stenosis represents a spectrum of subglottic disease without a clear underlying cause. Prior studies have implicated a pathogenic role of gastroesophageal reflux disease in idiopathic subglottic stenosis. The aim of this study was to examine the presence and pattern of gastroesophageal reflux in a large cohort of patients with idiopathic subglottic stenosis at a tertiary referral center. Methods. We performed a retrospective review of patients with idiopathic subglottic stenosis from January 2010 to December 2016 who had undergone combined pH impedance testing. Patients with prior gastric or esophageal surgery were excluded. Data obtained included esophageal acid exposure times, number of reflux events, patient position during reflux events (defined as upright, supine, or mixed), body mass index, and the presence of proton pump inhibitor therapy. Results. 159 patients with the idiopathic subglottic stenosis were identified, of whom 41 had undergone esophageal pH impedance testing. 40 (97.6%) were women, with a mean age of 54.8 (range 31–79) years and BMI of 31.0 (range 17–55). Overall, 19 (46.3%) patients were found to reflux as confirmed by abnormal esophageal acid exposure or abnormal number of reflux events. 15 of the 19 patients with reflux had predominantly upright gastroesophageal reflux disease, whereas 2 had supine and 2 mixed reflux. Discussion. In patients with idiopathic subglottic stenosis who underwent evaluation by combined pH impedance, close to half were found to have gastroesophageal reflux disease. The majority of gastroesophageal reflux occurred while the patients were in the upright position.

ABSTRACT Purpose To determine whether quantitative methods could separate golfers with a possible dystonic cause of the “yips” from those that appear to be nondystonic. Methods Twenty-seven golfers completed 10 two-handed and 10 right hand–only putts. Surface EMG assessed forearm muscle co-contraction and motion detectors monitored wrist and putter movements. Based on a videotape review, golfers were grouped into those with yips of dystonic etiology, those with the yips nondystonic, and those with no yips. Results On video review of two-handed putting, five golfers had yips that appeared to be dystonic, nine had yips that did not appear to be dystonic, and 13 had no yips. During two-handed putting co-occurrence of a yipped putt and wrist flexor/extensor and/or pronator/supinator co-contraction was significantly more frequent in those with dystonic yips. The dystonic group had no increase in the number of yipped putts or yips with co-contraction when putting right hand only, whereas the nondystonic group had significantly more yipped putts and more yipped putts with co-contraction with right hand only. Conclusions Quantitative methods were identified that appear to identify golfers with a dystonic etiology for the yips. It is not just the frequency of yips nor just specific motion patterns alone, rather it is also a combination of yips with co-occurring co-contraction when putting with two hands, and then right hand only, that distinguished this possible etiology. Despite being a small study, identifying a dystonic pattern, even in a nonpressure indoor setting, may aid in assessment and possible monitoring of treatment.

AimsThe aim of this study was to evaluate near-infrared spectroscopy (NIRS) as a continuous, non-invasive monitor for acute compartment syndrome (ACS).Patients and MethodsNIRS sensors were placed on 86 patients with, and 23 without (controls), severe leg injury. NIRS values were recorded for up to 48 hours. Longitudinal data were analyzed using summary and graphical methods, bivariate comparisons, and multivariable multilevel modelling.ResultsMean NIRS values in the anterior, lateral, superficial posterior, and deep posterior compartments were between 72% and 78% in injured legs, between 69% and 72% in uninjured legs, and between 71% and 73% in bilaterally uninjured legs. In patients without ACS, the values were typically > 3% higher in injured compartments. All seven limbs with ACS had at least one compartment where NIRS values were 3% or more below a reference uninjured control compartment. Missing data were encountered in many instances.ConclusionNIRS oximetry might be used to aid the assessment and management of patients with ACS. Sustained hyperaemia is consistent with the absence of ACS in injured legs. Loss of the hyperaemic differential warrants heightened surveillance. NIRS values in at least one injured compartment(s) were > 3% below the uninjured contralateral compartment(s) in all seven patients with ACS. Additional interventional studies are required to validate the use of NIRS for ACS monitoring. Cite this article: Bone Joint J 2018;100-B:787–97.