Citations

AbstractAn association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

AbstractMicroglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time‐lapse two‐photon imaging and whole‐cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid‐induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony‐stimulating factor 1 receptor (CSF‐1R) pathway. Pharmacological inhibition of CSF‐1R reduced seizure‐induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF‐1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.

AbstractBackgroundCompletion lymph node dissection (CLND) for sentinel lymph node (SLN) disease in melanoma patients is debated. We evaluated the impact of CLND on survival and assessed for predictors of nonsentinel node metastasis (positive CLND).MethodsPositive SLN melanoma patients were retrospectively identified in the Sentinel Lymph Node Working Group database. Clinicopathological factors were correlated with CLND status, overall survival (OS), and melanoma‐specific survival (MSS).ResultsThere were 953 positive SLN patients of whom 831 (87%) had CLND. Positive CLND was seen in 141 (17%) cases and was associated with worse OS and MSS (both P < 0.001). CLND was not performed (No‐CLND) in 122 of 953 positive SLN cases (13%), of whom 100 had follow‐up and 18 (18%) developed a nodal recurrence (NR). No significant differences in OS and MSS were seen comparing CLND with No‐CLND (P = 0.084, P = 0.161, respectively) and comparing positive CLND with No‐CLND NR patients (P = 0.565, P = 0.998, respectively). Gender, primary site, ulceration, and number of positive SLNs were correlated with nonsentinel node metastasis.ConclusionsPerformance of CLND provides prognostic information but is not associated with a survival benefit. Clinical variables can predict a positive CLND in patients who may be at high risk of recurrence.

Abstract Bacteriolytic strategies offer unique advantages to combat a broad range of cancers often refractive to conventional chemotherapies and/or radiotherapies. C. novyi-NT is an attenuated strain of Clostridium novyi, a spore-forming, gram-positive, obligate anaerobe that lacks a lethal alpha- toxin, expressed by the parental strain. When administered intravenously or intratumorally with percutaneous injection, C. novyi-NT colonizes and replicates within the hypoxic region of the tumors, eliciting robust, tumor-confined cell lysis. In this first-in-man phase 1 study, patients with injectable treatment-refractory solid tumors received a single intratumoral injection of C. novyi-NT spores across 6 dose cohorts (spore concentrations of 104, 3x104, 105, 3x105, 106, 3x106) using a 3+3 trial design. The primary endpoints were to assess the safety profile, the dose limiting toxicity, and the maximum tolerated dose of C. novyi-NT. Key secondary endpoints included assessments of the preliminary antitumor activity of the injected tumor, an overall response evaluated by RECIST v. 1.1, and the host immune and inflammatory response to C. novyi-NT. Twenty-four patients were enrolled between November, 2013 and April, 2017. A single intratumoral injection of C. novyi-NT led to germination and resultant tumor lysis of injected tumor masses in 46% of patients across all dosing cohorts. The cohort 5 dose of 106 spores was defined as the maximum tolerated dose. Dose-limiting toxicities were grade 4 sepsis and grade 4 gas gangrene (n=1), all in patients with germination. In the 22 evaluable patients, 21 (95%) had stable disease (SD) as the best response for the injected lesion (tumor shrinkage of &gt; 10% was observed in 21% of patients) and 19 (86%) had overall SD as the best response per RECIST 1.1. C. novyi-NT injection resulted in transient serum cytokine responses consistent with inflammasome activity, activation of innate immunity, tissue remodeling, and angiogenesis. Tumor antigen specific ELISPOT assays pre- and post- treatment documented enhanced secretion of IFNγ and TNFα by circulating T-cells, indicating improved systemic tumor specific T-cell responses. Multiparametric in situ immunostaining of core biopsies suggested improved immune cell infiltration in metastatic lesions. These early signs of improved antitumor activity in patients with advanced solid tumors have encouraged a new trial of C. novyi-NT in combination with immune checkpoint inhibitors. Citation Format: Filip Janku, Mrinal Gounder, Abdul Mohammad Pezeshki, Ravi Murthy, Andrea Wang-Gillam, Dale Shepard, David S. Hong, Sarina A. Piha-Paul, Anjali Raina, Alexey A. Leontovich, Gary DeCrescenzo, Brent L. Kreider, David Tung, Mary Varterasian, Halle H. Zhang, Khashayarsha Khazaie. First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A011.

Nasal septal abscesses (NSAs) occur between the mucoperichondrium and the nasal septum. They most often arise when an untreated septal hematoma becomes infected. The most commonly reported sequela is a loss of septal cartilage support, which can result in a nasal deformity. Other sequelae include potentially life-threatening conditions such as meningitis, cavernous sinus thrombosis, brain abscess, and subarachnoid empyema. We report the case of a 17-year-old boy who developed an NSA after he had been struck in the face with a basketball. He presented to his primary care physician 5 days after the injury and again the next day, but his condition was not correctly diagnosed. Finally, 7 days after his injury, he presented to an emergency department with more serious symptoms, and he was correctly diagnosed with NSA. He was admitted to the intensive care unit, and he remained hospitalized for 6 days. Among the abscess sequelae he experienced was septic arthritis, which has heretofore not been reported as a complication of NSA. He responded well to appropriate treatment, although he lost a considerable amount of septal cartilage. He was discharged home on intravenous antibiotic therapy, and his condition improved. Reconstruction of the nasal septum will likely need to be pursued in the future.

ObjectiveVoice outcomes following medialization laryngoplasty (ML) for unilateral vocal fold paralysis (UVFP) were compared to those who underwent ML plus arytenoid adduction (AA) (ML+AA).MethodsSingle institution retrospective review of patients with UVFP undergoing ML and ML+AA (2009–2017). Demographic information and history of laryngeal procedures were collected. Preoperative and postoperative Voice Handicap Index‐10 (VHI‐10) and Consensus Perceptual Auditory Evaluation of Voice (CAPE‐V) were assessed.ResultsOf 236 patients, 119 met study criteria. Of those, 70 (59%) underwent ML and 49 (41%) underwent ML+AA. Significant differences between groups at baseline were found for age at time of thyroplasty (P = 0.046), VHI‐10 scores (P < 0.001), and CAPE‐V scores (P = 0.007). Baseline VHI‐10 scores for ML+AA (28 ± 7) were greater than those for ML alone (24 ± 7). At 12 months, overall VHI‐10 scores improved compared to baseline for both groups (ML+AA = 9 ± 7, ML = 16 ± 9); however, there was greater improvement for the ML+AA group compared to ML group (P = 0.001). CAPE‐V scores at 3 or 12 months improved, but differences between the groups were not statistically significant once controlled for covariates.ConclusionBased on current findings, patients who undergo ML+AA likely have greater voice handicap at baseline compared to those undergoing ML alone. Patients selected for ML+AA improve as much or more than those who underwent ML alone. This highlights the importance of appropriate selection of candidates for AA.Level of Evidence4Laryngoscope, 129:1876–1881, 2019

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P &lt; 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Objectives/HypothesisTo evaluate trends, outcomes, and healthcare utilization following medialization laryngoplasty (ML) with or without arytenoid adduction (AA) over 10 years.Study DesignRetrospective observational study.MethodsUsing OptumLabs Data Warehouse, trends, outcomes, and healthcare utilization from 2006 to 2015 were examined with a focus on discharge type (same day or not). Predictors of postoperative emergency department (ED) use and hospitalization were determined by multivariable logistic regression.ResultsOverall rate of ML was 1.09 per 100 thousand enrollees per year. Of these, 7.8% ML were combined with an AA. Outpatient same‐day discharge represented 62.0% (1,142 of 1,843) of total patients, steadily increasing over the 10‐year period (P < 0.01). There was a 5.9% revision ML rate and 1.0% rate of tracheotomy within 1 day of ML. A total of 5.6% visited an ED, and 5.4% were admitted to a hospital following initial discharge within 30 days. Same‐day discharge was found to be a predictor of hospitalization within 30 days after ML (odds ratio [OR] 1.74, P = 0.0452), along with Elixhauser comorbidity index of 4 + (OR 5.74, P = 0.0001). Pulmonary embolism, pulmonary hypertension, and weight loss were top predictors of ED visit or hospitalization.ConclusionTo our knowledge, this is the first search evaluating national claims data for ML with or without AA. Overall rate of ML is low, and same‐day discharge has become more common over a 10‐year period, with an associated higher 30‐day hospital admission risk. Correct patient selection criteria for disposition status cannot be fully determined based on current data, but a high Elixhauser comorbidity index clearly carries increased risk for hospitalization after initial discharge.Level of Evidence4 Laryngoscope, 129:952–960, 2019