Beyond Depth of Invasion: Adverse Pathologic Tumor Features in Early Oral Tongue Squamous Cell Carcinoma.

OBJECTIVE: In small (≤2 cm) oral tongue squamous cell carcinoma (OTSCC), we sought to clarify the contribution of pathologic features including perineural invasion (PNI), lymphovascular invasion (LVI), and worst pattern of invasion-5 (WPOI-5) to clinical outcomes relative to tumor depth of invasion (DOI) of > or ≤ 4 mm. METHODS: Cases of ≤2 cm OTSCC treated surgically between 2000 and 2017 at an academic cancer center were reviewed, with retrospective pathologic slide review of DOI, LVI, PNI, and WPOI-5. Primary outcome measures included occult nodal positivity, 2-year locoregional recurrence (LRR), disease-specific survival (DSS), and overall survival (OS). RESULTS: One hundred tumors were included in analyses; 50 had DOI ≤ 4 mm, while 50 had DOI > 4 mm. When DOI was ≤4 mm, the presence of PNI, LVI, or WPOI-5 was not associated with higher rates of occult cervical metastasis, LRR, or OS. When DOI was >4 mm, there was no difference in rates of occult cervical metastasis or LRR with each feature. On multivariate analysis, only the presence of two or more adverse features was associated with higher LRR (OR 5.7, P = .01) and worse DSS (HR 6.5, P = .02). CONCLUSION: The rate of occult cervical metastases in small (≤2 cm) OTSCC when DOI is ≤4 mm is very low even when PNI, LVI, or WPOI-5 is present, and 2-year LRR is no different. When DOI is >4 mm, the strongest predictor of recurrence and survival on multivariate analysis is the presence of two or more features in the tumor. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1715-1720, 2020.

Automated Smartphone Audiometry: A Preliminary Validation of a Bone-Conduction Threshold Test App.

OBJECTIVE: To develop and validate an automated smartphone app that determines bone-conduction pure-tone thresholds. METHODS: A novel app, called EarBone, was developed as an automated test to determine best-cochlea pure-tone bone-conduction thresholds using a smartphone driving a professional-grade bone oscillator. Adult, English-speaking patients who were undergoing audiometric assessment by audiologists at an academic health system as part of their prescribed care were invited to use the EarBone app. Best-ear bone-conduction thresholds determined by the app and the gold standard audiologist were compared. RESULTS: Forty subjects with varied hearing thresholds were tested. Sixty-one percent of app-determined thresholds were within 5 dB of audiologist-determined thresholds, and 79% were within 10 dB. Nearly all subjects required assistance with placing the bone oscillator on their mastoid. CONCLUSION: Best-cochlea bone-conduction thresholds determined by the EarBone automated smartphone audiometry app approximate those determined by an audiologist. This serves as a proof of concept for automated smartphone-based bone-conduction threshold testing. Further improvements, such as the addition of contralateral ear masking, are needed to make the app clinically useful.

Secondary Ocular Hypertension and the Risk of Glaucoma Surgery After Dexamethasone Intravitreal Implant in Routine Clinical Practice.

BACKGROUND AND OBJECTIVES: To determine the rate of ocular hypertension (OHT) after dexamethasone intravitreal implant in routine clinical practice and identify patient characteristics associated with a risk for glaucoma surgery. PATIENTS AND METHODS: The charts of 260 eyes from 221 patients with diabetic macular edema, retinal vein occlusion, uveitis, and macular edema secondary to various causes treated with one or more dexamethasone implants were reviewed. Intraocular pressure (IOP), medications, and glaucoma interventions were collected before and after implantation. RESULTS: The mean baseline IOP was 14.3 mm Hg ± 3.6 mm Hg, and after receiving dexamethasone implant(s), 26.2% and 7.7% of patients had IOP greater than 25 mm Hg and 35 mm Hg, respectively. There was evidence (P < .001) of an association between preexisting glaucoma or glaucoma suspect status (103 eyes) and need for glaucoma surgery, and 4.62% (12 eyes) required glaucoma surgery. CONCLUSIONS: Secondary OHT induced by the dexamethasone implant can usually be controlled by medications, but the incidence of OHT requiring glaucoma surgery was high (4.62%) in our study relative to rates previously reported in the literature. All patients, especially those with preexisting glaucoma, should be advised of the possible need for glaucoma surgery prior to undergoing treatment with the dexamethasone implant. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:680-685.].

BET Inhibition Overcomes Receptor Tyrosine Kinase-Mediated Cetuximab Resistance in HNSCC.

Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK), including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK. Bromodomain-containing protein-4 (BRD4) has been shown to regulate the transcription of various RTK in the context of resistance to PI3K and HER2 inhibition in breast cancer models. We hypothesized that, in HNSCC, targeting BRD4 could overcome cetuximab resistance by depleting alternative RTK expression. We generated independent models of cetuximab resistance in HNSCC cell lines and interrogated their RTK and BRD4 expression profiles. Cetuximab-resistant clones displayed increased expression and activation of several RTK, such as MET and AXL, as well as an increased percentage of BRD4-expressing cells. Both genetic and pharmacologic inhibition of BRD4 abrogated cell viability in models of acquired and intrinsic cetuximab resistance and was associated with a robust decrease in alternative RTK expression by cetuximab. Combined treatment with cetuximab and bromodomain inhibitor JQ1 significantly delayed acquired resistance and RTK upregulation in patient-derived xenograft models of HNSCC. These findings indicate that the combination of cetuximab and bromodomain inhibition may be a promising therapeutic strategy for patients with HNSCC.Significance: Inhibition of bromodomain protein BRD4 represents a potential therapeutic strategy to circumvent the toxicities and financial burden of targeting the multiple receptor tyrosine kinases that drive cetuximab resistance in HNSCC and NSCLC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4331/F1.large.jpg Cancer Res; 78(15); 4331-43. ©2018 AACR.

Comprehensive characterization of DNA methylation changes in Fuchs endothelial corneal dystrophy.

Transparency of the human cornea is necessary for vision. Fuchs Endothelial Corneal Dystrophy (FECD) is a bilateral, heritable degeneration of the corneal endothelium, and a leading indication for corneal transplantation in developed countries. While the early onset, and rarer, form of FECD has been linked to COL8A2 mutations, the more common, late onset form of FECD has genetic mutations linked to only a minority of cases. Epigenetic modifications that occur in FECD are unknown. Here, we report on and compare the DNA methylation landscape of normal human corneal endothelial (CE) tissue and CE from FECD patients using the Illumina Infinium HumanMethylation450 (HM450) DNA methylation array. We show that DNA methylation profiles are distinct between control and FECD samples. Differentially methylated probes (10,961) were identified in the FECD samples compared with the control samples, with the majority of probes being hypermethylated in the FECD samples. Genes containing differentially methylated sites were disproportionately annotated to ontological categories involving cytoskeletal organization, ion transport, hematopoetic cell differentiation, and cellular metabolism. Our results suggest that altered DNA methylation patterns may contribute to loss of corneal transparency in FECD through a global accumulation of sporadic DNA methylation changes in genes critical to basic CE biological processes.