The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Sellar Reconstruction With a Bioabsorbable Plate After Endoscopic Transsphenoidal Pituitary Adenoma Resection: Safe and Efficacious.

OBJECTIVE: To report outcomes of a large cohort of patients who underwent endoscopic endonasal transsphenoidal surgery (EETS) for resection of a pituitary adenoma with subsequent Resorb-X plate (RXP) sellar reconstruction. METHODS: A retrospective review of 620 EETS operations performed at a single academic center between 2005 and 2020 was conducted. RESULTS: A total of 215 EETS operations of 208 patients were identified between 2012 and 2020 who underwent reconstruction with the RXP after EETS for pituitary tumor resection with a final pathologic diagnosis of pituitary adenoma. Analysis of pooled data revealed a mean preoperative tumor volume of 6.8 cm3 (range: 0.038-51.03 cm3). Postoperative cerebrospinal fluid leak occurred in 2 patients (0.93%). Postoperative meningitis occurred in 1 patient (0.47%). There were no cases of RXP extrusion. CONCLUSIONS: The rate of postoperative CSF leak and meningitis after use of the RXP for sellar reconstruction compares favorably to other methods, including use of autologous grafts and flaps. Use of RXP during EETS is a safe and efficacious method of sellar reconstruction and may obviate the need for autologous tissue reconstruction after pituitary adenoma resection.

Development and validation of a nomogram incorporating gene expression profiling and clinical factors for accurate prediction of metastasis in patients with cutaneous melanoma following Mohs micrographic surgery.

BACKGROUND: There is a need to improve prognostic accuracy for patients with cutaneous melanoma. A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk. OBJECTIVE: Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy. METHODS: In an IRB-approved study, 1124 patients from 9 Mohs micrographic surgery centers were prospectively enrolled, treated with Mohs micrographic surgery, and underwent 31-GEP testing. Data from 684 of those patients with at least 1-year follow-up or a metastatic event were included in nomogram development to predict metastatic risk. RESULTS: Logistic regression modeling of 31-GEP results and T stage provided the simplest nomogram with the lowest Bayesian information criteria score. Validation in an archival cohort (n = 901) demonstrated a significant linear correlation between observed and nomogram-predicted risk of metastasis. The resulting nomogram more accurately predicts the risk for cutaneous melanoma metastasis than T stage or 31-GEP alone. LIMITATIONS: The patient population is representative of Mohs micrographic surgery centers. Sentinel lymph node biopsy was not performed for most patients and could not be used in the nomogram. CONCLUSIONS: Integration of 31-GEP and T stage can gain clinically useful prognostic information from data obtained noninvasively.

Surgical Management of Bilateral Vocal Fold Paralysis in Children: A Systematic Review and Meta-analysis.

OBJECTIVES: To examine and compare the outcomes of various types of glottic widening surgery (GWS) for initial management of bilateral vocal fold paralysis (BVFP) in children, the outcomes of different GWS procedures in children who underwent initial tracheostomy, and the rate of decannulation in children who underwent tracheostomy alone versus tracheostomy followed by GWS. DATA SOURCES: PubMed, Web of Science, Cochrane Library, and Embase were searched following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses) on September 9, 2019, with no date restriction. REVIEW METHODS: Articles focusing on GWS or tracheostomy for initial management of BVFP were included. Articles describing patients who received no surgical intervention for BVFP were excluded. RESULTS: A total of 5989 articles were reviewed: 67 articles met inclusion criteria, and 240 patients were incorporated into the analysis. Patients who underwent primary GWS had an eventual tracheostomy rate of 6.0% (5/83). There were no statistically significant differences in the rate of tracheostomy, reoperation, or mortality among cricoid split, suture lateralization, and cordectomy/cordotomy. Patients who underwent primary tracheostomy failed to achieve decannulation in 36.9% (58/157) of cases. Decannulation was more likely in tracheostomized children who received GWS than those who did not (odds ratio, 6.336; P < .0001). CONCLUSIONS: Most children who undergo primary GWS for BVFP avoid tracheostomy or reoperation. These data demonstrated no differences in surgical outcomes among the most common types of GWS for BVFP. For children who receive a tracheostomy as their first intervention for BVFP, GWS is associated with a significantly improved rate of decannulation.

Sialographic Analysis of Radioiodine-Associated Chronic Sialadenitis.

OBJECTIVES/HYPOTHESIS: To apply a novel sialography classification system to identify parotid and submandibular ductal findings following I-131 therapy and to assess correlates to dose and duration of symptoms. STUDY DESIGN: Retrospective single-center case series. METHODS: Patients who underwent sialography between February 2008 and February 2019 after previously receiving I-131 treatment were identified via a retrospective chart review. Their sialograms were systematically evaluated and scored by applying the Iowa parotid sialogram scale to also include submandibular gland analysis. RESULTS: From 337 sialograms, 30 (five submandibular, 25 parotid) underwent analysis. Ductal stenosis was identified in all sialograms and was graded as moderate (>50%-75%) in 7/30 cases and severe (>75%) in 15/30 cases. The distal (main) duct was narrowed in 23/30 cases. No association was identified between degree of ductal stenosis and I-131 dose (P = .39), age (P = .81), or time from I-131 therapy to sialogram (P = .97). CONCLUSIONS: The Iowa parotid sialogram scale was successfully applied to report abnormalities of the parotid and submandibular ductal system. The most common manifestation of I-131-associated sialadenitis was a severe stenosis within the distal salivary duct. No statistically significant association was found between degree of ductal stenosis and dose of I-131, age, or duration of symptoms. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1450-E1456, 2021.

Photocatalytic and photo-fenton activity of iron oxide-doped carbon nitride in 3D printed and LED driven photon concentrator.

We have synthesized iron oxide doped carbon nitride with 0.5 to 2 wt.% iron oxide and characterized by XPS, TGA, FTIR, SEM, photoluminescence spectroscopy and photoelectrochemical measurements. A herbicide, dicamba was employed as model organic pollutant for degradation in presence with the catalyst and hydrogen peroxide. A 3D printed photon concentrator with two chips on board (COB) LEDs with visible light spectra and two complex parabolic mirror surfaces was used as photo-reactor. The findings revealed that both photocurrent and degradation of dicamba were functions of light intensity and concentrator geometry. The rapid degradation of dicamba can be attributed to the holistic and individual actions of structural components of the photocatalyst. Four distinct phenomena, including photocatalytic activity of carbon nitride, quenching of electron/hole pairs and generation of additional reactive hydroxyl radicals by hydrogen peroxide, Fenton and photo-Fenton activity of iron oxide component of carbon nitride in presence of hydrogen peroxide and photocatalytic activity of iron oxide alone in conjuncture with carbon nitride can contribute to the overall photocatalytic activity of the system. Liquid Chromatography-Mass spectrometry (LCMS) analysis of the degradation products showed loss of chlorine from the aromatic ring and evidence of free radical addition reactions in the course of photocatalysis.

The V-to-Y Advancement Flap for Distal Nasal Reconstruction: Our Experience With 39 Patients.

BACKGROUND AND OBJECTIVE: The V-to-Y advancement flap, also known as the island pedicle flap, is a single-stage repair option that can be used for defects on the distal nose. We report our experience using this flap for nasal defects following Mohs micrographic surgery, as well as describe optimal patient selection and flap design. MATERIALS AND METHODS: A retrospective review was conducted of all patient charts and operative photographs of nasal V-to-Y advancement flaps performed over 6 years at the Universtiy of Texas Southwestern Medical Center. Charts were reviewed for age, sex, tumour type and location, defect size, anticoagulation, immunosuppression, postoperative complications, revisions, and outcomes. RESULTS: Thirty-nine patients with defects ranging from 0.7 to 1.7 cm in size (median of 1 cm) were included. Most defects involved the inferior, paramedian nose, and after accounting for 7 postrepair interventions on 6 (15%) patients, 38 (97%) patients were noted to have good to excellent cosmetic outcomes while 1 patient experienced a persistent trapdoor effect. CONCLUSION: The V-to-Y advancement flap is an excellent single-stage option that can reliably provide good to excellent cosmetic results when used to repair small- to medium-size sized defects on the distal half of the nose.

Osteoactivin regulates head and neck squamous cell carcinoma invasion by modulating matrix metalloproteases.

Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP-10 expression in UMSCC14a (p = 0.0431) and SCC15 (p < 0.0001) cells, but decreased MMP-9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP-10 expression in UMSCC12 cells (p = 0.0001), and MMP-3 (p = 0.0005) and -9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP-2 (p = 0.0408) and MMP-9 gelatinase activity (p < 0.0001), respectively. OA depletion decreased MMP-2 (p = 0.0023) and -9 (p < 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p < 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion.

Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.

Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the ß1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. © 2015 Wiley Periodicals, Inc.

Clinical and Pathologic Factors Predictive of Positive Radiologic Findings in High-Risk Cutaneous Squamous Cell Carcinoma.

BACKGROUND: At present, there exists considerable clinical uncertainty regarding the role of radiologic imaging in the staging and management of high-risk cutaneous squamous cell carcinoma (hrSCC). OBJECTIVE: The authors sought to investigate the clinical and pathologic features predictive of bony invasion, perineural invasion, or lymphadenopathy in patients that had undergone head and neck imaging for hrSCC. MATERIALS AND METHODS: The authors conducted a single-center retrospective chart review of patients (n = 82) that had undergone head and neck imaging for hrSCC. RESULTS: Twenty-nine percent (24/82) of patients in the study had positive findings on radiologic imaging. Immunocompromised patients were more likely to have the radiologic finding of lymphadenopathy (p = .04). Tumor size was found to correlate with the radiologic finding of bony invasion (correlation coefficient = 0.40, p = .0002). There was no relationship between either high risk location or high risk histopathology and positive radiologic findings. The low number of patients and its retrospective nature are study limitations. CONCLUSION: The clinical features of host immunosuppression and tumor size are predictive of positive imaging findings in hrSCC. The decision to perform radiologic imaging in patients with hrSCC may be influenced by these factors, but continue to be more firmly guided by physical exam and clinical suspicion.

Site-specific analysis of inflammatory markers in discoid lupus erythematosus skin.

Prior studies identified T cells, B cells, and macrophages in the inflammatory infiltrate and up-regulation of their protein products in discoid lupus erythematosus (DLE) skin; however, they lacked rigorous analyses to define their specific locations in skin. Thus, we compared expressions of selected T cell, B cell, and macrophage markers in five areas of DLE, psoriasis, and normal skin. Immunostainings for CD3, CD4, CD8, CD20, CD68, CXCR3, CXCL10, and TIA-1 were performed in biopsies of 23 DLE lesional skin, 11 psoriasis lesional skin, and 5 normal skin. Three independent observers used a graded scale to rate each marker's presence in the epidermis, dermatoepidermal junction (DEJ), perivascular area, periadnexal area, and deep dermis. DLE lesional skin contained an increased abundance of CD3(+), CD8(+), and CD68(+) cells at the DEJ, and CD20(+) and CD68(+) cells in the periadnexal area versus psoriasis and normal skin. CXCR3, CXCL10, and TIA-1 were elevated in periadnexal sites of DLE lesional skin versus psoriasis lesional skin. The aggregation of T cells, B cells, macrophages, and their protein products (CXCR3, CXCL10, and TIA-1) in the DEJ and periadnexal area of DLE lesional skin may contribute to the pathology of DLE through a coordinated, sophisticated process.

Edematous lip in a HIV patient on highly active antiretroviral therapy.

A 59-year-old HIV-positive, hepatitis C positive man on highly active antiretroviral therapy presented with a 2-year history of extreme swelling of the lower lip. Granulomatous cheilitis was diagnosed.