Beauty Is in the Eye of the Beholder:Esthetic Outcome Assessment in Smile Reanimation Surgery in Patients With Facial Palsy

Layperson assessments are becoming increasingly important in the evaluation of surgical procedures of the face, including smile reanimation. In this study, the authors set out to answer 3 questions: (1) are esthetic scores more dependent on the assessor or the person that is being assessed, (2) how does smile reanimation change esthetic scores, (3) do sex and age of the patient and assessor explain some of the esthetic outcomes? Thirty-five assessors scored pre and postoperative photographs of 21 facial palsy patients undergoing smile reanimation. Linear mixed-effect models were used to investigate the effects of assessor and patient factors on esthetic outcome assessments, to examine changes after smile reanimation, and to determine whether sex and age explained part of the esthetic outcomes. Fifty-eight percent of variation in the esthetic scores can be explained by some assessors being more positive in their esthetic scoring compared to other assessors. Twenty-nine percent was attributed to patient baseline esthetic scores. Overall esthetic scores improved after smile reanimation. Sex and age of the patient and assessor could not explain variation in the esthetic scores. Esthetic appearance highly depends on "who is looking.'' These findings are important for preoperative counseling, and for those treating and educating patients with facial palsy

TLR9 Mediated Tumor-Stroma Interactions in Human Papilloma Virus (HPV)-Positive Head and Neck Squamous Cell Carcinoma Up-Regulate PD-L1 and PD-L2

Background: The co-inhibitory receptor PD-1 is expressed in many tumors including head and neck squamous cell carcinoma (HNSCC) and is an important immunotherapy target. However, the role of PD-1 ligands, PD-L1, and particularly PD-L2, in the tumor-stromal cell interactions that cause a tumor-permissive environment in HNSCC is not completely understood and is the focus of our study. Methods: Expression of PD-L1 and PD-L2 was analyzed by immunohistochemistry in situ in HNSCC tumor tissue. Co-cultures were established between stromal cells (fibroblasts and macrophages) and human papilloma virus (HPV)-positive and HPV-negative HNSCC cell lines (HNSCCs) and PD-1 ligands expression was analyzed using flow cytometry. Results: PD-L1 and PD-L2 were expressed both in tumor cells and stroma in HNSCC tissue in situ. In vitro, basal expression of PD-L1 and PD-L2 was low in HNSCCs and high on fibroblasts and macrophages. Interestingly, HPV-positive but not HPV-negative HNSCCs increased the expression of both PD-1 ligands on fibroblasts upon co-culture. This effect was not observed with macrophages. Conversely, both fibroblasts and macrophages increased PD-1 ligands on HPV-positive HNSCCs, whilst this was not observed in HPV-negative HNSCCs. Crucially, we demonstrate that up-regulation of PD-L1 and PD-L2 on fibroblasts by HPV-positive HNSCCs is mediated via TLR9. Conclusions: This work demonstrates in an in vitro model that HPV-positive HNSCCs regulate PD-L1/2 expression on fibroblasts via TLR9. This may open novel avenues to modulate immune checkpoint regulator PD-1 and its ligands by targeting TLR9

Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy

Aims Anal squamous cell carcinomas (ASCC) are strongly associated with human papillomaviruses. Standard of care is chemoradiotherapy at uniform doses with no treatment stratification. Immunohistochemical staining for p16INK4A (p16), a surrogate for human papillomaviruses, is prognostic for outcomes. We investigated this alongside clinical-pathological factors, including tumour infiltrating lymphocyte (TIL) scores. Materials and methods Using an independent, multicentre cohort of 257 ASCC treated with chemoradiotherapy, pretreatment biopsies were stained and scored for p16 and TIL. Kaplan–Meier curves were derived for outcomes (disease-free survival [DFS], overall survival and cancer-specific survival), by stage, p16 and TIL scores and Log-rank tests were carried out to investigate prognostic effect. A multivariate analysis was carried out using Cox regression. Results Stage, sex, p16 and TILs were independently prognostic. Hazard ratios for death (overall survival) were 2.51 (95% confidence interval 1.36–4.63) for p16 negative versus p16 positive, 2.17 (1.34–3.5) for T3/4 versus T1/2, 2.42 (1.52–3.8) for males versus females and 3.30 (1.52–7.14) for TIL1 versus TIL3 (all P < 0.05). Conclusions We have refined prognostic factors in ASCC. p16 adds to stratification by stage with respect to DFS in early disease and overall survival/DFS in locally advanced cancers. Our data support the role of the host immune response in mediating outcomes. These factors will be prospectively evaluated in PLATO (ISRCTN88455282)

Systemic aminoglycosides-induced vestibulotoxicity in humans

Objectives: This systematic review aimed to investigate the prevalence and characteristics of vestibular adverse effects of aminoglycoside (AG) therapy in humans and to analyze objective vestibular tests for the detection of AG-induced vestibulotoxicity. Design: PubMed, Cochrane Database, Web of Science, and reference lists of all included studies were screened by two independent researchers. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Studies were included according to preset inclusion criteria and reported outcomes of studies evaluating vestibular function using one or more objective vestibular function tests in adults and children after systemic AG administration. The methodological quality of each study was assessed using the quality assessment tool for quantitative studies. Interrater reliability was established using Cohen's Kappa. Results: Twenty-seven studies were included, with the vast majority showing AG-induced vestibulotoxic side effects, ranging from 0 to 60%. Most studies reported AG-induced abnormalities by caloric and rotatory testing, whereas only a few studies reported using video Head Impulse test and vestibular evoked myogenic potential testing. Conclusions: Because type I hair cells (particularly of the semicircular canals) are more susceptible to ototoxicity, video Head Impulse test and vestibular evoked myogenic potential testing seem more promising for the early detection of vestibulotoxicity than caloric and rotatory testing. Prospective studies using an extensive vestibular test battery are needed to further characterize the impact of AGs on the different vestibular end organs and to identify the most sensitive vestibular technique for the early detection of vestibulotoxicity

Functional Hair Cell Mechanotransducer Channels Are Required for Aminoglycoside Ototoxicity

Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss