Randomized Controlled Trial of Awake Transnasal Laser-Assisted Surgery for Benign Laryngeal Lesions.

OBJECTIVE: To compare functional and cost-effectiveness of awake transnasal laser assisted-surgery versus microlaryngeal surgery for benign laryngeal lesions. METHODS: This was a prospective non-inferiority randomized controlled trial conducted from May 2021 to December 2022 at two tertiary referral hospitals in Hong Kong. Patients were block-randomized to receive either awake transnasal laser-assisted surgery or microlaryngeal surgery, with post-operative follow-up in a multidisciplinary voice clinic for 1-year. Primary outcome was Voice Handicap Index (VHI-30). Secondary outcomes included operation time, complications, length of stay, peri-operative discomfort, recurrence, and medical costs. RESULTS: Sixty-one patients were randomized to either awake transnasal laser-assisted surgery (n = 30) and microlaryngeal surgery (n = 31). Both groups had comparable demographics and laryngeal pathologies. Both groups showed significant improvement of VHI-30 score over time and had comparable post-operative VHI-30. Awake transnasal laser-assisted surgery group had a significantly shorter length of stay (0.5 vs. 1 day) and less throat discomfort (2 vs. 4) compared to microlaryngeal surgery group. Intraoperative complications were more common in microlaryngeal surgery group (14.3% vs. 0%). Otherwise, both groups had similar operative time and recurrence rate. Cost-analysis showed a significantly lower hospital cost for awake transnasal laser-assisted surgery (USD 3090) compared to microlaryngeal surgery group (USD 5120). CONCLUSION: Awake transnasal laser-assisted surgery was safe, functionally non-inferior, as measured by VHI-30, to microlaryngeal surgery in managing benign laryngeal lesions, while superior to microlaryngeal surgery in peri-operative discomfort and medical costs. LEVEL OF EVIDENCE: Level 2 Laryngoscope, 2024.

Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers.

The unique virus-cell interaction in Epstein-Barr virus (EBV)-associated malignancies implies targeting the viral latent-lytic switch is a promising therapeutic strategy. However, the lack of specific and efficient therapeutic agents to induce lytic cycle in these cancers is a major challenge facing clinical implementation. We develop a synthetic transcriptional activator that specifically activates endogenous BZLF1 and efficiently induces lytic reactivation in EBV-positive cancer cells. A lipid nanoparticle encapsulating nucleoside-modified mRNA which encodes a BZLF1-specific transcriptional activator (mTZ3-LNP) is synthesized for EBV-targeted therapy. Compared with conventional chemical inducers, mTZ3-LNP more efficiently activates EBV lytic gene expression in EBV-associated epithelial cancers. Here we show the potency and safety of treatment with mTZ3-LNP to suppress tumor growth in EBV-positive cancer models. The combination of mTZ3-LNP and ganciclovir yields highly selective cytotoxic effects of mRNA-based lytic induction therapy against EBV-positive tumor cells, indicating the potential of mRNA nanomedicine in the treatment of EBV-associated epithelial cancers.

Human Papillomavirus-Associated Oropharyngeal Cancer: Global Epidemiology and Public Policy Implications.

Global trends in human papillomavirus (HPV)-associated head and neck cancers (HNC), specifically in the oropharynx subsite, have been dynamically changing, leading to new staging and treatment paradigms. Epidemiologic studies have noted regional variations in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). While HPV vaccination remains the main preventative approach, vaccination policy in relation to gender neutrality is heterogeneous and particularly sparse in low- and middle-income countries, where the burden of global cancer cases and HPV-associated HNC are not well-characterized in certain regions. This review summarizes the existing literature on regional variations of HPV-associated OPSCC and gender-neutral vaccine policies. Based on available data, the incidence of HPV-associated OPSCC is highest in North America, Europe, and Oceania. As of 2022, 122 of 195 (63%) World Health Organization (WHO) member states had incorporated HPV vaccinations nationally; of these, 41 of 122 (34%) member states have introduced gender-neutral vaccine coverage. Future research is needed to describe continued evolving trends in HPV-associated OPSCC, understand underlying risk factors leading to regional variation in disease, and implement gender-neutral policy more broadly.

High-Density Surface Electromyography for Swallowing Evaluation in Post-Radiation Dysphagia.

OBJECTIVES: Our study aimed to investigate the feasibility of using high-density surface electromyography (HD-sEMG) for swallowing assessment by comparing the quantitative parameters and topographic patterns of HD-sEMG between post-irradiated patients and healthy individuals. METHODS: Ten healthy volunteers and ten post-irradiated nasopharyngeal carcinoma patients were recruited. 96-channel HD-sEMG was recorded although each participant consumed different consistencies of food (thin and thick liquid, puree, congee, and soft rice). Dynamic topography was generated from the root mean square (RMS) of the HD-sEMG signals to illustrate the anterior neck muscle function in the swallowing process. The averaged power of muscles and the symmetry of swallowing patterns were assessed by objective parameters including average RMS, Left/Right Energy Ratio, and Left/Right Energy Difference. RESULTS: The study showed different swallowing patterns between patients with dysphagia and healthy individuals. The mean RMS values were higher in the patient group compared to the healthy group, but the difference was not statistically significant. Asymmetrical patterns were shown in patients with dysphagia. CONCLUSION: HD-sEMG is a promising technique that could be used to quantitatively evaluate the average power of neck muscles and the symmetry of swallowing activities in patients with swallowing difficulties. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:2920-2928, 2023.

Extracellular Vesicles as Biomarkers in Head and Neck Squamous Cell Carcinoma: From Diagnosis to Disease-Free Survival.

Head and neck squamous cell carcinomas (HNSCCs) arising from different anatomical sites present with different incidences and characteristics, which requires a personalized treatment strategy. Despite the extensive research that has conducted on this malignancy, HNSCC still has a poor overall survival rate. Many attempts have been made to improve the outcomes, but one of the bottlenecks is thought to be the lack of an effective biomarker with high sensitivity and specificity. Extracellular vesicles (EVs) are secreted by various cells and participate in a great number of intercellular communications. Based on liquid biopsy, EV detection in several biofluids, such as blood, saliva, and urine, has been applied to identify the existence and progression of a variety of cancers. In HNSCC, tumor-derived EVs exhibit many functionalities by transporting diverse cargoes, which highlights their importance in tumor screening, the determination of multidisciplinary therapy, prediction of prognosis, and evaluation of therapeutic effects. This review illustrates the classification and formation of EV subtypes, the cargoes conveyed by these vesicles, and their respective functions in HNSCC cancer biology, and discloses their potential as biomarkers during the whole process of tumor diagnosis, treatment, and follow-up.

Soft robotic manipulator for intraoperative MRI-guided transoral laser microsurgery.

Magnetic resonance (MR) imaging (MRI) provides compelling features for the guidance of interventional procedures, including high-contrast soft tissue imaging, detailed visualization of physiological changes, and thermometry. Laser-based tumor ablation stands to benefit greatly from MRI guidance because 3D resection margins alongside thermal distributions can be evaluated in real time to protect critical structures while ensuring adequate resection margins. However, few studies have investigated the use of projection-based lasers like those for transoral laser microsurgery, potentially because dexterous laser steering is required at the ablation site, raising substantial challenges in the confined MRI bore and its strong magnetic field. Here, we propose an MR-safe soft robotic system for MRI-guided transoral laser microsurgery. Owing to its miniature size (Ø12 × 100 mm), inherent compliance, and five degrees of freedom, the soft robot ensures zero electromagnetic interference with MRI and enables safe and dexterous operation within the confined oral and pharyngeal cavities. The laser manipulator is rapidly fabricated with hybrid soft and hard structures and is powered by microvolume (<0.004 milliter) fluid flow to enable laser steering with enhanced stiffness and lowered hysteresis. A learning-based controller accommodates the inherent nonlinear robot actuation, which was validated with laser path-following tests. Submillimeter laser steering accuracy was demonstrated with a mean error < 0.20 mm. MRI compatibility testing demonstrated zero observable image artifacts during robot operation. Ex vivo tissue ablation and a cadaveric head-and-neck trial were carried out under MRI, where we employed MR thermometry to monitor the tissue ablation margin and thermal diffusion intraoperatively.

A useful landmark to locate the external branch of the superior laryngeal nerve during thyroidectomy.

BACKGROUND: To determine whether the insertion of the sternothyroid muscle onto the oblique line of the thyroid cartilage can be used to reliably locate the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy. METHODS: This is a prospective descriptive case series. The EBSLN was identified and confirmed with a nerve stimulator during thyroid surgery. The entry point of the EBSLN into the inferior constrictor/cricothyroid muscle was measured in relation to the insertion and anterior border of the sternothyroid muscle. The perpendicular distance from the insertion of the sternothyroid muscle onto the oblique line was designated the vertical distance (VD) of the nerve entry point (NEP), and the perpendicular distance from the anterior border of the sternothyroid muscle was designated the horizontal distance. RESULTS: Ninety patients underwent 130 thyroid lobectomies (60 female, 30 male) (mean age 53.5 years, range, 18-91 years). An attempt to identify the nerve was made in 127 thyroid lobectomies. The EBSLN was identified in 111 cases (87.4%). The mean VD of the NEP from the muscle insertion was 1.1 mm (SD 1.1 mm, range, 0-5 mm) and the mean horizontal distance (HD) was 9.5 mm (SD 3.8 mm, range, 2-21 mm). CONCLUSIONS: The EBSLN muscle entry point usually lies 1.1 mm from the sternothyroid insertion onto the oblique line, and 5-12 mm from the anterior border of the muscle. These useful landmarks allow the nerve to be consistently located, identified and preserved during thyroid surgery prior to ligating the superior thyroid vessels.

Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) lacks predictive biomarkers for drug responses. By targeted sequencing, we identified two MAPK1 mutations in recurrent HNSCC, MAPK1p.D321N, and p.R135K. We previously reported an exceptional erlotinib responder with MAPK1p.E322K. Here, by in silico and drug studies, we determined functions of these two recurrence-associated MAPK1 mutations. Residues D321, R135, and E322 are in 3D proximity. MAPK1p.D321N drives marked in vivo erlotinib sensitivity, while p.R135K's effect is moderate.

MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling.

MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only "CD8+ T-cell-inflamed" tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3-4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.

Meta-analysis does not support routine traditional nuclear medicine studies for malignant otitis.

OBJECTIVES: The role of traditional nuclear medicine studies in the management of malignant otitis externa (MOE) is unclear and there are ongoing debates regarding their diagnostic value. The authors perform a systematic review and meta-analysis to assess the sensitivity and specificity of traditional nuclear medicine studies in the diagnosis of MOE. METHODS: In accordance with PRISMA guidelines, a query of the Medline, Embase, Web of Science, and Cochrane databases was undertaken. The primary outcomes of interest were the sensitivity and specificity of traditional nuclear medicine studies to detect MOE. RESULTS: Of the initial 1317 hits from the four databases, 20 articles with a combined 608 patients were ultimately included in the review. The pooled sensitivities for Technetium-99 and Gallium-67 were 85.1% (95% CI, 72.0-98.1%) and 71.2% (95% CI, 55.1-87.3%) respectively. The available evidence suggested poor specificity of these modalities, but was insufficient for meta-analysis. Neither modality was shown to be effective in the assessment of disease resolution. CONCLUSION: The sensitivities of Technetium-99 and Gallium-67 to detect MOE are less favorable than was initially thought. Given this finding and their poor specificity, lack of anatomic resolution, unproven ability to detect disease resolution and variable availability, this review does not support the routine use of these studies in the management of MOE. LEVEL OF EVIDENCE: N/A Laryngoscope, 130:1812-1816, 2020.

Narrow Band Imaging Endoscopy of the Nasopharynx for Malignancy: An Inter- and Intraobserver Study.

OBJECTIVE: To assess interobserver agreement and intraobserver reproducibility when assessing the nasopharynx for malignancy under white light and narrow band imaging endoscopy because the decision to biopsy hinges on the examiner's perceived chance of malignancy. METHODS: An interobserver and intraobserver agreement study utilizing white light and narrow band endoscopic images of the nasopharynx. The setting was an academic referral hospital. Participants were 156 adults with suspected nasopharyngeal carcinoma who underwent white light and narrow band imaging endoscopy and biopsy. Images of the nasopharynges were subsequently scored for malignancy by four otolaryngologists. The nasopharynx was scored on 4-point scales under white light and narrow band imaging endoscopy for the likelihood of malignancy or abnormality, respectively. RESULTS: Intraclass correlation coefficients for intraobserver agreement for nasopharyngeal malignancy for four observers under white light were 0.86, 0.89, 0.79 and 0.88 (mean 0.855), respectively; and under narrow band imaging they were 0.64, 0.68, 0.64, and 0.66 (mean 0.655), respectively (all P values < 0.001). The coefficient for interobserver reliability under white light was 0.79 (95% confidence interval [CI] 0.76-0.82; P < 0.001), which indicated strong agreement. The coefficient for interobserver reliability under narrow band imaging was 0.56 (95% CI 0.50-0.61; P < 0.001), which indicated moderate agreement. CONCLUSIONS: Intraobserver and interobserver agreement for nasopharyngeal malignancy was strong on white light endoscopy but only moderate on narrow band imaging endoscopy. Agreement may be improved by adopting a standard set of assessment guidelines, including an objective detailed morphological analysis under white light and vasculature analysis under narrow band imaging. LEVEL OF EVIDENCE: 2a Laryngoscope, 129:1374-1379, 2019.

The Association Between Diabetes and Olfactory Function in Adults.

Diabetes is a significant chronic disease that in limited studies has been linked with olfactory dysfunction. We investigated the cross-sectional association between diabetes and olfactory dysfunction in 3151 adults aged ≥40 years who participated in US National Health and Nutrition Examination Survey 2013-2014 with information on olfactory dysfunction and diabetes. Diabetes was defined from fasting serum glucose ≥126 mg/dL, oral glucose tolerance test ≥200 mg/dL, HbA1c levels ≥6.5%, physician-diagnosed diabetes, or current use of oral hypoglycemic agents and/or insulin. Self-reported olfactory dysfunction was defined as a positive answer to any of the following questions: 1) "Have you had problem with smell in the past 12 months?"; 2) "Have you had a change in the ability to smell since age 25?", or 3) "Do you have phantom smells?". Participants were considered to have severe hyposmia or anosmia if they had <5 correct answers in the 8-item pocket smell test. Analyses were adjusted for the main confounders, including olfactory dysfunction risk factors. Compared to non-diabetics, diabetics under insulin treatment showed a higher prevalence of phantom odors [OR(95% CI): 2.42 (1.16; 5.06)] and a non-significant higher prevalence of severe hyposmia/anosmia [OR(95% CI): 1.57 (0.89; 2.78)]. Amongst diabetics, there was a significant trend to severe hyposmia/anosmia for those on more aggressive treatments [OR (95% CI) including oral and insulin treatment compared to those who reported no use of drug treatment, respectively: 1.33 (0.60; 2.96) and 2.86 (1.28; 6.40); P trend 0.01]. No association was observed between diabetes duration and prevalence of olfactory dysfunction.