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Background Radiotherapy, along with laser surgery, is considered a standard treatment option for patients with early glottic squamous cell cancer (SCC). Historically, patients have received complete larynx radiotherapy (CL-RT) due to fear of swallowing and respiratory laryngeal motion and this remains the standard approach in many academic institutions. Local control (LC) rates with CL-RT have been excellent, however this treatment can carry significant toxicities include adverse voice and swallowing outcomes, along with increased long-term risk of cerebrovascular morbidity. A recent retrospective study reported improved voice quality and similar local control outcomes with focused vocal cord radiotherapy (VC-RT) compared to CL-RT. There is currently no prospective evidence on the safety of VC-RT. The primary objective of this Bayesian Phase II trial is to compare the LC of VC-RT to that of CL-RT in patients with T1N0 glottic SCC. Methods One hundred and fifty-five patients with T1a-b N0 SCC of the true vocal cords that are n ot candidate or declined laser surgery, will be randomized in a 1:3 ratio the control arm (CL-RT) and the experimental arm (VC-RT). Randomisation will be stratified by tumor stage (T1a/T1b) and by site (each site will be allowed to select one preferred radiation dose regimen, to be used in both arms). CL-RT volumes will correspond to the conventional RT volumes, with the planning target volume extending from the top of thyroid cartilage lamina superiorly to the bottom of the cricoid inferiorly. VC-RT volumes will include the involved vocal cord(s) and a margin accounting for respiration and set-up uncertainty. The primary endpoint will be LC at 2-years, while secondary endpoints will include patient-reported outcomes (voice impairment, dysphagia and symptom burden), acute and late toxicity radiation-induced toxicity, overall survival, progression free survival, as well as an optional component of acoustic and objective measures of voice analysis using the Consensus Auditory-Perceptual Evaluation of Voice. Discussion This study would constitute the first prospective evidence on the efficacy and safety of VC-RT in early glottic cancer. If positive, this study would result in the adoption of VC-RT as standard approach in early glottic cancer. Trial registration ClinicalTrials.gov Identifier: NCT03759431 Registration date: November 30, 2018

Objectives With smartphones and wearable devices becoming ubiquitous, they offer an opportunity for large-scale voice sampling. This systematic review explores the application of deep learning models for the automated analysis of voice samples to detect vocal cord pathologies. Methods We conducted a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. We searched MEDLINE and Embase databases for original publications on deep learning applications for diagnosing vocal cord pathologies between 2002 and 2022. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Results Out of the 14 studies that met the inclusion criteria, data from a total of 3037 patients were analyzed. All studies were retrospective. Deep learning applications targeted Reinke's edema, nodules, polyps, cysts, unilateral cord paralysis, and vocal fold cancer detection. Most pathologies had detection accuracy above 90%. Thirteen studies (93%) exhibited a high risk of bias and concerns about applicability. Conclusions Technology holds promise for enhancing the screening and diagnosis of vocal cord pathologies. While current research is limited, the presented studies offer proof of concept for developing larger-scale solutions.

Glottic insufficiency results from impaired vocal fold contact, leading to a gap between the folds and manifesting as hoarseness and respiratory difficulties. Vocal folds injection is a commonly utilized therapeutic approach to rectify this gap by augmenting vocal folds volume; however, the optimal injectable material remains undetermined. Dedifferentiated fat cells (DFATs), derived from mature adipocytes, exhibit robust proliferative capacity and multipotency, establishing them as potential candidates for treating glottic insufficiency. This study investigated the therapeutic efficacy of DFATs in a rat model of recurrent laryngeal nerve paralysis. Twenty-five rats were used for the therapeutic evaluation: the recurrent laryngeal nerve of each rat was resected unilaterally, and 5 weeks later, the atrophied vocal fold muscles were injected with either 10 μl of saline (control), 1.0 × 10 6 DFATs in 10 μl (DFAT group), or 1.0 × 10 6 DFATs combined with 500 ng of basic fibroblast growth factor (bFGF) in 10 μl (DFAT + bFGF group). At 4 weeks post-injection, laryngeal endoscopy evaluated the glottic gap, followed by histological analyses of muscle atrophy, collagen deposition. To investigate mechanisms, an independent cohort of 25 rats received identical treatments and was evaluated 2 weeks post-injection for cell proliferation (Ki-67) and apoptosis (TUNEL). To confirm DFAT engraftment, GFP-labeled DFATs were evaluated at 2, 4, and 6 weeks post-injection. Results indicated that both the DFAT and DFAT + bFGF groups exhibited significantly reduced glottic gaps, increased collagen deposition, and decreased TUNEL-positive apoptotic cells compared to controls. Notably, the DFAT + bFGF group displayed superior outcomes, including a greater vocal muscle area and enhanced Ki-67-positive cell proliferation, indicating reduced atrophy. GFP-positive DFATs remained detectable for up to 6 weeks, confirming engraftment. These findings underscore the potential of DFATs, particularly with bFGF, as an innovative and effective therapy for glottic insufficiency secondary to recurrent laryngeal nerve paralysis.

Objectives: The nature and interpretation of vocal fold leukoplakia has been limited by small study sizes. The present study reviewed institutional data and the published literature to better characterize vocal fold leukoplakia. Methods: At our institution, the histopathology, age, and malignant conversion rates of 136 patients (208 biopsies) with vocal fold leukoplakia from 1990 to 2005 were reviewed. Results: No dysplasia (ND), mild and/or moderate dysplasia (MM), and severe dysplasia and/or squamous cell carcinoma in situ (SS) was identified in, respectively, 110 of 208 (53%), 38 of 208 (18%), and 31 of 208 (15%) biopsies. After 30 months (range, 1 to 134 months), malignant transformation was observed in 8 patients on subsequent biopsies. Additionally, a literature search was performed from 1960 to 2005 for the medical subject headings (MeSH) premalignant laryngeal lesions, laryngeal dysplasia, laryngeal leukoplakia, vocal cord dysplasia, and hyperkeratosis of the larynx. Fifteen reports were included for review. When these were combined with our institutional data, 1,173 of 2,188 biopsies (53.6%) revealed ND. Mild and/or moderate dysplasia and SS were present in 717 of 2,140 (33.5%) and 375 of 2,471 (15.2%) biopsies, respectively. Squamous cell carcinoma developed in 52 of 1,388 (3.7%), 83 of 824 (10.1%), and 56 of 310 (18.1%) patients whose initial biopsies demonstrated ND, MM, or SS. Conclusions: More than half of the reported leukoplakia lesions with biopsies showed ND. However, even lesions characterized as ND were associated with an increased risk of development of squamous cell carcinoma. Importantly, the risk of developing malignancy appears to correlate with the severity of dysplasia present on initial biopsy. Because clinical examination does not accurately predict the risk of malignancy, future studies, including genomic evaluation of this lesion, may be necessary to further characterize its biologic behavior.

Objectives: We sought to better characterize pathologic changes that occur in the human vocal fold after radiotherapy for head and neck cancer. Methods: In a blinded, controlled study of archived tissue, we evaluated postirradiation salvage laryngectomy vocal fold tissue without evidence of malignant disease. Clinical and demographic patient data were collected. In a blinded fashion, irradiated tissue was compared to nonirradiated, benign control tissue. Histomorphometric analysis was used to assess muscle and collagen organization, superficial lamina propria (SLP) and vocal ligament thickness, vocalis muscle fiber area, collagen content, and hyaluronic acid content. Immunohistochemical analysis was used to assess the content of type I collagen, type IV collagen, vimentin, fibronectin, α–smooth muscle actin, matrix metalloproteinase 9, and laminin. Results: Twenty irradiated vocal folds were evaluated and compared to control specimens. Collagen and muscle disorganization was noted in the irradiated specimens. The SLP and vocal ligament thicknesses and the mean muscle fiber diameters did not differ significantly. The SLP fibronectin and the vocalis muscle and SLP collagen content were significantly increased in the irradiated vocal folds, and the SLP collagen content increased significantly with time between irradiation and resection. The laminin content of irradiated vocalis muscles was significantly decreased. Conclusions: Radiotherapy results in significant vocal fold tissue changes. Having more precisely defined these changes, we plan continued investigation seeking targeted preventive and therapeutic interventions for improved vocal quality following radiotherapy.

Objectives We investigated acute changes in extracellular matrix (ECM) gene expression and histologic changes in the deposition of collagen and hyaluronan (hyaluronic acid; HA) after basic fibroblast growth factor (bFGF) treatment of the aged rat vocal fold. Methods For the polymerase chain reaction (PCR) experiments, we divided ten 18-month-old Sprague-Dawley rats into two groups that received serial injections of sham (saline solution) or bFGF (2 ng/uL) and euthanized them 2 weeks after the initial injection to investigate acute changes in ECM gene expression. We treated a separate group of 5 animals unilaterally and sacrificed them 4 weeks after the initial injection to investigate histologic changes in the deposition of collagen and HA. Results Real-time PCR revealed significantly up-regulated HA synthase (HAS)-2, HAS-3, matrix metalloproteinase (MMP)-2, and procollagen type I gene expression in the bFGF treatment group as compared to the sham treatment group. Histologic staining revealed significantly increased deposition of HA in the bFGF-treated vocal fold as compared to the sham-treated vocal fold. No differences in ECM collagen levels were observed between treatment sides. Conclusions Basic fibroblast growth factor induced the up-regulation of HAS-2, HAS-3, MMP-2, and procollagen type I. Histologically, aged vocal folds treated with bFGF revealed increased deposition of HA as compared to sham-treated vocal folds.

Voice change is often the first sign of laryngeal cancer, leading to diagnosis through hospital laryngoscopy. Screening for laryngeal cancer solely based on voice could enhance early detection. However, identifying voice indicators specific to laryngeal cancer is challenging, especially when differentiating it from other laryngeal ailments. This study presents an artificial intelligence model designed to distinguish between healthy voices, laryngeal cancer voices, and those of the other laryngeal conditions. We gathered voice samples of individuals with laryngeal cancer, vocal cord paralysis, benign mucosal diseases, and healthy participants. Comprehensive testing was conducted to determine the best mel-frequency cepstral coefficient conversion and machine learning techniques, with results analyzed in-depth. In our tests, laryngeal diseases distinguishing from healthy voices achieved an accuracy of 0.85–0.97. However, when multiclass classification, accuracy ranged from 0.75 to 0.83. These findings highlight the challenges of artificial intelligence-driven voice-based diagnosis due to overlaps with benign conditions but also underscore its potential.

Accurate CT staging plays a crucial role in guiding effective management of laryngeal carcinoma, as endoscopic assessment alone may not provide a comprehensive evaluation of tumor spread. Consequences of non-compliance to parallel vocal cord plane for tumors remained unexplored in existing literature. We aimed to compare T-staging parameters of laryngeal carcinoma on CT neck in non-parallel and parallel to vocal cord axial planes and analyse degree of discrepancy between them. We retrospectively studied 34 larynges with squamous cell carcinoma on non-parallel plane① and parallel to vocal cord plane② axial CT scan. Quantitative (anteroposterior AP, transverse Tr, anterior commissure ACom) and qualitative (site, intralaryngeal and extralaryngeal extension) T-staging variables were interpreted in both planes and differences between them were registered. Kappa analysis was employed to get level of disagreement between tumor reporting of each plane. There was minimal to worse agreement between T-staging in these planes (k = −0.059 to 0.353). Difference between means of ACom was significant, but not AP and Tr dimensions. Categorical variables in plane② showed majority of glottic origin (70.5%) and T1a (38.2%) stage, while plane① had subglottic (52.9%) and T2 (41.1%). Overall plane① showed 41.1% altered staging (mostly T1,T2), out of which 71.2% were upstaged. Rest unaffected larynges (28.8%, n = 20) showed either change in origin (41.2%) or ACom involvement (58.8%). Consequently, 73.5% (n = 25) patients in plane ① manifested at least one change, so can jeopardise targeted management. Results established that non-adherence to reporting on parallel CT larynx can result in significant variability in principal qualitative and quantitative T-stage tumor parameters, hence imperiling patients to over or undertreatment.

Systemic hydration is known to promote optimal functioning of bodily systems—including the vocal folds. The impact of systemic dehydration on the biology of the vocal folds and the downstream effects of dehydration on voice output are not well understood. An in vivo rat model of systemic dehydration was employed to investigate vocal fold gene expression, histological changes, and acoustic changes in vocalization. Ultrasonic vocalizations (USVs) were recorded every day for 5 days (baseline), in male and female Long-Evans rats (N = 36, ages: 3–4 months) using an anticipatory reward paradigm. Next, rats were dehydrated (N = 18) using a published water-restriction model for 5 days or euhydrated (N = 18) and provided ad libitum access to water for 5 days. USVs were recorded daily during the dehydration/euhydration period. The USV variables were averaged at baseline and following dehydration/euhydration for individual animals, and the difference between these time periods was used for statistical analysis. USV analysis included total USV count, complexity ratio, duration (s), frequency range (kHz), and maximum intensity (dB). At the end of dehydration/euhydration, animals were euthanized, and kidney and vocal fold tissue samples were dissected and processed for histology and gene expression analysis. Compared to euhydrated rats, dehydrated male and female rats had significantly up-regulated gene expression of kidney renin (male p = 0.047; female p = 0.018), indicating physiologic dehydration. There were no statistically significant differences in the USV acoustic profile or histopathology between the two groups. Differential expression ( p < 0.05) of several genes related to extracellular matrix remodeling, inflammatory responses, and water ion transport in the vocal folds was present. Our results indicate that mild systemic dehydration impacts gene expression in the vocal fold mucosa; however, these gene expression changes are not evident in the acoustic profile of vocalizations.

To determine the prognostic value of laryngoscopy in predicting the recovery of unilateral vocal fold paralysis. A prospective study was carried out of all patients with unilateral vocal fold paralysis without a progressive lesion or arytenoid dislocation. Among the 66 candidates, 15 recovered. Patients with interarytenoid paralysis (p < 0.001) or posterolateral tilt of the arytenoid (p = 0.028) had less chance of recovery. Among 51 patients who did not recover, 25.49 per cent regained phonatory function by compensatory movement of the normal side; the rest required an intervention. Intervention requirement was significantly less for those patients who had isolated glottic level compensation. The paralysed vocal fold was at the same level in 32.35 per cent of patients, higher in 38.23 per cent and lower in 29.42 per cent. In those in whom vocal folds were in the abducted position (46.67 per cent), the affected vocal fold was at a lower position on phonation. Inter-observer reliability assessment revealed excellent to good agreement for all criteria. Interarytenoid paralysis and posterolateral tilt of the arytenoid were predictors of poor recovery.