Objectives/Hypothesis Vocal fold atrophy, scar, and sulcus reduce the vibratory function of the vocal fold mucosa, which causes severe refractory dysphonia. We have reported encouraging preliminary results using an intracordal injection of basic fibroblast growth factor (bFGF) and showed improvement in phonatory parameters and voice. The present study summarizes our experience with 100 cases of stiffened vocal folds that were treated with bFGF injections. Study Design Retrospective chart review with Interstitial Review Board (IRB) approval. Methods Local injection of bFGF was performed in 100 cases of vocal fold pathology, which included 43 cases of vocal fold atrophy, 41 cases with scar, and 16 cases with sulcus. Ten micrograms of bFGF were injected into the vocal folds under topical anesthesia 4 times in each patient. Therapeutic outcomes were examined with maximum phonation time (MPT), voice handicap index‐10 (VHI‐10), and GRBAS scale. Results MPT, VHI‐10, and GRBAS scores significantly improved in all pathology groups. An improvement on the VHI‐10 greater than five points was observed in 82% of atrophy cases, 78% of scar cases, and 67% of sulcus cases. Improvement on the VHI‐10 was significantly better in the atrophy group than the scar or sulcus groups. The mild/moderate cases of scar and sulcus showed better improvement than severe cases. Conclusions The current large case series indicates positive effects of intracordal injection of bFGF for improvement of voice with no severe adverse events. The effects appeared best for cases of atrophy, while the treatment of severe scar and sulcus requires further improvement. Level of Evidence 4 Laryngoscope, 131:2059–2064, 2021

Objectives/Hypothesis We aimed to investigate and validate the cellular activity patterns and the potential topographical organization of neurons of the medullary swallowing pattern generator (Sw‐CPG). We used the perfused brainstem preparation as an innovative experimental model that allows for stable neuronal recording in the brainstem. Study Design Animal model. Methods Experiments were conducted in 14 juvenile Wistar rats. The activities of the phrenic, vagus, and hypoglossal nerves were recorded at baseline, and fictive swallowing was elicited by stimulation of the superior laryngeal nerve. Extracellular action potentials of 72 swallowing‐related neurons were recorded in the Sw‐CPG of the dorsal medulla oblongata. Results Neurons could be classified into three types: sensory relay, and neurons that were excited or inhibited during fictive swallowing. Approximately one‐third of the neurons likely received monosynaptic input from the laryngeal afferents. One‐third of neurons recorded showed respiratory‐related activity, most of which exhibited inspiratory modulation. The neurons were widely distributed in the nucleus tractus solitarius and reticular formation. Conclusions The perfused brainstem preparation of rat fully preserves the Sw‐CPG. The recorded cellular activities and general topographical organization of swallowing neurons are in accordance with previous in vivo studies. Thus, the perfused brainstem preparation is an ideal experimental model to advance the understanding of neuronal mechanisms underlying swallowing. Level of Evidence NA Laryngoscope, 129:E72–E79, 2019

Sensory-motor control of the pharyngeal swallow requires sensory afferent inputs from the pharynx and larynx evoked by introducing bolus into the pharynx. Patients with reduced sensitivity of the pharynx and larynx are likely to have a swallowing impairment, such as pre-swallow aspiration due to delayed swallow triggering. Interferential current stimulation applied to the neck is thought to improve the swallowing function of dysphagic patients, although the mechanism underlying the facilitatory effect of such stimulation remains unknown. In the present study, we examined the changes in the elicitability of swallowing due to the stimulation and the responses of the swallowing-related neurons in the nucleus tractus solitarius and in the area adjacent to the stimulation in decerebrate and paralyzed guinea pigs. The swallowing delay time was shortened by the stimulation, whereas the facilitatory effect of eliciting swallowing was attenuated by kainic acid injection into the nucleus tractus solitarius. Approximately half of the swallowing-related neurons responded to the stimulation. These data suggest that the interferential current stimulation applied to the neck could enhance the sensory afferent pathway of the pharynx and larynx, subserving excitatory inputs to the neurons of the swallowing pattern generator, thereby facilitating the swallowing reflex.

Acidity in the tumor microenvironment has been reported to promote cancer growth and metastasis. In our study, we examined a potential relation between extracellular acidity and expression level of the immune checkpoint molecule programmed cell death protein 1 (PD-L1) in murine squamous cell carcinoma (SCC) and melanoma cell lines. PD-L1 expression in the tumor cells was upregulated by culturing in a low pH culture medium. Tumor-bearing mice were allowed to ingest sodium bicarbonate, resulting in neutralization of acidity in the tumor tissue, a decrease in PD-L1 expression in tumor cells and suppression of tumor growth in vivo. Proton-sensing G protein-coupled receptors, T-cell death-associated gene 8 (TDAG8) and ovarian cancer G-protein-coupled receptor 1 (OGR1), were upregulated by low pH, and essentially involved in the acidityinduced elevation of PD-L1 expression in the tumor cells. Human head and neck SCC RNAseq data from the Cancer Genome Atlas also suggested a statistically significant correlation between expression levels of the proton sensors and PD-L1 mRNA expression.These findings strongly suggest that neutralization of acidity in tumor tissue may result in reduction of PD-L1 expression, potentially leading to inhibition of an immune checkpoint and augmentation of antitumor immunity.

Objectives The purpose of this study was to investigate the influence of laryngeal afferent inputs on brainstem circuits that mediate and transmit swallowing activity to the orofacial musculature. Methods Experiments were performed on 19 arterially perfused juvenile rats. The activities of swallowing interneurons in relation to their respective motor outputs in the hypoglossal and vagus nerves were assessed during fictive swallowing with or without concurrent laryngeal sensory stimulation at intensities of 20, 40, and 60 μA. Results The hypoglossal nerve activity was gradually enhanced with increasing intensity of the sensory stimulation, while the vagus nerve activity was not altered. The activities of various interneurons were modulated by the laryngeal stimulation, but more than 50% of the recorded neurons were inhibited by the stimulation. Some interneurons demonstrated no obvious change in their discharge rates with laryngeal sensory stimulation during fictive swallowing. Conclusion Laryngeal afferent inputs partially modulated the swallowing motor activity via enhanced or suppressed activities of the swallowing interneurons, while the essential motor pattern underlying the pharyngeal stage of swallowing remained basically unchanged. Thus, the output patterns of the complex sequential movements of swallowing could be basically predetermined and further adjusted according to sensory information related to the properties of the ingested food by a swallowing central pattern generator. Level of Evidence NA Laryngoscope, 130: 1885–1893, 2020