A randomized comparison of three intubation techniques/tube materials for nasotracheal intubation.

PURPOSE: We sought to compare three intubation methods using different intubation techniques/tube materials for tube advancement from the nasal cavity into the oral cavity during nasotracheal intubation. METHODS: We conducted a randomized clinical trial with adult patients scheduled to undergo elective surgery requiring nasotracheal intubation for general anesthesia. Participants were randomly allocated to a polyvinyl chloride (PVC) tube group (group P), PVC tube attached to a rubber catheter group (group PR), or velvet-soft PVC tube group (group V). Tracheal intubation was then performed based on group allocation. The primary outcome was the first-attempt success rate of tube advancement into the oral cavity; secondary outcomes included the time required for tube advancement into the oral cavity, total intubation time, and the incidence of epistaxis. RESULTS: A total of 149 patients were included in the study. The first-attempt success rate in group V (90%) was significantly higher than that in group P (58%) (odds ratio, 6.5; 95% confidence interval [CI], 2.2 to 19.2), but similar to that in group PR (100%). The mean (standard deviation) time required for tube advancement into the oral cavity was significantly shorter in group V (16 [13] sec) than in group PR [40 (10) sec; 95% CI of mean difference, 17 to 30] and group P (26 [16] sec; 95% CI of mean difference, 3 to 16). Total intubation time was longest in group PR. Epistaxis occurred the least in group V. CONCLUSIONS: Among the three intubation techniques/tube materials for nasotracheal intubation, the velvet-soft PVC tube provided the highest first-attempt success rate, most expeditious advancement into the oral cavity, and lowest incidence of epistaxis. STUDY REGISTRATION: ClinicalTrials.gov (NCT04695444); first submitted 30 December 2020.

RéSUMé: OBJECTIF: Nous avons cherché à comparer trois méthodes d'intubation utilisant différentes techniques d'intubation / matériaux de sondes pour l'avancement de la sonde de la cavité nasale dans la cavité buccale pendant l'intubation nasotrachéale. MéTHODE: Des patient·es devant recevoir une intubation nasotrachéale ont été réparti·es au hasard dans un groupe avec sondes en polychlorure de vinyle (PVC) (groupe P), un groupe avec sondes en PVC attachées à un cathéter en caoutchouc (groupe PR) ou un groupe avec sondes en PVC doux comme du velours (groupe V). L'intubation trachéale a ensuite été réalisée en fonction de l'affectation du groupe. Le critère d'évaluation principal était le taux de réussite de la première tentative d'avancement de la sonde dans la cavité buccale; les critères d'évaluation secondaires comprenaient le temps nécessaire à l'avancement de la sonde dans la cavité buccale, la durée totale de l'intubation et l'incidence d'épistaxis. RéSULTATS: Au total, 149 patient·es ont été inclus·es dans l'étude. Le taux de réussite de l'intubation à la première tentative était significativement plus élevé dans le groupe V (90 %) que dans le groupe P (58 %) (rapport de cotes, 6,5; intervalle de confiance à 95 % [IC], 2,2 à 19,2), mais similaire à celui du groupe PR (100 %). Le temps moyen (écart type) nécessaire pour l'avancement de la sonde dans la cavité buccale était significativement plus court dans le groupe V (16 [13] sec) que dans le groupe PR (40 [10] sec; IC 95 % de la différence moyenne, 17 à 30) et dans le groupe P (26 [16] sec; IC 95 % de la différence moyenne, 3 à 16). La durée totale d'intubation était la plus longue dans le groupe PR. C'est dans le groupe V que l'épistaxis a été la moins fréquente. CONCLUSION: Parmi les trois techniques d'intubation/matériaux de sonde pour l'intubation nasotrachéale, le tube en PVC doux comme du velours a fourni le taux de réussite de première tentative le plus élevé, l'avancement le plus rapide dans la cavité buccale et l'incidence d'épistaxis la plus faible. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04695444); première soumission le 30 décembre 2020.

Single clonal glandular stem cells derived from human parotid glands do not attain malignant phenotype during long-term in vitro culture.

Mesenchymal stem cells (MSCs) are being intensively investigated as future therapeutics for various human diseases. One of the most important challenges to the clinical application of MSCs is the possibility of malignant transformation during long-term in vitro culturing. However, there have been no reports on the tumorigenicity of salivary gland-derived MSCs following long-term in vitro culturing. Here, we isolated a single clonal glandular stem cells from human parotid gland stem cells (hpGSCs) using a modified sub-fractionation culturing method. The possibility of malignant transformation of these cells following long-term culturing was evaluated under in vitro and in vivo culture conditions. Single clonal glandular stem cells from the human parotid gland have unique multipotent MSCs traits. hpGSCs at passage 18 stained strongly for ß-galactosidase expression and the long-term culture of hpGSCs led to a reduction in telomerase activity. hpGSCs could not survive in a soft agar environment and did not cause tumor formation in a xenograft mouse model. In addition, the expression of salivary cancer-related oncogenes was not elevated in hpGSCs following the long-term culture. In conclusion, we demonstrated that there is no possibility of acquiring a malignant transformation during long-term in vitro cell expansion of hpGSCs.

Factors influencing long-term treatment response to botulinum toxin injection for spasmodic dysphonia.

OBJECTIVE: The purpose of this study was to evaluate the outcomes of long-term botulinum toxin type A (BoNTA) treatment for adductor spasmodic dysphonia (AdSD) and to determine the factors predictive of treatment response by investigating dose stability and average intervals. DESIGN: Retrospective cohort study. SETTING: Academic tertiary medical centre. EXPOSURES: A total of 470 patients with adductor spasmodic dysphonia, who received electromyography-guided BoNTA injections over 12 years, were retrospectively enrolled in this study. MAIN OUTCOMES AND MEASURES: The patients' demographic data, baseline voice dynamics and treatment profiles (dose, frequency and intervals) were evaluated. Factors correlating with the dose adjustment ratio (number of increasing dosing/total number of BoNTA toxin injections) and changes in intervals between injections were statistically analysed. RESULTS: A total of 122 patients, who received ≥ 4 injections and whose average treatment interval was < 240 days, were finally evaluated. Of them, 115 (94.3%) were female and seven (5.7%) were male, and the mean age at initial treatment was 34.89 ± 13.07 and 41.14 ± 12.71 years, respectively. On average, patients received 18.00 ± 13.33 injections (1.67 ± 0.60 U/injection) to alternating unilateral vocal folds. The treatment period was 65.07 ± 43.28 months and the mean interval between injections was 4.16 ± 1.28 months. The mean dose adjustment ratio among patients who received ≥ 4 injections was 0.15 ± 0.13, and dose changes occurred 4.36 times/patient. The patients' age and gender significantly affected the treatment response, where younger or female patients showed greater dosing variability and shorter intervals between injections. However, the baseline voice dynamics (voice handicap index, fundamental frequency, jitter, shimmer, noise-to-harmonic ratio, maximum phonation time and degree of voice breaks) did not predict the dose adjustment ratio or interval changes. In addition, patients with fluctuating doses showed lower age and higher VHI subscale scores, and patients with short-treatment interval (< 100 days) showed higher SDF0. CONCLUSIONS: Almost all patients received stable low doses of BoNTA over time, irrespective of the baseline results. Patients' age, gender and VHI scores were correlated with poor treatment responses, such as frequent dose changes and shorter intervals between injections.

Characterization of novel genetic alterations in salivary gland secretory carcinoma.

Secretory carcinoma is a salivary gland tumor with a characteristic chromosomal translocation that results in an ETV6-NTRK3 fusion gene. Secretory carcinoma shows relatively frequent rates of lymph-node metastasis and tumor recurrence and has a characteristic histology. Except for the ETV6 translocation, genomic alterations in secretory carcinoma have not been reported. In the present study, we characterized the novel recurrent genetic mutations of secretory carcinoma. On the basis of histology, immunohistochemistry, and ETV6 gene break-apart fluorescence in situ hybridization assays, 22 tumors were classified as secretory carcinomas (19 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) and their clinicopathologic characteristics were reviewed. Targeted deep sequencing analyses were performed on 20 secretory carcinomas (17 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) to investigate their genetic alterations. The A16V (C→T) mutation in PRSS1, which encodes a cationic trypsinogen and has a mutation associated with hereditary pancreatitis and pancreatic adenocarcinoma, was observed in 40% (8/20) (7/17 of ETV6 translocation-positive and 1/3 of ETV6 translocation-negative secretory carcinomas). Pathogenic variants of MLH1, MUTYH, and STK11 were also identified. Variants of uncertain significance included mutations in KMT5A. These novel characteristic genetic alterations may advance current understandings of secretory carcinoma tumorigenesis and progression, leading to improved diagnoses and treatment strategies.

Comparison of Surgical Outcomes of Robotic and Conventional Approaches in Patients with Pre- and Poststyloid Parapharyngeal Space Tumors.

BACKGROUND: Benefits and drawbacks of robotic surgical approaches for parapharyngeal space (PPS) tumors remain undetermined. The purpose of this study is to compare surgical outcomes of PPS tumor patients who underwent robotic surgery with those of patients who received conventional surgical treatment. PATIENTS AND METHODS: We retrospectively analyzed clinicopathologic data from 136 patients who underwent surgical removal of PPS tumors via conventional or robotic approaches. RESULTS: We identified PPS tumors in pre- and poststyloid regions in 87 (64%) and 49 (36%) patients, respectively. There were 48 (35.3%) pleomorphic adenomas, 36 (26.5%) schwannomas, and 24 (17.6%) paragangliomas. Conventional surgical techniques were performed in 83 patients, and robotic surgical approaches were administered to 53 patients. Transcervical-parotid and transcervical approaches were most commonly performed in conventional surgery, while transoral and retroauricular approaches were the preferred surgical methods in robotic surgery for pre- and poststyloid PPS tumors, respectively. Robotic surgery resulted in less estimated blood loss during poststyloid PPS tumor surgery. Postoperative cranial nerve complications were noted in 36 of 83 cases (43.4%) in the conventional surgery group and in 17 of 53 cases (32.1%) in the robotic surgery group. Intraoperative tumor spillage of pleomorphic adenoma showed no significant differences between the two groups (13.6% in conventional vs. 15.4% in robotic surgery). The mean follow-up time was 4.9 ± 3.4 years, and recurrences were observed in two patients during follow-up without a significant difference between the two groups (4.5% in conventional vs. 3.8% in robotic surgery). CONCLUSIONS: Robotic surgery in PPS tumors is feasible through transoral, retroauricular, or combined approaches and provides treatment outcomes comparable to those of conventional open surgery.

The First Human Trial of Transoral Robotic Surgery Using a Single-Port Robotic System in the Treatment of Laryngo-Pharyngeal Cancer.

BACKGROUND: This study aimed to evaluate the feasibility and safety of the DaVinci SP system for performing transoral robotic surgery (TORS) in patients with head and neck cancer. METHODS: From October 2018 to April 2019, the medical records of 41 patients who underwent TORS using the DaVinci SP system were retrospectively reviewed. RESULTS: During TORS, three robotic arms could be used to perform a geometric resection of the lesion in a narrow working space. The mean total operation time was 60 min, and the average time required to set up the robotic system was 10 min or less. All patients successfully underwent TORS. All robotic arms were inserted through a single port, which widened the working space around the patient's head and allowed the operative assistant an easy approach to the patient during the operation. The joggle joint of the robotic arms aided easy manipulation within the confined working space. The joggle joints of the endoscopic arm were controlled through the navigation system, which was very helpful in securing superior visualization of the surgical site, especially in the area of the larynx and the hypopharynx. CONCLUSION: The study confirmed that the DaVinci SP system provided technical advantages above the Si and Xi systems for performing TORS. It was especially helpful in ensuring proper visualization of the surgical field and in performing precise surgery during surgery to the tongue base or the hypopharyngeal lesion.

Hypoxia-Activated Adipose Mesenchymal Stem Cells Prevents Irradiation-Induced Salivary Hypofunction by Enhanced Paracrine Effect Through Fibroblast Growth Factor 10.

To explore the effects and mechanisms of paracrine factors secreted from human adipose mesenchymal stem cell (hAdMSCs) that are activated by hypoxia on radioprotection against irradiation-induced salivary hypofunction in subjects undergoing radiotherapy for head and neck cancers. An organotypic spheroid coculture model to mimic irradiation (IR)-induced salivary hypofunction was set up for in vitro experiments. Human parotid gland epithelial cells were organized to form three-dimensional (3D) acinus-like spheroids on growth factor reduced -Matrigel. Cellular, structural, and functional damage following IR were examined after cells were cocultured with hAdMSCs preconditioned with either normoxia (hAdMSCNMX ) or hypoxia (hAdMSCHPX ). A key paracrine factor secreted by hAdMSCsHPX was identified by high-throughput microarray-based enzyme-linked immunosorbent assay. Molecular mechanisms and signaling pathways on radioprotection were explored. Therapeutic effects of hAdMSCsHPX were evaluated after in vivo transplant into mice with IR-induced salivary hypofunction. In our 3D coculture experiment, hAdMSCsHPX significantly enhanced radioresistance of spheroidal human parotid epithelial cells, and led to greater preservation of salivary epithelial integrity and acinar secretory function relative to hAdMSCsNMX . Coculture with hAdMSCsHPX promoted FGFR expression and suppressed FGFR diminished antiapoptotic activity of hAdMSCsHPX . Among FGFR-binding secreted factors, we found that fibroblast growth factor 10 (FGF10) contributed to therapeutic effects of hAdMSCsHPX by enhancing antiapoptotic effect, which was dependent on FGFR-PI3K signaling. An in vivo transplant of hAdMSCsHPX into irradiated salivary glands of mice reversed IR-induced salivary hypofunction where hAdMSC-released FGF10 contributed to tissue remodeling. Our results suggest that hAdMSCsHPX protect salivary glands from IR-induced apoptosis and preserve acinar structure and functions by activation of FGFR-PI3K signaling via actions of hAdMSC-secreted factors, including FGF10. Stem Cells 2018;36:1020-1032.

Inhibitor of DNA binding 2 is a novel therapeutic target for stemness of head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are highly lethal epithelial tumours containing self-renewal cancer stem cells (CSCs). CSCs in HNSCCs are strongly associated with tumour initiation, invasion, and chemoradiation resistance. However, the important factors regulating stemness in HNSCCs remain unclear. Here, we investigated the molecular roles and clinical significance of inhibitor of DNA binding 2 (Id2) protein to determine if it constitutes a novel therapeutic target for ablating HNSCC cells with stemness. METHODS: We performed in vitro and in vivo studies of Id2 function and its effects on stemness using HNSCC cells. We also examined whether Id2 expression could be used as a prognostic indicator through immunohistochemical staining of 119 human HNSCC tumours. RESULTS: Expression of Id2 was higher in HNSCC cells with stemness compared with differentiated HNSCC cells. Overexpression of Id2 increased proliferation, self-renewal, and expression of the putative stemness marker CD44 in HNSCC cells in vitro and in vivo. In contrast, silencing of Id2 using short hairpin RNA attenuated the stemness phenotype of HNSCC cells by reducing self-renewal, CD44 expression, cisplatin chemoresistance, and xenograft tumourigenicity. Most importantly, increased expression of Id2 was closely associated with poorer post-treatment survival rates in HNSCC patients. CONCLUSIONS: Inhibitor of DNA binding2 represents a novel and promising therapeutic target for treating and improving the clinical outcomes for patients with HNSCC.

Usefulness of Magnetic Resonance Sialography for the Evaluation of Radioactive Iodine-Induced Sialadenitis.

PURPOSE: Radioactive iodine (RAI) ablation therapy after thyroidectomy commonly leads to obstructive sialadenitis. Magnetic resonance (MR) sialography is an emerging imaging modality that enables morphological and functional changes to be evaluated. This study was conducted to investigate the usefulness of MR sialography for the evaluation of RAI sialadenitis. In addition, the authors evaluated the correlation of MR sialographic grading with symptom severity using a symptom questionnaire (SQ), and salivary gland (SG) functions as determined by salivary flow rates (SFRs) and salivary scintigraphy (SSG) parameters. METHODS: Eighteen patients with RAI sialadenitis who underwent MR sialography imaging were retrospectively enrolled. Subjective symptom scores were assessed and objective SG functions were evaluated. MR sialographic characteristics were analyzed and correlations between MR sialographic findings and clinicopathologic data, SQ, SFRs, and SSG parameters were investigated. RESULTS: MR sialography demonstrated diagnostic findings of ductal stenosis and sialectasis, non-visualized ducts, and glandular atrophy mainly involving parotid glands. A significant correlation was found between obstructive symptom scores and ductal stenosis and sialectasis grades (both p < 0.05). Degrees of ductal stenosis and sialectasis were significantly correlated with SSG excretory variables [time from stimulation to minimum count (t min) and maximum secretion; all p < 0.05]. Significant linear correlations were found between duct nonvisualization and uptake variables [uptake ratio (UR) and maximum accumulation (MA); both p < 0.05]. Glandular volumes were also significantly correlated with UR and MA (both p < 0.05). CONCLUSIONS: MR sialography images are useful for evaluating RAI sialadenitis, and its findings are in accordance with disease severity. An MR sialographic grading system is suggested to describe the severity of obstructive sialadenitis and SG dysfunction.

The Usefulness of Salivary Gland Organoids for Evaluation of the Potency of Botulinum Neurotoxin.

BACKGROUND AND OBJECTIVES: Botulinum neurotoxin (BoNT) is a substance used to treat chronic sialorrhea, muscle dystonia, and is used in cosmetic applications. Measuring the potency of BoNT is crucial because it acts even with a small amount. However, the current methods for measuring the potency of BoNT involve using two-dimensional neuroblastoma cell line-based methods. In this study, we aimed to develop a new method to measure the potency of BoNT using a three-dimensional organoid culture system. MATERIALS AND METHOD: We established the optimal conditions for coculturing N2a neuronal cells with murine salivary gland organoids (SGOs). After determining the appropriate chemical concentrations, we treated the SGOs cocultured with N2a cells with BoNT type A (BoNT/A). We confirmed the expression of salivary gland-related genes and proteins using real-time polymerase chain reaction (PCR) and immunofluorescence staining. RESULTS: The SGOs cocultured with N2a cells showed that the dendrites or axons of neuronal cells were in contact with the outermost layer of the SGOs. When we applied acetylcholine and neostigmine to the coculture systems, the mRNA expression of Aqp5 and Bhlha15, associated with salivary gland secretory cells, increased. However, this effect was reversed when BoNT/A was applied, as confirmed through real-time PCR. CONCLUSION: We found that the coculture system of SGOs and N2a neuronal cells can potentially serve as a potency testing platform for BoNT. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2697-2704, 2024.

Bone marrow-derived clonal mesenchymal stem cells as a source of cell therapy for promoting vocal fold wound healing.

OBJECTIVES: We investigated whether mouse bone marrow-derived clonal mesenchymal stem cells (BM-cMSCs) could promote vocal fold (VF) wound healing by using a xenograft animal model. METHODS: Homogeneous BM-cMSCs isolated by a subfractionation culturing method from the bone marrow aspirates of green fluorescent protein transgenic mice were injected into the VFs of rabbits immediately after direct mechanical injury. Macroscopic, biomechanical (rheometric), histologic, immunohistochemical, and transcriptional evaluations were performed on the scarred VFs 1 to 3 months after injury. Engraftment of the implanted BM-cMSCs was determined by detection of green fluorescent protein cells in the recipient VF by confocal microscopy. RESULTS: The BM-cMSC-treated VFs showed improved morphological properties and viscoelasticity as compared to control VFs injected with phosphate-buffered saline solution. Histologic and immunohistochemical evaluations showed less excessive collagen deposition and increased density of glycosaminoglycans in the BM-cMSC-treated VFs as compared to the control VFs at 3 months after injury (p = 0.003 and p = 0.037, respectively). BM-cMSC transplantation led to a significant attenuation of fibronectin (p = 0.036) and transforming growth factor beta1 (p = 0.042) messenger RNA expression at 1 month after injury. Green fluorescent protein-expressing BM-cMSCs engrafted in recipient VFs were found at 1 month after implantation. CONCLUSIONS: BM-cMSCs appeared to survive in the injured xenogeneic VFs after transplantation for up to 1 month and favorably enhanced the wound healing of VFs after injury. We conclude that BM-cMSCs are a possible source of cell therapy for vocal fold regeneration.

Comprehensive Index of Vocal Fatigue (CIVF): Development and Clinical Validation.

OBJECTIVES: In this study, we sought to investigate whether auditory-perceptual and acoustic measures change after a passage-reading task and to develop a multidimensional index of performance fatigue in voice disorders. The clinical usefulness and cut-off scores of the newly developed index were also explored. METHODS: A total of 150 patients (age = 35.65 ± 11.44 years) with voice disorders and 100 healthy controls (age = 35.04 ± 11.26 years) were enrolled in the study. Overall severity (OS) and acoustic measures of sentence samples were obtained before and after a passage-reading task and compared between the two positions. Acoustic features included cepstral peak prominence (CPP), σCPP, L/H spectral ratio (SR), and σSR. Using the changes (Δ) in those acoustic measures and the scores of the Vocal Fatigue Index (VFI), a predictive model of the ΔOS was established. The clinical cut-off point of the index was also identified. RESULTS: For the patient group, OS was higher, but CPP and σCPP were lower for the rear position (after reading the passage) compared to the front position (before reading the passage). A significant portion (adjusted R2 = 77.7%) of the ΔOS was predicted by ΔCPP, tiredness score of the VFI, ΔσCPP, ΔσSR, and ΔSR. The area under the curve of the newly developed index was .864 (sensitivity, 78.67%; specificity, 78.00%), and the index's criterion was >2.6489. CONCLUSIONS: The newly developed Comprehensive Index of Vocal Fatigue (CIVF) can quantify vocal fatigue in voice disorders, reflecting both acoustic and auditory perceptual changes after a passage-reading task. Further studies should explore the responsiveness of the CIVF and the impact of related factors on the CIVF in various voice disorders.

Surgical margin status and role of adjuvant therapy in human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: We analyzed the difference in treatment results according to safety margin range and studied the role of adjuvant therapy in patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: A total of 279 patients with HPV+ OPSCC were included in this study. RESULTS: Surgical margin and T classification were significant prognostic factors related to death. The difference in locoregional recurrence was analyzed by dividing the safety margin into groups of <1, 1-5, and >5 mm. There was no significant difference in local-regional recurrence for T1-T2 lesions between the three groups. Adjuvant therapy can significantly reduce disease recurrence in HPV+ OPSCC patients with risk factors. CONCLUSIONS: In T1-T2 lesions without other risk factors, even with a safety margin ≥1 mm, adjuvant therapy can potentially be omitted. Adjuvant therapy can significantly reduce disease recurrence in HPV+ OPSCC patients with risk factors.

Correlations of MR Sialographic Gradings with the Clinical Measures of Sjögren's Syndrome.

OBJECTIVES: Sjögren syndrome (SS) features salivary gland architectural changes such as ductal deformities and fat deposition secondary to inflammatory cell infiltrates; however, the anatomical and pathophysiological correlations of SS remain to be determined. This study aimed to determine the correlations of imaging findings based on the magnetic resonance (MR) sialography with the clinical and laboratory aspects of SS patients. METHODS: We evaluated the MR sialographic findings of two pairs of parotid glands (PGs) and submandibular glands (SMGs) from 41 SS patients. The distinct MR sialographic features were then compared with the clinical symptoms, biological (anti-SSA/Ro antibody positivity), histological (labial gland focus score), and functional (salivary flow and scintigraphy) data. RESULTS: Ductal deformities such as sialectasis in the PG ducts were exclusively observed in SS, and fat replacement in SMGs was more distinct in patients with SS than in non-SS sicca patients. Of the 82 PGs and SMGs from 41 SS patients, the grade of sialectasis in PGs on MR sialographic images and fat stage in SMGs showed strong correlations with anti-SSA/Ro-positivity. PG sialectasis was found more frequently in patients with dry mouth and decreased salivary gland function. A significant correlation was found between fat deposition in PGs and SMGs and decreased salivary gland function. CONCLUSION: These results suggest that MR sialography is a reliable, adjunctive anatomical and functional study to assess SS. Detail aspects of sialectasis and fat accumulation encountered on MR sialography in SS patients can help physicians assume the disease status in SS. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:307-316, 2023.

Ductal delivery of extracellular vesicles promote the recovery from salivary gland inflammation.

Salivary gland dysfunction worsens the quality of life, but treatment for restoration of salivary gland function is limited. Although previous reports have demonstrated the therapeutic potentials of extracellular vesicles (EVs) in different preclinical models, the role of EVs in salivary glands remains elusive. Furthermore, little is known about the roles of salivary gland-derived EVs in tissue repair or regeneration compared to other EVs. In this study, EVs secreted from salivary gland-derived mesenchymal stem cells (sgMSCs) were comparatively analyzed with those from Wharton's jelly-derived MSC (wjMSCs). sgMSCs secreted more significant amounts of EVs than wjMSCs, and salivary gland epithelial cells showed a more efficient uptake of sgMSC-EVs than wjMSC-EVs. The possibility of immune regulation was tested via macrophage polarization and LPS-induced epithelial inflammation, resulting in an M1-to-M2 shift and reversal of acinar-to-ductal metaplasia by sgMSC-EV. Furthermore, the roles of sgMSC-EV-mediated immune regulation and tissue repair were clarified in vivo via retroductal delivery of sgMSC-EVs in a mouse model of obstructive sialadenitis. Collectively, our data demonstrate the superior role of sgMSC-EVs in the recovery from salivary gland inflammation and injury and suggest EVs as therapeutic tools for salivary gland dysfunction.

Reliability of Acoustic Measures in Dysphonic Patients With Glottic Insufficiency and Healthy Population: A COVID-19 Perspective.

OBJECTIVES: The COVID-19 pandemic has affected the voice assessment protocols for dysphonic patients. In this study, we compared the changes in acoustic measures of the healthy population as well as dysphonic patients due to glottic insufficiency between the pandemic period requiring face masks and the prepandemic period when the masks were not essential. The clinical reliability of the acoustic measures with and without face masks was explored. METHODS: A total of 120 patients (age = 42.3 ± 11.9 yrs) with glottic insufficiencies such as UVFP and sulcus vocalis and 40 healthy population (age = 40.5 ± 11.2 yrs) cohorts were enrolled during the pandemic period. Age- and gender-matched 120 patients and 40 healthy population cohorts who underwent voice assessment without face masks before the pandemic were enrolled as prepandemic controls. Acoustic measures and overall severity estimates of vowel and speech samples were compared, which included cepstral peak prominence (CPP), L/H spectral ratio (SR), their standard deviations, F0, jitter percent (Jitt), shimmer percent (Shim), noise-to-harmonic ratio (NHR), Cepstral Spectral Index of Dysphonia (CSID), and Acoustic Psychometric Severity Index of Dysphonia. RESULTS: Both patients and healthy cohorts showed higher SRv and SRs but lower CSIDv during the pandemic compared to the prepandemic period. F0 of the healthy male controls during the pandemic was higher than during the prepandemic periods, while the CSIDs was lower for the pandemic period. The pandemic patient cohort showed lower σSRs compared to the prepandemic patient cohort. When the acoustic measures of patients were compared to the healthy population cohort, the patient cohort showed lower CPP and σCPPs, while higher σCPPv, Jitt, Shim, and NHR during both pandemic and prepandemic period. Overall, the area under the curve of the acoustic measures and overall severity estimates was similar between the mask and non-mask groups, although the AUC of the SR measures was poor. CONCLUSIONS: Wearing face masks during the pandemic did not compromise the overall reliability of the acoustic analysis in patients with glottic insufficiency, suggesting the current protocol of acoustic analysis can be carried out reliably while wearing a mask to ensure safety in the pandemic era.

Machine learning and magnetic resonance imaging radiomics for predicting human papilloma virus status and prognostic factors in oropharyngeal squamous cell carcinoma.

BACKGROUND: We attempted to predict pathological factors and treatment outcomes using machine learning and radiomic features extracted from preoperative magnetic resonance imaging (MRI) of oropharyngeal squamous cell carcinoma (OPSCC) patients. METHODS: The medical records and imaging data of 155 patients who were diagnosed with OPSCC were analyzed retrospectively. RESULTS: The logistic regression model showed that the area under the receiver operating characteristic curve (AUC) of the model was 0.792 in predicting human papilloma virus (HPV) status. The LightGBM model showed an AUC of 0.8333 in predicting HPV status. The performance of the logistic model in predicting lymphovascular invasion, extracapsular nodal spread, and metastatic lymph nodes showed AUC values of 0.7871, 0.6713, and 0.6638, respectively. In predicting disease recurrence, the LightGBM model showed an AUC of 0.8571. In predicting patient death, the logistic model showed an AUC of 0.8175. CONCLUSIONS: A machine learning model using MRI radiomics showed satisfactory performance in predicting pathologic factors and treatment outcomes of OPSCC patients.

Long-term outcomes of early stage oral tongue cancer: Main cause of treatment failure and second primary malignancy.

Objective: We attempted to investigate the long-term outcomes, prognostic factors, treatment failures, second primary malignancies, and salvage therapies in early (pT1-2N0) oral tongue squamous cell carcinoma (OTSCC). Methods: We retrospectively analyzed the medical records of 295 early stage OTSCC patients. Results: Two hundred ninety-five patients were enrolled. The average follow-up period was 64.5 months (range, 1-190 months). Five-year recurrence-free survival rate was 84.8% and disease-specific survival rate was 91.2%. On multivariate analysis, only the depth of invasion (DOI) exhibited significant correlations with the disease recurrence. Patient's age and DOI demonstrated a significant association with survival. A total of 53 recurrence and 35 death events occurred, with the main cause of treatment failure being regional or local recurrence. In recurrent cases, the success rate of salvage treatment was 42% at 5 years. During the follow-up period, second primary malignancy occurred in 13 patients, and 8 (61.5%) of those patients were successfully treated. Conclusions: In pT1-2N0 OTSCC, regional or local recurrence is the main recurrence pattern, whereas age and DOI >5 mm are significant prognostic factors related to recurrence and survival. Since several patients experienced second primary malignancies in the head and neck, careful and thorough surveillance may be required to detect second primary lesions. Level of Evidence: 4.

Thermoresponsive fiber-based microwells capable of formation and retrieval of salivary gland stem cell spheroids for the regeneration of irradiation-damaged salivary glands.

Three-dimensional spheroid culture enhances cell-to-cell interactions among stem cells and promotes the expression of stem cell properties; however, subsequent retrieval and delivery of these cells remain a challenge. We fabricated a thermoresponsive fiber-based microwell scaffold by combining electrospinning and hydrogel micropatterning. The resultant scaffold appeared to facilitate the formation of cellular spheroids of uniform size and enabled the expression of more stem cell-secreting growth factor genes (EGF, IGF-1, FGF1, FGF2, and HGF), pluripotent stem cell-related genes (SOX2 and NANOG), and adult epithelial stem cell-related genes (LGR4, LGR5, and LGR6) than salivary gland stem cells in a monolayer culture (SGSCmonolayer). The spheroids could be retrieved efficiently by decreasing temperature. SGSC-derived spheroid (SGSCspheroid) cells were then implanted into the submandibular glands of mice at 2 weeks after fractionated X-ray irradiation at a dose of 7.5 Gy/day. At 16 weeks post-irradiation, restoration of salivary function was detected only in SGSCspheroid-implanted mice. The production of submandibular acini specific mucin increased in SGSCspheroid-implanted mice, compared with PBS control. More MIST1+ mature acinar cells were preserved in the SGSCspheroid-implanted group than in the PBS control group. Intriguingly, SGSCspheroid-implanted mice exhibited greater amelioration of tissue damage and preservation of KRT7+ terminally differentiated luminal ductal cells than SGSCmonolayer-implanted mice. The SGSCspheroid-implanted mice also showed less DNA damage and apoptotic cell death than the SGSCmonolayer-implanted mice at 2 weeks post-implantation. Additionally, a significant increase in Ki67+AQP5+ proliferative acinar cells was noted only in SGSCspheroid-implanted mice. Our results suggest that a thermoresponsive fiber-based scaffold could be of use to facilitate the production of function-enhanced SGSCspheroid cells and their subsequent retrieval and delivery to damaged salivary glands to alleviate radiation-induced apoptotic cell death and promote salivary gland regeneration.