Publications by authors named "Yo Kishimoto"

62 Publications

Pediatric Vocal Fold Paresis and Paralysis: A Narrative Review.

JAMA Otolaryngol Head Neck Surg 2021 Jun 10. Epub 2021 Jun 10.

School of Communication Sciences and Disorders, McGill University, Montreal, Canada.

Importance: Vocal fold paralysis (VFP) results from the disruption of neural motor outputs to laryngeal muscles. Children with VFP manifest various degrees of difficulties in phonation, breathing, and swallowing. Although the etiologic characteristics and symptoms of VFP are well established in adults, corresponding clinical profiles are notably different in children. Clinical management of VFP is particularly challenging in children because their larynges are still actively developing and the recovery of disrupted laryngeal nerves is often unpredictable. This review discusses the neurologic conditions and diagnostic and treatment considerations in pediatric VFP.

Observations: Injury to the peripheral laryngeal nerves and certain central nervous system diseases, such as Arnold-Chiari malformation type II, can result in VFP in infants and children. The incidence of unilateral vs bilateral VFP is variable across pediatric studies. Most reported VFP cases are associated with injury of the recurrent laryngeal nerve. Laryngeal electromyography requires needle insertion that must be performed under anesthesia with special care in the pediatric setting. Neither normative values nor standardized procedures of laryngeal electromyography are currently established for the pediatric population. Laryngeal reinnervation, endoscopic arytenoid abduction lateropexy, and laryngeal pacing are plausible treatment options for pediatric VFP. Despite these new advances in the field, no corresponding efficacy data are available for clinicians to discern which type of patients would be the best candidates for these procedures.

Conclusions And Relevance: The neuroanatomy and neurophysiology of VFP remain more elusive for the pediatric population than for adults. Basic and clinical research is warranted to fully comprehend the complexity of this laryngeal movement disorder and to better inform and standardize clinical practice.
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http://dx.doi.org/10.1001/jamaoto.2021.1050DOI Listing
June 2021

High-resolution magnetic resonance and mass spectrometry imaging of the human larynx.

J Anat 2021 May 25. Epub 2021 May 25.

Department of Entomology, University of Wisconsin-Madison, Madison, WI, USA.

High-resolution, noninvasive and nondestructive imaging of the subepithelial structures of the larynx would enhance microanatomic tissue assessment and clinical decision making; similarly, in situ molecular profiling of laryngeal tissue would enhance biomarker discovery and pathology readout. Towards these goals, we assessed the capabilities of high-resolution magnetic resonance imaging (MRI) and matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) imaging of rarely reported paediatric and adult cadaveric larynges that contained pathologies. The donors were a 13-month-old male, a 10-year-old female with an infraglottic mucus retention cyst and a 74-year-old female with advanced polypoid degeneration and a mucus retention cyst. MR and molecular imaging data were corroborated using whole-organ histology. Our MR protocols imaged the larynges at 45-117 μm in-plane resolution and capably resolved microanatomic structures that have not been previously reported radiographically-such as the vocal fold superficial lamina propria, vocal ligament and macula flavae; age-related tissue features-such as intramuscular fat deposition and cartilage ossification; and the lesions. Diffusion tensor imaging characterised differences in water diffusivity, primary tissue fibre orientation, and fractional anisotropy between the intrinsic laryngeal muscles, mucosae and lesions. MALDI-MS imaging revealed peptide signatures and putative protein assignments for the polypoid degeneration lesion and the N-glycan constituents of one mucus retention cyst. These imaging approaches have immediate application in experimental research and, with ongoing technology development, potential for future clinical application.
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http://dx.doi.org/10.1111/joa.13451DOI Listing
May 2021

Airway ciliated cells regenerated on collagen sponge implants acquire planar polarities towards nearby edges of implanted areas.

J Tissue Eng Regen Med 2021 May 19. Epub 2021 May 19.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Tissue-engineered tracheae have been developed to replace defective tracheae. However, the direction of ciliated cells in the regenerated epithelium remains unclear. We investigated planar polarity formed in the regenerated airway epithelium after tracheal graft implantation. We partially resected the rat trachea and implanted a collagen scaffold. The direction of the basal foot was assessed by transmission electron microscopy. Immunofluorescence staining was performed to examine the biased distribution of Vangl1 and Frizzled6 proteins. The direction of mucociliary transport was analyzed by video microscopy. Our results showed that the basal feet of cilia in the proximal and distal regions of the implanted areas were respectively oriented toward the proximal and distal directions. The biased distribution of Vangl1 and Frizzled6, and the directions of mucociliary transport showed that planar polarities formed in the regenerated epithelium were oriented toward the proximal, distal, left, and right directions in the proximal, distal, left, and right regions of the implanted area. These polarities persisted until nine months after implantation. Hence, the results suggest that planar polarities formed in epithelia regenerated on tracheal grafts are directed toward the nearby edges of implanted areas and are preserved for a prolonged period. The polarities can, at least partially, contribute to clearing external materials from the implanted areas by transporting them to a normal region.
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http://dx.doi.org/10.1002/term.3220DOI Listing
May 2021

Treatment outcomes of transoral robotic and non-robotic surgeries to treat oropharyngeal, hypopharyngeal, and supraglottic squamous cell carcinoma: A multi-center retrospective observational study in Japan.

Auris Nasus Larynx 2021 Jun 22;48(3):502-510. Epub 2021 Feb 22.

Department of Otorhinolaryngology-Head and Neck Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Objectives: The aim of this multicenter retrospective cohort study was to compare efficacy and subsequent postoperative treatment between transoral robotic surgery (TORS) and any non-robotic transoral surgery in Japanese patients with early oropharyngeal squamous cell carcinoma (OPSCC), hypopharyngeal SCC (HPSCC), or supraglottic SCC (SGSCC).

Materials And Methods: Clinical information and surgical outcomes were compared between patients with early-stage OPSCC, HPSCC, and SGSCC who underwent TORS (TORS cohort) and those who underwent non-robotic transoral surgery, including transoral videolaryngoscopic surgery (TOVS), endoscopic laryngopharyngeal surgery (ELPS), and transoral laser microsurgery (TLM) (non-robotic cohort). The data of the Head and Neck Cancer Registry of Japan (registry cohort) were used to validate the comparison. The main outcomes were the presence of positive margins under pathology and the requirement for postoperative therapy, including radiotherapy or chemoradiotherapy.

Results: Sixty-eight patients in the TORS cohort, 236 patients in the non-robotic cohort, and 1,228 patients in the registry cohort were eligible for this study. Patients in the TORS cohort were more likely to have oropharyngeal tumor disease and T2/3 disease than those in the other cohorts (P<0.001 and P=0.052, respectively). The TORS cohort had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.018), as well as fewer patients who underwent postoperative treatment, although the difference was not significant (P=0.069). In the subgroup analysis of patients with OPSCC, a total of 57 patients in the TORS cohort, 73 in the non-robotic cohort, and 171 in the registry cohort were eligible for the present study. Patients with OPSCC who underwent TORS were more likely to have lateral wall lesions than those in the other cohorts (P=0.003). The TORS cohort also had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.026), and no patients in the TORS cohort underwent any postoperative treatment for OPSCC, although the difference was not significant (P=0.177).

Conclusions: Our results suggest that TORS leads to fewer positive surgical margins than non-robotic transoral surgeries. The clinical significance of TORS may be further validated through the results of all-case surveillance for patients who underwent TORS running in Japan in the future.
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http://dx.doi.org/10.1016/j.anl.2021.01.024DOI Listing
June 2021

In vivo regeneration of rat laryngeal cartilage with mesenchymal stem cells derived from human induced pluripotent stem cells via neural crest cells.

Stem Cell Res 2021 04 11;52:102233. Epub 2021 Feb 11.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The laryngotracheal cartilage is a cardinal framework for the maintenance of the airway for breathing, which occasionally requires reconstruction. Because hyaline cartilage has a poor intrinsic regenerative ability, various regenerative approaches have been attempted to regenerate laryngotracheal cartilage. The use of autologous mesenchymal stem cells (MSCs) for cartilage regeneration has been widely investigated. However, long-term culture may limit proliferative capacity. Human-induced pluripotent stem cell-derived MSCs (iMSCs) can circumvent this problem due to their unlimited proliferative capacity. This study aimed to investigate the efficacy of iMSCs in the regeneration of thyroid cartilage in immunodeficient rats. Herein, we induced iMSCs through neural crest cell intermediates. For the relevance to prospective future clinical application, induction was conducted under xeno-free/serum-free conditions. Then, clumps fabricated from an iMSC/extracellular matrix complex (C-iMSC) were transplanted into thyroid cartilage defects in immunodeficient rats. Histological examinations revealed cartilage-like regenerated tissue and human nuclear antigen (HNA)-positive surviving transplanted cells in the regenerated lesion. HNA-positive cells co-expressed SOX9, and type II collagen was identified around HNA-positive cells. These results indicated that the transplanted C-iMSCs promoted thyroid cartilage regeneration and some of the iMSCs differentiated into chondrogenic lineage cells. Induced MSCs may be a promising candidate cell therapy for human laryngotracheal reconstruction.
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http://dx.doi.org/10.1016/j.scr.2021.102233DOI Listing
April 2021

A retrospective analysis of revision framework surgeries for unilateral vocal fold paralysis.

Braz J Otorhinolaryngol 2020 Dec 26. Epub 2020 Dec 26.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Introduction: Revision framework surgeries might be required for unilateral vocal fold paralyses. However, outcomes and indications of revision surgeries have not been adequately documented. For a better understanding of indications for the procedure and to help in achieving better vocal outcomes, we performed a retrospective chart review of patients who underwent revision framework surgeries for unilateral vocal fold paralysis.

Objectives: This study aimed to present clinical features of patients who underwent revision framework surgeries for the treatment of unilateral vocal fold paralysis.

Methods: Of the 149 framework surgeries performed between October 2004 and October 2019, 21 revision framework surgeries were performed in 19 patients. Self-assessments by patients using the voice handicap index-10 questionnaire, and objective aerodynamic and acoustic assessments performed pre- and post-operatively were analyzed using the Wilcoxon's signed-rank test for paired comparisons.

Results: Undercorrection was indicated as reasons for revision surgeries in all cases. The revision techniques included type I thyroplasty, type IV thyroplasty, and arytenoid adduction, and revision surgeries were completed without any severe complication in all cases. Pre- and post-operative voice handicap index-10 scores were obtained in 12 cases, and other parameters were evaluated in 18 cases. Significant improvements were observed in voice handicap index-10 scores, maximum phonation time, mean flow rate, Current/Direct Current ratio, and pitch perturbation quotient.

Conclusion: Undercorrection was observed in all patients who underwent revision framework surgeries for unilateral vocal fold paralysis, and the initial assessment and planning are thought to be important in order to avoid revision surgeries. Revision surgeries were performed safely in all cases, and significantly improved vocal outcomes were observed, even after multiple procedures. Revision surgery should be considered for patients with unsatisfactory vocal functions after primary framework surgeries for unilateral vocal fold paralysis.
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http://dx.doi.org/10.1016/j.bjorl.2020.11.016DOI Listing
December 2020

Hyperactive sensorimotor cortex during voice perception in spasmodic dysphonia.

Sci Rep 2020 10 14;10(1):17298. Epub 2020 Oct 14.

Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Spasmodic dysphonia (SD) is characterized by an involuntary laryngeal muscle spasm during vocalization. Previous studies measured brain activation during voice production and suggested that SD arises from abnormal sensorimotor integration involving the sensorimotor cortex. However, it remains unclear whether this abnormal sensorimotor activation merely reflects neural activation produced by abnormal vocalization. To identify the specific neural correlates of SD, we used a sound discrimination task without overt vocalization to compare neural activation between 11 patients with SD and healthy participants. Participants underwent functional MRI during a two-alternative judgment task for auditory stimuli, which could be modal or falsetto voice. Since vocalization in falsetto is intact in SD, we predicted that neural activation during speech perception would differ between the two groups only for modal voice and not for falsetto voice. Group-by-stimulus interaction was observed in the left sensorimotor cortex and thalamus, suggesting that voice perception activates different neural systems between the two groups. Moreover, the sensorimotor signals positively correlated with disease severity of SD, and classified the two groups with 73% accuracy in linear discriminant analysis. Thus, the sensorimotor cortex and thalamus play a central role in SD pathophysiology and sensorimotor signals can be a new biomarker for SD diagnosis.
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http://dx.doi.org/10.1038/s41598-020-73450-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566443PMC
October 2020

A novel method for live imaging of human airway cilia using wheat germ agglutinin.

Sci Rep 2020 09 2;10(1):14417. Epub 2020 Sep 2.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Multiciliated epithelial cells in the airway are essential for mucociliary clearance. Their function relies on coordinated, metachronal and directional ciliary beating, appropriate mucus secretion and airway surface hydration. However, current conventional methods for observing human airway ciliary movement require ciliated cells to be detached from airway tissues. Determining the directionality of cilia is difficult. We developed a novel method to stain airway epithelial cilia to observe their movement without releasing ciliated cells. Human tracheae were obtained from patients (n = 13) who underwent laryngectomies to treat malignancies or swallowing disorders. The tracheae were treated with fluorescently labeled wheat germ agglutinin, which interacts with the acidic mucopolysaccharides present on the cilia. Epithelial surfaces were observed using an epi-fluorescence microscope equipped with a water-immersion objective lens and a high-speed camera. Ciliary movement was observable at 125 fps (13/13 samples). Ciliated cells in close proximity mostly exhibited well-coordinated ciliary beats with similar directionalities. These findings indicated that wheat germ agglutinin renders ciliary beats visible, which is valuable for observing human airway ciliary movements in situ.
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http://dx.doi.org/10.1038/s41598-020-71049-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468155PMC
September 2020

Indications and postoperative outcomes of surgery for laryngotracheal stenosis: A descriptive study.

Auris Nasus Larynx 2021 Feb 15;48(1):110-115. Epub 2020 Jul 15.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 650-8507, Japan.

Objective: Tracheal reconstruction is a rare surgical procedure and the actual incidence of or indications for this procedure have not been thoroughly elucidated. We performed the nationwide database analysis to clarify the real-world situation of laryngotracheal surgery requiring cervical tracheal reconstruction.

Methods: Patients who underwent surgical treatment for laryngotracheal stenosis or defect from 2008 to 2016 were identified from the Diagnosis Procedure Combination inpatient database, collected from 270 acute care hospitals in Japan. Patients were divided into two groups based on presence/absence of malignancy, and T-tube or tracheotomy dependence at 6 months after surgery was compared between the two groups.

Results: One hundred and thirty-four patients (75 males) were identified. The median age at surgery was 65.5 years. The most common indication for surgery was malignancy (n = 60, 44.8%), followed by iatrogenic (n = 25, 18.6%), trauma (n = 6, 4.5%), malformation of the larynx and trachea (n = 6, 4.5%), and chronic inflammatory disease (n = 4, 2.8%). Thyroid cancer was the most common malignancy (n = 38). Thirty patients (22.4%) failed to decannulate within 6 months and malignancy was associated with a lower dependence on T-tube or tracheotomy at 6 months after surgery (adjusted odds ratio: 0.25, 95% confidence interval: 0.08-0.79).

Conclusion: A Japanese health insurance claims database provided a useful overview of the clinical features and outcomes of patients who underwent cervical tracheal reconstruction surgery for laryngotracheal stenosis or defect.
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http://dx.doi.org/10.1016/j.anl.2020.06.011DOI Listing
February 2021

Endoscopic laryngopharyngeal surgery for hypopharyngeal lesions.

Oral Oncol 2020 07 20;106:104655. Epub 2020 Apr 20.

Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Japan.

Objectives: Transoral approaches for laryngeal/pharyngeal malignancies have been widely accepted as minimally invasive treatment options; however, hypopharyngeal lesions treated by transoral surgery have rarely been reported due to the difficulties in visualizing the hypopharynx. Since 2010, we have treated superficial hypopharyngeal lesions with endoscopic laryngopharyngeal surgery (ELPS), and herein report the outcomes of this transoral procedure.

Materials And Methods: One hundred and eighteen patients with superficial hypopharyngeal lesions were treated by ELPS from February 2010 to February 2017, and the clinical courses of the patients were reviewed.

Results: Four females and 114 males (average: 65.6 y-o) were included in this study. Some patients had multiple lesions and a total of 154 superficial hypopharyngeal lesions (dysplasia: 29, Tis: 52, T1: 44, T2: 20, T3: 9) were treated with ELPS. Ten patients had only dysplasia and no carcinoma. Five patients presented with nodal metastases and 11 patients had simultaneous oropharyngeal lesions. In all cases, the hypopharynx was well visualized with sufficient working space, and no cases required a change in surgical approach. All post-operative complications were safely managed. In regard to the oncological outcomes, of the 108 patients with malignant lesions, the 3-year and 5-year overall survival (OS) rate was 93.6% and 85.5%, respectively.

Conclusions: During ELPS, the hypopharynx was well visualized providing sufficient working space for the resection. The procedure was safe and feasible for superficial hypopharyngeal lesions and exhibited very good oncological outcomes. ELPS is thought to be a very effective surgical alternative for superficial hypopharyngeal lesions.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104655DOI Listing
July 2020

Indications and outcomes of paediatric tracheotomy: a descriptive study using a Japanese claims database.

BMJ Open 2019 12 17;9(12):e031816. Epub 2019 Dec 17.

Department of Otolaryngology-Head and Neck Surgery, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan.

Objective: To examine the incidence of and indications for paediatric tracheotomy to clarify the disease burden relevant to tracheotomy in a population-based context.

Design: A descriptive analysis of a retrospective cohort.

Setting: This study utilised a nationwide claims database in Japan constructed by JMDC (Tokyo, Japan). The database includes claims data for approximately 3.75 million insured persons (approximately 3.1% of the population of Japan) comprising mainly company employees and their family members.

Participants: We identified children registered to have undergone tracheotomy from 2005 to 2017 among about 1.2 million children aged 0-15 years.

Main Outcome Measures: The characteristics of the study population, and indications for tracheotomy, duration of hospital stay, duration of mechanical ventilation, duration of tracheotomy dependence, complications related to tracheotomy and death were assessed. When there were multiple indications, classification for a child into multiple groups was allowed.

Results: The study included 215 children (120 males, 56%). The median age at tracheotomy was 0.8 years. The most common age at tracheotomy was less than 12 months (n=127, 59.1%). The most common indications for tracheotomy were chronic lung disease (n=79, 36.7%), followed by neuromuscular disease (n=77, 35.8%), cardiovascular disease (n=53, 24.3%), upper airway obstruction (n=43, 20%), premature birth and related conditions (n=34, 15.8%), trauma (n=16, 7.4%), prolonged ventilation due to other causes (n=12, 5.6%) and malignancy (n=9, 4.2%). The median duration of tracheotomy dependence was 17.2 months. During the follow-up period, decannulation was achieved in 84 children (39.1%), and the median time from tracheotomy to decannulation was 12.0 months.

Conclusions: Most paediatric tracheotomies were performed due to chronic underlying diseases, and the mean duration of tracheotomy dependence was nearly 1-½ years. The long-term duration of tracheotomy dependence might have some impacts on patients' physical and mental development and the quality of life.
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http://dx.doi.org/10.1136/bmjopen-2019-031816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937105PMC
December 2019

Recurrent laryngeal nerve regeneration using a self-assembling peptide hydrogel.

Laryngoscope 2020 10 5;130(10):2420-2427. Epub 2019 Dec 5.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives/hypothesis: To regenerate defected recurrent laryngeal nerves (RLNs), various methods have been developed. However, no consistently effective treatments are currently available because of their insufficient functional recovery. RADA16-I, a self-assembling peptide used clinically as a hemostat, reportedly supports neurite outgrowth and functional synapse formation in vitro. The purpose of this study was to investigate the effect of RADA16-I hydrogels on transected RLNs in rats.

Study Design: Animal experiments with controls.

Methods: Fifteen adult rats were divided into the following three groups: RADA16-I (+), RADA16-I (-), and neurectomy. A 6-mm gap of the left RLN was bridged using an 8-mm silicone tube in the RADA16-I (-) and RADA16-I (+) groups. Subsequently, RADA16-I hydrogel was injected into the tube in the RADA16-I (+) group. The surgical incisions were closed without any further treatment in the neurectomy group. After 8 weeks, laryngoscopy and electrophysiological and histological examinations were performed to evaluate the effect of RADA16-I on nerve regeneration and thyroarytenoid muscle atrophy.

Results: Although most rats in the three groups exhibited no improvements of their vocal fold movement, partial recovery was observed in one rat in the RADA16-I (+) group. The neurofilament-positive areas and the number of myelinated nerves in the RADA16-I (+) group were significantly higher than in the RADA16-I (-) group. The area of the left thyroarytenoid muscle in the RADA16-I (+) group was significantly larger than that of the neurectomy group.

Conclusions: Our results suggested that RADA16-I hydrogel was effective for RLN regeneration.

Level Of Evidence: NA Laryngoscope, 130:2420-2427, 2020.
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http://dx.doi.org/10.1002/lary.28434DOI Listing
October 2020

Dedifferentiated liposarcoma of the thyroid gland: A case report.

Mol Clin Oncol 2019 Sep 18;11(3):219-224. Epub 2019 Jun 18.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

Liposarcoma is one of the most common soft tissue tumors that affect adults. Liposarcoma is typically identified in the retroperitoneum, trunk and extremities as a slow-growing mass, yet is rare in the thyroid gland. Herein, we report a case of dedifferentiated liposarcoma that developed in the thyroid gland, and performed a literature review. A 66-year-old male with a history of well-differentiated liposarcoma in the thymus presented with a rapidly enlarging mass in the thyroid gland. Malignancy was suspected due to the local extension of the tumor, and complete resection of the tumor was achieved. Tissue diagnosis from the tumor following surgery revealed that dedifferentiated liposarcoma, and tumor progression was difficult to control with adjuvant radiation and chemotherapy. This is, to the best of our knowledge, the first case to report dedifferentiated liposarcoma in the thyroid gland, and the difficulty in initial diagnosis as well as the aggressive features of dedifferentiated liposarcoma are highlighted.
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http://dx.doi.org/10.3892/mco.2019.1882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636207PMC
September 2019

Reversal of Vocal Fold Mucosal Fibrosis Using siRNA against the Collagen-Specific Chaperone Serpinh1.

Mol Ther Nucleic Acids 2019 Jun 22;16:616-625. Epub 2019 Apr 22.

Division of Otolaryngology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. Electronic address:

Vocal fold (VF) mucosal fibrosis results in substantial voice impairment and is recalcitrant to current treatments. To reverse this chronic disorder, anti-fibrotic therapies should target the molecular pathology of aberrant collagen accumulation in the extracellular matrix. We investigated the therapeutic potential of siRNA against Serpinh1, a collagen-specific chaperone that enables cotranslational folding and assembly of procollagens in the endoplasmic reticulum. We implemented a previously validated siRNA construct, conducted transfection experiments using in vitro and in vivo rat models, and measured knockdown efficiency, dose responses, delivery strategies, and therapeutic outcomes. Liposome-mediated delivery of Serpinh1-siRNA downregulated collagen production in naive and scar VF fibroblasts as well as naive VF mucosa; moreover, sustained Serpinh1 knockdown in fibrotic VF mucosa reversed scar-associated collagen accumulation within 4 weeks. Analysis of therapeutic effects at the transcriptome level showed evidence of cell cycle upregulation, catabolism, matrix disassembly, and morphogenesis. These findings indicate that Serpinh1-siRNA holds potential as a molecular therapy for chronic VF mucosal fibrosis.
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http://dx.doi.org/10.1016/j.omtn.2019.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520554PMC
June 2019

Transplantation of multiciliated airway cells derived from human iPS cells using an artificial tracheal patch into rat trachea.

J Tissue Eng Regen Med 2019 06 24;13(6):1019-1030. Epub 2019 Apr 24.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Tracheal resection is often performed for malignant tumours, congenital anomalies, inflammatory lesions, and traumatic injuries. There is no consensus on the best approach for the restoration of tracheal functionality in patients with tracheal defects. Artificial grafts made of polypropylene and collagen sponge have been clinically used by our group. However, 2 months are required to achieve adequate epithelialization of the grafts in humans. This study aimed to investigate the feasibility of transplantation therapy using an artificial trachea with human-induced pluripotent stem cell (hiPSC)-derived multiciliated airway cells (hiPSC-MCACs). Collagen vitrigel membrane, a biocompatible and absorbable material, was used as a scaffold to cover the artificial trachea with hiPSC-MCACs. Analyses of hiPSC-MCACs on collagen vitrigel membrane were performed by immunocytochemistry and electron microscopy and by assessing ciliary beat frequency. Along with the artificial trachea, hiPSC-MCACs were transplanted into surgically created tracheal defects of immunodeficient rats. The survival of transplanted cells was histologically evaluated at 1 and 2 weeks after the transplantation. The hiPSC-MCACs exhibited motile cilia on collagen vitrigel membrane. The surviving hiPSC-MCACs were observed in the endotracheal epithelium of the tracheal defect at 1 and 2 weeks after transplantation. These results suggest that hiPSC-MCAC is a useful candidate for tracheal reconstruction.
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http://dx.doi.org/10.1002/term.2849DOI Listing
June 2019

Collagen sponge scaffolds containing growth factors for the functional regeneration of tracheal epithelium.

J Tissue Eng Regen Med 2019 05 9;13(5):835-845. Epub 2019 Apr 9.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Tracheal epithelia have barrier and mucociliary clearance functions that prevent invasion of extraneous particles and infectious materials. Hence, following tracheal reconstructions, functional and morphological regeneration of epithelia is required to prevent respiratory declines and infectious diseases. Although growth factors (GFs) promote the regeneration of tracheal epithelial morphologies, it remains unclear whether tracheal grafts containing GFs are beneficial for regeneration of tracheal epithelial functions. Thus, we fabricated collagen sponge scaffolds containing insulin-like GF-1 (IGF-1) and the basic fibroblast, hepatocyte, and epidermal GFs (bFGFs, HGFs, and EGFs, respectively), and we evaluated the effects of the grafts on the functional regeneration of tracheal epithelia. Partial tracheal defects were imposed surgically, and collagen sponges containing IGF-1, bFGF, HGF, or EGF were then transplanted to defect sites. Subsequent immunofluorescence studies suggested that EGF and bFGF contribute to regular distributions of tight junction molecules, and tracer permeability assays suggested that EGF and bFGF promote regeneration of barrier function. Increased ciliogenesis was also observed using scanning electron microscopy in reconstructed regions treated with EGF- and bFGF-supplemented collagen sponges. However, bFGF-supplemented collagen sponges led to greater microsphere transport than did EGF-supplemented sponges. The present data suggested that collagen sponge scaffold containing bFGF promotes functional regeneration of tracheal epithelial tissues.
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http://dx.doi.org/10.1002/term.2835DOI Listing
May 2019

Alterations in macrophage polarization in injured murine vocal folds.

Laryngoscope 2019 04 30;129(4):E135-E142. Epub 2018 Dec 30.

Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: Macrophages are prominent inflammatory cells in wounds, and their phenotypes are altered during wound healing. They are reported to contribute to not only inflammatory responses but also tissue remodeling. However, few studies in vocal fold biology have focused on the function of macrophages. The purpose of this study was to investigate macrophage polarization and distribution in injured murine vocal folds.

Study Design: Animal experiments with controls.

Method: Unilateral vocal fold stripping was performed on C57BL/6 mice, and larynges were harvested 1, 3, 5, 7, and 14 days postinjury. Immunohistochemical analysis of the vocal fold lamina propria was performed to detect the expression of classically activated (M1) and alternatively activated (M2) macrophage markers (inducible nitric oxide synthase [iNOS] and CD206, respectively) in F4/80 macrophages.

Results: The proportion of F4/80 iNOS cells out of all F4/80 cells tended to increase from day 1. F4/80 iNOS cell percentage tended to be high at days 1 through 7 and declined to close to a normal level by day 14. F4/80 CD206 cell percentage tended to decrease at day 1 and then to increase the rest of the time. In the normal vocal fold, the majority of F4/80 macrophages were only positive for CD206. F4/80 iNOS CD206 cells were observed at days 1 through 7.

Conclusion: The main population of injured sites gradually shifted from M1 to M2 marker-positive macrophages in murine vocal folds. However, coexistence of M1 and M2 markers in the same macrophages was observed. Our results suggest that macrophage phenotypes are regulated by complex tissue-derived signals and exhibit dynamic changes during wound healing.

Level Of Evidence: NA Laryngoscope, 129:E135-E142, 2019.
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http://dx.doi.org/10.1002/lary.27523DOI Listing
April 2019

Characterization of aged rat vocal fold fibroblasts.

Laryngoscope 2019 03 19;129(3):E94-E101. Epub 2018 Nov 19.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives/hypothesis: To elucidate the aging physiology of the vocal folds, we examined the characters of aged vocal fold fibroblasts (VFFs) in various conditions.

Study Design: In vitro study.

Methods: VFFs from young (12-week-old) and aged (19-month-old) Sprague-Dawley rats were compared. Proliferative capacity, ratio of myofibroblast to fibroblast, myofibroblast function, and extracellular matrix production were examined in the following conditions: naïve, basic fibroblast growth factor (bFGF) supplemented, and hepatocyte growth factor (HGF) supplemented.

Results: Aged VFFs demonstrated reduced proliferation by cell counting, though the ratio of Ki-67-positive cells showed no difference. Aged VFFs exhibited an increased expression of α-smooth muscle actin (α-SMA); however, they demonstrated no enhanced contractile ability in a gel contraction assay. Type I collagen protein was increased age dependently, accompanied with decreased Mmp1 and unchanged Col1a1 transcription. Type I collagen protein and α-SMA represented quite similar reduction patterns to bFGF or HGF administration.

Conclusions: The following possible characteristics of aged VFFs were implied: long duration of mitosis, increased myofibroblast population size with certain dysfunctions, reduced type I collagen turnover, and correlation between α-SMA expression and type I collagen metabolism. Further investigations of these features will help to clarify presbyphonia's pathology and establish treatment strategies.

Level Of Evidence: NA Laryngoscope, 129:E94-E101, 2019.
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http://dx.doi.org/10.1002/lary.27464DOI Listing
March 2019

Endoscopic laryngo-pharyngeal surgery for elderly patients.

Auris Nasus Larynx 2019 Apr 8;46(2):279-284. Epub 2018 Sep 8.

Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Japan.

Objective: Due to the rising number of elderly patients and advances in endoscopic devices, early laryngeal and pharyngeal cancers are increasingly found in elderly patients. In these cases, minimally invasive endoscopic larygo-pharyngeal surgery (ELPS) may be indicated. However, the safety and efficacy of ELPS in elderly populations has not been established. The purpose of this study was to investigate the safety, outcomes and feasibility of ELPS in very elderly patients.

Methods: Between February 2010 and April 2016, 29 pharyngeal cancerous or pre-cancerous lesions in 19 patients aged 75 years or older were treated with ELPS. Twenty-six resections were performed in total, and the patients' clinical courses were reviewed.

Results: Sixteen patients had multiple comorbidities and moderate to severe comorbidities were observed in 17 patients. The average surgical time and hospitalization period was 54.3min and 18.8 days, respectively. On average, oral intake began 4.4days after the procedure, and all patients eventually received nourishment by mouth; no percutaneous endoscopic gastrostomy dependency was observed. Complications included post-operative bleeding and aspiration pneumonia in two cases each, and all complications were safely managed. The 3-year overall survival rate was 90.2% and the 3-year disease-specific survival rate was 100%.

Conclusion: ELPS was safely performed in elderly patients, suggesting that it is a feasible treatment option for pharyngeal lesions in very elderly patients.
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http://dx.doi.org/10.1016/j.anl.2018.08.008DOI Listing
April 2019

Long-term preservation of planar cell polarity in reversed tracheal epithelium.

Respir Res 2018 02 2;19(1):22. Epub 2018 Feb 2.

Department of Otolaryngology-Head & Neck Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Planar cell polarity (PCP) coordinates the patterning and orientation of cells and their structures along tissue planes, and although its acquisition during the formation of airway epithelium has been described, the mechanisms for its maintenance and reconstruction are poorly understood. We aimed to clarify whether ambient environment change by orthotropic autologous transplantation affected PCP at the cellular level.

Methods: We performed orthotropic autologous transplantation by inverting tracheal segments in rats, and then performed morphological evaluation by microscopy. The PCP of the tracheal epithelium was assessed over time by analyzing the directions of mucociliary transport and ciliary beat, the positional relationship between the basal body and basal foot, and the bias of Vang-like protein 1 (Vangl1) at 2, 4, and 6 months postoperatively.

Results: After 2 months, the directions of mucociliary transport and ciliary beat were preserved toward the lung in the inverted tracheal segments. The positional relationship between the basal body and the basal foot, and the bias of Vangl1, also indicated preservation of PCP in the inverted tracheal segments. Similar results were obtained at 6 months.

Conclusion: The PCP of ciliated epithelium was preserved in reversed trachea, even after long-term observation.
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http://dx.doi.org/10.1186/s12931-018-0726-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797350PMC
February 2018

Flexible next-generation robotic surgical system for transoral endoscopic hypopharyngectomy: A comparative preclinical study.

Head Neck 2018 Jan 11;40(1):16-23. Epub 2017 Nov 11.

Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University, Palo Alto, California.

Background: The purpose of this cadaveric study was to determine the efficacy of a flexible, next-generation robotic surgical system for transoral robotic hypopharyngectomy.

Methods: A comparative evaluation study of the flexible versus rigid robotic surgical systems for the hypopharynx was conducted using 3 cadavers. Endpoints for assessment were visualization of the hypopharynx, access to the hypopharynx, and difficulty of dissection. Hypopharyngectomy was performed on 3 other cadavers using the da Vinci Sp surgical system.

Results: Access to the apex of the pyriform sinus and the esophageal inlet was easier with the da Vinci Sp than with the da Vinci Si. Dissection with the da Vinci Sp was easier in all areas of the hypopharynx than with the da Vinci Si. Robotic hypopharyngectomy was successfully completed on all cadavers using the da Vinci Sp surgical system.

Conclusion: Preclinical testing in human cadavers suggests that flexible robotic surgery may facilitate successful transoral hypopharyngectomy.
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http://dx.doi.org/10.1002/hed.24868DOI Listing
January 2018

Regenerative Effects of Basic Fibroblast Growth Factor on Restoration of Thyroarytenoid Muscle Atrophy Caused by Recurrent Laryngeal Nerve Transection.

J Voice 2018 Nov 27;32(6):645-651. Epub 2017 Oct 27.

Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address:

Objectives: Vocal fold atrophy following unilateral vocal fold paralysis is caused by atrophy of the thyroarytenoid (TA) muscle and remains a challenge. Medialization procedures are popular treatment options; however, hoarseness often remains due to the reduction in mass or tension of the TA muscle. Therefore, in addition to medialization procedures, TA muscle reinnervation is desirable. In vivo studies have shown the potential for basic fibroblast growth factor (bFGF) to affect muscular and nerve regeneration. The present study aimed to examine the regenerative effects of bFGF on restoration of TA muscle atrophy caused by recurrent laryngeal nerve transection.

Study Design: Prospective animal experiments with controls.

Methods: TA muscle atrophy was induced by unilateral transection of the recurrent laryngeal nerve. One month after transection, different doses (200 ng, 100 ng, 10 ng) of bFGF in 50 µL were repeatedly injected into the TA muscle four times with an interval of 1 week between injections. Saline only was injected in the sham group. Larynges were harvested for histologic and immunohistochemical examination 4 weeks after the final injection.

Results: The cross-sectional TA muscle area was significantly larger in the bFGF-treated groups compared with the sham-treated groups. Immunohistochemistry indicated that bFGF significantly increases the number of neuromuscular junctions and satellite cells in the TA muscle.

Conclusions: These results suggest that local application of bFGF to the TA muscle may improve TA muscle atrophy caused by recurrent laryngeal nerve paralysis. Furthermore, bFGF may have regenerative effects on both nerves and muscles.
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http://dx.doi.org/10.1016/j.jvoice.2017.09.019DOI Listing
November 2018

Process of tight junction recovery in the injured vocal fold epithelium: Morphological and paracellular permeability analysis.

Laryngoscope 2018 04 31;128(4):E150-E156. Epub 2017 Oct 31.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives/hypothesis: The vocal fold epithelium that includes tight junction (TJ)-based barrier function protects underlying connective tissues from external insults. TJs play an important role to control paracellular permeability of not only solutes but also ions, and preserve the vocal fold homeostasis. However, the distribution of TJs and paracellular diffusion barrier across the entire vocal fold epithelium are still unknown. The aim of this study was to identify the distribution of TJs in the vocal fold epithelium and to characterize the recovery process of TJ-based paracellular diffusion barrier in a rat model of vocal fold injury.

Study Design: Animal experiments with controls.

Methods: Normal and vocal fold-injured rats were used. Larynges were harvested for immunohistochemical examination of TJ proteins. For functional analysis, a tracer permeability assay was performed using EZ-Link Sulfo-NHS-LC-Biotin.

Results: TJ proteins occludin and zonula occludens 1 signals were localized to the junctional regions of the most luminal cell layers of the vocal fold epithelium. The injured region had been recovered with epithelium at 5 days postinjury, but the paracellular diffusion barrier assays revealed that biotinylation reagents diffused into the lamina propria at 5 days postinjury, and were blocked at the epithelium at 14 and 28 days postinjury.

Conclusions: It was strongly suggested that TJs in the vocal fold epithelium exist at the junctional regions of the first layer of stratified squamous epithelium. TJ-based paracellular diffusion barrier following vocal fold injury is recovered by 14 days postinjury, and this period corresponds with the time course of structural changes in the regenerating epithelium layer.

Level Of Evidence: NA. Laryngoscope, 128:E150-E156, 2018.
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http://dx.doi.org/10.1002/lary.26959DOI Listing
April 2018

A phase I/II exploratory clinical trial for intracordal injection of recombinant hepatocyte growth factor for vocal fold scar and sulcus.

J Tissue Eng Regen Med 2018 04 25;12(4):1031-1038. Epub 2017 Dec 25.

Department of Otolaryngology, Kitano Hospital, Osaka, Japan.

Vocal fold scar and sulcus are intractable diseases with no effective established treatments. Hepatocyte growth factor (HGF) has preclinically proven to have potent antifibrotic and regenerative effects on vocal fold scar. The current Phase I/II clinical trial aims to examine the safety and effectiveness of intracordal injection of a recombinant human HGF drug for patients with vocal fold scar or sulcus. This is an open-label, dose-escalating, first-in-human clinical trial. Eighteen patients with bilateral vocal fold scar or sulcus were enrolled and divided into three groups: Step I received 1 μg of HGF per vocal fold; Step II received 3 μg of HGF; and Step III received 10 μg of HGF. Injections were administered once weekly for 4 weeks. The protocol treatment was performed starting with Step I and escalating to Step III. Patients were followed for 6 months post-treatment. Local and systemic safety aspects were examined as primary endpoints, and therapeutic effects were assessed as secondary endpoints using voice handicap index-10; maximum phonation time; vocal fold vibratory amplitude; grade, rough, breathy, asthenic, strained scale; and jitter. The results indicated no serious drug-related adverse events in either the systemic or local examinations. In whole-subject analysis, voice handicap index-10, vocal fold vibratory amplitude, and grade, rough, breathy, asthenic, strained scale were significantly improved at 6 months, whereas maximum phonation time and jitter varied. There were no significant differences in phonatory data between the step groups. In conclusion, intracordal injection of a recombinant human HGF drug was safe, feasible, and potentially effective for human patients with vocal fold scar or sulcus.
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http://dx.doi.org/10.1002/term.2603DOI Listing
April 2018

Complications After Endoscopic Laryngopharyngeal Surgery.

Laryngoscope 2018 07 10;128(7):1546-1550. Epub 2017 Oct 10.

Department of Otolaryngology-Head and Neck Surgery.

Objectives/hypothesis: Endoscopic laryngopharyngeal surgery (ELPS), a hybrid of head and neck surgery and gastrointestinal endoscopic treatment, has been attracting attention as a new therapeutic modality for superficial laryngopharyngeal cancers. Although this technique is less invasive than traditional open procedures, some complications including postoperative bleeding, subcutaneous emphysema, or aspiration pneumonia can occur after treatment. The purpose of this study was to investigate the complications associated with ELPS to better understand the indications for this procedure.

Study Design: Retrospective medical chart review.

Methods: One hundred five patients with 159 laryngeal or pharyngeal lesions were treated with ELPS between August 2009 and September 2015 at Kyoto University Hospital. In total, 147 resections were performed, and complications after the resections were reviewed.

Results: Of the 147 resections, postoperative bleeding, subcutaneous emphysema, and aspiration pneumonia were observed in 10, 17, and 10 cases, respectively. All cases with postoperative bleeding and aspiration pneumonia occurred in patients over 65 years of age. A history of taking anticoagulation/platelet medications, and macroscopic 0-IIa lesions were shown to correlate with postoperative bleeding after ELPS. Resection of lesions in the pyriform sinus was found to be associated with subcutaneous emphysema.

Conclusions: All complications after ELPS were safely managed. A history of taking anticoagulation/platelet medications and macroscopic 0-IIa lesions were identified as risk factors for postoperative bleeding, whereas resection of pyriform sinus lesions was found to be a risk factor for subcutaneous emphysema. These risk factors should be carefully considered when treating pharyngeal and laryngeal lesions by ELPS.

Level Of Evidence: 4. Laryngoscope, 128:1546-1550, 2018.
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http://dx.doi.org/10.1002/lary.26953DOI Listing
July 2018

Effects of Voice Therapy on Laryngeal Motor Units During Phonation in Chronic Superior Laryngeal Nerve Paresis Dysphonia.

J Voice 2018 Nov 28;32(6):729-733. Epub 2017 Sep 28.

Department of Otolaryngology Head & Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address:

Objectives: Injury to the superior laryngeal nerve can result in dysphonia, and in particular, loss of vocal range. It can be an especially difficult problem to address with either voice therapy or surgical intervention. Some clinicians and scientists suggest that combining vocal exercises with adjunctive neuromuscular electrical stimulation may enhance the positive effects of voice therapy for superior laryngeal nerve paresis (SLNP). However, the effects of voice therapy without neuromuscular electrical stimulation are unknown. The purpose of this retrospective study was to demonstrate the clinical effectiveness of voice therapy for rehabilitating chronic SLNP dysphonia in two subjects, using interspike interval (ISI) variability of laryngeal motor units by laryngeal electromyography (LEMG).

Methods: Both patients underwent LEMG and were diagnosed with having 70% recruitment of the cricothyroid muscle, and 70% recruitment of the cricothyroid and thyroarytenoid muscles, respectively. Both patients received voice therapy for 3 months. Grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, stroboscopic examination, aerodynamic assessment, acoustic analysis, and Voice Handicap Index-10 were performed before and after voice therapy. Mean ISI variability during steady phonation was also assessed.

Results: After voice therapy, both patients showed improvement in vocal assessments by acoustic, aerodynamic, GRBAS, and Voice Handicap Index-10 analysis. LEMG indicated shortened ISIs in both cases.

Conclusions: This study suggests that voice therapy for chronic SLNP dysphonia can be useful for improving SLNP and voice quality.
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http://dx.doi.org/10.1016/j.jvoice.2017.08.026DOI Listing
November 2018

Adipose-derived mesenchymal stromal cells prevented rat vocal fold scarring.

Laryngoscope 2018 01 20;128(1):E33-E40. Epub 2017 Sep 20.

Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Objectives/hypothesis: This study aimed to reveal the effects of adipose-derived mesenchymal stromal cells (ASCs) on prevention of vocal fold scarring by investigating how the immediate ASCs transplantation into the injured rat vocal fold affect the levels of gene transcription and translation.

Study Design: Prospective animal experiments with controls.

Methods: ASCs harvested from green fluorescent protein transgenic rat (ASCs group) or saline (sham group) were injected into the thyroarytenoid muscle of Sprague-Dawley rats immediately after stripping the vocal fold. For histological examinations, larynges were extirpated at 3, 14, and 56 days after the injection. Quantitative real-time polymerase chain reaction (PCR) analyses were performed at 3 and 14 days after the injection.

Results: Transplanted ASCs were detected only in larynges at day 3. At days 14 and 56, histological examination showed significantly higher amounts of hyaluronic acid and lower deposition of collagen in the ASCs group compared to the sham group. Real-time PCR revealed that the ASCs group showed low expression of procollagen (Col)1a1, Col1a3, matrix metalloproteinase (Mmp)1 and Mmp8 in each time points. The ASCs group showed high expression of fibroblast growth factor (Fgf)2 and Hepatocyte growth factor (Hgf) compared to the sham group at day 14.

Conclusions: ASCs increased expressions of Fgf2 and Hgf, and suppressed excessive collagen deposition during vocal fold wound healing. Given the fact that ASCs survived no more than 14 days, ASCs were thought to induce upregulations of growth factors' genes in surrounding cells. These results suggested that ASCs have potential to prevent vocal fold scarring.

Level Of Evidence: NA. Laryngoscope, 128:E33-E40, 2018.
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http://dx.doi.org/10.1002/lary.26855DOI Listing
January 2018

Successful recovery from a subclavicular ulcer caused by lenvatinib for thyroid cancer: a case report.

World J Surg Oncol 2017 Jan 14;15(1):24. Epub 2017 Jan 14.

Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: There are currently no effective therapeutic methods for locally recurrent, metastatic, or progressive radioactive iodine (RAI)-refractory differentiated thyroid cancer. However, multitargeted tyrosine kinase inhibitors (TKIs) such as lenvatinib or sorafenib have been approved for patients with RAI-refractory differentiated thyroid cancer as a second targeted therapy, and these agents can prolong patient survival. However, several cases have been reported that TKIs have caused fatal complications such as fistula formation or bleeding.

Case Presentation: We report a case of a 53-year-old woman, who underwent repeated neck dissections and RAI therapy after total thyroidectomy in an outside hospital. Pathology revealed a papillary carcinoma of the tall cell variant. Locoregional recurrence was not under control; therefore, she visited our hospital. Although surgery was performed for locoregional recurrences three times in our hospital, they were not under control and distant metastases were found in the lung and bone a year later. Therefore, although sorafenib was initiated, the locoregional recurrence progressed 6 months later and computed tomography (CT) showed a 7-cm mass in the right subclavicular lesion. Lenvatinib was started at a dose of 24 mg daily. However, although tumor was rapidly reduced, an ulcer occurred in the right subclavicular lesion and was gradually increasing in size. The pulsation of subclavicular artery was found in the deep portion of the ulcer. Therefore, a pectoralis major myocutaneous flap was transplanted to cover the ulcer. Lenvatinib was an antiangiogetic TKI; therefore, it was preoperatively discontinued for 8 days and postoperatively for 12 days. The postoperative course was uneventful.

Conclusions: Fistula formation or bleeding is known to be a severe side effect of antiangiogenic TKIs such as lenvatinib or sorafenib. There is a possibility that severe complications can occur when initiating TKIs in patients whose tumor has invaded into the skin, vessels, trachea, esophagus, and other areas. Therefore, it is necessary to use antiangiogenic TKIs very carefully. It is important to determine the appropriate time to start TKIs; however, there is no established protocol for this, and it is a problem that needs urgent attention.
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http://dx.doi.org/10.1186/s12957-017-1096-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237504PMC
January 2017

High- and ultrahigh-field magnetic resonance imaging of naïve, injured and scarred vocal fold mucosae in rats.

Dis Model Mech 2016 11 16;9(11):1397-1403. Epub 2016 Sep 16.

Department of Surgery, Division of Otolaryngology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA

Subepithelial changes to the vocal fold mucosa, such as fibrosis, are difficult to identify using visual assessment of the tissue surface. Moreover, without suspicion of neoplasm, mucosal biopsy is not a viable clinical option, as it carries its own risk of iatrogenic injury and scar formation. Given these challenges, we assessed the ability of high- (4.7 T) and ultrahigh-field (9.4 T) magnetic resonance imaging to resolve key vocal fold subepithelial tissue structures in the rat, an important and widely used preclinical model in vocal fold biology. We conducted serial in vivo and ex vivo imaging, evaluated an array of acquisition sequences and contrast agents, and successfully resolved key anatomic features of naïve, acutely injured, and chronically scarred vocal fold mucosae on the ex vivo scans. Naïve lamina propria was hyperintense on T1-weighted imaging with gadobenate dimeglumine contrast enhancement, whereas chronic scar was characterized by reduced lamina propria T1 signal intensity and mucosal volume. Acutely injured mucosa was hypointense on T2-weighted imaging; lesion volume steadily increased, peaked at 5 days post-injury, and then decreased - consistent with the physiology of acute, followed by subacute, hemorrhage and associated changes in the magnetic state of hemoglobin and its degradation products. Intravenous administration of superparamagnetic iron oxide conferred no T2 contrast enhancement during the acute injury period. These findings confirm that magnetic resonance imaging can resolve anatomic substructures within naïve vocal fold mucosa, qualitative and quantitative features of acute injury, and the presence of chronic scar.
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http://dx.doi.org/10.1242/dmm.026526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117232PMC
November 2016

Optimal Duration for Voice Rest After Vocal Fold Surgery: Randomized Controlled Clinical Study.

J Voice 2017 Jan 1;31(1):97-103. Epub 2016 Aug 1.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address:

Objectives: Voice rest is commonly recommended after phonomicrosurgery to prevent worsening of vocal fold injuries. However, the most effective duration of voice rest is unknown. Recently, early vocal stimulation was recommended as a means to improve wound healing. The purpose of this study is to examine the optimal duration of voice rest after phonomicrosurgery.

Study Design: Randomized controlled clinical study.

Methods: Patients undergoing phonomicrosurgery for leukoplakia, carcinoma in situ, vocal fold polyp, Reinke's edema, and cyst were chosen. Participants were randomly assigned to voice rest for 3 or 7 postoperative days. Voice therapy was administered to both groups after voice rest. Grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, stroboscopic examination, aerodynamic assessment, acoustic analysis, and Voice Handicap Index-10 (VHI-10) were performed pre- and postoperatively at 1, 3, and 6 months. Stroboscopic examination evaluated normalized mucosal wave amplitude (NMWA). Parameters were compared between both groups.

Results: Thirty-one patients were analyzed (3-day group, n = 16; 7-day group, n = 15). Jitter, shimmer, and VHI-10 were significantly better in the 3-day group at 1 month post operation. GRBAS was significantly better in the 3-day group at 1 and 3 months post operation, and NMWA was significantly better in the 3-day group at 1, 3, and 6 months post operation compared to the 7-day group.

Conclusions: The data suggest that 3 days of voice rest followed by voice therapy may lead to better wound healing of the vocal fold compared to 7 days of voice rest. Appropriate mechanical stimulation during early stages of vocal fold wound healing may lead to favorable functional recovery.
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http://dx.doi.org/10.1016/j.jvoice.2016.02.009DOI Listing
January 2017
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