Healthcare service use and medical outcomes of tracheostomy-dependent children: a nationwide study.

BACKGROUND: Despite the rising trend of tracheostomies in children, there is a lack of comprehensive resources for families to navigate the challenges of living with a tracheostomy, emphasising the need for evidence-based support in understanding postoperative care and long-term adjustments. This study aimed to examine the pattern of using healthcare services and nationwide medical outcomes in children who underwent a tracheotomy before the age of 2 years. METHODS: This retrospective study used the National Health Insurance System database from 2008 to 2016 and included all children codified with tracheotomy procedure codes before their second birthday. Healthcare utilisation, such as medical costs, number of hospital visits, home healthcare nursing and medical diagnoses on readmission, in the first 2 years after tracheotomy was evaluated. Multivariable logistic regression analysis was used to determine the factors affecting mortality. RESULTS: In total, 813 patients were included in this study. Their use of healthcare services and the accompanying expenses were higher than the national medians for similar age groups; however, both metrics decreased in the second year. The major causes of admission within 2 years of surgery were respiratory and neurological diseases. The mortality rate within 2 years was 37.8%. Higher risks of mortality were associated with having two or more complex chronic conditions. Use of home healthcare nursing services was associated with a lower mortality risk. CONCLUSION: Paediatric patients with more complex chronic conditions tended to have higher mortality rates within 2 years after surgery. However, receiving home healthcare nursing was significantly associated with a reduced risk of death. Many causes of hospitalisation may be preventable with education and supportive care. Therefore, further research for establishing an integrated care system for these patients and their caregivers is required.

The Clinical Features and Risk Factors of Subglottic Cysts in Children: A Clinical Experience Using the Spontaneous Respiration Technique.

OBJECTIVES: Subglottic cysts (SGCs) are a rare cause of respiratory distress resulting from upper airway obstruction in infants and young children. Risk factors other than prematurity with a history of endotracheal intubation have not yet been well elucidated. Therefore, we aimed to describe the clinical features and analyze the risk factors of SGCs. METHODS: We conducted a retrospective review of medical records of pediatric patients who underwent marsupialization for SGCs between January 2017 and March 2022. These records were then compared with those of controls with a history of neonatal intubation, with a case-to-control ratio of 1:3. RESULTS: Eleven patients (eight boys and three girls) diagnosed with SGCs and 33 control patients (26 boys and seven girls) were included. All patients had a history of premature birth and neonatal intubation. Symptoms of SGCs appeared at a mean age of 8.2 months (range, 1-14 months) after extubation. The mean duration of intubation was 21.5 days (range, 2-90 days), and the intubation period was longer in patients with SGCs than in controls (21.5±24.8 days vs. 5.3±7.1 days; P<0.001). Furthermore, gestational age (28.3±4.2 weeks vs. 33.8±4.4 weeks; P=0.001) and birth weight (1,134.1±515.1 g vs. 2,178.2±910.1 g; P=0.001) were significantly lower in patients with SGCs than in controls. Multivariable analysis identified the intubation period as an independent risk factor. CONCLUSION: This study showed that gestational age, birth weight, and the intubation period were significantly associated with the development of SGCs. Pediatric patients presenting with progressive dyspnea who have the corresponding risk factors should undergo early laryngoscopy for the differential diagnosis of SGC.

Assessment of Esophageal Reconstruction via Bioreactor Cultivation of a Synthetic Scaffold in a Canine Model.

OBJECTIVES: Using tissue-engineered materials for esophageal reconstruction is a technically challenging task in animals that requires bioreactor training to enhance cellular reactivity. There have been many attempts at esophageal tissue engineering, but the success rate has been limited due to difficulty in initial epithelialization in the special environment of peristalsis. The purpose of this study was to evaluate the potential of an artificial esophagus that can enhance the regeneration of esophageal mucosa and muscle through the optimal combination of a double-layered polymeric scaffold and a custom-designed mesenchymal stem cell-based bioreactor system in a canine model. METHODS: We fabricated a novel double-layered scaffold as a tissue-engineered esophagus using an electrospinning technique. Prior to transplantation, human-derived mesenchymal stem cells were seeded into the lumen of the scaffold, and bioreactor cultivation was performed to enhance cellular reactivity. After 3 days of cultivation using the bioreactor system, tissue-engineered artificial esophagus was transplanted into a partial esophageal defect (5×3 cm-long resection) in a canine model. RESULTS: Scanning electron microscopy (SEM) showed that the electrospun fibers in a tubular scaffold were randomly and circumferentially located toward the inner and outer surfaces. Complete recovery of the esophageal mucosa was confirmed by endoscopic analysis and SEM. Esophagogastroduodenoscopy and computed tomography also showed that there were no signs of leakage or stricture and that there was a normal lumen with complete epithelialization. Significant regeneration of the mucosal layer was observed by keratin-5 immunostaining. Alpha-smooth muscle actin immunostaining showed significantly greater esophageal muscle regeneration at 12 months than at 6 months. CONCLUSION: Custom-designed bioreactor cultured electrospun polyurethane scaffolds can be a promising approach for esophageal tissue engineering.

Tongue Reduction Surgery Improves Mandibular Prognathism in Beckwith-Wiedemann Syndrome Without Compromising Tongue Function.

OBJECTIVES: This study evaluated the surgical outcomes of patients with Beckwith-Wiedemann syndrome who underwent tongue-reduction surgery and analyzed whether the malocclusion and mandibular prognathism caused by macroglossia could be improved. METHODS: A retrospective medical record review was performed for 11 patients with Beckwith-Wiedemann syndrome whose macroglossia was surgically treated. Demographic data, symptoms and signs, and intraoperative and postoperative surgical outcomes were evaluated. Surgery was performed by a single surgeon using the "keyhole" technique, involving midline elliptical excision and anterior wedge resection. Preoperative and postoperative plain skull lateral X-rays were evaluated to assess prognathism improvement. RESULTS: The median age at the time of surgery was 35.09 months, and the ratio of males to females was 4:7. The median surgical time was 98±31.45 minutes, and the median duration of the postoperative intensive care unit stay was 3.81±2.4 days. There were no airway complications. Two patients (18.2%) had postoperative wound dehiscence; however, there was no nerve damage, recurrence, or other complications. Among the five patients who underwent postoperative speech evaluation, all showed normal speech development, except one patient who had brain dysfunction and developmental delay. Measurements of the A point-nasion-B point (ANB) angles and sella-nasion-B point (SNB) angles (point A is the most concave point of the anterior maxilla; point B is the most concave point on the mandibular symphysis) on plain X-rays showed a significant decrease in the postoperative SNB angle (P <0.001) and a significant increase in the ANB angle (P <0.011). CONCLUSION: Tongue-reduction surgery is an effective and safe technique for severe forms of macroglossia associated with Beckwith-Wiedemann syndrome. In addition, it improves mandibular prognathism in young Beckwith-Wiedemann syndrome patients with macroglossia.

The Expression of Defensin-Associated Genes May Be Correlated With Lymph Node Metastasis of Early-Stage Tongue Cancer.

OBJECTIVES: We aimed to assess the genetic differences between cases of early-stage tongue cancer that were positive or negative for lymph node metastasis. METHODS: In total, 35 cases of tongue cancer with RNA sequencing data were enrolled in this study. The gene expression profile of the following two groups was compared: N0 group (T stage 1 or 2 with N0 stage) and N+ group (T stage 1 or 2 with N+ stage). Using the R and limma packages in the Bioconductor program, we extracted the differentially expressed genes (DEGs). Gene ontology and pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integration Discovery (DAVID) online tool. Immune cell infiltration was analyzed using the CIBERSORT online program. Immunochemical staining of the cancer tissue was evaluated and The Cancer Genome Atlas (TCGA) data were analyzed to validate the identified DEGs. RESULTS: No significant differences were found in the infiltration of 22 types of immune cells. Among a total of 51 identified DEGs, 14 genes were significantly upregulated, while 37 genes were significantly downregulated (P<0.01; fold change >2). Pathway analysis revealed significant associations with the arachidonic acid metabolism-related pathway, calcium signaling, and the muscle contraction pathway. The following DEGs were the most significantly different between the two groups: DEFB4A, SPRR2B, DEFB103B, SPRR2G, DEFB4B, and FAM25A. TCGA data showed that DEFB4A and DEFB103B were more highly expressed in the N0 group than in the N+ group, although the difference did not achieve statistical significance. Immunochemical staining of cancer tissue revealed significantly higher expression of defensin in the N0 group. CONCLUSION: . Defensin (DEFB4A, DEFB103B, DEFB4B) may be a novel biomarker for early regional metastasis in T1/2 tongue cancer.

Use of high-flow nasal oxygen in spontaneously breathing pediatric patients undergoing tubeless airway surgery: A prospective observational study.

The use of high-flow nasal oxygen is gaining popularity in apneic and spontaneously breathing adult patients during anesthesia. This prospective observational study evaluated the effect of high-flow nasal oxygen in maintaining adequate oxygenation and ventilation in spontaneously breathing pediatric patients with dynamic airway obstruction, undergoing tubeless airway surgery. Oxygenation was provided via an age-appropriate, high-flow nasal cannula at a flow rate of 2 L kg-1 min-1. Propofol and remifentanil were used to maintain anesthesia while preserving spontaneous respiration. We sought to determine the incidence and risk factors of rescue ventilation. Rescue ventilation with a face mask was performed when the pulse oximetry oxygen saturation was <90% or transcutaneous carbon dioxide was >80 mm Hg. In total, 27 patients were included in the final analysis. Median (interquartile range) of pulse oximetry and transcutaneous carbon dioxide were 100% (99%-100%) and 58.4 mm Hg (51.4-70.3 mm Hg), respectively. Altogether, 9 (33.3%) patients needed rescue ventilation during anesthesia. Of these, 7 patients (25.9%) developed oxygen desaturation (<90%) and 2 patients (7.4%) developed hypercarbia. Patients who required rescue ventilation were significantly younger (8.2 vs 28.8 months, P = .02) and required a longer anesthesia time (55.7 vs 41.0 minutes, P = .04) than those who did not. In conclusion, High-flow nasal oxygen is an alternative technique to maintain oxygenation in children undergoing airway surgeries. However, younger age and longer anesthesia time are significant risk factors leading to the requirement of rescue ventilation in these patients. Further studies with large sample size are required for clinical application of these techniques.

Hypofractionated radiotherapy for early stage glottic cancer: efficacy of 3.5 Gy per fraction.

PURPOSE: The purpose of this study was to evaluate the treatment outcomes and toxicity profile of patients with early glottic cancer who underwent hypofractionated radiation therapy (RT) with 3.5 Gy per fraction. MATERIALS AND METHODS: A retrospective review was performed of the medical records of 35 patients with early stage (T1-2N0M0) glottic cancer who underwent definitive RT. The dose fractionation scheme was 59.5 Gy in 17 fractions. Posterior commissure was excluded from the clinical target volume (CTV) for 26 patients (74.3%) without glottic lesions close to this region. RESULTS: With a median follow-up of 16.23 months (range, 6.82 to 67.15 months), no local, regional, or distant recurrence was reported. Acute hoarseness (65.7%), mucositis (68.6%), radiation dermatitis (60.0%) was frequent. One patient (2.9%) reported grade 3 acute toxicity (mucositis) and there was no grade 4-5 acute toxicity. There was no grade ≥3 late toxicities; however, grade 1 late intermittent hoarseness was frequent (45.7%). The receiver operative characteristic analysis revealed that mean hypopharyngeal dose was predictive for acute grade ≥2 mucositis (area under the curve=0.9314; 95% confidence interval, 0.8524-1). The optimal threshold of mean hypopharyngeal dose for occurrence of acute grade ≥2 mucositis was 26.31 Gy, with a specificity and sensitivity of 83.3% and 88.2%, respectively. CONCLUSION: Hypofractionated RT with fraction size of 3.5 Gy for early glottic cancer is effective. The hypopharyngeal mean dose could predict the occurrence of grade ≥2 acute mucositis. The posterior commissure can be safely excluded from the CTV.

Primary versus modified secondary closure techniques for persistent tracheocutaneous fistula in pediatric patients.

PURPOSE: This study aimed at compating two closure techniques for tracheocutaneous fistulas (TCFs) in pediatric patients. METHODS: A total of 106 consecutive pediatric patients who underwent closure of a persistent TCF between April 2007 and February 2021 at a tertiary pediatric hospital were evaluated, and 103 pediatric patients aged between 12 months and 18 years were included. The clinical characteristics, perioperative outcomes, and postoperative outcomes were compared between TCF closure by primary closure (Group 1) and a modified secondary healing technique (Group 2). RESULTS: Of the 103 patients, 58 were classified into Group 1, and 45 into Group 2. The mean age at tracheostomy and TCF closure was significantly younger in Group 2, and the interval between decannulation to TCF closure was significantly shorter in Group 2. Procedural time and hospital stay were significantly shorter in Group 2 than Group 1. Group 2 had a significantly lower complication rate, need for revision surgery, and recannulation rate than Group 1. CONCLUSIONS: Modified secondary healing was more efficient in terms of procedural time and hospital stay, and safer (i.e., fewer complications). It is an effective surgical technique for closing a persistent TCF in younger patients more quickly after decannulation compared to primary closure.

Application and Efficiency of Transnasal Humidified Rapid-Insufflation Ventilatory Exchange in Laryngeal Microsurgery.

OBJECTIVES/HYPOTHESIS: This study aimed to analyze the feasibility of transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) during laryngeal microsurgery (LMS) and investigated its efficiency and application according to the location of the lesion. STUDY DESIGN: Retrospective chart review. METHODS: Patients over 20 years of age who underwent LMS without underlying cardiac, pulmonary, or cerebrovascular disease were retrospectively reviewed. Overall, 54 patients with endotracheal intubation (ETI) and 44 patients with THRIVE were included. The operation and anesthesia time, induction and emergence time, oxygen saturation (SpO2 ), and transcutaneous carbon dioxide (TcCO2 ) levels were analyzed and compared between the two ventilation methods according to disease subsite. RESULTS: Compared with ETI, patients with THRIVE presented reduced operation time (16.3 ± 9.69 min vs. 21.9 ± 12.0 min), anesthesia time (33.6 ± 11.4 min vs. 45.4 ± 13.9 min), emergence time (6.73 ± 2.49 min vs. 8.52 ± 3.17 min), without significant decreases in SpO2 but with increased TcCO2 (10.9 ± 6.12% vs. 7.33 ± 3.86%). Comparing THRIVE to ETI for lesions at the glottis yielded similar findings, which were particularly more significant. However, lesions above the glottis presented no significant difference for any parameters between THRIVE and ETI groups. Lesions involving multiple subsites and prolonged operation time were risk factors for the intraoperative conversion of ventilation method. CONCLUSION: THRIVE is reliable for maintaining oxygenation during LMS and is efficient in reducing the operation and emergence times, leading to shorter anesthesia time, especially for lesions at the glottis. However, caution is required administering THRIVE, when lesion involves multiple subsites, and when operation time is prolonged. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1061-1068, 2022.

Effects of percutaneous injection laryngoplasty on voice and swallowing problems in cancer-related unilateral vocal cord paralysis.

BACKGROUND: Unilateral vocal cord paralysis may result from nerve compression by tumors or direct nerve injuries during tumor resections, which can cause dysphonia or dysphagia, and reduced quality of life. OBJECTIVES: This prospective, single-group study aimed to investigate the effect of percutaneous injection laryngoplasty on voice and swallowing function in patients with cancer-related unilateral vocal cord paralysis. METHODS: Patients underwent percutaneous injection laryngoplasty with hyaluronic acid under local anesthesia. Stroboscopy and videofluoroscopic swallowing study were conducted to evaluate the voice- and swallowing-related outcome measures, respectively. The participants were evaluated before injection laryngoplasty, as well as after two weeks and three months. RESULTS: Injection laryngoplasty significantly improved the glottal gap, vocal fold position, Maximum Phonation Time, and Voice Handicap Index-10. Post-hoc analysis using Bonferroni correction showed that the improvements occurred within two post-treatment weeks and remained at three post-treatment months. In the subgroup analysis, the patients who underwent injection laryngoplasty within 8 weeks from onset showed significantly higher improvements in the videofluoroscopic dysphagia scale and swallowing function than the patients who received the procedure after 8 weeks or more. CONCLUSION: Percutaneous injection laryngoplasty improves glottal closure and voice in patients with cancer-related unilateral vocal cord paralysis. Early injection laryngoplasty may lead to greater benefits on swallowing function. LEVEL OF EVIDENCE: 4.

Hyaluronic Acid Coating on Hydrophobic Tracheal Scaffold Enhances Mesenchymal Stem Cell Adhesion and Tracheal Regeneration.

BACKGROUND: Long segmental tracheal repair is challenging in regenerative medicine due to low adhesion of stem cells to tracheal scaffolds. Optimal transplantation of stem cells for tracheal defects has not been established. We evaluated the role of hyaluronic acid (HA) coating of tracheal scaffolds in mesenchymal stem cell (MSC) adhesion and tracheal regeneration in a rabbit model. METHODS: A three-dimensionally printed tubular tracheal prosthesis was incubated with dopa-HA-fluorescein isothiocyanate in phosphate-buffered saline for 2 days. MSCs were incubated with an HA-coated scaffold, and their adhesion was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. HA coated scaffolds with or without MSC seeding were transplanted at the circumferential tracheal defect in rabbits, and survival, rigid bronchoscopy, radiologic findings, and histologic findings were compared between the two groups. RESULTS: HA-coated scaffolds showed better MSC adhesion than non-coated scaffolds. The HA-coated scaffolds with MSC group showed a wider airway and greater mucosal regeneration compared to the HA-coated scaffolds without MSC group. CONCLUSION: HA coating of scaffolds can promote MSC adhesion and tracheal regeneration.

Role of concurrent chemoradiation on locally advanced unresectable adenoid cystic carcinoma.

BACKGROUND/AIMS: Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor characterized by indolence, with a high rate of local recurrence and distant metastasis. This study aimed to investigate the effect of concurrent chemoradiation (CCRT) on locally advanced unresectable ACC. METHODS: We retrospectively analyzed clinical data from 10 patients with pathologically confirmed ACC of the head and neck who received CCRT with cisplatin in Seoul National University Hospital between 2013 and 2018. RESULTS: Ten patients with unresectable disease at the time of diagnosis or with positive margins after surgical resection received CCRT with weekly cisplatin. Eight patients (80%) achieved complete remission, of which three later developed distant metastases without local relapse; one patient developed distant metastasis and local relapse. Two patient achieved partial remission without progression. Patients experienced several toxicities, including dry mouth, radiation dermatitis, nausea, and salivary gland inflammation of mostly grade 1 to 2. Only one patient showed grade 3 oral mucositis. Median relapse-free survival was 34.5 months (95% confidence interval, 22.8 months to not reached). CONCLUSION: CCRT with cisplatin is effective for local control of ACC with manageable toxicity and may be an effective treatment option for locally advanced unresectable ACC.

Pediatric airway surgery under spontaneous respiration using high-flow nasal oxygen.

OBJECTIVES: In pediatric airway surgery, SponTaneous Respiration using IntraVEnous anesthesia and Hi-flow nasal oxygen (STRIVE Hi) has not been well explored. Here, we report our experience of using STRIVE Hi in endoscopic evaluations and surgeries of the pediatric airway. METHODS: This retrospective review was based on 45 airway procedures conducted under STRIVE Hi, performed by a single surgeon at a single institute from May 2017 to September 2018. After induction of anesthesia, continuous infusion with propofol and remifentanil was provided to ensure an adequate level of anesthesia and supply of humidified oxygen via a nasal cannula. Monitoring was conducted using a transcutaneous CO2 sensor and a pulse oximeter, and the oxygen reserve and bispectral indexes were measured. No muscle relaxant was administered. RESULTS: The median age of the patients was 16.0 months (range: 1-215 months) and the median weight was 10.2 kg (range: 2.4-38.5 kg). The median duration of spontaneous respiration was min 40 (range: 10-140 min). The airway procedures included diagnostic microlaryngoscopy, tracheocutaneous fistula excision, balloon dilation, supraglottoplasty, laryngeal cleft repair, injection laryngoplasty, papilloma excision, and subglottic cyst removal. During these procedures, STRIVE Hi facilitated evaluation of dynamic obstruction of the airway and the immediate outcome of surgical treatment and provided a good surgical view. Intubation and the termination of spontaneous respiration were required in only five patients. CONCLUSIONS: STRIVE Hi is an effective and feasible anesthesia option in pediatric airway surgery. It provides unobstructed surgical access and is applicable to a wide range of procedures.

Transplantation of a 3D-printed tracheal graft combined with iPS cell-derived MSCs and chondrocytes.

For successful tracheal reconstruction, tissue-engineered artificial trachea should meet several requirements, such as biocompatible constructs comparable to natural trachea, coverage with ciliated respiratory mucosa, and adequate cartilage remodeling to support a cylindrical structure. Here, we designed an artificial trachea with mechanical properties similar to the native trachea that can enhance the regeneration of tracheal mucosa and cartilage through the optimal combination of a two-layered tubular scaffold and human induced pluripotent stem cell (iPSC)-derived cells. The framework of the artificial trachea was fabricated with electrospun polycaprolactone (PCL) nanofibers (inner) and 3D-printed PCL microfibers (outer). Also, human bronchial epithelial cells (hBECs), iPSC-derived mesenchymal stem cells (iPSC-MSCs), and iPSC-derived chondrocytes (iPSC-Chds) were used to maximize the regeneration of tracheal mucosa and cartilage in vivo. After 2 days of cultivation using a bioreactor system, tissue-engineered artificial tracheas were transplanted into a segmental trachea defect (1.5-cm length) rabbit model. Endoscopy did not reveal granulation ingrowth into tracheal lumen. Alcian blue staining clearly showed the formation of ciliated columnar epithelium in iPSC-MSC groups. In addition, micro-CT analysis showed that iPSC-Chd groups were effective in forming neocartilage at defect sites. Therefore, this study describes a promising approach for long-term functional reconstruction of a segmental tracheal defect.

Severe late dysphagia after multimodal treatment of stage III/IV laryngeal and hypopharyngeal cancer.

BACKGROUND: Long-term side effects after radiotherapy for organ preservation 'could deteriorate' the laryngeal function. This study intended to identify the incidence of severe late dysphagia following the multimodal treatment for stage III/IV laryngeal and hypopharyngeal cancer 'to evaluate the function of larynx'. METHODS: The medical records of patients successfully treated for laryngeal and hypopharyngeal cancer with a multimodal approach, including radiotherapy, were retrospectively analyzed. 'Functional larynx was defined as tolerable oral diet without severe late dysphagia or tracheostoma'. RESULTS: The study included 99 patients with a median follow-up period of 72 months. 'Tracheostomy during the follow-up period was required in only one patient due to aspiration pneumonia, and dysphagia is the main determinant for functional larynx'. The probability of maintaining functional larynx was 63% for 10 years, when the treatment was started with radiotherapy or concurrent chemoradiotherapy. In upfront surgery (operation first and adjuvant radiotherapy/concurrent chemoradiotherapy) group, 37% of patients required total laryngectomy as primary treatment and 43% of patients could maintain laryngeal function for 10 years. And severe late dysphagia in the latter group developed mainly after laryngeal preservation surgery. The patients aged ≥65 years showed significantly higher incidence of dysphagia. Severe late dysphagia was very rare in laryngeal cancer successfully cured with radiotherapy/concurrent chemoradiotherapy (1/25, 4%); however, it gradually increased over time in hypopharyngeal cancer patients showing a statistically significant difference from laryngeal cancer patients (P = 0.040). CONCLUSION: Severe late dysphagia occurred in 19.2% of patients treated for laryngeal and hypopharyngeal cancers, regardless of whether treatment started with radiotherapy/concurrent chemoradiotherapy or surgery.

Dysregulation of ectonucleotidase-mediated extracellular adenosine during postmenopausal bone loss.

Adenosine and its receptors play a key role in bone homeostasis and regeneration. Extracellular adenosine is generated from CD39 and CD73 activity in the cell membrane, through conversion of adenosine triphosphate to adenosine monophosphate (AMP) and AMP to adenosine, respectively. Despite the relevance of CD39/CD73 to bone health, the roles of these enzymes in bona fide skeletal disorders remain unknown. We demonstrate that CD39/CD73 expression and extracellular adenosine levels in the bone marrow are substantially decreased in animals with osteoporotic bone loss. Knockdown of estrogen receptors ESR1 and ESR2 in primary osteoprogenitors and osteoclasts undergoing differentiation showed decreased coexpression of membrane-bound CD39 and CD73 and lower extracellular adenosine. Targeting the adenosine A2B receptor using an agonist attenuated bone loss in ovariectomized mice. Together, these findings suggest a pathological association of purine metabolism with estrogen deficiency and highlight the potential of A2B receptor as a target to treat osteoporosis.

Lung metastasis in adenoid cystic carcinoma of the head and neck.

BACKGROUND: Distant metastasis of adenoid cystic carcinoma (ACC) is most commonly identified in the lung, but risk factors are still on debate. METHODS: Risk factors for lung metastasis were evaluated by using Cox proportional hazards model and Kaplan-Meier curves. RESULTS: Of 112 patients, 48% had distant metastasis; 94.4% of whom had lung metastasis. Univariable analysis revealed sublingual or minor salivary gland, tumor size ≥2.5 cm, and perineural invasion as risk factors (hazard ratio [HR]: 1.99 [1.02-3.91], 2.57 [1.19-5.58], and 2.46 [1.28-4.74], respectively), whereas size, perineural invasion, and local recurrence were risk factors in multivariable analysis (HR: 2.29 [1.05-4.96], 2.32 [1.09-4.96], and 2.68 [1.24-5.79], respectively). CONCLUSION: Sublingual gland or minor salivary glands ACC has a higher risk of lung metastasis. If the site is not considered, the following factors increased the risk of lung metastasis; (a) size ≥2.5 cm, (b) perineural invasion, and (c) local recurrence.

Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients.

The purpose of this study was to evaluate the prognostic impact of major histocompatibility complex (MHC) class I expression and programmed death-ligand 1 (PD-L1) expression in patients with head and neck squamous cell carcinoma (HNSCC). A total of 158 patients with HNSCC were evaluated retrospectively. The expression of MHC class I and PD-L1 was analyzed in tumor specimens using immunohistochemistry. The association between MHC class I/PD-L1 expression and clinical outcome was evaluated by Kaplan-Meier and Cox regression analyses. Among 158 patients, 103 (65.2%) showed positive PD-L1 expression, and 20 (12.7%) showed no detectable expression of MHC class I. The frequency of PD-L1 positive expression with concomitant MHC class I loss was 7.0%. In the PD-L1-positive group, MHC class I loss was associated with a significantly worse survival compared with MHC class I positivity (median overall survival 39.3 months vs. not reached; P = 0.005), whereas MHC class I status provided no prognostic impact in the PD-L1 negative group. Neither PD-L1 nor MHC class I alone showed a significant difference in overall survival. The loss of MHC class I expression in PD-L1-positive HNSCC was associated with a poor clinical outcome. This suggested that MHC class I expression status might be useful for the prognosis of tumor progression in HNSCC when combined with PD-L1 expression status. External validation with enough numbers of participants in such subgroup should be needed for validation.

Early Closure of a Phase 1 Clinical Trial for SABR in Early-Stage Glottic Cancer.

PURPOSE: The early results of a phase 1 study of stereotactic ablative radiation therapy for early-stage glottis cancer were previously reported. However, additional late adverse events occurred in the second arm during the follow-up period. In this study, the dose-limiting toxicities and premature closure of the clinical trial are reported. METHODS AND MATERIALS: Thirteen patients with cT1-2N0M0 squamous cell carcinoma of the glottis were enrolled between May 2015 and July 2018. Seven patients in the first arm received 59.5 Gy to the gross tumor volume and 47.6 Gy to the remaining larynx, delivered in 17 fractions. The second arm dose was 55 Gy and 40.7 Gy in 11 fractions to the gross tumor volume and the remaining larynx, respectively. Patients were treated according to the simultaneous integrated boost approach with volumetric modulated arc therapy. RESULTS: The median follow-up was 37 months (range, 6-41.4) for the first arm and 14.5 months (range, 4.8-21.5) for the second arm. Maximum acute toxicity was grade 2 laryngeal mucositis for each arm. Maximum chronic toxicity was grade 3 laryngeal inflammation, occurring in 2 patients (33.3%) in the second arm. One patient underwent a laryngomicrosurgical biopsy for a vocal cord ulcer, and another patient underwent supraglottic laryngectomy because of arytenoid cartilage necrosis. In the first arm, chronic toxicity was not observed, except for grade 1 laryngeal edema in 1 patient. CONCLUSIONS: The phase 1 dose escalation study was terminated early because of the unexpected dose-limiting toxicities occurring in patients in the second arm. It was concluded that stereotactic ablative radiation therapy is not feasible for early-stage glottic cancer owing to treatment-related toxicity.

Injectable basic fibroblast growth factor-loaded alginate/hyaluronic acid hydrogel for rejuvenation of geriatric larynx.

Increase in the geriatric population has led to an increase in the number of elderly patients with laryngeal atrophy and dysfunction. Symptoms of voice change, dysphagia, and aspiration pneumonia negatively influence patient's health status, quality of life, and life span. Injection laryngoplasty used to treat laryngeal dysfunctions does not recover intrinsic functions of the larynx. Thus, we fabricated an injectable basic fibroblast growth factor (bFGF)-loaded alginate (ALG)/hyaluronic acid (HA) hydrogel for inducing rejuvenation of geriatric laryngeal muscles. Optimal in situ-forming bFGF-loaded ALG/HA hydrogel for injection laryngoplasty was prepared and the release profile of bFGF was analyzed. For in vivo analysis, the bFGF-loaded ALG/HA hydrogel was injected into the laryngeal muscles of 18-month-old Sprague-Dawley rats. The rejuvenation efficacy of bFGF-loaded ALG/HA hydrogel in geriatric laryngeal muscle tissues 4- and 12-weeks post-injection was evaluated by quantitative polymerase chain reaction (qPCR), histology, immune-fluorescence staining and functionality analysis. The bFGF-loaded ALG/HA hydrogel induced an increase in the expression of myogenic regulatory factor-related genes, hypertrophy of muscle fiber, proliferation of muscle satellite cells, and angiogenesis and decreased interstitial fibrosis. Administration of the bFGF-loaded ALG/HA hydrogel caused successful glottal gap closure. Thus, the bFGF-loaded ALG/HA hydrogel could be a promising candidate for laryngoplasty aimed at rejuvenating geriatric larynx. STATEMENT OF SIGNIFICANCE: In this manuscript, optimal in situ-forming bFGF-loaded ALG/HA hydrogel for injection laryngoplasty was prepared and the release profile of bFGF was analyzed. Herein, we introduced the materials and methods of injection laryngoplasty for geriatric rat experiment. In addition, we studied effects of bFGF-loaded ALG/HA hydrogel on the therapeutic rejuvenation of geriatric rat larynx. The bFGF-loaded ALG/HA hydrogel induced an increase in the expression of myogenic regulatory factor-related genes, hypertrophy of muscle fiber, proliferation of muscle satellite cells, and angiogenesis and decreased interstitial fibrosis. Furthermore, our functional analysis through the high-speed camera setup demonstrated that the administration of the bFGF-loaded ALG/HA hydrogel induced successful glottal gap closure. Thus, the bFGF-loaded ALG/HA hydrogel could be a promising candidate for injection laryngoplasty with therapeutic effects.