Tracheostomy in otorhinolaryngology education and training programs: A Japanese nationwide survey.

OBJECTIVE: Surgical airway management is one of the most effective techniques for safe airway management. Within the training programs relating to knowledge and skills required by otorhinolaryngologists, tracheostomy and postoperative management are important items that must be fully understood by airway surgeons. We performed a nationwide survey to identify problems within tracheostomy and postoperative management in Japan in order to establish practical and safe guidelines for surgical airway management. METHODS: We conducted a questionnaire survey of the current status of tracheostomy and postoperative management at core institution of otorhinolaryngology training programs in Japan. RESULTS: Responses were obtained from all 101 core training institutions in Japan. Tracheostomy was performed in the operating room at 61.4% of institutions and in the ICU at 26.7%. 89.1% of them performed surgical tracheostomy (ST) in all cases. Even in the remaining 10.9%, percutaneous dilatational tracheostomy (PDT) was performed in less than 10% of cases. The primary surgeon was an otorhinolaryngology resident at 89.1% of institutions. The method of securing the tube immediately after surgery was by securing it with an attached cord at 48.5% of institutions, by suturing to the skin at 25.7%, and using a Velcro band at 24.8%. The first tube change after tracheostomy was performed on the seventh postoperative day at 81.2% of institutions. 87.1% had more than one person performing the first tube change. The tracheostomy postoperative complications within the past year were as follows: tracheostomal granulation: 89.1%; subcutaneous and/or mediastinal emphysema: 62.4%; tube stenosis: 55.4%; accidental tube removal: 50.5%; incorrect tube insertion or misplacement: 15.8%; hemorrhage from tracheal foramen requiring hemostasis in the operating room: 14.9%; pneumothorax: 4.0%; tracheo-innominate arterial fistula: 2.0%; and tracheoesophageal fistula: 1.0%. The method for educating otorhinolaryngology residents about tracheostomy was on-the-job training at 98.0% of institutions. CONCLUSIONS: For airway management in otorhinolaryngology training programs, after learning the basics of ST, PDT should also be well understood. Furthermore, in order to create safe educational programs for intraoperative and postoperative management, it is necessary to train otorhinolaryngologists with accurate knowledge and skills, and to strengthen collaboration with multiple professions in their leadership roles as airway surgeons.

Quantitative Model Analysis and Simulation of Pharmacokinetics and Metastasis-Associated Lung Adenocarcinoma 1 RNA Knockdown Effect After Systemic Administration of Cholesterol-Conjugated DNA/RNA Heteroduplex Oligonucleotide Crossing Blood-Brain Barrier of Mice.

The cholesterol-conjugated heteroduplex oligonucleotide (Chol-HDO) is a double-stranded complex; it comprises an antisense oligonucleotide (ASO) and its complementary strand with a cholesterol ligand. Chol-HDO is a powerful tool for achieving target RNA knockdown in the brains of mice after systemic injection. Here, a quantitative model analysis was conducted to characterize the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD), non-coding RNA metastasis-associated lung adenocarcinoma 1 (Malat1) RNA, of Chol-HDO, in a time-dependent manner. The established PK model could describe regional differences in the observed brain concentration-time profiles. Incorporating the PD model enabled the unique knockdown profiles in the brain to be explained in terms of the time delay after single dosing and enhancement following repeated dosing. Moreover, sensitivity analysis of PK exposure/persistency, target RNA turnover, and knockdown potency identified key factors for the efficient and sustained target RNA knockdown in the brain. The simulation of an adequate dosing regimen quantitatively supported the benefit of Chol-HDO in terms of achieving a suitable dosing interval. This was achieved via sufficient and sustained brain exposure and subsequent strong and sustained target RNA knockdown in the brain, even after systemic injection. The present study provides new insights into drug discoveries and development strategies for HDO in patients with neurogenic disorders. SIGNIFICANCE STATEMENT: The quantitative model analysis presented here characterized the PK/PD relationship of Chol-HDO, enabled its simulation under various conditions or assumptions, and identified key factors for efficient and sustained RNA knockdown, such as PK exposure and persistency. Chol-HDO appears to be an efficient drug delivery system for the systemic administration of desired drugs to brain targets.

Physiologically-based pharmacokinetic model-based translation of OATP1B-mediated drug-drug interactions from coproporphyrin I to probe drugs.

The accurate prediction of OATP1B-mediated drug-drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically-based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP-I) by CysA. In vivo Ki of unbound CysA for OATP1B (Ki,OATP1B ), and the overall intrinsic hepatic clearance per body weight of CP-I (CLint,all,unit ) were optimized to account for the CP-I data (Ki,OATP1B , 0.536 ± 0.041 nM; CLint,all,unit , 41.9 ± 4.3 L/h/kg). DDI simulation using Ki,OATP1B reproduced the dose-dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro Ki,OATP1B failed. The Cluster Gauss-Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP-I (ß, CLint, all , Fa Fg , Rdif , fbile , fsyn , and vsyn ), and Ki,OATP1B and Ki,MRP2 of CysA. Based on the accepted 546 parameter sets, the range of CLint, all and Ki,OATP1B was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP-I is a promising translational approach to predict OATP1B-mediated DDIs in drug development.

Brain microvascular endothelial cells derived from human induced pluripotent stem cells as in vitro model for assessing blood-brain barrier transferrin receptor-mediated transcytosis.

The blood-brain barrier (BBB), a selective barrier formed by brain microvascular endothelial cells (BMEC), represents a major challenge for the efficient accumulation of pharmaceutical drugs into the brain. The receptor-mediated transcytosis (RMT) has recently gained increasing interest for pharmaceutical industry as it shows a great potential to shuttle large-sized therapeutic cargos across the BBB. Confirming the presence of the RMT pathway by BMEC is therefore important for the screening of peptides or antibody libraries that bind RMT receptors. Herein, a comparative study was performed between a human cell line of BMEC (HBEC) and human induced pluripotent stem cells-derived BMEC-like cells (hiPS-BMEC). The significantly higher gene and protein expressions of transporters and tight junction proteins, excepting CD31 and VE-cadherin were exhibited by hiPS-BMEC than by HBEC, suggesting more biomimetic BBB features of hiPS-BMEC. The presence and functionality of transferrin receptor (TfR), known to use RMT pathway, were confirmed using hiPS-BMEC by competitive binding assays and confocal microscopy observations. Finally, cysteine-modified T7 and cysteine modified-Tfr-T12 peptides, previously reported to be ligands of TfR, were compared regarding their permeability using hiPS-BMEC. The hiPS-BMEC could be useful for the identification of therapeutics that can be transported across the BBB using RMT pathway.

Effect of Cyclosporin A and Impact of Dose Staggering on OATP1B1/1B3 Endogenous Substrates and Drug Probes for Assessing Clinical Drug Interactions.

This study was designed to assess the quantitative performance of endogenous biomarkers for organic anion transporting polypeptide (OATP) 1B1/1B3-mediated drug-drug interactions (DDIs). Ten healthy volunteers orally received OATP1B1/1B3 probe cocktail (0.2 mg pitavastatin, 1 mg rosuvastatin, and 2 mg valsartan) and an oral dose of cyclosporin A (CysA, 20 mg and 75 mg) separated by a 1-hour interval (20 mg (-1 hour), and 75 mg (-1 hour)). CysA 75 mg was also given with a 3-hour interval (75 mg (-3 hours)) to examine the persistence of OATP1B1/1B3 inhibition. The area under the plasma concentration-time curve ratios (AUCRs) were 1.63, 3.46, and 2.38 (pitavastatin), 1.39, 2.16, and 1.81 (rosuvastatin), and 1.42, 1.77, and 1.85 (valsartan), at 20 mg, 75 mg (-1 hour) and 75 mg (-3 hours) of CysA, respectively. CysA effect on OATP1B1/1B3 was unlikely to persist at the dose examined. Among 26 putative OATP1B1/1B3 biomarkers evaluated, AUCR and maximum concentration ratio (Cmax R) of CP-I showed the highest Pearson's correlation coefficient with CysA AUC (0.94 and 0.93, respectively). Correlation between AUCR of pitavastatin, and Cmax R or AUCR of CP-I were consistent between this study and our previous study using rifampicin as an OATP1B1/1B3 inhibitor. Nonlinear regression analysis of AUCR-1 of pitavastatin and CP-I against CysA Cmax yielded Ki,OATP1B1/1B3,app (109 ± 35 and 176 ± 42 nM, respectively), similar to the Ki ,OATP1B1/1B3 estimated by our physiologically-based pharmacokinetic model analysis described previously (107 nM). The endogenous OATP1B1/1B3 biomarkers, particularly Cmax R and AUCR of CP-I, corroborates OATP1B1/1B3 inhibition and yields valuable information that improve accurate DDI predictions in drug development, and enhance our understanding of interindividual variability in the magnitude of DDIs.

Prognostic value of C-reactive protein/albumin ratio for patients with hypopharyngeal and laryngeal cancer undergoing invasive surgery involving laryngectomy.

BACKGROUND: The C-reactive protein/albumin (CRP/Alb) ratio has been recently established as a prognostic indicator in various cancer types. However, few reports regarding the prognostic value of the CRP/Alb ratio in head and neck cancer exist. This study aimed to investigate the significance of the CRP/Alb ratio in clinical outcomes after invasive surgery involving laryngectomy for hypopharyngeal and laryngeal cancer. METHODS: We evaluated 56 patients who underwent total laryngectomy or total pharyngolaryngectomy between 2003 and 2012. Univariate and multivariate analyses were retrospectively performed to examine the prognostic value of the CRP/Alb ratio in these patients. RESULTS: The optimal cutoff value of the CRP/Alb ratio was 0.32. Multivariate analysis showed that the CRP/Alb ratio was a significant and independent predictor of poor overall and disease-free survival. CONCLUSION: The CRP/Alb ratio may be a novel and useful indicator for predicting postoperative outcomes in patients with hypopharyngeal and laryngeal cancer.

Adenoid cystic carcinoma of the larynx presenting with unusual subglottic mass: Case report.

A 33-year-old woman presented with an unusual subglottic bulging mass accompanied by prolonged cough and wheeze. Laryngeal endoscopy revealed a bilateral, symmetrical mass immediately below the vocal cords with marked airway obstruction. Chronic subglottic laryngitis with inflammation or another condition such as amyloidosis was initially suspected. Cervicothoracic computed tomography revealed an obvious reduction of laryngeal caliber caused by an engulfing mass extending from just under the vocal cords to the cricoid ring, which was associated with thyroid, arytenoid, and cricoid cartilage destruction. Histopathological diagnosis of a biopsy specimen collected via a tracheotomy revealed that the lesion was a cT4aN0M0 adenoid cystic carcinoma (ACC) originating from the laryngeal minor salivary glands. The patient was treated by total laryngectomy with elective bilateral neck dissection under general anesthesia. Gross inspection of resected tissue confirmed yellowish-white, solid tumor mainly circumferentially encompassing the lumina of the cricoid ring. The histopathological findings confirmed typical ACC accompanied by a predominant cribriform appearance with no evidence of lymph node metastasis. The patient remains well and free of recurrence or metastasis. We herein describe laryngeal ACC and discuss radiological images and the surgical pathology.

Acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma of the thyroid: A complicated case.

The fibrous variant of Hashimoto thyroiditis is uncommon, accounting for approximately 10% of all cases of Hashimoto thyroiditis. We report a case of this variant that behaved like a malignant neoplasm. The patient was a 69-year-old man who presented with a right-sided anterior neck mass that had been rapidly growing for 2 weeks. Fine-needle aspiration cytology revealed clusters of large multinucleated cells suggestive of an anaplastic carcinoma. A week after presentation, we ruled out that possibility when the mass had shrunk slightly. Instead, we diagnosed the patient with an acute exacerbation of Hashimoto thyroiditis on the basis of laboratory findings. We performed a right thyroid lobectomy, including removal of the isthmus, to clarify the pathology and alleviate pressure symptoms. The final diagnosis was the fibrous variant of Hashimoto thyroiditis, with no evidence of malignant changes. Physicians should keep in mind that on rare occasions, Hashimoto thyroiditis mimics a malignant neoplasm.

[A rare case of pharyngeal mesenchymoma demonstrating a variety of histopathological findings].

We encountered a 38-years-old female patient who was complaining of an unpleasant sensation of the left cervical area due to a recurrent tumor originating from the middle pharynx. She had a history of surgically resected neurofibroma and lipoma from the anterior oropharyngeal wall respectively 5 years and 11 years previously. The preoperative diagnosis of a benign, non-epithelial neoplasm was made based on the imaging studies and surgical treatment was scheduled. An extended surgical resection of the middle pharynx including normal mucosa and a part of the tongue base was successfully accomplished. To cover the pharyngeal defect, a right antero-lateral thigh musculo-cutaneous flap was used for reconstruction. Microscopically, the surgically resected tissue showed a mixed condition of mature cartilaginous, bony and fibroadipose tissue without atypia. The final diagnosis was a benign mesenchymoma which was thought to have developed from pluripotential mesenchymal cells. We considered that the past tumorous lesions had possibly originated in those cells. Because pluripotential mesenchymal cells cannot easily be identified with ordinary histopathological examination, the determination of optimal surgical margins is difficult. In the case of mesenchymoma, substantial marginal tissue should be resected in order to prevent recurrence even in the case of a pathologically-proven benign tumor.

[Comparison of B-mode ultrasonography and computed tomography in the evaluation of maxillary sinusitis in pediatric patients].

The use of ultrasonography in the diagnosis of maxillary sinusitis in pediatric patients has been reported recently because of the improvement of the accuracy of ultrasound technology. We thus compared B-mode ultrasonography and computed tomography in the diagnosis of maxillary sinusitis in pediatric patients. Thirty-six maxillary sinuses in 18 patients (10 females, 8 males, ages ranging from 7-15 years with an average age of 10.4 years) were examined. Ultrasonography of the maxillary sinus was performed in the horizontal and the vertical direction. Paranasal computed tomography and B-mode ultrasonography were performed within a few days. In some of these patients the maxillary sinuses were examined with a fiberscope. Sensitivity, specificity, false-positive, false-negative, positive predictive value and negative predictive value of B-mode ultrasonography compared with computed tomography were 92.6%, 100%, 0%, 7.4%, 100% and 81.8%, respectively. It appeared that ultrasonography was more sensitive than X-ray imaging, because the sensitivity and specificity of X-ray imaging of the maxillary sinus in pediatric patients compared with CT was reportedly 70-80%. A meaningful correlation of ultrasonography and CT was accepted as an assessment of desease severity. There are some problems with diagnosis by ultrasonography. There is no differentiation of mucosal thicking, cyst and discharge and imaging are less useful in pediatric patients. Because of these reasons, clinical sign and views in the nose are important for a correct diagnosis in pediatric patients. Furthermore, the most suitable age range to diagnose maxillary sinusitis correctly in pediatric patients must be examined.

New technique using an energy-based device versus conventional technique in open thyroidectomy.

OBJECTIVE: Thyroid surgery is a common basic procedure in otorhinolaryngology. The purpose of this study was to assess the efficiency of using a new LigaSure(®) vessel sealing system (LigaSure(®) Small Jaw Instrument; Covidien, Boulder, CO, USA). METHODS: We evaluated 83 patients who underwent thyroid surgery between July 2009 and June 2012. The patients were allocated to two groups, which underwent thyroid surgery using either the LigaSure(®) Small Jaw Instrument or conventional techniques. We investigated the duration of operation, estimated blood loss, pathological characteristics, postoperative complications, and length of hospital stay. As for duration of operation and estimated blood loss, we also performed analyses by subgroups according to the extent of thyroid resection, as either total thyroidectomy or hemithyroidectomy. RESULTS: The study groups showed no significant differences in age, sex, indications, extent of operation and estimated blood loss. Complication rates for recurrent laryngeal nerve palsy, hypoparathyroidism, hematoma, and wound infection did not differ between groups, except for temporary hypoparathyroidism. Operation time was significantly shorter in the LigaSure(®) Small Jaw Instrument group than in the conventional group for all extents of thyroid resection. CONCLUSION: Use of the LigaSure(®) Small Jaw Instrument seems likely to reduce the operating time for thyroid surgery without increasing estimated blood loss or the frequency of postoperative complications compared to conventional techniques.

[Community-based hearing screening project in Tochigi prefecture and results thorough audiometric test].

Community-based hearing screening projects have the objectives of screening hearing to identify early and intervene in cases of hearing-impaired infants and to consider how to implement mass screening, education, and support suitable. This project started in Tochigi prefecture in 2002. Of 6198 infants undergoing automatic auditory brainstem response (ABR), those rescreened accounted for 1.1% and those referred for diagnostic testing for 0.7%. After initial thorough audiometric testing, 20 infants were suggested to have bilateral hearing loss, although this was finally reduced to 17. Inconsistency between automatic and conventional ABR was found in 10 cases. Automatic ABR showed 7 false-positive and 3 false-negative cases, all of which finally proved to be within normal range hearing. Newborn-hearing screening enabled infants with hearing loss to be identified early. Japan has yet, however, to implement needed medical treatment and appropriate educational and support systems for hearing-impaired infants.

[A case of laryngeal sarcoidosis difficult to diagnose].

Sarcoidosis is a multiorgan granulomatous disease of unknown cause, named after the characteristic histopathological findings of the disease. In this article, we shall report a case in which biopsy needed to be repeated three times until a final diagnosis of laryngeal sarcoidosis could be made. Since sarcoidosis associated with only a laryngeal pathology may not be associated with any laboratory abnormalities in many cases, first priority should be attached in suspected cases to detect the presence of noncaseating epithelioid cell granulomas. In this case, the results of the first and second laryngeal biopsies did not show non-caseating epithelioid cell granulomas, while the third biopsy showed noncaseating epithelioid cell granulomas with giant cells. Finally, the diagnosis of laryngeal sarcoidosis was made after the results of whole-body imaging became available. Laryngeal sarcoidosis must be borne in mind as a suspected diagnosis in cases where the larynx shows yellowish-white diffuse swelling.

Intramuscular hemangioma of masseter muscle with prominent formation of phleboliths: a case report.

A 14-year-old girl was referred for evaluation and management of progressive, painful swelling of the right cheek. Swelling had been present since 3-year old and had gradually increased in size. Magnetic resonance imaging (MRI) revealed a well-circumscribed, brighter mass in the right masseter muscle with numerous rounded areas of signal hypointensity. Preoperative diagnosis was intramuscular hemangioma of the masseter muscle and surgery was performed. The tumor was completely removed except for a few, small phleboliths. Pathological examination of resected tissue led to a high suspicion of cavernous hemangioma with phlebolithiasis. Nine months postoperatively, the patient developed another painful mass in the right masseter muscle. MRI indicated recurrent hemangioma and further surgery was performed. Careful exploration resulted in completely removal of residual phleboliths accompanied with fibroadipose tissue. Part of the buccal branch of the facial nerve was excised to achieve complete resection of the lesion. Histological examination revealed distinct venous formation in phleboliths adjacent to fibroadipose tissue, demonstrating that both phleboliths and feeding vessels had been left by the previous operation. The present report reviews the literature on intramuscular hemangiomas of the masseter muscle, and discusses diagnostic methods and optimal surgical treatment.

[A rare case of ectopic, normally functioning thyroid tissue presenting as a left submandibular mass].

This report describes the case of a 53-year-old female, who presented with a painless swelling in the left submandibular region which had gradually increased in size. Thirty years ago, this patient underwent subtotal thyroidectomy at another hospital and her thyroid function subsequently appeared normal. She presented no symptoms of hypothyroidism when she visited our hospital. A clinical diagnosis of a benign tumor arising from the submandibular gland was made with enhanced CT scan, MRI and technesium scintigraphy. The submandibular mass was surgically excised and the resected tissue revealed a well-delineated, encapsulated, solid and reddish-brown colored mass. Histological examination confirmed ectopic thyroid tissue with partial adenomatous goiter including vacuolated rich colloid in the thyroid follicles which suggested compensatory hyperplasia. Because this patient presented with post-operative hypothyroidism, we concluded that this ectopic lesion had continued to secrete thyroid hormone. Ectopic thyroid tissue should be considered in the differential diagnosis of swellings involving the submandibular area, especially if the ectopic tissue would be the only functioning thyroid tissue.

Bone-specific drug delivery systems: approaches via chemical modification of bone-seeking agents.

Despite several decades of progress, bone-specific delivery is still limited by the unique anatomical features of bone, which mainly consists of inorganic hydroxyapatite. A practical approach to this problem is to produce targeted drugs that have a high affinity for hydroxyapatite. Bisphosphonates are a class of synthetic compounds structurally related to pyrophosphate. Bisphosphonates rapidly localise on the bone surface after being administered either intravenously or orally, since the P-C-P portion of the bisphosphonate structure has high affinity for hydroxyapatite. Therefore, bisphosphonate modification might be a promising method for targeting drugs selectively to the bone. Bisphosphonate-conjugated drugs are hydrophilic and highly water-soluble due to the acidic nature of the bisphosphonate moiety at physiological pH, and therefore they hardly permeate through the biological membrane of soft tissues. These physicochemical changes also reduce the intrinsic susceptibility of the drug to metabolism, promoting urinary or biliary excretion as unchanged drug. All these physicochemical and pharmacokinetic alterations contribute to the exceptional skeletal disposition of bisphosphonate-conjugated drugs. Bisphosphonate conjugation is based on chemical modification of the targeting molecule, and therapeutically optimised bisphosphonate derivatives have to be custom-developed on a case-by-case basis. The bisphosphonate moiety is usually coupled with the targeting drug through a specific linkage. The high affinity of bisphosphonate conjugates for the bone is not simply dependent on the bisphosphonate moiety but on the resultant molecule as a whole, including the linker and the linked drug. Lipophilicity (represented as log P) appears to be an appropriate index for predicting the osteotropic properties of bisphosphonate derivatives. Several strategies using bisphosphonate-conjugated drugs have been investigated at a laboratory level with the aim of obtaining therapeutically optimised treatments for conditions such as osteoporosis, osteoarthritis and bone cancer. In each case, the intention is to achieve prolonged local exposure to high concentrations of the targeting drug, thereby improving therapeutic index by enhancing pharmacological efficacy and minimising systemic adverse effects. Although most examples of bone-specific drug delivery via bone-seeking agents still remain in preclinical studies, several phosphonate-coupled radiopharmaceuticals, such as samarium-153 complexed to tetraphosphonate, are expected to be an effective pain palliation therapies for metastatic bone cancer and are currently being developed in clinical trials. Furthermore, recent reports on bisphosphonate-modified proteins have illustrated the feasibility of bone-specific delivery of biologically active protein drugs, such as cytokines and growth factors.