Ryo Asato

Alpha-Klotho as a regulator of calcium homeostasis

α-klotho was identified as a gene associated with premature aging–like phenotypes characterized by short lifespan. In mice, we found the molecular association of α-Klotho (α-Kl) and Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and provide evidence for an increase of abundance of Na+,K+-ATPase at the plasma membrane. Low concentrations of extracellular free calcium ([Ca2+]e) rapidly induce regulated parathyroid hormone (PTH) secretion in an α-Kl- and Na+,K+-ATPase–dependent manner. The increased Na+ gradient created by Na+,K+-ATPase activity might drive the transepithelial transport of Ca2+ in cooperation with ion channels and transporters in the choroid plexus and the kidney. Our findings reveal fundamental roles of α-Kl in the regulation of calcium metabolism.

Regenerative medicine of the trachea: the first human case.

Objectives: The objective of the present study was to demonstrate regenerative medicine of the tracheal tissue by using an in situ tissue engineering technique for airway reconstruction. Methods: Based on the previous successful experimental animal studies, the current regenerative technique was applied to repair of the trachea of a 78-year-old woman with thyroid cancer. A Marlex mesh tube covered by collagen sponge was used as a tissue scaffold. The operative intervention included right hemithyroidectomy, resection of the trachea, and tracheoplasty using the scaffold. The right half of three rings of the trachea was resected, and the scaffold material was sutured to the defect of the trachea. Results: After 2 weeks, the mesh collagen structure of the artificial material could be seen with endoscopy in most of the implanted area. The artificial material was covered with epithelial growth after 2 months. Epithelialization continued to cover the artificial material completely for 2 years without any complications. Conclusions: The current regenerative technique avoided tracheotomy, a second operation, and deformity. Good epithelialization has been observed on the tracheal luminal surface without any complications for 2 years. Although long-term observation is required, regenerative medicine of the tracheal tissue appears feasible for airway reconstruction.

Clinical application of in situ tissue engineering using a scaffolding technique for reconstruction of the larynx and trachea.

Objectives: The objective of the present study was to demonstrate the efficacy of the clinical application of in situ tissue engineering using a scaffolding technique for laryngeal and tracheal tissue. Methods: We have developed a tissue scaffold made from a Marlex mesh tube covered by collagen sponge. Based on successful animal experimental studies, in situ tissue engineering with a scaffold implant was applied to repair the larynx and trachea in 4 patients. Results: In 1 patient with subglottic stenosis, the thyroid cartilage, cricoid cartilage, and cervical trachea with scarring and granulation were resected and reconstructed by use of the scaffold. In 3 patients with thyroid cancer, the trachea and cricoid cartilage with tumor invasion were resected and the scaffold was implanted into the defect. Postoperative endoscopy during the observation period of 8 to 34 months showed a well-epithelialized airway lumen without any obstruction. Conclusions: Our current technique of in situ tissue engineering using a scaffold shows great potential for use in the regeneration of airway defects.

Elastic Moduli of Thyroid Tissues under Compression

The aim of this study was to evaluate the elastic moduli of thyroid tissues under uniaxial compression and to establish the biomechanical fundamentals for accurate interpretation of thyroid elastograms. A total of 67 thyroid samples (24 samples of normal thyroid tissue, 2 samples of thyroid tissue with chronic thyroiditis, 12 samples of adenomatous goiter lesions and 7 samples of follicular adenoma, 19 samples of papillary adenocarcinoma (PAC) and 3 samples of follicular adenocarcinoma (FAC)) obtained from 36 patients who had received thyroid surgery were subjected to biomechanical testing within three hours after surgical resection at precompression strains of 5%, 10% and 20% and applied strains of 1%, 2%, 5% and 10% of sample height. As a result, the mean values of elastic moduli for benign thyroid lesions at all examined precompression levels were significantly higher than those for normal thyroid tissue measured at the same load (p<0.01). At low precompression (5%) and compression (1–2%) levels, benign thyroid nodule samples were 1.7 times harder than normal thyroid tissue. At high precompression (20%) and compression (10%) levels, this difference increased to 2.4 times. Stiffness of PAC samples was significantly higher than those for normal thyroid tissue and benign thyroid tumors measured at the same load (p<0.01). At low precompression (5%) and compression (1–2%) levels, PAC samples were 5.0 times harder than normal thyroid tissue. At high precompression (20%) and compression (10%) levels, this difference increased to 17.7 times. In contrast, samples of FAC were much softer than PAC (p<0.05) and were comparable in stiffness to normal thyroid tissues. The significant differences in the stiffness between normal thyroid tissue and thyroid tumors may provide useful information for accurate interpretation of thyroid elastograms.

A method for vector displacement estimation with ultrasound imaging and its application for thyroid nodular disease

Ultrasound elastography is a promising imaging technique that can assist in diagnosis of thyroid cancer. However, the complexity of the tissue movements under freehand compression requires the use of a parametric displacement model and a specific estimation method adapted to sub-pixel motion. Therefore, the aim of this study was to develop a motion estimation method for ultrasound elastography and test its performances compared to a classical block matching technique. The proposed method, referred to as Bilinear Deformable Block Matching (BDBM), uses a bilinear model with eight parameters for controlling the local mesh deformation. In addition, a technique of motion initialization based on a triangle scan of the images adapted to ultrasound elastography is proposed. The BDBM method includes an iterative multi-scale process. This iterative approach is shown to decrease the absolute error of the displacement estimation by a factor of 1.4 when passing from 1 to 2 iterations. The method was tested on simulated images and the results show that absolute displacement estimation error was reduced by a factor of 4 compared to classical block matching. We applied the BDBM method on three experimental sets of data. In the first data set, a phantom designed for ultrasound elastography was used. The two other sets of data involve the thyroid gland and were acquired using freehand tissue compression by ultrasound probe of a clinical ultrasound scanner modified for research. A similarity measurement based on local cross-correlation shows that, for experimental data, the BDBM method outperforms the usual block matching.

Quantitative Analysis of Tumor Vascularity in Benign and Malignant Solid Thyroid Nodules

The purpose of our study was to analyze the accuracy of quantitative analysis of tumor vascularity on power Doppler sonograms in differentiating malignant and benign solid thyroid nodules using tumor histologic evaluation as the reference standard.

Long-term outcome of transoral organ-preserving pharyngeal endoscopic resection for superficial pharyngeal cancer.

BACKGROUND Early detection of pharyngeal cancer has been difficult. We reported that narrow-band imaging (NBI) endoscopy can detect superficial pharyngeal cancer, and these lesions can be treated endoscopically. OBJECTIVE To assess the safety and long-term efficacy of transoral organ-preserving pharyngeal endoscopic resection (TOPER) for superficial pharyngeal cancer. DESIGN AND SETTING Retrospective 2-center cohort study. PATIENTS The study included 104 consecutive patients with superficial pharyngeal cancer. INTERVENTION TOPER with the patients under general anesthesia. MAIN OUTCOME MEASUREMENTS Safety of the procedure, long-term survival, clinical outcome. RESULTS A total of 148 consecutive lesions were resected in 104 patients. There was no severe adverse event. Temporary tracheostomy was required in 17 patients (16%) to prevent airway obstruction. The median fasting period and hospital stay after TOPER were 2 days (range 1-20 days) and 8 days (range 3-58 days), respectively. Ninety-six patients (92%) had no local recurrence or distant metastases. Local recurrence at the primary site developed in 6 patients, but all were resolved by repeat TOPER. With a median follow-up period of 43 months (range 3-96 months), the overall survival rate at 5 years was 71% (95% CI, 59-82). Cause-specific survival rate at 5 years was 97% (95% CI, 93-100). The cumulative development rate of multiple cancers in pharyngeal mucosal sites at 5 years was 22% (95% CI, 12-33). The pharynx was preserved in all patients, and they experienced no loss of function. LIMITATION Retrospective design. CONCLUSIONS Peroral endoscopic resection of superficial pharyngeal cancer is a feasible and effective treatment with curative intent.

Epidermal growth factor receptor gene mutations in papillary thyroid carcinoma.

Recent studies have indicated that somatic mutations in the epidermal growth factor receptor (EGFR) gene have been identified in a subset of patients with nonsmall‐cell lung cancer (NSCLC) and are associated with sensitivity to the EGFR‐tyrosine‐kinase inhibitors. These mutations have been reported to be almost exclusively found in a pulmonary adenocarcinoma subgroup of NSCLC, with a low frequency in other solid tumors. We describe a patient with advanced‐stage papillary thyroid carcinoma (PTC) whose disease had been diagnosed as pulmonary adenocarcinoma at first, and who had a marked response to the EGFR‐tyrosine‐kinase inhibitor, gefitinib. An in‐frame deletion in exon 19 that eliminated 4 amino acids at positions 746 through 750, which is one of the common drug‐sensitive mutations in pulmonary adenocarcinoma, and a serine‐to‐proline substitution at codon 752, were found in a tumor specimen of the patient. We subsequently searched for mutations in the EGFR tyrosine kinase domain in primary tumors from 23 patients with PTC, and drug‐sensitive mutations commonly observed in pulmonary adenocarcinoma were found in 7 of these patients. Our observation of a high frequency of the EGFR‐activating mutations in PTC suggests that the EGFR mutation may be an important event in the development of PTC. EGFR gene amplification, also considered to be a predictor of response to EGFR‐tyrosine‐kinase inhibitors, was evaluated by fluorescence in situ hybridization (FISH); however, only 1 FISH‐positive tumor was detected. Our data suggest that EGFR‐tyrosine‐kinase inhibitors may deserve consideration in the treatment of a subset of patients with PTC, just as with pulmonary adenocarcinoma.

Therapeutic outcomes of laryngeal cancer at Kyoto University Hospital for 10 years.

Conclusion: It is important to prevent regional lymph node recurrence and distant metastasis to achieve better survival of laryngeal cancer. Objective: Therapeutic outcomes of 130 cases with laryngeal cancer treated at Kyoto University Hospital between 1995 and 2004 were reviewed. Patients and methods: In all, 121 males and 9 females were involved. Their ages ranged from 40 years to 92 years (average 66 years). All tumors were squamous cell carcinoma – arising at the glottis in 111 cases, the supraglottis in 18, and the subglottis in 1 case. Most glottic cancers (77.5%) were classified as stage I or II, while most supraglottic cancers (77.8%) were at stage III or IV. Stage I/II cancers were basically treated by conventional radiotherapy (60–66 Gy) and twice-daily hyperfractionated radiotherapy (70–74 Gy), respectively, attempting to preserve the larynx. Total laryngectomy with neck dissection was performed in the treatment of stage III/IV cases. Results: Five-year disease-specific survival rates were 100%, 96%, 100%, and 68% for stage I, II, III, and IV, respectively. Five-year laryngeal preservation rates were 98%, 100%, 86%, 0%, and 0% for T1a, T1b, T2, T3, and T4 of glottic cancer, respectively. Local recurrence occurred in five cases of stage I/II glottic cancer, which was successfully salvaged. Regional lymph node recurrence occurred in five cases including four patients with glottic cancer and one with supraglottic cancer. Two of them died of disease despite undergoing salvage therapy. Distant metastasis occurred in the lung in four cases including one glottic and three supraglottic cancer patients after initial treatment.

Transmaxillary and transmandibular approach to a C1 chordoma.

Study Design. Case report. Objectives. To demonstrate the efficacy of a transmaxillary and transmandibular approach in achieving a wide view and the aggressive resection of a retropharyngeal chordoma originating from C1. Summary of Background Data. Although aggressive surgical resection has been recommended for the treatment of chordomas, wide exposure of the tumors in the upper cervical region is a challenge. Methods. A 19-year-old man presented with a large ossified retropharyngeal chordoma (6 cm in diameter) originating from the right side of the anterior arch of C1, and extending from the clivus to the C2/3 intervertebral disc level in the sagittal plane. A posterior occipitocervical (O–C3) fusion with an iliac bone graft was first performed. Ten days after the fusion, the tumor was resected using a mandible and tongue midsplitting approach combined with a Le Fort I (transmaxillary) osteotomy, which allowed us to expose the entire tumor. The tumor was hard and immovable because of ossification. The main part of the tumor was resected from the anterior arch of C1, and then the C1 anterior arch was resected en bloc. The retropharyngeal wall was reconstructed using a vascularized radial forearm flap. Radiation therapy (60 Gy) was performed after surgery. Results. No local recurrence or metastasis was observed 3 years after the operation. The patient had no complaints and has returned to his previous job as a manual laborer. Conclusions. A transmaxillary and transmandibular approach allowed us to obtain a complete view of a large immovable chordoma located ventral to the upper cervical spine. This enabled us to resect totally the tumor into 2 pieces without major complications or sequelae. This approach is useful for the resection of large tumors located in the median upper cervical spine.