Palliative use of self-expanding metal stents in initially anticancer treatment-intolerant patients with esophageal cancer.

BACKGROUND: The post-insertion clinical course of esophageal self-expandable metal stents (SEMS) in initially frail patients with esophageal carcinoma (EC) with dysphagia remains unclear. This study aimed to assess dysphagia improvement and evaluate prognosis in initially frail patients with advanced EC following SEMS insertion. METHODS: We retrospectively reviewed EC patients with EC who underwent esophageal SEMS insertion at our institution between January 2014 and March 2023. Inclusion criteria comprised Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3 or ECOG PS 2 for individuals aged ≥ 75 years and recommendation for best supportive care by a multidisciplinary team. RESULTS: Forty-six patients met the inclusion criteria. Among them, 37 patients (80.4%) were ≥ 75 years old, and 21 patients (45.7%) exhibited ECOG PS 3 or 4. Dysphagia score (DS) ≥ 3 was observed in 27 patients (58.7%). All esophageal SEMS insertions were successfully completed. Post-procedure, there were two fatal cases of aspiration pneumonia and one perforation incident. DS improved to ≤ 1 in 25 patients (54.3%), with multivariate analysis indicating DS 3-4 and Glasgow Prognostic Score (GPS) 1-2 as negative predictive factors. The median overall survival was 4.1 months (95% confidence interval 1.8-6.5). CONCLUSIONS: Esophageal SEMS insertion effectively alleviated dysphagia in initially frail EC patients, yet prognosis remained poor, with occurrences of some fatal adverse events. Careful selection of candidates for esophageal SEMS insertions is crucial in this demographic, particularly considering the challenges in improving dysphagia for patients with DS 3-4 and GPS 1-2.

Optimization of therapeutic strategy for p16-positive oropharyngeal squamous cell carcinoma: Multi-institutional observational study based on the national Head and Neck Cancer Registry of Japan.

BACKGROUND: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date. METHODS: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality. RESULTS: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m2 ; 17 patients). CONCLUSIONS: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m2 .

The Presence of HPV DNA in Neck Lymph Node Metastasis Correlates with Improved Overall Survival of Patients with Oropharyngeal Cancer Undergoing Surgical Treatment.

BACKGROUND: Few studies have addressed how human papilloma virus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) affects the outcome of surgical therapy; furthermore, the relationship between the presence of HPV DNA and neck lymph node (LN) metastasis has not been well established. METHODS: A total of 65 patients who underwent surgery as a first-line therapy for OPSCC were enrolled in this study. In HPV-positive patients, the presence of HPV DNA in metastatic neck LN lesions was evaluated. RESULTS: The HPV-positive patients had significantly better overall survival than the HPV-negative patients (log-rank test, p = 0.04), whereas HPV infection status did not significantly affect disease-free survival (log-rank test, p = 0.65). In all of the HPV-positive OPSCC patients who developed cervical LN metastasis, the same HPV DNA type was found in both the primary tumour and the metastases. CONCLUSIONS: The present results suggest that HPV infection is a determining factor for good prognosis in patients undergoing first-line surgical therapy for OPSCC.

Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.

BACKGROUND: Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse. METHODS: We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively. RESULTS: UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method. CONCLUSIONS: These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

[Total Glossolaryngectomy of an Advanced Oropharyngeal and Tongue Squamous-Cell Carcinoma: A 29-Case Series Study].

We report herein on 29 patients with advanced oropharyngeal and tongue squamous-cell carcinoma who underwent a total glossolaryngectomy at the Cancer Institute Hospital of the JFCR between July 2005 and June 2013. In this study, we tried to evaluate associations between several variables of the primary tumor and prognosis in these 29 patients. The cause-specific 5-year survival rate with the Kaplan-Meier method was 45% in all patients. Tumor recurrence occurred in 15 patients. Four patients had recurrence in the primary site, 11 patients in neck lymph nodes or in the lungs or bone. The multivariate analysis revealed that the number of neck lymph node metastases, age and alcohol drinking were poor prognostic markers for patients undergoing a total glossolaryngectomy. Cause-specific survival was compared between patients with salvage surgery and initial surgery using Kaplan-Meier survival curves with log-rank tests. There was no significant association with survival (log-rank test: p = 0.13). The overall local control rate was 69% in all patients. Regarding salvage surgery, 9 of 16 patients had no recurrence in the primary site or neck lymph nodes. The limitations of this study include the small number of patients especially regarding the prognosis study and may have included a selection bias regarding undergoing a total glossolaryngectomy.

Prevalence of human papillomavirus in oropharyngeal cancer: a multicenter study in Japan.

BACKGROUND: The incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) have risen steadily in the USA and in northern Europe. These increases are thought to be a consequence of persistent infection with high-risk human papillomavirus (HPV) in OPSCC patients. HPV is an emerging etiologic factor in OPSCC. In Japan, the incidence of OPSCC has significantly increased over the last three decades. However, the population of HPV-positive OPSCC patients is currently unknown. We examined the nationwide trends with regard to HPV incidence in OPSCC patients at 21 specific sites, and examined the relationship between the presence of HPV and survival in OPSCC patients in Japan. METHODS: Tumor samples were obtained from patients with OPSCC prior to treatment, and HPV infection was investigated by polymerase chain reaction (PCR). Hybrid Capture 2 (HC2) was also adopted for swab examination on the surface of fresh tumors. RESULTS: HPV was detected by PCR in 79 (50.3%) out of 157 OPSCC patients. The clinical features of HPV-positive OPSCC were low differentiation, a tendency to involve the lateral wall, and high nodal staging. The sensitivity and specificity of HC2 were 93.7 and 96.2%, respectively, indicating its utility as a screening test. HPV-positive patients had significantly better overall survival and disease-free survival than HPV-negative patients.

Complete response induced by nivolumab monotherapy in gastric neuroendocrine carcinoma: a case report.

No standard treatment has been established for gastric neuroendocrine carcinoma (G-NEC). We present the case of a patient with recurrent G-NEC who achieved a complete response (CR) with nivolumab. A woman in her 70 s, with no significant medical or family history of illness, underwent an upper gastrointestinal endoscopy, which revealed a Borrmann type 2 tumor in the gastric antrum. Malignant tumor cells were not detected in the endoscopic biopsy samples; however, a malignant gastric tumor was strongly suspected. Therefore, surgical resection was performed, and the tumor was pathologically diagnosed as a G-NEC with liver metastases. Adjuvant etoposide plus carboplatin was administered for four cycles, but recurrence in the liver was observed 5 months after the completion of adjuvant chemotherapy. Ramucirumab plus paclitaxel and irinotecan were introduced as second and third-line treatments. After these treatments, the mesenteric lymph node metastases expanded. Tumor mutation burden (TMB) was low (five mutations/megabase), and microsatellite instability remained stable. However, programmed death-ligand 1 Combined Positive Score (CPS) was ≥ 5 in the resected sample. Therefore, nivolumab monotherapy was introduced as a fourth-line treatment. The mesenteric lymph node metastases exhibited swelling 3 weeks after the initiation of nivolumab; however, they rapidly shrank, and CR was later achieved. Treatment with nivolumab is currently ongoing for 12 months. This is the first report of nivolumab monotherapy in a patient with G-NEC who showed pseudo-progression. Even in TMB-low and microsatellite stable cases, nivolumab may be a viable option for patients with G-NEC.

The expression of protease-activated receptors in chronic rhinosinusitis.

BACKGROUND: A recent study suggested that protease-activated receptors (PARs) are involved in allergic respiratory diseases, such as asthma. Chronic rhinosinusitis (CRS) is one of the most common chronic airway diseases, but little is understood about its pathogenesis. The purpose of this study was to compare the expression and distribution of PARs in biopsy specimens obtained from CRS and control patients. METHODS: Biopsy specimens were obtained from 7 pituitary tumor patients as controls, 8 CRS patients with aspirin-tolerant asthma (ATA), 7 CRS patients with aspirin-induced asthma (AIA), and 7 CRS patients without asthma (CRS). Sections were stained for PAR-1, PAR-2, PAR-3 and PAR-4 using specific polyclonal antibodies. Staining was scored semiquantitatively for both intensity and distribution. To confirm the presence of PARs on inflammatory cells, double staining with eosinophil cationic protein (EG2) and elastase was also performed. RESULTS: Both the epithelium and the infiltrating inflammatory cells in the CRS with asthma groups showed significant upregulation of the expression of PAR-2 and PAR-3 compared with the CRS without asthma group and the control group. In the patients with CRS complicated by asthma, eosinophils were increased among PAR-2- and PAR-3-positive cells. In the patients with CRS not complicated by asthma, neutrophils were increased among PAR-2-positive cells. CONCLUSIONS: Differences in the expression of PAR-2 and PAR-3 on epithelial cells, eosinophils and neutrophils may be involved in the pathogenesis of CRS. CRS may be able to be treated by targeting PAR-2 and PAR-3.

Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma.

BACKGROUND: Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drives cancer development. Although mutations in the downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers, extensive mutation and copy number analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC). METHODS: We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients.We used DNA sequencing to detect mutations and the copy number changes were evaluated by qPCR and array comparative genomic hybridization (CGH) analysis. RESULTS: We examined the mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. We identified 3 mutations (2.6%) in K-RAS and 3 mutations (2.6%) in PIK3CA. Copy number amplification was found in 37 cases (32.2%) for PIK3CA, 10 cases (8.7%) for K-RAS and 2 cases (1.7%) for BRAF. Kaplan-Meier survival analysis revealed that copy-number amplification of PIK3CA was markedly associated with cancer relapse in patients without lymph node metastasis. (Log-rank test, p = 0.026) CONCLUSIONS: Copy number amplification of the PIK3CA gene is associated with poor prognosis in HNSCC patients without lymph node metastasis. The PIK3CA copy number status will serve as a marker of poor prognosis in patients with HNSCC.

[Endoscopic sinus surgery complications a prospective multicenter study].

OBJECTIVE: Our objective was to determine the rate of complications in endoscopic sinus surgery (ESS) and associated risk factors. METHODS: We prospectively studied 1,382 subjects undergoing ESS for rhinosinusitis and cystic sinus disease at 16 hospitals during 2007 and 2008. Surgeons provided information on peri-and postoperative complication occurrence. RESULT: Results of complications were seen in 80 subjects (5.8%), the most frequent was perioperative lamina papyracea injury. Analysis showed the complication rate to be linked to gender, and anesthesia type, but not the grade of surgeon. CONCLUSIONS: While care should be taken to avoid them, complications should be identified and treated in a timely and accurate manner.

Adequate Number of Swallows for Pharyngeal Pressure Measurement of a Subject using High-resolution Manometry.

Introduction The number of pressure measurements that need to be recorded using high-resolution manometry (HRM) for the accurate evaluation of pharyngeal function is not well established. Objective The purpose of this study is to clarify the number of swallows required to obtain an accurate pharyngeal manometric profile of a person. Methods Forty healthy adults performed a dry swallow and bolus swallows using 3-, 5-, or 10 ml of water and underwent measurements using the Starlet HRM system. Each subject underwent 10 swallows for each of the four bolus volume conditions. Results The mean of up to seven measurements of maximum pre-swallow upper esophageal sphincter pressure with 10 ml of swallow was close to the mean of up to eight measurements in 95% of the subjects. Similarly, the rate of change of the average for the eighth and ninth measurements and the rate of change for the average of the ninth and tenth measurements were less than 5%. When the other parameters were similarly measured up to the sixth measurement, no major change in the average value was observed even if more measurements were taken. Conclusion A minimum of six measurements are required, and seven swallows are sufficient for evaluating the pharyngeal manometric profile of a single person. This number of measurements can be a useful criterion when performing HRM measurements on individual subjects.

Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen.

BACKGROUND: Sustained chronic inflammation in the prostate promotes prostate carcinogenesis. Since an elevated level of prostate-specific antigen (PSA) per se reflects the presence of inflammation in the prostate, intervention to improve the PSA value might potentially have beneficial effects for the prevention of the development of prostate cancer. Isoflavones and curcumin have anti-inflammatory and anti-oxidant properties. We examined the biological effects of soy isoflavones and curcumin on LNCaP cells. After that, we conducted a clinical trial for men who received prostate biopsies, but were not found to have prostate cancer, to evaluate the effects of soy isoflavones and curcumin on serum PSA levels. METHODS: The expression of androgen receptor and PSA were examined in LNCaP cells before and after treatment of isoflavones and/or curcumin. Eighty-five participants were randomized to take a supplement containing isoflavones and curcumin or placebo daily in a double-blind study. Subjects were subdivided by the cut-off of their baseline PSA value at 10 microg/ml. We evaluated values of PSA before and 6 months after treatment. RESULTS: The production of PSA were markedly decreased by the combined treatment of isoflavones and curcumin in prostate cancer cell line, LNCaP. The expression of the androgen receptor was also suppressed by the treatment. In clinical trials, PSA levels decreased in the patients group with PSA >or= 10 treated with supplement containing isoflavones and curcumin (P = 0.01). CONCLUSIONS: Our results indicated that isoflavones and curcumin could modulate serum PSA levels. Curcumin presumably synergizes with isoflavones to suppress PSA production in prostate cells through the anti-androgen effects.

Associations among smoking, MGMT hypermethylation, TP53-mutations, and relapse in head and neck squamous cell carcinoma.

BACKGROUND: Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair enzyme via promoter hypermethylation (hmMGMT) may increase mutations in the TP53 oncosuppressor gene and contribute to carcinogenesis. The effects of smoking, which is a risk factor for head and neck squamous cell carcinoma (HNSCC), were investigated to determine whether they up- or down-regulate hmMGMT. Additionally, the impact of hmMGMT and disruptive TP53-mutations on relapse was investigated in patients with HNSCC. METHODS: This study included 164 patients with HNSCC who were negative for both p16 protein expression and human papilloma virus infection. The association of smoking and hmMGMT was investigated using multiple logistic regression analysis. Competing risk regression was used to evaluate the effects of hmMGMT and TP53-mutations in exon 2 to 11 on relapse of HNSCC. RESULTS: hmMGMT was observed in 84% of the 164 patients. TP53-mutations, specifically, G:C>A:T transition, were more frequent in patients with hmMGMT (32%) than in those without hmMGMT (8%). The frequency of disruptive TP53-mutations was not significantly different between groups. Compared with nonsmoking, heavy smoking of 20 pack-years or more was significantly associated with decreased hmMGMT (adjusted odds ratio, 0.08; 95% CI, 0.01 to 0.56; P = 0.01). Patients who had both hmMGMT and disruptive TP53-mutations showed a significantly higher relapse rate than all other patients (subdistribution hazard ratio, 1.77; 95% CI, 1.07 to 2.92; P = 0.026). CONCLUSIONS: It was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC.

Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma.

The molecular status of the epidermal growth factor receptor (EGFR) has not been as well studied in head and neck squamous cell carcinoma (HNSCC) as in lung cancer. We examined the frequencies of EGFR mutations as well as the expression/phosphorylation status of the EGFR protein in HNSCC patients. Moreover, we tried to elucidate associations between EGFR molecular status and patient characteristics and disease-free survival. In this prospective cohort study, clinical data and samples were obtained from 82 consecutive patients who had not been treated with EGFR molecular targeting therapy. Full-length EGFR was sequenced, and expression and phosphorylation of the EGFR protein were measured by Western blotting. Four novel mutations (E709K, V765G, Ins770G, and G1022S) and one mutation well-known in lung cancer (L858R) were identified in six HNSCC samples (7%), but we could not find any mutations in the extracellular domain of EGFR, such as EGFRvIII, in this study. E709K and Ins770G as well as L858R appear to be functional mutations based on the use of Ba/F3 cells. In terms of patient characteristics, the number of metastatic lymph nodes and node stage were associated with phosphorylation of EGFR. No patients with EGFR mutations relapsed during the study period. Excluding mutated cases, patients whose tumor samples showed phosphorylated EGFR relapsed significantly earlier than those without phosphorylated EGFR. This finding was still significant after adjusting for mutation and overexpression of EGFR protein using the Cox proportional hazard model. In conclusion, phosphorylated EGFR without mutations may be a marker of poor prognosis in patients with HNSCC.

Autologous human nasal epithelial cell sheet using temperature-responsive culture insert for transplantation after middle ear surgery.

Postoperative mucosal regeneration of the middle ear cavity and the mastoid cavity is of great importance after middle ear surgery. However, the epithelialization of the mucosa in the middle ear is retarded because chronic inflammation without epithelialization aggravates gas exchange and clinical function. These environmental conditions in the middle ear lead to postoperative retraction and adhesion of the newly-formed tympanic membrane. Therefore, if the mucosa on the exposed middle ear bone surface can be rapidly regenerated after surgery, the surgical treatments for cholesteatoma and adhesive middle ear disease can potentially be improved. In this study, we successfully generated a cell sheet designed for the postoperative treatment of cholesteatoma. We used nasal cells to create an artificial middle ear mucosal cell sheet with a three-dimensional (3D) configuration similar to that of the middle ear mucosa. The sheets consisted of multi-layered mucosal epithelia and lower connective tissue and were similar to normal middle ear mucosa. This result indicates that tissue-engineered mucosal cell sheets would be useful to minimize complications after surgical operations in the middle ear and future clinical applications are expected. Copyright © 2015 John Wiley & Sons, Ltd.

Adequate Number of Swallows for Pharyngeal Pressure Measurement of a Subject using High-resolution Manometry

Abstract Introduction The number of pressure measurements that need to be recorded using high-resolution manometry (HRM) for the accurate evaluation of pharyngeal function is not well established. Objective The purpose of this study is to clarify the number of swallows required to obtain an accurate pharyngeal manometric profile of a person. Methods Forty healthy adults performed a dry swallow and bolus swallows using 3-, 5-, or 10 ml of water and underwent measurements using the Starlet HRM system. Each subject underwent 10 swallows for each of the four bolus volume conditions. Results The mean of up to seven measurements of maximum pre-swallow upper esophageal sphincter pressure with 10 ml of swallow was close to the mean of up to eight measurements in 95% of the subjects. Similarly, the rate of change of the average for the eighth and ninth measurements and the rate of change for the average of the ninth and tenth measurements were less than 5 %. When the other parameters were similarly measured up to the sixth measurement, no major change in the average value was observed even if more measurements were taken. Conclusion A minimum of six measurements are required, and seven swallows are sufficient for evaluating the pharyngeal manometric profile of a single person. This number of measurements can be a useful criterion when performing HRM measurements on individual subjects.

Standardized Scalp Massage Results in Increased Hair Thickness by Inducing Stretching Forces to Dermal Papilla Cells in the Subcutaneous Tissue.

OBJECTIVE: In this study, we evaluated the effect of scalp massage on hair in Japanese males and the effect of stretching forces on human dermal papilla cells in vitro. METHODS: Nine healthy men received 4 minutes of standardized scalp massage per day for 24 weeks using a scalp massage device. Total hair number, hair thickness, and hair growth rate were evaluated. The mechanical effect of scalp massage on subcutaneous tissue was analyzed using a finite element method. To evaluate the effect of mechanical forces, human dermal papilla cells were cultured using a 72-hour stretching cycle. Gene expression change was analyzed using DNA microarray analyses. In addition, expression of hair cycle-related genes including IL6, NOGGIN, BMP4, and SMAD4 were evaluated using real-time reverse transcription-polymerase chain reaction. RESULTS: Standardized scalp massage resulted in increased hair thickness 24 weeks after initiation of massage (0.085 ± 0.003 mm vs 0.092 ± 0.001 mm). Finite element method showed that scalp massage caused z-direction displacement and von Mises stress on subcutaneous tissue. In vitro, DNA microarray showed gene expression change significantly compared with nonstretching human dermal papilla cells. A total of 2655 genes were upregulated and 2823 genes were downregulated. Real-time reverse transcription-polymerase chain reaction demonstrated increased expression of hair cycle-related genes such as NOGGIN, BMP4, SMAD4, and IL6ST and decrease in hair loss-related genes such as IL6. CONCLUSIONS: Stretching forces result in changes in gene expression in human dermal papilla cells. Standardized scalp massage is a way to transmit mechanical stress to human dermal papilla cells in subcutaneous tissue. Hair thickness was shown to increase with standardized scalp massage.

Middle ear mucosal regeneration with three-dimensionally tissue-engineered autologous middle ear cell sheets in rabbit model.

The likelihood of recurrent retraction and adhesion of newly formed tympanic membrane is high when middle ear mucosa is extensively lost during cholesteatoma and adhesive otitis media surgery. If rapid postoperative regeneration of the mucosa on the exposed bone surface can be achieved, prevention of recurrent eardrum adhesion and cholesteatoma formation, for which there has been no definitive treatment, can be expected. Suture-less transplantation of tissue-engineered mucosal cell sheets was examined immediately after the operation of otitis media surgery in order to quickly regenerate middle ear mucosa lost during surgery in a rabbit model. Transplantable middle ear mucosal cell sheets with a three-dimensional tissue architecture very similar to native middle ear mucosa were fabricated from middle ear mucosal tissue fragments obtained in an autologous manner from middle ear bulla on temperature-responsive culture surfaces. Immediately after the mucosa was resected from middle ear bone bulla inner cavity, mucosal cell sheets were grafted at the resected site. Both bone hyperplasia and granulation tissue formation were inhibited and early mucosal regeneration was observed in the cell sheet-grafted group, compared with the control group in which only mucosal removal was carried out and the bone surface exposed. This result indicates that tissue engineered mucosal cell sheets would be useful to minimize complications after the surgical operation on otitis media and future clinical application is expected.