Published papers

Objectives/Hypothesis: This study was designed to assess the feasibility of the submucosal infusion technique combined with microflap dissection as a radical therapeutic and diagnostic option for precancerous laryngeal leukoplakia. Study Design: Retrospective study. Methods: Severe dysplasia or carcinoma in situ was diagnosed after phonomicrosurgical dissections in 25 patients with unilateral laryngeal leukoplakia. Of these, 15 patients preferred no additional surgery (observation group), whereas 10 patients underwent further laser subligamental cordectomy (additional surgery group). The relationship between the initial surgical margin and histopathological characteristics of additionally excised tissues was assessed to evaluate diagnostic reliability. Disease control was assessed to determine the oncologic efficacy of the therapeutic procedure. Comparative multidimensional vocal assessments were performed in both groups to evaluate functional advantages of one-stage excision. Results: After the initial phonomicrosurgical resection, three patients had residual dysplastic lesions near the vocal process and anterior commissure, whereas three other patients had lesions suspicious for recurrence. No postoperative malignant transformation was observed in any patient. Although well-preserved vocal function was observed in the observation group, vocal quality deteriorated shortly after laser surgery in the additional surgery group. Regarding acoustics, aerodynamics, and quality-of-life evaluations, statistically equivalent scores were observed between the observation and control groups, whereas scores were inferior in the additional surgery group than in the control group. Conclusions: Phonomicrosurgical resection may be a therapeutic option with oncologic efficacy against precancerous laryngeal leukoplakia. This radical management might achieve more satisfactory postoperative vocal function. Level of Evidence: NA Laryngoscope, 127:153–158, 2017.

Globus sensation is a common symptom seen daily in ear-nose-throat (ENT) clinics. Globus is affected by multiple factors, and of these, gastroesophageal reflux disease (GERD), has been recognized as a relatively more manageable cause of globus than the other causes. However, we still commonly encounter globus patients with unclear backgrounds who require multiple diagnostic and therapeutic modalities. To provide an appropriate treatment approach and create favorable situations for these patients, we developed and applied an intramural algorithm to manage globus considering GERD, laryngeal allergy, and psychological problems as major factors of this pathology. Twenty-six patients with globus sensation who visited our voice clinic from June 2012 to March 2015 were enrolled in this study. All these patients had undergone general ENT examinations, including naso-pharyngo-laryngeal endoscopies and cervicothoracic computed tomographic scans. Upper gastrointestinal endoscopy revealed 2 cancers. Further study classified 23 patients into the GERD group and 1 patient into the allergy group. Proton pump inhibitor (PPI) therapy was successful in 11 patients of the GERD group (response rate, 47.2%). Improvement in subjective symptoms of globus were measured by the scores of questionnaires, including the F scale and Reflux Symptom Index. Significant improvement in these scores were observed 1 month after PPI prescription in the PPI-responder group in this study. Further assessment of medical history as well as the scores of questionnaires to measure the severity levels of depression (Self-rating Depression Scale) and anxiety (State-Trait Anxiety Inventory-Form JYZ, STAI) proved that relatively longer lasting symptoms (≥4 months) or relatively higher anxiety scores (STAIS50 points) were predictive of PPI resistance. Our study results suggested that the pathology of globus is affected by multiple factors and that a multidisciplinary team approach is required for better management of this disease.

Background & aims: Malnutrition is common in patients with head and neck cancer (HNSCC). It may be related to severe adverse toxicity as a result of radiotherapy. The aim was to investigate nutritional screening factors for severe adverse events. Methods: A retrospective chart review of 101 patients who underwent radiotherapy from 2009 to 2013 was performed. The relationships among severe adverse events and pretreatment nutritional parameters, including static variables (serum albumin, total protein, total lymphocyte counts, body mass index), dynamic variables (retinol-binding protein, transferrin, pre-albumin), and nutritional screening tools (Onodera's Prognostic Nutrition Index [O-PNI]; Nutrition Risk Index; Controlling Nutritional Status [CONUT] score; Nutritional Risk Screening 2002) were evaluated in addition to patient and treatment factors. Results: According to the static parameters, approximately 30% of patients were malnourished before treatment. Twenty-four patients exhibited severe adverse events. On univariate analysis, combined chemotherapy, advanced staging, O-PNI <40, and CONUT score ≥5 were significant predictors of severe adverse events. Multivariate analysis revealed that O-PNI <40 and combined chemotherapy independently predict severe adverse events. Conclusions: O-PNI is considered a useful nutritional factor for predicting severe adverse events in HNSCC patients undergoing chemoradiotherapy and facilitates the planning of aggressive nutritional interventions prior to treatment.

The mechanisms regulating viral pathogenesis of human papillomavirus (HPV) associated oropharyngeal squamous cell cancers (OPSCC) are not well understood. In the cervix, activation of DNA damage repair pathways is critical for viral replication but little is known about their role in OPSCC. APOBEC factors have been shown to be increased in OPSCC but the significance of this is unclear. We therefore examined activation of DNA damage and APOBEC factors in HPV-induced OPSCC. Our studies show significantly increased levels of pCHK1, FANCD2, BRCA1, RAD51, pSMC1 and γH2AX foci in HPV-positive samples as compared to HPV-negative while the ATM effector kinase, pCHK2, was not increased. Similar differences were observed when the levels of proteins were examined in OPSCC cell lines. In contrast, the levels of APOBEC3B and 3A were found to be similar in both HPV-positive and -negative OPSCC. Our studies suggest members of ATR pathway and FANCD2 may be important in HPV-induced OPSCC.

Background and Aims: Allergic rhinitis annually reach epidemic proportions in Japan. Approximately 30 to 40% of the population suffers from allergic rhinitis during the spring season. Symptoms comprise rhinorrhea, nasal congestion, and sneezing accompanied by irritation and itching of the eyes. The Ohshiro Clinic started using the conventional Nd:YAG laser for the treatment of allergic rhinitis in 1993, and from 2005 we started using a diode laser-pumped Nd:YAG laser. From 2010, we adopted a novel 810 nm diode laser, and the present retrospective study examined the efficacy rate of the treatment of allergic rhinitis in the 2018 season with this system, compared with a previous study in 2011. We aimed to confirm the degree of improvement for each symptom to evaluate effectiveness of the diode laser treatment. Subjects and methods: Between January 8, 2018 and April 30, 2018, a large number of patients consulted our clinic with the major complaint of seasonal allergic rhinitis. They underwent a blood test, and the antigen-specific serum IgE antibody titers were measured for a definitive diagnosis of cedar pollinosis. A total of 211 target patients were treated during the trial period. The average age of the target group was 36.3 years, 134 males, and 77 females. The target patients were treated with lower nasal turbinate mucosal irradiation using a diode laser (ADL-20, Asuka Medical) delivering 810 nm at 7.5 W, with a total energy per treatment of 240 J/cm2. We adopted a five-step evaluation in accordance with the Japanese Guidelines for Allergic Rhinitis 2014 for the symptoms of rhinorrhea, sneezing and nasal obstruction. We assessed the degree of improvement in the severity of these symptoms following diode laser treatment from baseline to one month after treatment, in addition to assessing patient satisfaction with the degree of improvement in their quality of life (QOL). Results: The 211 patients positive for cedar pollinosis by the antigen-specific serum IgE antibody tests were broken down by month by number and by improvement, no change or exacerbation as follows. January, 18 patients: 33.4%, 44.4% and 22.2%, respectively. February, 29: 10.4%, 44.4% and 22.2%, respectively. March, 146: 60.3%, 31.5% and 8.2%, respectively. April, 18: 77.8%, 16.7% and 5.5%, respectively. The monthly respective improvement, no change or worse patient QOL as percentages were as follows: January: 16.7%, 44.4% and 38.9%. February: 17.3%, 13.8% and 68.9%. March: 61.6%, 29.5% and 8.9%. April: 94.4%, 0.0% and 5.6%. The values for prevention of exacerbation versus exacerbation for each month were: January, 77.8% vs 22.2%; February, 41.4% vs 58.6%; March, 91.8% vs 8.2%; and April, 94.4% vs 5.6%. The mean efficacy rate for the trial period in the present study was therefore 52.6% which compared very favorably with the mean efficacy rate in the 2011 study of 53.4%. Conclusions: The results showed that the 810 nm diode laser offered a safe and effective solution for the uncomfortable symptoms of allergic rhinitis and could be well applied during the season of Japanese cedar pollen dispersion. Furthermore, a tendency towards high efficacy was demonstrated for laser treatment in class 6 cedar pollinosis patients, based on the specific IgE antibody test.

Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets.

Topoisomerases regulate higher-order chromatin structures through the transient breaking and religating of one or both strands of the phosphodiester back-bone of duplex DNA. TOP2β is a type II topoisomerase that induces double-strand DNA breaks at topologically associated domains (TADS) to relieve torsional stress aris-ing during transcription or replication. TADS are anchored by CCCTC-binding factor (CTCF) and SMC1 cohesin proteins in complexes with TOP2β. Upon DNA cleavage, a covalent intermediate DNA-TOP2β (TOP2βcc) is transiently generated to allow for strand passage. The tyrosyl-DNA phosphodiesterase TDP2 can resolve TOP2βcc, but failure to do so quickly can lead to long-lasting DNA breaks. Given the role of CTCF/ SMC1 proteins in the human papillomavirus (HPV) life cycle, we investigated whether TOP2β proteins contribute to HPV pathogenesis. Our studies demonstrated that levels of both TOP2β and TDP2 were substantially increased in cells with high-risk HPV genomes, and this correlated with large amounts of DNA breaks. Knockdown of TOP2β with short hairpin RNAs (shRNAs) reduced DNA breaks by over 50% as determined through COMET assays. Furthermore, this correlated with substantially reduced formation of repair foci such as phosphorylated H2AX (γH2AX), phosphorylated CHK1 (pCHK1), and phosphorylated SMC1 (pSMC1) indicative of impaired activation of DNA damage repair pathways. Importantly, knockdown of TOP2β also blocked HPV genome replication. Our previous studies demonstrated that CTCF/SMC1 factors associate with HPV genomes at sites in the late regions of HPV31, and these correspond to regions that also bind TOP2β. This study identifies TOP2β as responsible for enhanced levels of DNA breaks in HPV-positive cells and as a regulator of viral replication.

74歳男性。嗄声および咽頭違和感を主訴とした。乳頭腫の診断で経過観察されていたが増大傾向となった。喉頭ファイバーで声門上に右仮声帯を基部とする大きな腫瘍を認め、声門の視認はできなかった。鼻内からの喉頭ファイバー挿管は困難であったため、初回は無挿管ニューロレプト麻酔下手術で腫瘍の減量を行い、二期的に全身麻酔下に喉頭微細手術を行った。残存した腫瘍は、約4ヵ月後に全身麻酔下でCO2レーザーによる蒸散を行った。退院後の外来での喉頭ファイバーでは、肉眼的に腫瘍の残存は認められない。

Preoperative diagnosis of lymph node metastasis from thyroid carcinoma is usually confirmed by using fine needle aspiration cytology(FNAC)when thyroid carcinoma is suspected based on the clinical findings. However, the result of FNAC sometimes leads to a false negative, especially in cases of hypocellular lesions such as metastases with cystic change. Thyroglobulin measurement in fine needle aspirates(FNA-Tg)has been shown to be a useful technique to detect the protein specifically secreted by thyroid follicular cells. Elevated FNA-Tg levels in an extra-thyroidal lesion means that the lesion comprises thyroid-originated tissue, most of which suggests the metastasis from thyroid carcinoma. Thus, FNA-Tg is expected to improve the sensitivity of FNAC for the aforementioned purpose. Patients and Methods : From 2008 to 2012, 49 extra-thyroidal lesions from 43 patients with thyroid carcinoma were examined using both FNAC and FNA-Tg, followed by surgical resection with a histopathological diagnosis. The results were retrospectively reviewed and analyzed. Results : Among 49 lesions, 47 were metastatic lymph nodes from thyroid carcinoma-46 papillary carcinoma and one follicular carcinoma-, one was a metastatic lymph node from submandibular gland adenocarcinoma, and one was an ectopic thyroid gland. In the 47 cases of thyroid carcinoma, the sensitivity of FNAC was 57.4%(27/47), whereas that of FNA-Tg was 76.6%(36/47). When both methods were combined, the sensitivity increased to 93.6%(44/47). Metastasis from submandibular gland adenocarcinoma was considered to be an example of a false positive from FNAC, whereas an ectopic thyroid gland was an FNA-Tg false positive. Three lesions were negative for both FNAC and FNA-Tg, although metastases were suspected by imaging studies and confirmed by histopathological diagnosis, which were consistent with examples of a false negative from both FNAC and FNA-Tg findings. Conclusions : FNAC reflects whether the lesion has malignant cells, whereas FNA-Tg reflects whether the lesion has thyroid-originated tissue that specifically secrets thyroglobulin. Therefore, FNAC and FNA-Tg are considered to be complementary to each other for the preoperative diagnosis of lymph node metastasis from thyroid carcinoma. FNA-Tg was validated to improve the preoperative diagnostic sensitivity especially when combined with FNAC, however, it is attended with the possibility of a false positive or negative finding, which requires caution in interpretation of the findings.

BACKGROUND: Preoperative diagnosis of lymph node metastasis from thyroid carcinoma is usually confirmed by using fine needle aspiration cytology (FNAC) when thyroid carcinoma is suspected based on the clinical findings. However, the result of FNAC sometimes leads to a false negative, especially in cases of hypocellular lesions such as metastases with cystic change. Thyroglobulin measurement in fine needle aspirates (FNA-Tg) has been shown to be a useful technique to detect the protein specifically secreted by thyroid follicular cells. Elevated FNA-Tg levels in an extra-thyroidal lesion means that the lesion comprises thyroid-originated tissue, most of which suggests the metastasis from thyroid carcinoma. Thus, FNA-Tg is expected to improve the sensitivity of FNAC for the aforementioned purpose.PATIENTS AND METHODS: From 2008 to 2012, 49 extra-thyroidal lesions from 43 patients with thyroid carcinoma were examined using both FNAC and FNA-Tg, followed by surgical resection with a histopathological diagnosis. The results were retrospectively reviewed and analyzed.RESULTS: Among 49 lesions, 47 were metastatic lymph nodes from thyroid carcinoma (46 papillary carcinoma and one follicular carcinoma), one was a metastatic lymph node from submandibular gland adenocarcinoma, and one was an ectopic thyroid gland. In the 47 cases of thyroid carcinoma, the sensitivity of FNAC was 57.4% (27/47), whereas that of FNA-Tg was 76.6% (36/47). When both methods were combined, the sensitivity increased to 93.6% (44/47). Metastasis from submandibular gland adenocarcinoma was considered to be an example of a false positive from FNAC, whereas an ectopic thyroid gland was an FNA-Tg false positive. Three lesions were negative for both FNAC and FNA-Tg, although metastases were suspected by imaging studies and confirmed by histopathological diagnosis, which were consistent with examples of a false negative from both FNAC and FNA-Tg findings.CONCLUSIONS: FNAC reflects whether the lesion has malignant cells, whereas FNA-Tg reflects whether the lesion has thyroid-originated tissue that specifically secrets thyroglobulin. Therefore, FNAC and FNA-Tg are considered to be complementary to each other for the preoperative diagnosis of lymph node metastasis from thyroid carcinoma. FNA-Tg was validated to improve the preoperative diagnostic sensitivity especially when combined with FNAC, however, it is attended with the possibility of a false positive or negative finding, which requires caution in interpretation of the findings.