Characteristic Laryngeal Findings in Patients with Pemphigus Vulgaris.

OBJECTIVE: Pemphigus Vulgaris (PV) is a rare autoimmune disease that could cause laryngeal lesions; however, only a few studies have described the localization of the laryngeal lesions associated with this disease owing to its rarity. Therefore, this study aimed to determine the localization of laryngeal lesions in patients with PV. METHODS: Fourteen patients with PV accompanied by laryngeal or pharyngeal lesions, who underwent flexible laryngeal endoscopy performed by laryngologists, were examined retrospectively. RESULTS: The arytenoid area was the most frequently affected site in the larynx, followed by the epiglottis and aryepiglottic folds. Vocal folds and ventricular bands were the least affected. CONCLUSION: Lesions in the arytenoid area were observed more frequently in this study than in previous studies. This result suggests that a more careful inspection of arytenoid lesions in patients with PV is required under laryngeal fiber observation. Moreover, we proposed a novel classification system for laryngeal findings in patients with PV and a systematic observation method. This novel classification and method would be useful not only for determining the lesions but also for careful inspection in this field. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2024.

Sarcopenia accompanied by systemic inflammation can predict clinical outcomes in patients with head and neck cancer undergoing curative therapy.

Objectives: Evaluation of sarcopenia accompanied by systemic inflammation status is a more beneficial prognostic marker than sarcopenia alone in various cancers. However, few studies have focused on this combination in patients with head and neck squamous cell cancer (HNSCC). In this study, we investigated how the combination of sarcopenia and systemic inflammation could affect survival in patients with HNSCC. Moreover, we explored which systemic inflammation markers could be better prognostic indicators when accompanied by sarcopenia. Materials and methods: We retrospectively reviewed the medical records of patients with HNSCC treated between 2012 and 2016. Sarcopenia was defined by the skeletal muscle area measured on a computed tomography image slice at the level of the third cervical vertebra. The neutrophil/lymphocyte, platelet/lymphocyte, and lymphocyte/monocyte ratios (NLR, PLR, and LMR, respectively) were used as systemic inflammation markers that were combined with sarcopenia to evaluate prognosis. Results: A total of 100 patients were enrolled, and 71 patients were considered sarcopenia. Patients with sarcopenia had significantly lower LMR and higher NLR and PLR. They also showed worse overall survival (OS) and progression-free survival (PFS). The comparative assessment of multiple combination patterns of sarcopenia and systemic inflammation indices proved that sarcopenia plus LMR considered as most reliable indicator for prognosis in HNSCC patients. Sarcopenia plus low LMR was a significantly poor prognostic factor both for OS and PFS with greater HR values than sarcopenia alone. Conclusions: The combination of sarcopenia and LMR was considered the most sensitive prognostic factor in patients with HNSCC, suggesting it might be beneficial for identifying poor outcome risks.

Utility and optimal management of planned drug holidays during lenvatinib treatment in patients with unresectable differentiated thyroid cancer: a real-world multi-center study.

PURPOSE: Lenvatinib achieves favorable therapeutic outcomes for patients with radioactive iodine therapy refractory differentiated thyroid cancer (DTC); however, its use is associated with a high incidence of adverse events. To avoid severe adverse events, planned drug holidays (PDH) have been proposed. This study aimed to evaluate treatment effects, identify prognostic factors, and investigate the usefulness of PDH in patients with unresectable DTC who received lenvatinib across the multi-institutions. METHODS: Fifty-one patients with unresectable DTC treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated, and prognostic factors were assessed. OS, PFS, and time to treatment failure (TTF) were compared between patients with and without PDH. Lenvatinib administration schedule was evaluated in PDH. RESULTS: The 3-year OS and PFS rate were 53.5% and 42.1%, respectively. Multivariate analysis revealed that presence of maximum size of lung metastasis ≥10 mm was independent prognostic factor for poorer OS and PFS, and histology other than papillary thyroid carcinoma was the independent prognostic factor for poorer PFS. Twenty-five patients (49%) treated with PDH. There were significant differences in OS, PFS, and TTF between patients with and without PDH. Various schedules were used in PDH. Eight (32%) patients required switch to the different administration schedule. CONCLUSION: Our results suggest that PDHs may extend OS, PFS, and TTF. In patients with PDH, various schedules used for lenvatinib administration highlight the difficulty in determining a uniform administration schedule. Therefore, it is crucial to consider the optimal lenvatinib administration schedule on a case-by-case basis.

Low-Dose Cisplatin-Based Radiation Therapy for Refractory Recurrent Respiratory Papillomatosis.

Recurrent respiratory papilloma (RRP) often presents multiple lesions in the respiratory tract and sometimes becomes fatal because of severe airway obstruction. We report the case of a 69-year-old woman who had juvenile-onset RRP in the trachea that was refractory to surgical treatment, and complete remission was achieved by low-dose cisplatin combined with de-escalated radiotherapy without any side effects. This case report is the first to illustrate the data on low-dose cisplatin for refractory benign RRP, and our experience reinforces the opinion that low-dose cisplatin combined with de-escalated radiotherapy can be an effective and safe treatment alternative for uncontrollable and lethal RRP. Laryngoscope, 134:2335-2337, 2024.

Effectiveness of vocal fold medialization surgery on the swallowing function of patients with unilateral vocal fold paralysis.

Objectives: Vocal fold medialization surgery is generally considered a phonosurgical procedure for improvement of vocal function in patients with glottic insufficiency. However, the literature describing this procedure for the management of dysphagia is limited. This study aims to assess the effects of medialization surgery on swallowing function in patients with unilateral vocal fold paralysis (UVFP). Methods: We enrolled 32 patients with UVFP undergoing vocal fold medialization surgery (medialization laryngoplasty combined with arytenoid adduction [ML + AA], 12 cases; injection laryngoplasty [IL], 20 cases). We assessed the aerodynamic vocal function including maximum phonation time and mean flow rate to evaluate glottal closure status. The Hyodo score determined by flexible endoscopic evaluation and Functional Oral Intake Scale (FOIS) were evaluated pre- and postoperatively. Results: Almost 60% of patients with UVFP had dysphagia, and one-third were at high risk for aspiration. Aerodynamic parameters effectively improved after IL and ML + AA. With regard to swallowing, both the FOIS and total Hyodo score were significantly improved postoperatively. We found a particularly significant improvement in pharyngeal clearance. However, patients with high vagal nerve paralysis and postoperative insufficient glottal closure showed poor swallowing benefits after the interventions. In patients with recurrent laryngeal nerve palsy, there were no significant differences in postoperative swallowing function between the ML + AA and IL groups. Conclusion: Vocal fold medialization surgery was effective in improving swallowing function in most cases with UVFP, except for those with high vagal paralysis and insufficient postoperative glottal closure. Both IL and ML + AA showed an equivalent effect on swallowing improvement. Level of evidence: 3b.

Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses.

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.

Topoisomerase 2ß Induces DNA Breaks To Regulate Human Papillomavirus Replication.

Topoisomerases regulate higher-order chromatin structures through the transient breaking and religating of one or both strands of the phosphodiester backbone of duplex DNA. TOP2ß is a type II topoisomerase that induces double-strand DNA breaks at topologically associated domains (TADS) to relieve torsional stress arising during transcription or replication. TADS are anchored by CCCTC-binding factor (CTCF) and SMC1 cohesin proteins in complexes with TOP2ß. Upon DNA cleavage, a covalent intermediate DNA-TOP2ß (TOP2ßcc) is transiently generated to allow for strand passage. The tyrosyl-DNA phosphodiesterase TDP2 can resolve TOP2ßcc, 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 TOP2ß proteins contribute to HPV pathogenesis. Our studies demonstrated that levels of both TOP2ß and TDP2 were substantially increased in cells with high-risk HPV genomes, and this correlated with large amounts of DNA breaks. Knockdown of TOP2ß 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 TOP2ß 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 TOP2ß. This study identifies TOP2ß as responsible for enhanced levels of DNA breaks in HPV-positive cells and as a regulator of viral replication.IMPORTANCE High-risk human papillomaviruses (HPVs) infect epithelial cells and induce viral genome amplification upon differentiation. HPV proteins activate DNA damage repair pathways by inducing high numbers of DNA breaks in both viral and cellular DNAs. This activation is required for HPV genome replication. TOP2ß is a type II topoisomerase that induces double-strand DNA breaks at topologically associated domains (TADS) to relieve torsional stress arising during transcription or replication. Our studies demonstrate that TOP2ß levels are increased in HPV-positive cells and that this is required for HPV replication. Importantly, our studies further show that knockdown of TOP2ß reduces the number of breaks by over 50% in HPV-positive cells and that this correlates with substantially impaired activation of DNA repair pathways. This study identifies a critical mechanism by which HPV replication is regulated by the topoisomerase TOP2ß through DNA break formation.

Activation of DNA damage repair factors in HPV positive oropharyngeal cancers.

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.

Efficacy of seasonal allergic rhinitis using an 810 nm diode laser system.

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.

Phonosurgical resection using submucosal infusion technique for precancerous laryngeal leukoplakia.

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.

Pre-therapeutic nutritional assessment for predicting severe adverse events in patients with head and neck cancer treated by radiotherapy.

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.

Multidimensional vocal assessment after laser treatment for recurrent respiratory papillomatosis.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a benign epithelial tumor that exhibits a high frequency of recurrence. This study assesses the vocal function after laser treatment for RRP, particularly in relation to the frequency of surgery. STUDY DESIGN: Retrospective study. METHODS: Thirty RRP patients who underwent laser surgery that controlled the tumor were included. Preoperative and postoperative Grade, Roughness, Breathiness, Asthenia, and Strain Scale, videostroboscopic findings, aerodynamic and acoustic parameters, and self-assessment questionnaires were measured and compared with an age- and sex-matched control group. Subsequently, to evaluate the association between postoperative voice quality and the number of surgeries, the patients were divided into three groups (group 1: single surgery, group 2: 2-5 surgeries, group3: >6 surgeries), and comparative multidimensional vocal assessments were performed. RESULTS: The mean number of surgeries was 3.4 (range, 1-8). Although all patients exhibited poorer vocal function than the control group preoperatively, they showed improvement in postoperative subjective and objective parameters. However, four patients who underwent one surgery with relatively aggressive ablation exhibited vocal cord scarring and deteriorated objective parameters. All remaining patients showed voice quality that was on par with the control group. Subgroup analysis proved no association between post-therapeutic voice quality and the patient characteristics, including preoperative staging and the number of surgical treatments performed. CONCLUSIONS: RRP patients can achieve a close to normal voice with high satisfaction even after recurrent surgical treatment when ablation of a subepithelial lesion using sufficient laser energy is adequate. LEVEL OF EVIDENCE: 3b Laryngoscope, 127:679-684, 2017.

[Usefulness and Limitation of Thyroglobulin Measurement in Fine Needle Aspirates (FNA-Tg) for Diagnosis of Neck Lymph Node Metastasis from Thyroid Carcinoma].

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.

Comparative multidimensional assessment of laryngeal function and quality of life after radiotherapy and laser surgery for early glottic cancer.

BACKGROUND: This study was designed to comparatively assess laryngeal function and quality of life (QOL) of patients after laser surgery (LS) or radiotherapy (RT) for early glottic cancer. METHODS: Sixty-four patients with T1 glottic cancer treated with RT or type II cordectomy underwent both subjective and objective vocal assessments. The LS group was divided into the following: (1) vaporization with defocused mode (laser surgery [LS]-Vap); and (2) excision with focused mode using lower power (LS-Ex). RESULTS: Auditory-perceptual evaluation and videostroboscopic images in the LS-Ex group worsened shortly after treatment and time-dependent recovery was quicker than in the LS-Vap group. The LS-Ex group showed equivalent posttherapeutic vocal function with the RT group by acoustics, aerodynamics, and self-assessment questionnaire analysis, whereas the LS-Vap group showed statistically significant worse function. CONCLUSION: The multidimensional assessment showed that early glottic cancer could be successfully treated by either RT or LS-Ex with equivalent posttherapeutic laryngeal function and QOL. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1085-1090, 2016.

Clinical Review of Globus Patients with a Focus on GERD Cases.

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 (STAI≥50 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.