Mitochondrial DNA with a Large-Scale Deletion Causes Two Distinct Mitochondrial Disease Phenotypes in Mice

Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (∆mtDNA), but there is no direct experimental evidence for this. To determine whether ∆mtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ∆mtDNA (mito-mice∆). Late-stage embryos carrying ≥50% ∆mtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ∆mtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ∆mtDNA in various tissues of the surviving mito-mice∆ increased with time, and Kearns-Sayre syndrome−like phenotypes were expressed when the proportion of ∆mtDNA in various tissues reached >70–80%. Our model mouse study clearly showed that a single ∆mtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of ∆mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice

Transoral surgery for superficial head and neck cancer: National Multi‐Center Survey in Japan

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1–75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2–357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1–113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment

Restoration of function in the paralyzed laryngeal muscles by functional electrical stimulation in cats

Elsevier, Akihiro, Katada ; Satoshi, Nonaka ; Isamu, Kunibe ; Masanobu, Imada ; Tatsuya, Hayashi ; Yasuaki, Harabuchi, International Coｎgress Series, 1240, 2003, 839-842. authorFunctional electrical stimulation (FES) has been debated as an innovative treatment in the management of patients with laryngeal paralysis. In this study, we examined whether FES to the paralyzed laryngeal adductor muscles improves the voice sounds impaired by unilateral laryngeal paralysis. We confirmed that the FES to the paralyzed thyroarytenoid muscle (TA) induced the adduction of vocal fold in decerebrate cats. Electrical stimulation delivered to periaqueductal grey (PAG) induced vocalization in the cats with unilateral laryngeal paralysis. We estimated the changes in duration of voice sounds, subglottic pressure, and quality of voice during vocalization with or without FES to the paralyzed TA muscle. The duration of voice sounds was prolonged by delivering the FES to paralyzed laryngeal adductor TA muscle. The subglottic pressure increased during vocalization with FES. The intensity of voice sounds increased, and the quality of voice sounds improved with FES. These results suggested that the FES to paralyzed adductor TA muscle could be expected to improve the quality of voice sounds in the animals with unilateral laryngeal paralysis. This study indicates the possibility that FES to the paralyzed laryngeal adductor muscles is accepted as a new therapy for patients with unilateral laryngeal paralysis

Functional electrical stimulation of laryngeal adductor muscle restores mobility of vocal fold and improves voice sounds in cats with unilateral laryngeal paralysis.

Elsevier, Katada, Akihiro ; Nonaka, Satoshi ; Adachi, Masaaki ; Kunibe, Isamu ; Arakawa, Takuya ; Imada, Masanobu ; Hayashi, Tatsuya ; Zealear, David L. ; Harabuchi, Yasuaki, Neuroscience Research, 50(2), 2004, 153-159. authorFunctional electrical stimulation (FES) has been proposed as a potential treatment for restoring motor functions of denervated motor systems. We investigated whether FES of paralyzed laryngeal adductor muscles could restore adduction to the vocal folds. In addition, we studied the effect of stimulated vocal fold adduction on the intensity and overall quality of voice production. We recorded movement of the vocal fold, electromyographic activity of muscles recruited for vocalization, and sound production in unanesthetized decerebrate cats during FES of the paralyzed thyroarytenoid (TA) muscle. FES of the paralyzed TA muscle induced adduction of the vocal fold. Appropriate stimulus parameters for induction was 1.5–3.0 mA intensity pulses delivered at a frequency of 30–50 pulses per second (pps). FES of the paralyzed TA muscle prolonged phonation time and increased intensity of voice sounds during vocalization induced by electrical stimulation (0.2 ms, 20–50 μA, 50 pps) of the periaqueductal gray (PAG). The quality of voice sounds evaluated by sound spectrography was shown to improve during vocalization with FES. We conclude that FES of the paralyzed laryngeal adductor muscle was effective in restoring adduction of the vocal fold and improving voice sounds impaired by unilateral laryngeal paralysis

Treatment outcomes of alternating chemoradiotherapy for nasopharyngeal carcinoma: a single-center safety and efficacy study

Objective: To evaluate the efficacy and safety of Alternating Chemoradiotherapy (ACRT) using cisplatin and 5-Fluorouracil (5-FU) in patients with nasopharyngeal carcinoma. Methods: This was a retrospective study in which patients’ clinical records were reviewed to identify patients with a new diagnosis of nasopharyngeal carcinoma at our institution between January 2005 and January 2019. Thirty-seven eligible patients were identified; of these, the clinical details of 27 patients treated with ACRT were evaluated. Patient outcomes, including overall survival and progression-free survival, and adverse events were assessed. Results: Of these initial 37 patients, 1, 10, 13, 10, and 3 were staged as I, II, III, IVA, and IVB, respectively, as defined by the 8th edition of the TNM classification system. Twenty-seven patients received ACRT comprising sequential administration of chemotherapy, radiotherapy (wide field), chemotherapy, radiotherapy (shrinking field), and chemotherapy. The 5-year overall survival and progression-free survival rates were 83.7% and 88.9%, respectively. Treatment compliance was 93%, which is comparable to that of previous reports. Conclusion: ACRT using cisplating and 5-fluorouracil was well tolerated with acceptable efficacy. Level of Evidence: IV