Biophysical properties of the neck skin indicating potential complications of salvage surgery for laryngeal/hypopharyngeal cancer.

BACKGROUND: Chemoradiation therapy is standard practice for hypopharyngeal and laryngeal cancer, but its impact on skin health can cause complications if salvage surgery is required. AIMS/OBJECTIVES: To develop simple objective indices for the early detection of complications following head-and-neck salvage surgery. MATERIAL AND METHODS: Preoperatively and on postoperative days 1, 3, 5 and 7, we measured skin hardness (N), interstitial liquid content (П) and intracellular liquid content (W) as biophysical properties in patients who underwent post-CRT salvage therapy and those who underwent total organ resection without CRT as controls. We then analyzed these data in relation to occurrence of complications. RESULTS: In 11 patients undergoing salvage surgery and 23 controls, complications tended to be higher (p = .54) in the salvage group. N values were significantly higher in the salvage and complication groups on days 5 and 7, П values were higher in the complication group on day 7, and W values were lower in the complication group on day 3 and in the salvage group preoperatively and on days 1 and 5. CONCLUSIONS AND SIGNIFICANCE: N, П and W are useful measurements for the early identification of patients likely to develop complications.

Pattern of Recurrence After Platinum-Containing Definitive Therapy and Efficacy of Salvage Treatment for Recurrence in Patients with Squamous Cell Carcinoma of the Head and Neck.

Background: In first-line systemic therapy for unresectable recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), regimens are generally selected by time-to-relapse with 6 months cutoff after platinum (Pt)-containing definitive therapy, Pt-refractory or Pt-sensitive recurrence, but clinical characteristics between Pt-refractory and Pt-sensitive recurrence of R/M SCCHN has not been fully investigated. This study aimed to evaluate pattern of recurrence and efficacy for salvage treatment for recurrence after Pt-containing definitive therapy for R/M SCCHN in a real-world setting. Methods: We retrospectively reviewed 150 patients treated with Pt-containing definitive therapy and analyzed the pattern of recurrence and efficacy of salvage therapy for 63 patients with R/M SCCHN. Results: Pt-refractory recurrence, Pt-sensitive recurrence, second primary cancer (SPC), and no relapse occurred in 23.3%, 18.7%, 14.7%, and 43.3% of patients, respectively. In the cases with distant metastatic recurrence, symptomatic recurrence was significantly more common in the Pt-refractory recurrence, while asymptomatic recurrence was significantly more common in the Pt-sensitive recurrence. The timing of detection of SPC was after 2 years in 59.0% of cases after the completion of definitive therapy and 63.6% of SPC were asymptomatic. There was a significant difference in ΔNLR2 (NLR after definitive therapy minus NLR at detection recurrence; p = 0.028) and in prognosis after the detection of recurrence for the overall population (p = 0.021), and for salvage treatment group (p = 0.023), and systemic therapy group (p = 0.003) between Pt-refractory and Pt-sensitive groups. Conclusions and Significance: Our analysis revealed the recurrence pattern after Pt-containing definitive therapy and showed the validity of dividing patients into Pt-refractory and Pt-sensitive recurrence with different prognosis in salvage therapy, especially systemic therapy.

Retreatment with nivolumab for patients with recurrent and/or metastatic head and neck cancer.

BACKGROUND: After treatment with an immune checkpoint inhibitor (ICI) is discontinued, retreatment with an ICI is a potential sequential treatment, but the clinical efficacy/safety data for this treatment of recurrent and/or metastatic head and neck cancer (R/M-HNC) are limited. AIMS/OBJECTIVES: This study aimed to evaluate the efficacy and safety of retreatment with nivolumab in R/M HNC. MATERIALS AND METHODS: We divided the 29 eligible R/M-HNC patients who discontinued ICI treatment at our hospital into two cohorts to analyze the clinical characteristics and the efficacy of the salvage therapy: the Niv cohort (nivolumab retreatment) and the no-Niv cohort (no nivolumab retreatment). RESULTS: The Niv cohort's median overall survival (OS) of 17.5 months (95% confidence interval [CI]: 2.7-32.3) was significantly prolonged compared to that of the no-Niv cohort: 5.8 months (95%CI: 2.4-9.2, p = .034). The Niv cohort achieved objective response rate of 16.7% and a disease control rate of 50.0%. No adverse events > grade 3 occurred in the Niv cohort. CONCLUSION: Nivolumab retreatment is an option for sequential treatment post-immunotherapy.

Frequency-specific prediction model of hearing outcomes in patients with idiopathic sudden sensorineural hearing loss.

PURPOSE: The hearing outcome of idiopathic sudden sensorineural hearing loss (ISSNHL) is hard to predict. We herein constructed a multiple regression model for hearing outcomes in each frequency separately in an attempt to achieve practical prediction in ISSNHL. METHODS: We enrolled 235 consecutive in-patients with ISSNHL who were treated in our department from 2015 to 2020 (average hearing level at 250-4000 Hz ≥ 40 dB; time from onset to treatment ≤ 14 days; 126 males/109 females; age range 17-87 years (average 61.0 years)). All patients received systemic prednisolone administration combined with intratympanic dexamethasone injection. The pure-tone hearing threshold of 125-8000 Hz was measured at every octave before (HLpre) and after (HLpost) treatment. A multiple regression model was constructed for HLpost (dependent variable) using five explanatory variables (age, days from onset to treatment, presence of vertigo, HLpre, and hearing level of the contralateral ear). RESULTS: The multiple correlation coefficient increased as the frequency increased. Strong correlations were seen in high frequencies, with multiple correlation coefficients of 0.784/0.830 for 4000/8000 Hz. The width of the 70% prediction interval was narrower for 4000/8000 Hz (± 18.2/16.3 dB) than for low to mid-frequencies. Among the five explanatory variables, HLpre showed the largest partial correlation coefficient for any frequency. The partial correlation coefficient for HLpre increased as the frequency increased, which may partially explain the high multiple correlation coefficients for high frequencies. CONCLUSION: The present model would be of practical use for predicting hearing outcomes in high frequencies in patients with ISSNHL.

Expression of T-Type Voltage-Gated Calcium Channel in the Cilia of Human Nasal Epithelial Cells.

INTRODUCTION: The mucociliary transport function of the airway epithelium is largely dependent on ciliary beating. The control signal of ciliary beating is thought to be intracellular Ca2+. We herein investigated the expression of T-type voltage-gated calcium channel (VGCC), a generator of intracellular Ca2+ oscillation, in the human nasal mucosa. METHODS: The inferior turbinate was collected from patients with chronic hypertrophic rhinitis. The expression of T-type VGCC α1 subunits was examined by immunohistochemistry, transmission immunoelectron microscopy, Western blot, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Participation of T-type VGCC in the ciliary beat regulation was examined by pharmacological inhibition tests using specific blockers of T-type VGCC in ex vivo measurements of the ciliary beat frequency (CBF) and ATP release and in intracellular Ca2+ imaging of isolated ciliated cells. RESULTS: Immunohistochemical staining showed the expressions of T-type VGCC α1 subunits, Cav3.1 and Cav3.3, on the surface of the epithelial cells. At the ultrastructural level, immunoreactivity for Cav3.1 was localized on the surface of the cilia, and that for Cav3.3 was localized in the cilia and at the base of the cilia. The existence of Cav3.1 and Cav3.3 was confirmed at the protein level by Western blot and at the transcriptional level by real-time RT-PCR. Specific blockers of T-type VGCC, mibefradil and NNC 55-0396, significantly inhibited CBF. These blockers also inhibited a CBF increase induced by 8-bromo-cAMP/8-bromo-cGMP and significantly lowered the intracellular Ca2+ level of isolated ciliated cells in a time-dependent manner. On the other hand, the ATP release from the nasal mucosa was not changed by mibefradil or NNC 55-0396. CONCLUSION: These results indicate that T-type VGCC α1 subunits, Cav3.1 and Cav3.3, exist at the cilia of the nasal epithelial cells and participate in the regulation of ciliary beating and that these channels act downstream of cAMP/cGMP.

Decreased CFTR/PPARγ and increased transglutaminase 2 in nasal polyps.

OBJECTIVE: Transglutaminase (TGM)2 and peroxisome proliferator-activated receptor (PPAR)γ are thought to participate in the pathogenesis of nasal polyp formation in cystic fibrosis (CF). We herein investigated expressions of cystic fibrosis transmembrane conductance regulator (CFTR), TGM2, PPARγ and isopeptide bonds, a reaction product of TGM, in non-CF nasal polyps. METHODS: Nasal polyps and inferior turbinates were collected from chronic rhinosinusitis patients without CF during transnasal endoscopic sinonasal surgery. Expressions of CFTR, TGM2, isopeptide bonds and PPARγ were examined by fluorescence immunohistochemistry and quantitative RT-PCR. Expression of CFTR was also analyzed by Western blot. RESULTS: Immunohistochemical fluorescence of the nasal polyp was significantly lower for CFTR and PPARγ, and significantly higher for TGM2 and isopeptide bonds than that of the turbinate mucosa. Lower expression of CFTR in the nasal polyp than in the turbinate mucosa was also observed in Western blot. Expression of PPARG mRNA was significantly lower in the nasal polyp than in the turbinate mucosa, whereas expressions of CFTR mRNA or TGM2 mRNA did not differ between the two tissues. Immunohistochemical fluorescence for CFTR showed significant negative correlation with that for TGM2 and isopeptide bonds, and significant positive correlation with that for PPARγ. The fluorescence for TGM2 was positively correlated with that for isopeptide bonds and negatively correlated with that for PPARγ. The fluorescence for isopeptide bonds tended to be negatively correlated with that for PPARγ. CONCLUSIONS: These results suggest a possible role of the CFTR-TGM2-PPARγ cascade in the pathogenesis of nasal polyp formation in non-CF patients as in CF patients.

Calmodulin Regulates Ciliary Beats in the Human Nasal Mucosa Through Adenylate/Guanylate Cyclases and Protein Kinases A/G.

BACKGROUND: The ciliary beat of the airway epithelium, including the sinonasal epithelium, has a significant role in frontline defense and is thought to be controlled by the level of intracellular Ca2+. Involvement of calmodulin and adenylate/guanylate cyclases in the regulation of ciliary beats has been reported, and here we investigated the interrelation between these components of the ciliary beat regulatory pathway. METHODS: The inferior turbinates were collected from 29 patients with chronic hypertrophic rhinitis/rhinosinusitis during endoscopic sinonasal surgery. The turbinate mucosa was cut into thin strips, and mucociliary movement was observed under a phase-contrast light microscope equipped with a high-speed digital video camera. RESULTS: The ciliary beat frequency (CBF) was significantly increased by stimulation with 100 µM CALP3 (calmodulin agonist), which was completely suppressed by adding 100 µM SQ22536 (adenylate cyclase inhibitor) and 10 µM ODQ (guanylate cyclase inhibitor) together and by adding 1 µM KT5720 (protein kinase A inhibitor) and 1 µM KT5823 (protein kinase G inhibitor) together. The CBF was significantly increased by stimulation with 10 µM forskolin (adenylate cyclase activator) and 10 µM BAY41-2272 (guanylate cyclase activator) and by stimulation with 100 µM 8-bromo-cAMP (cAMP analog) and 100 µM 8-bromo-cGMP (cGMP analog), which was not changed by adding 1 µM calmidazolium (calmodulin antagonist). CONCLUSIONS: These results confirmed that the regulatory pathway of ciliary beats in the human nasal mucosa involves calmodulin, adenylate/guanylate cyclases, and protein kinases A/G and indicate that adenylate/guanylate cyclases and protein kinases A/G act downstream of calmodulin, but not vice versa, and that these cyclases relay calmodulin signaling.

Video-Assisted Thyroidectomy Using a Surgical Energy Device: Initial Experience in a Japanese Single-Center Cohort.

OBJECTIVE: Video-assisted thyroidectomy (VAT) was approved for coverage under the Japanese public health insurance system in 2016. In our department, we introduced VAT in 2018, and we have since been performing the procedure with the assistance of surgical energy devices. We herein summarize our cases undergoing VAT, including a review of points to consider when introducing the procedure, and characteristics of the surgical energy devices. METHODS: We enrolled 24 patients (14 women and 10 men; age: 24-83 years; mean: 59.0 years) with thyroid/parathyroid tumors who underwent VAT between January 2018 and March 2021 at our department. The medical records of the patients were reviewed, and demographic data, clinical characteristics, histological type, treatment outcomes, and complications were analyzed. RESULTS: The surgical energy devices used were LigaSure® in the first 4 cases, Acrosurg®. Scissors S17 in the next 13 cases, and Acrosurg®. Revo S15 in the latest 7 cases. The operation time (range: 72-250 min; mean: 147 min), intraoperative blood loss (range: 5-370 mL; mean: 33 mL), indwelling time of wound drain (range: 2-6 days; mean: 3.5 days), and hospitalization period (range: 3-8 days; mean: 5.5 days) were within acceptable ranges. In this study, it is suggested that Acrosurg®. Revo S15 can shorten the indwelling time and the hospitalization period. There were no serious complications, but 1 patient developed transient vocal cord paralysis, which improved 3 months after surgery. It was suggested that the microwave energy devices, Acrosurg®. Scissors S17 and Acrosurg®. Revo S15, may be more effective with respect to sealing/hemostasis/coagulation capacity and controllability than the high-frequency electrosurgical device, LigaSure®. CONCLUSION: Based on this initial experience, VAT using surgical energy devices appeared to be a safe, effective, and minimally invasive procedure for the treatment of thyroid/parathyroid tumors. Further studies confirming these early findings are needed.

Frequency-specific efficacy of intratympanic steroid on idiopathic sudden sensorineural hearing loss.

Background: Hearing recovery would be different in each sound frequency in patients with idiopathic sudden sensorineural hearing loss (ISSNHL).Aims/objectives: To analyze frequency-specific efficacy of intratympanic steroid on ISSNHL.Materials and methods: Of a total of 381 patients with ISSNHL (hearing threshold ≥40 dB; ≤30 days until treatment), 174 patients (174 ears) received systemic steroid plus hyperbaric oxygen therapy (HBO group), and 207 patients (208 ears) received systemic plus intratympanic steroid (IT group). Hearing thresholds at 125-8000 Hz were measured at every octave before and after treatment.Results: % of patients with hearing gains ≥10 dB in the IT group was significantly higher for 500 Hz and the average of 5 mid-frequencies, tended to be higher for 1000 Hz, but was significantly lower for 8000 Hz, compared to the HBO group. Multiple regression analysis showed that hearing recovery was negatively correlated with patients' age for 125/2000/4000/8000 Hz and with days from onset to treatment for all frequencies, and also revealed better hearing recovery at 500/1000 Hz in the IT group than in the HBO group.Conclusions: Intratympanic steroid is more effective than hyperbaric oxygen to yield better hearing outcomes at mid-frequencies and would be advantageous to restore sound/speech perception.Significance: Superiority of intratympanic steroid over hyperbaric oxygen for treating ISSNHL was verified.

Expression of Cl- channels/transporters in nasal polyps.

PURPOSE: Nasal polyp formation is a common sequela of prolonged chronic rhinosinusitis, but the mechanism underlying this disease state is still controversial. We compared the expressions of Cl- channels/transporters in nasal polyps with those in inferior turbinates to explore whether a deficiency in Cl- transport may participate in the pathophysiology of nasal polyp formation as in patients with cystic fibrosis. METHODS: Nasal polyps and inferior turbinates were collected from 12 chronic rhinosinusitis patients with hypertrophic rhinitis and/or nasal polyps. Expressions of cystic fibrosis transmembrane conductance regulator (CFTR), pendrin, Na+-K+-2Cl- cotransporter 1 (NKCC1), SLC26A3, TMEM16A and anion exchanger 2 (AE2) were examined by fluorescence immunohistochemistry using Alexa Fluor 488. RESULTS: CFTR was weakly expressed on the epithelial surface of the turbinate mucosa whereas the nasal polyps showed almost no fluorescence. Pendrin was mainly expressed on the epithelial surface in both tissues. The fluorescence was moderate in the nasal polyps and strong in the turbinate mucosa. For NKCC1, moderate fluorescence was observed throughout the entire epithelial layer of the nasal polyps, but the turbinate mucosa exhibited almost no fluorescence. On the other hand, no fluorescence for SLC26A3, TMEM16A or AE2 was seen in either tissue. CONCLUSION: These results suggest that CFTR, pendrin and NKCC1 may participate in the pathogenesis of nasal mucosal edema and play roles in the mechanism of nasal polyp formation.

Calmodulin and protein kinases A/G mediate ciliary beat response in the human nasal epithelium.

BACKGROUND: Mucociliary clearance of the airway epithelium is an essential function for mucosal defense. We recently proposed a hypothetical mechanism of ciliary beat regulation, in which the pannexin-1 (Panx1)-P2X7 unit serves as an oscillator generating a periodic increase in intracellular Ca2+ ([Ca2+ ]i ). In the present study, we examined the localization of Panx1 and P2X7 at the ultrastructural level, and investigated the regulatory pathway subsequent to [Ca2+ ]i increase. METHODS: The inferior turbinate mucosa was collected from patients with chronic hypertrophic rhinitis during endoscopic sinonasal surgery. The mucosa was examined by transmission immunoelectron microscopy for Panx1 and P2X7. Alternatively, the mucosa was cut into thin strips, and ciliary beat frequency (CBF) was measured under a phase-contrast light microscope with a high-speed digital video camera. RESULTS: In immunoelectron microscopy, immunoreactivities for Panx1 and P2X7 were localized along the plasma membrane of the entire length of the cilia. CBF was significantly increased by stimulation with 100 µM acetylcholine (Ach). The Ach-induced CBF increase was significantly inhibited by calmidazolium (calmodulin antagonist), SQ22536 (adenylate cyclase inhibitor), ODQ (guanylate cyclase inhibitor), KT5720 (protein kinase A inhibitor), and KT5823 (protein kinase G inhibitor). Fluorodinitrobenzene (creatine kinase inhibitor) completely inhibited the ciliary beat in a time- and dose-dependent manner. CONCLUSION: These results indicate that Panx1 and P2X7 coexist at the cilia of the human nasal epithelial cells and that the ciliary beat is regulated by calmodulin, adenylate/guanylate cyclases and protein kinases A/G, and crucially depends on creatine kinase.

Decreased ciliary beat responsiveness to acetylcholine in the nasal polyp epithelium.

OBJECTIVE: We investigated the difference in ciliary beat responsiveness to acetylcholine in ex vivo and the difference in the expressions of associated molecules (M1/M3 muscarinic receptors, pannexin-1 and P2X7 purinergic receptor) between the nasal polyp and turbinate mucosa. STUDY DESIGN: Laboratorial study. PARTICIPANTS: Nasal polyp and inferior turbinate were collected from patients with hypertrophic rhinitis and/or nasal polyp during endoscopic sinonasal surgery. MAIN OUTCOME MEASURES: The mucosa was cut into thin strips, and ciliary movement was observed under a phase-contrast light microscope equipped with a high-speed digital video camera. The samples were also examined by scanning electron microscopy, fluorescence immunohistochemistry, and quantitative reverse transcription-polymerase chain reaction. RESULTS: Cilia were well preserved in both tissues at the ultrastructural level. The baseline ciliary beat frequency (CBF) was not different between the two tissues. The CBF of the turbinate was significantly increased by stimulation with acetylcholine (P < 0.001), but that of the polyp was not. The ratio of the acetylcholine-stimulated CBF to the baseline CBF was significantly lower in the polyp than in the turbinate (P < 0.001). Immunohistochemical study revealed that immunoreactivities for M3, pannexin-1 and P2X7 were weaker in the polyp than in the turbinate. The mRNA expressions of M1, M3 and P2X7 were significantly lower and that of pannexin-1 tended to be lower in the polyp than in the turbinate. CONCLUSIONS: These results indicate that ciliary beat responsiveness to acetylcholine is decreased in the nasal polyp. This may be explained by the decreased expressions of M3, P2X7 and probably pannexin-1 in this tissue.

Anaplastic Thyroid Carcinoma Treated with Lenvatinib.

OBJECTIVE: We report a case of anaplastic thyroid carcinoma (ATC) with local recurrence and distant metastasis that responded very well to treatment with lenvatinib, a new molecular-targeted anticancer drug. CASE REPORT: A 91-year-old Japanese woman presented with a 5-month history of a painless mass in her left anterior neck. She had a past history of total thyroidectomy and neck dissection for papillary carcinoma of the thyroid. Here she underwent neck dissection, and the histopathological diagnosis was lymph node metastasis of papillary carcinoma with anaplastic transformation. Five months later, a cervical lymph node swelled up again. Computed tomography demonstrated an enhanced mass in the neck and multiple nodules in both lungs. Recurrent ATC with multiple lung metastases was diagnosed, and molecular-targeted therapy with lenvatinib was initiated. The neck tumor reduced in 1 week, and the pulmonary nodules became completely hollow within 1 month. However, we had to discontinue lenvatinib because of severe side effects including high blood pressure, hypocalcemia, and hypoalbuminemia. Soon after discontinuation, the side effects subsided, but the tumor rapidly regrew. The patient died of lymphangiosis carcinomatosa 6 days after discontinuation. CONCLUSION: Although recent advances in molecular-targeted therapy have provided powerful cancer therapy tools, the negative side of this therapy must be addressed.

Presence of osteoclasts in middle ear cholesteatoma: a study of undecalcified bone sections.

CONCLUSIONS: Osteoclasts are unlikely to be involved in bone resorption in middle ear cholesteatoma. OBJECTIVE: The authors searched for osteoclasts in undecalcified bone sections in patients with middle ear cholesteatoma to determine whether and to what extent these cells are involved in this disease. METHODS: Twelve patients, eight men and four women, aged 30-87 years, who underwent tympanomastoidectomy were enrolled. Six patients had primary acquired middle ear cholesteatoma (cholesteatoma group) and the other six patients had other otologic diseases including otosclerosis, non-cholesteatomatous chronic otitis media, adhesive otitis media, perilymphatic fistula and ossicular malformation (control group). The scutum bone was collected during surgery, fixed with ethanol, stained with Villanueva bone stain, and embedded in methyl methacrylate. Five-micrometer-thick sections were prepared and examined under a polarizing microscope. Images were analyzed using a semiautomatic graphics system. RESULTS: No osteoclasts were seen in any of the samples in either group. To avoid the risk of under-estimating the presence of osteoclasts, the number of osteoclasts was considered to be <1 in each sample, and the osteoclast density was calculated. The osteoclast densities in both the cholesteatoma and control groups were significantly lower than the sex- and age-matched standard value of the normal iliac cortical bone (p = .028).

Transgenic approach to express the channelrhodopsin 2 gene in arginine vasopressin neurons of rats.

Optogenetics provides a powerful tool to regulate neuronal activity by light-sensitive ion channels such as channelrhodopsin 2 (ChR2). Arginine vasopressin (AVP; also known as the anti-diuretic hormone) is a multifunctional hormone which is synthesized in the magnocellular neurosecretory cells (MNCs) of the hypothalamus. Here, we have generated a transgenic rat that expresses an AVP-ChR2-enhanced green fluorescent protein (eGFP) fusion gene in the MNCs of the hypothalamus. The eGFP fluorescence that indicates the expression of ChR2-eGFP was observed in the supraoptic nucleus (SON) and in the magnocellular division of the paraventricular nucleus (PVN) that is known to contain AVP-secreting neurons. The eGFP fluorescence intensities in those nuclei and posterior pituitary were markedly increased after chronic salt loading (2% NaCl in drinking water for 5days). ChR2-eGFP was localized mainly in the membrane of AVP-positive MNCs. Whole-cell patch-clamp recordings were performed from single MNCs isolated from the SON of the transgenic rats, and blue light evoked repetitive action potentials. Our work provides for the first time an optogenetic approach to selectively activate AVP neurons in the rat.

Treatment outcome of ion beam therapy in eight patients with head and neck cancers.

Ion beam therapy has enabled us to treat formerly untreatable malignant tumors. The aim of the present study was to investigate the long-term follow-up course of patients with head and neck cancers who received ion beam therapy. The subjects were 8 patients (3 men and 5 women aged 43-78 years) with head and neck cancers who visited our department from 2006 to 2015 and received ion beam therapy. Six patients received carbon ion beam therapy, and the other two patients received proton beam therapy. The medical records of the patients were retrospectively analyzed. The primary site was the nasal and paranasal sinuses in six cases, nasopharynx in one case, and external auditory canal in one case. The histological type was olfactory neuroblastoma, malignant melanoma, and adenoid cystic carcinoma in two cases each, and chondrosarcoma and squamous cell carcinoma in one case each. The exposure dose ranged from 64 to 70.4 GyE. The average follow-up period was 42.0 months. Early adverse events were generally mild, and complete therapeutic response was obtained in all cases. However, five patients developed severe late complications including craniospinal dissemination, osteoradionecrosis of the maxilla and skull base, brain necrosis, and loss of eyesight. Three patients died of distant metastasis, local recurrence and/or brain necrosis within 2 years, and four patients have been surviving with distant metastasis or severe late complications. Ion beam therapy exhibits outstanding antitumor effects, but the severe late complications of the therapy must also be recognized.

Hearing outcome does not depend on the interval of intratympanic steroid administration in idiopathic sudden sensorineural hearing loss.

We studied the effect of intratympanic steroid administration with different intervals on hearing outcomes in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). The subjects were 197 consecutive patients (197 ears) with ISSNHL (hearing level ≥40 dB, interval between onset and treatment ≤30 days). They received systemic administration of prednisolone (100 mg followed by tapered doses) combined with intratympanic injection of dexamethasone (4 mg/ml). Intratympanic injection was performed once a week for 4 weeks in 105 patients (long-interval group), or 4 times in 1 week in 92 patients (short-interval group). The hearing outcomes were evaluated at two points of time: 1 week from the start of treatment, and 1-2 months after the completion of treatment when the hearing level reached a plateau. There was no significant difference in the cure rate, marked-recovery rate, recovery rate, hearing gain, hearing level, or percent hearing improvement between the long- and short-interval groups at either point of time. Multiple regression analysis also showed that the final hearing level did not depend on the interval of intratympanic steroid injection. These results indicate that the hearing outcome of ISSNHL does not improve even if the interval of intratympanic injection is shortened. This implies that a lower total number of intratympanic steroid injections may be as effective as the present protocol.

Electrical Impedance and Expression of Tight Junction Components of the Nasal Turbinate and Polyp.

PURPOSE: We investigated the electrical impedance and expression of tight junction components of the turbinate mucosa, nasal polyp, and normal skin. PROCEDURES: The inferior turbinate and nasal polyp of patients with chronic rhinosinusitis and the postauricular skin of patients with otitis media were examined. Electrical impedance was measured in vivo using a tissue conductance meter. Expressions of claudin-1 and tricellulin were examined by fluorescence immunohistochemistry and quantitative RT-PCR. RESULTS: Electrical impedance was higher in the skin than in the turbinate and polyp, but did not differ between the turbinate and polyp. Immunoreactivities for claudin-1 and tricellulin were seen in the epithelial/epidermal layer. Expression of claudin-1 was higher in the skin than in the turbinate and polyp. The polyp tended to show higher expression of claudin-1 but showed lower expression of tricellulin than the turbinate. The ratio of claudin-1 to tricellulin was highest in the skin and lowest in the turbinate. The correlation between expressions of the two tight junction components was strongly positive in the skin (r = 0.964) and negative (r = -0.527) in the turbinate and polyp. CONCLUSIONS: These results suggest that the roles of claudin-1 and tricellulin in barrier function may be complementary, and may thereby maintain a constant level of permeability of the mucosal tissues.

Possible involvement of TRPV1 and TRPV4 in nociceptive stimulation- induced nocifensive behavior and neuroendocrine response in mice.

Members of the transient receptor potential (TRP) family of ion channels play important roles in inflammation and pain. Here, we showed that both TRPV1 and TRPV4 might contribute to biphasic nocifensive behavior and neuroendocrine response following a formalin test. We subcutaneously injected saline, formalin, or the TRPV4 agonist, 4α-phorbol 12,13-didecanoate (4α-PDD) into one hindpaw of wild-type (WT), TRPV1-deficient (Trpv1(-/-)), and TRPV4-deficient (Trpv4(-/-)) mice to investigate nocifensive behaviors (phase I [0-10 min] and phase II [10-60 min]) and Fos expression in the dorsal horn of the spinal cord and other brain regions related to pain, in the paraventricular nucleus (PVN), paraventricular nucleus of the thalamus, the medial habenular nucleus, the medial nucleus of the amygdala and capsular part of the central amygdala. Subcutaneous (s.c.) injection of formalin caused less nocifensive behavior in Trpv1(-/-) and Trpv4(-/-) mice than in WT mice during phase I. In phase II, however, formalin induced less nocifensive behavior only in the Trpv1(-/-) mice, but not in the Trpv4(-/-) mice, relative to WT mice. The number of Fos-like immunoreactive (LI) neurons in laminae I-II of the dorsal horn increased in all types of mice 90 min after s.c. injection of formalin; however, there was no difference in the other regions between saline- and formalin-treated mice. Furthermore, s.c. injection of 4α-PDD did not induce nociceptive behavior nor influence the number of Fos-LI neurons in the all above mentioned regions in any of the mice. These results suggest that TRPV4-mediated nociceptive information from the peripheral tissue excluding the spinal pathway might be involved the formalin behavioral response during phase I. Only TRPV1 might regulate the formalin behavioral response in peripheral neuron.

Effects of a subconvulsive dose of kainic acid on the gene expressions of the arginine vasopressin, oxytocin and neuronal nitric oxide synthase in the rat hypothalamus.

Arginine vasopressin (AVP) synthesis in the hypothalamo-neurohypophysial system (HNS) is up-regulated by kainic acid (KA)-induced seizure in rats. However, it remains unknown whether a subconvulsive dose of KA affects the HNS. Here we examined the effects of subcutaneous (s.c.) administration of a low dose of KA (4 mg/kg) on the gene expressions of the AVP, oxytocin (OXT) and neuronal nitric oxide synthase (nNOS) in the supraoptic (SON) and paraventricular nuclei (PVN) of the rat hypothalamus, using in situ hybridization histochemistry. The expression of the AVP gene in the SON and PVN was judged to be up-regulated in KA-treated rats in comparison with saline-treated rats as controls. Next, the expression of the OXT gene was significantly increased in the SON at 6-24h and in the PVN at 6 and 12h after s.c. administration of KA. Finally, the expression of the nNOS gene was significantly increased in the SON and PVN at 3 and 6h after s.c. administration of KA. These results suggest that up-regulation of the gene expressions of the AVP, OXT and nNOS in the rat hypothalamus may be differentially affected by peripheral administration of a subconvulsive dose of KA.