Effects of high-dose betahistine on intractable dizziness in patients with uncompensated unilateral vestibulopathy.

OBJECTIVE: In the present study, we examined the effects of high-dose betahistine on dizziness handicap inventory (DHI) scores in patients with unilateral vestibulopathy. METHODS: An uncontrolled, open-label, multicenter clinical trial was conducted. Fifteen patients with unilateral vestibulopathy, such as vestibular neuritis, who complained of intractable dizziness for more than three months were enrolled. Initially, all patients were orally administered betahistine at a dose of 36 mg/day for four weeks, which is the standard dose and dosing period for the treatment of dizziness in Japan. The patients were then administered betahistine at a double dose of 72 mg/day for four weeks. Six patients who became aware of the benefits of high-dose betahistine were further administered betahistine at 72 mg/day for an additional 12 weeks (a total of 16 weeks). Perceived disability due to dizziness was assessed by DHI scores. RESULTS: In all 15 patients, short-term administration with high-dose (72 mg/day) betahistine for four weeks, but not low-dose betahistine (36 mg/day) for four weeks significantly decreased DHI scores. In particular, in six responding patients with self-reported benefits after short-term administration with high-dose betahistine, long-term administration with high-dose betahistine for 16 weeks further significantly decreased DHI scores. However, DHI scores of the remaining nine non-responding patients were not changed after short-term administration with high-dose betahistine for four weeks. CONCLUSION: Short-term administration with the standard dose and dosing period of betahistine did not improve DHI scores in the enrolled patients, indicating that they were not compensated for unilateral vestibulopathy with intractable dizziness. The present findings suggest that long-term administration with high-dose betahistine facilitates vestibular compensation to improve intractable dizziness in some, but not all patients with uncompensated unilateral vestibulopathy.

Effects of transtympanic intermittent pressure therapy using a new tympanic membrane massage device for intractable Meniere's disease and delayed endolymphatic hydrops: a prospective study.

BACKGROUND: The retrospective study showed that the effect of the middle ear pressure treatment by the tramstympanic membrane massage (TMM) device was similar to that of the Meniett device. OBJECTIVES: The new TMM device named EFET device was prospectively evaluated in patients with Meniere's disease (MD) and delayed endolymphatic hydrops (DEH) and we compared the effects to the Meniett device. MATERIALS AND METHODS: 23 ears of 19 patients were treated with an EFET device, and 17 ears of 15 patients were treated with the Meniett device. All patients suffering from intractable MD and DEH were treated for 4 months. The insertion of a transtympanic ventilation tube was necessary for the Meniett device, but not the EFET device. RESULTS: In patients treated by the EFET and Meniett devices, the frequency of vertigo significantly improved after treatment. The distribution of vertigo outcomes at 4 months after treatment did not differ between patients treated with the both devices. CONCLUSIONS AND SIGNIFICANCE: Middle ear pressure treatment by the EFET device is effective and provides minimally invasive options for intractable MD and DEH like the Meniett device.

The importance of FDG-PET/CT parameters for the assessment of the immune status in advanced HNSCC.

OBJECTIVE: Cancer cells secrete large amounts of lactic acid via aerobic glycolysis. We have shown that lactic acid plays an important role as a proinflammatory and immunosuppressive mediator and promotes tumor progression. Fluorine-18 fluorodeoxyglucose (FDG) uptake detected by positron emission tomography/computed tomography (PET/CT) is considered as a good indicator of aerobic glycolysis in cancer. In this study, we examined the relationships between systemic inflammatory parameters and FDG-PET/CT parameters in advanced head and neck squamous cell carcinoma (HNSCC). Furthermore, we investigated the relationships between FDG-PET/CT parameters and M2-macrophage polarization in HNSCC by assessing the ratio of CD163, a M2-macrophage marker, to CD68, a pan-macrophage marker. METHODS: This study included 73 advanced HNSCC patients. We assessed the C-reactive protein (CRP) level, white blood cell (WBC) count, neutrophil count, lymphocyte count, and monocyte count as systemic inflammatory markers. Additionally, we assessed the maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) as FDG-PET/CT parameters. RESULTS: The CRP level, WBC count, and neutrophil count were correlated with whole-body FDG-PET/CT parameters. The CD163/CD68 ratio was correlated with SUVmax and SUVmean. Our results suggest that systemic inflammation, which is associated with neutrophils, develops in patients with HNSCC having tumors with a larger volume and increased glucose uptake and that M2-macrophage polarization is promoted in HNSCC with increased glucose uptake, SUVmax, and SUVmean. FDG-PET/CT has the potential to reflect cancer-related chronic inflammation and immunosuppressive conditions in cancer patients. CONCLUSIONS: FDG-PET/CT parameters appear to be useful in assessing the immune status in HNSCC.

The Long-Term Efficacy of Cochlear Implantation for Hearing Loss in Muckel-Wells Syndrome.

Muckle-Wells syndrome (MWS), a subclass of cryopyrin-associated periodic syndrome (CAPS), sometimes includes complications of bilateral progressive sensorineural hearing loss. A 48-year-old woman had been diagnosed with pediatric rheumatic arthritis at aged 6 years; however, systematic therapy with prednisolone and methotrexate showed limited efficacy for her general fatigue and arthritic pain, and it never improved the hearing level. She underwent a cochlear implant surgery for progressive profound bilateral hearing loss. After 7 years of cochlear implant surgery, she was diagnosed with MWS by genetic tests. Interleukin (IL)-1ß monoclonal antibody therapy (canakinumab) improved general fatigue and arthritic pain but showed no effect on cochlear symptoms. Owing to successful cochlear implant surgery, she reacquired the hearing and communication function while being able to understand over 90% of monosyllables and words in the sound field of her daily life at 65 dB SPL for the next 13 years of her life. This suggests that peripheral cochlear damage induced by chronic inflammation contributes to the sensorineural hearing loss in cases with MWS, and that cochlear implantation can provide long-term hearing efficacy for patients with MWS with irreversible profound hearing loss.

Cedar Pollinosis and Mortality: A Population-Based Prospective Cohort Study in Japan.

BACKGROUND: Cedar pollinosis is one of the most prevalent forms of seasonal allergic reaction in Japan. Only one prospective study has examined the association between cedar pollinosis and mortality. Using a symptom-based questionnaire on cedar pollinosis, we investigated the association of cedar pollinosis with all-cause and cause-specific mortality. METHODS: Data came from the Takayama Study, which recruited residents aged ≥35 years in 1992 from Takayama city in Gifu Prefecture, Japan. The current study used information on cedar pollinosis that was obtained from the second survey in 2002. A total of 12,471 persons who were 45-80 years old and had no history of cancer, coronary heart disease, or stroke responded to a questionnaire asking about four symptoms related to cedar pollinosis. Mortality and migration data were obtained throughout the follow-up period up to March 2013. Cox proportional hazard models were used to examine the relation between cedar pollinosis and mortality. RESULTS: A total of 1,276 persons died during follow-up period. Among these, there were 504 neoplasm, 278 cardiovascular, and 181 respiratory deaths. After adjusting for potential confounders, cedar pollinosis was associated with significantly lower all-cause mortality (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95) and respiratory mortality (HR 0.38; 95% CI, 0.18-0.82). There was no significant association between cedar pollinosis and mortality due to neoplasm or cardiovascular disease. CONCLUSIONS: We found an inverse association between cedar pollinosis and the risk of all-cause and respiratory mortality. Further research is needed to elucidate the association between cedar pollinosis and mortality.

In vivo reprogramming drives Kras-induced cancer development.

The faithful shutdown of the somatic program occurs in the early stage of reprogramming. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We show that the transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in the transient repression of acinar cell enhancers, which are similarly observed in pancreatitis. We next demonstrate that Kras and p53 mutations are insufficient to induce ERK signaling in the pancreas. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce the robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma. In contrast, the forced expression of acinar cell-related transcription factors inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers.

Japanese standard for clinical stabilometry assessment: Current status and future directions.

Stabilometry is a useful tool for examining patients with functional disorders of the vestibular system. However, measurement techniques and devices vary by country. Therefore, international standardization of stabilometry is mandatory to validate the exchange of important findings. This was advocated at the 1983 Posturography Meeting in Kyoto but has not been adopted worldwide, and each country has continued to use unique regional measurement methods. In Japan, stabilometry has widespread application in medical practice in conjunction with research into its applications. With a goal of international standardization, we present details of stabilometry measurement methods and their application in Japan, together with a brief history and potential future directions of stabilometry.

M2-like macrophage polarization in high lactic acid-producing head and neck cancer.

Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect and results in increased lactic acid secretion into the tumor microenvironment. We have previously shown that lactic acid has important roles as a pro-inflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of LDHA and GLUT1, which are related to the Warburg effect, in human head and neck squamous cell carcinoma (HNSCC). Tumors expressing lower levels of LDHA and GLUT1 had a higher concentration of lactic acid than those with higher LDHA and GLUT1 expression. Lactic acid also suppressed the expression of LDHA and GLUT1 in vitro. We previously reported that lactic acid enhances expression of an M2 macrophage marker, ARG1, in murine macrophages. Therefore, we investigated the relationship between the lactic acid concentration and polarization of M2 macrophages in HNSCC by measuring the expression of M2 macrophage markers, CSF1R and CD163, normalized using a pan-macrophage marker, CD68. Tumors with lower levels of CD68 showed a higher concentration of lactic acid, whereas those with higher levels of CSF1R showed a significantly higher concentration of lactic acid. A similar tendency was observed for CD163. These results suggest that tumor-secreted lactic acid is linked to the reduction of macrophages in tumors and promotes induction of M2-like macrophage polarization in human HNSCC.

[Eight Cases of Small Cell Neuroendocrine Carcinoma of the Head and Neck].

Small cell neuroendocrine carcinoma of the head and neck is a rarely occurring poorly differentiated and high-grade malignant neoplasm characterized by highly active proliferation of neuroendocrine tumor cells. There are no established therapies for this disease. To clarify the clinical course and develop effective treatment(s) for the carcinoma, we reviewed the data of 8 patients of small cell neuroendocrine carcinoma of the head and neck treated by us between 2006 and 2014 at the Department of Otolaryngology, Gifu University School of Medicine and our affiliated hospitals. The patients consisted of 3 men and 5 women, ranging in age from 38 to 84 years old (mean : 60.9 years). The tumor arose from the nasal cavity or the paranasal sinuses in 3 cases, from the parotid grand in 2 cases, from the oropharynx in 2 cases, and from the hypopharynx in 1 case. The tumor that arose from the hypopharynx was a combined small-cell carcinoma with squamous cell carcinomas, and the one that arose from the oropharynx had already metastasized to the brain. Most of the patients were treated by chemotherapy and radiotherapy based on the treatment employed for small cell carcinoma of the lung. Only the patient in whom the tumor arose from a paranasal sinus was treated by surgery despite the definitive diagnosis of small cell carcinoma. We selected CPT-11 and a platinum agent for 4 patients, and VP-16 and a platinum agent for 3 patients as the first-line chemotherapy. Although two patients showed carcinoma-free survival, one died of recurrence of the regional lymph node metastases and five died of distant metastases despite the absence of locoregional recurrence. The 5-year survival rate was a dismal 25%, suggesting that we need to establish effective treatment(s) for the control of distant metastases in cases of the small cell neuroendocrine carcinoma of the head and neck.

Invasive epiglottic aspergillosis: A case report and literature review.

Invasive aspergillosis is a life-threatening infection in immunocompromised hosts and occurs most frequently in the lungs. Invasive laryngeal aspergillosis is extremely rare. Due to the potential progression of invasive aspergillosis, antifungal therapy must be started immediately in cases involving clinical suspicion of the disease. A 65-year-old male with agranulocytosis complained of sore throat and dysphagia. His epiglottis was covered with caseating granulomatous lesions and the tissue was easily disrupted. A histopathological examination showed an aggressive invasion of Aspergillus species and cartilage destruction. Therefore, we made a diagnosis of primary invasive epiglottic aspergillosis. The invasive aspergillosis resolved with antifungal therapy and an increase in neutrophils. It is therefore necessary to include invasive laryngeal aspergillosis in the differential diagnosis when encountering immunocompromised patients presenting with laryngeal granulomatous lesions and laryngitis-like symptoms.

A characteristic pattern in the postural sway of unilateral vestibular impaired patients.

The statistical properties of the center of pressure (COP) change over time, and -invariant methods of the COP analysis is not sufficient to monitor the changes. Therefore, dynamic temporal information of the COP signals has been important in assessing the postural stability. The purpose of this study was to evaluate the characteristic pattern of time-frequency dynamics during the upright stance in patients with unilateral vestibular dysfunction (UVD). This study included 20 dizzy patients with UVD and age-matched 20 control subjects without any vestibular disorder. The COP signals were collected using a single standard force platform and a spectral analysis including the time-frequency dynamics was carried out on the basis of the maximum entropy method (MEM) by using a segment time series analysis. The power spectral density (PSD) analysis exhibited an exponential decreasing shape (1/f (-)(ß)) when plotted on a double logarithmic scale. The average value of ß in the low frequency range of less than 1 Hz in the UVD group was significantly lower than that in the control group (p < 0.05) in the medial-lateral (ML) direction under eyes closed condition. In the segment time series analysis, the peak frequency of the COP signals in the patients with UVD gradually converged to the frequency range of 0.1-0.2 Hz in the ML direction under EC condition. Our results suggest that the segment time series analysis of the COP signals can derive a characteristic pattern related to the UVD. It may indicate an increased reflexivity of the COP fluctuation by the UVD, resulting in inducing the instability.

[A case of idiopathic neck bleeding from a parathyroid cyst].

Bleeding from parathyroid cysts is rare. The retropharyngeal space has a very soft structure and if bleeding spreads to this space, airway obstruction can easily occur. We report on a 50-year-old female case with idiopathic neck bleeding from a left parathyroid cyst without any episode of injury. The patient complained of neck swelling after exercise and went to a nearby hospital. At the hospital, the doctor thought this swelling was caused by retropharyngeal bleeding from a tumor behind the left thyroid gland. Embolization of the left thyroid artery was performed. However, the next day, airway obstruction.was occurred and she was brought to our hospital. An emergency operation was performed to open the left neck swelling region. The operation findings and pathological examination showed that the bleeding was caused by a parathyroid cyst and airway obstruction had occurred because of retropharyngeal edema. In this case, the bleeding may have been caused by torsion of the neck when the patient exercised. The retropharyngeal edema probably resulted from the delay of delivery of the lymphatic and venous return and the arterial embolization. 1 year after the operation, the patient is very well and there has been no recurrence.

Association between tinnitus and sleep disorders in the general Japanese population.

OBJECTIVES: There are few studies about the association between tinnitus and sleep disorders in the general population worldwide. This study assessed this association in a Japanese community. METHODS: A total of 14,027 participants 45 to 79 years of age who were in the Takayama Study responded to a self-administered questionnaire about tinnitus and sleep disorders. RESULTS: Of this population, 13.3% of men and 10.6% of women had current tinnitus. The percentages of insomnia, respectively, among individuals with and without tinnitus were 28.1% in men and 36.1% in women and 18.8% in men and 21.5% in women. There were 1.7-fold (95% confidence interval [CI], 1.4 to 2.1) and 1.8-fold (95% CI, 1.5 to 2.2) increases in the odds ratios (ORs) of insomnia for those with tinnitus compared with those without tinnitus in men and women, respectively. Loud or very loud tinnitus was associated with 2.8-fold (95% CI, 1.8 to 4.3) and 3.3-fold (95% CI, 1.9 to 5.6) increases in the OR of insomnia in men and women, respectively. Even low (ie, quiet) or moderate tinnitus was significantly associated with insomnia. Difficulty initiating sleep, difficulty maintaining sleep, and a poor perceived quality of sleep were also significantly associated with tinnitus. CONCLUSIONS: Insomnia and other sleep disorders were significantly associated with tinnitus in Japanese adults.

The association between impaired perception of verticality and cerebral white matter lesions in the elderly patients with orthostatic hypotension.

BACKGROUND: The morbidity of orthostatic hypotension (OH) increases with aging and the elderly often complain of dizziness associated with OH, which is implicated in white matter lesions (WMLs) on MRI. However little is known how WMLs are contributed to the development of dizziness in elderly patients. OBJECTIVE: We evaluated the involvement of cerebral WMLs in the vertical perception in the elderly with OH. METHODS: This study consisted of 71 dizzy patients who underwent the examinations including the Schellong orthostatic test and subjective visual vertical (SVV) test. RESULTS: The male patients aged <65 years with OH (1.9 ± 0.9°) showed a significantly higher magnitude of variance of SVV, which reflects an impaired vertical perception, in comparison with the male patients aged <65 years without OH and the male patients aged < 65 years with OH (1.0 ± 0.4°, 0.9 ± 0.4°, p < 0.05). The variance of SVV significantly correlated with the volume of WMLs in both sides on MRI in the male, but not female patients (p < 0.01). CONCLUSIONS: Our results suggest that severe WMLs in the elderly with OH are involved in impaired perception of verticality, resulting in inducing subjective dizziness.

Tracing Sox10-expressing cells elucidates the dynamic development of the mouse inner ear.

The inner ear is constituted by complicated cochlear and vestibular compartments, which are derived from the otic vesicle, an embryonic structure of ectodermal origin. Although the inner ear development has been analyzed using various techniques, the developmental events have not been fully elucidated because of the intricate structure. We previously developed a Sox10-IRES-Venus mouse designed to express green fluorescent protein under the control of the Sox10 promoter. In the present study, we showed that the Sox10-IRES-Venus mouse enabled the non-destructive visualization and understanding of the morphogenesis during the development of the inner ear. The expression of the transcription factor Sox10 was first observed in the invaginating otic placodal epithelium, and continued to be expressed in the mature inner ear epithelium except for the hair cells and mesenchymal cells. We found that Sox10 was expressed in immature hair cells in the developing inner ear, suggesting that hair cells were generated from the Sox10-expressing prosensory cells. Furthermore, we demonstrated that scattered Sox10-expressing cells existed around the developing inner ear, some of which differentiated into pigmented melanocytes in the stria vascularis, suggesting that they were neural crest cells. Further analyzing the Sox10-IRES-Venus mice would provide important information to better understand the development of the inner ear.

Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity.

The activation of oncogenic signaling pathways induces the reprogramming of glucose metabolism in tumor cells and increases lactic acid secretion into the tumor microenvironment. This is a well-known characteristic of tumor cells, termed the Warburg effect, and is a candidate target for antitumor therapy. Previous reports show that lactic acid secreted by tumor cells is a proinflammatory mediator that activates the IL-23/IL-17 pathway, thereby inducing inflammation, angiogenesis and tissue remodeling. Here, we show that lactic acid, or more specifically the acidification it causes, increases arginase I (ARG1) expression in macrophages to inhibit T-cell proliferation and activation. Accordingly, we hypothesized that counteraction of the immune effects by lactic acid might suppress tumor development. We show that dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinases, targets macrophages to suppress activation of the IL-23/IL-17 pathway and the expression of ARG1 by lactic acid. Furthermore, lactic acid-pretreated macrophages inhibited CD8+ T-cell proliferation, but CD8+ T-cell proliferation was restored when macrophages were pretreated with lactic acid and DCA. DCA treatment decreased ARG1 expression in tumor-infiltrating immune cells and increased the number of IFN-γ-producing CD8+ T cells and NK cells in tumor-bearing mouse spleen. Although DCA treatment alone did not suppress tumor growth, it increased antitumor immunotherapeutic activity of Poly(IC) in both CD8+ T cell- and NK cell-sensitive tumor models. Therefore, DCA acts not only on tumor cells to suppress glycolysis but also on immune cells to improve the immune status modulated by lactic acid and to increase the effectiveness of antitumor immunotherapy.

Damping control of balance in the medial/lateral direction and the risk of falling in the elderly.

AIMS: A proportional-integral-derivative (PID) control has recently been used as a control algorithm of body balance. The purpose of this study was to elucidate an association of the proportional and derivative gain based on the PID control gain for balance for quiet standing with the risk factor for falls in the elderly. METHODS: The movement of a marker on the back of 23 elderly participants (age 75.6±6.6 years) was measured by our developed device with a complementary metal oxide semiconductor video camera and the trunk sway speed in the medial/lateral (M/L) direction (TSSX) was calculated as absolute values of the whole time series. The PID control gain (proportional gain: K(P), integral gain: K(I), derivative gain: K(D)) was identified using the trunk sway data, and normalized by individual height and weight (K(P)n, K(D)n and K(I)n). Individual risk factor for falls was additionally assessed with the Tinetti Performance Oriented Mobility Assessment (POMA) and the fall risk questionnaire. RESULTS: The score in the POMA and the K(D)n significantly decreased with age (P<0.01). The score in the POMA showed a positive correlation with the K(D)n, and negative correlations with the TSSX and K(P)/K(D) ratios (P<0.01). The average K(D)n and the score in the POMA of fallers were significantly lower than those of non-fallers (P<0.05). CONCLUSION: These results suggest that the decreased damping control by derivative gain for balance in the M/L direction is one of the risk factors for falls in the elderly.

[Surgery in the lateral area of the cervicothoracic border].

Surgery is not usually indicated for the involvement of cervical lymph node metastasis to the subclavian vein. Although surgery is indicated for the involvement of cervical lymph node metastasis to the venous angle, the usual visual field associated with cervical lymph node dissection cannot sufficiently visualize the subclavian vein, and the possibility exists of causing great vessel injury when involved lymph nodes are large and their mobility is restricted. In such cases, surgical excision may be avoided based on the expectation that ligating or cutting the internal jugular vein will be difficult. We examined 10 patients who underwent surgery for the adhesion or invasion of the primary tumor or involved lymph nodes to the venous angle or subclavian vein. The clavicle was removed or displaced to secure the visual field. The sternoclavicular joint was conserved and the clavicle, separated from the first rib, was lifted in 4 patients, while the medial two thirds of the clavicle was removed in 6 patients. Involved lymph nodes could be securely dissected without causing great vessel injury. A chylous leak occurred in one patient undergoing the procedure on the left side.

Clinical outcomes of single or oligo-fractionated stereotactic radiotherapy for head and neck tumors using micromultileaf collimator-based dynamic conformal arcs.

PURPOSE: To assess the clinical outcomes of single or oligo-fractionated stereotactic radiotherapy (SRT) using dynamic conformal arcs (DCA) for head and neck tumors (HNTs). METHODS: Thirty-four consecutive patients with 35 lesions treated between 2005 and 2009 were retrospectively evaluated, of whom 85.7 % had recurrent or metastatic disease, and 45.7 and 34.3 % had previous radiotherapy and surgery, respectively. The median SRT dose was 22.3 Gy (11.2-32.8) in 2-4 fractions with a median interval of 7 days and 10.4 Gy (9.2-12.4) in one fraction. SRT was combined with upfront conventionally fractionated RT in 48.6 % of patients. RESULTS: The median follow-up periods were 18.4 months (2-84.1) for the entire cohort and 49.6 months for the survivors. The 1- and 2-year local control (LC) rates were 84.3 and 70.5 %, with the 1- and 2-year overall survival (OS) rates of 78.6 and 51.6 %. LC was significantly better for tumor volumes <25.6 cm(3) (p = 0.001). OS was significantly longer in patients without any disease outside the SRT site (p < 0.001), whereas LC after the SRT did not affect the OS. Late adverse events occurred in 9 patients, including cranial nerve (CN) injury (grade 3/4) in 2, brain radionecrosis in 5 (grade 1), and fatal bleeding in 2 patients harboring uncontrolled lesions abutting the carotid artery. CONCLUSIONS: DCA-based SRT can confer relatively long-term LC with acceptable toxicity in selected patients with HNTs. The patients with CN involvement or tumor volume ≥25.6 cm(3) were deemed unsuitable for this treatment regimen.