Vestibular compensation: Neural mechanisms and clinical implications for the treatment of vertigo.

After unilateral peripheral vestibular lesions, the neural activity of neurons in the ipsi-lesional medial vestibular nucleus (ipsi-MVe) are markedly decreased, resulting in static and dynamic asymmetries of the vestibulo-ocular and vestibulo-spinal reflexes. Consequently, static vestibular symptoms such as spontaneous nystagmus and postural deviation and dynamic vestibular symptoms such as oscillopsia and swaying gait are induced. However, these behavioral asymmetries gradually recover after the lesion. Progressive balance restoration is termed vestibular compensation, which is divided into two phases: static and dynamic. Static vestibular compensation is further divided into initial and late processes. In the initial process of static vestibular compensation after unilateral labyrinthectomy (UL) in rats, plastic changes in the cerebello-vestibular and vestibular commissural inhibitory pathways suppress neurons in the contra-lesional MVe (contra-MVe), resulting in the restoration of symmetrical resting activity of MVe neurons on both sides at low levels. The declining frequency of spontaneous nystagmus after UL is an index of the initial process, and short-term administration of diazepam, a GABAA receptor agonist, has been shown to accelerate the initial process in rats. Accordingly, short-term administration of diazepam is recommended for the treatment of acute vertigo in patients with unilateral vestibular dysfunction. In the late process of static vestibular compensation after UL in rats, the resting activity of ipsi-MVe neurons gradually recovers due to changes in cell membrane properties, resulting in the reinforcement of balanced intervestibular nuclear activities to nearly normal levels without the suppression of contra-MVe neurons. The declining number of MK801-induced Fos-positive neurons in contra-MVe after UL is an index of the late process, and long-term administration of betahistine, a histamine H3 receptor antagonist, has been shown to accelerate the late process in rats. Accordingly, long-term administration of betahistine is recommended for the treatment of subacute vertigo in patients who were not compensated for unilateral vestibular dysfunction. In the process of dynamic vestibular compensation after UL, the sensitivity of ipsi-MVe neurons to head velocity and acceleration is restored due to synaptic changes such as long-term potentiation and sprouting of commissures, resulting in the restoration of the dynamic vestibulo-ocular and vestibulo-spinal reflexes. To facilitate dynamic vestibular compensation, early ambulation and subsequent vestibular rehabilitation exercise are recommended for the treatment of chronic vertigo in patients with uncompensated unilateral vestibular dysfunction. Although vestibular compensation after bilateral vestibular loss is not expected, vestibular rehabilitation with a sensory-substitution strategy can improve imbalance in patients with bilateral vestibular lesions.

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.

The effects of continuous administration of diazepam on the recovery of lesion-induced nystagmus in unilaterally labyrinthectomised rats.

BACKGROUND: Diazepam, a gamma-aminobutyric acid type A receptor agonist, is classified as a vestibular suppressant and is effective in treating acute vertigo. However, its effects on vestibular compensation (VC) remain unclear. OBJECTIVES: We examined the effects of continuous administration of diazepam on the frequency of spontaneous nystagmus (SN) after unilateral labyrinthectomy (UL) as an index of the initial process of VC in rats. MATERIALS AND METHODS: Diazepam was continuously administered at doses of 3.5 and 7.0 mg/kg/day, intraperitoneally, via an osmotic minipump. The frequency of SN beating against the lesion side after UL was measured. Potassium chloride (KCl) solution (1 M) was injected intratympanically to induce SN beating to the injection side. RESULTS: Continuous administration of diazepam significantly and dose-dependently decreased the frequency of SN after UL, and also reduced the x intercept of the nonlinear regression curve of the decline in UL-induced SN with time in rats. However, the continuous administration of diazepam did not affect the frequency of intratympanic KCl-induced SN in the rats. CONCLUSION: These findings suggested that continuous administration of diazepam accelerates the initial process of VC; however, it does not suppress the nystagmus-driving mechanisms in rats.

Risk factors of first bite syndrome after surgical resection of parapharyngeal space tumors.

OBJECTIVE: First bite syndrome is a complication of surgical resection of parapharyngeal space tumors and the development of cramping pain in the parotid region with the first bite of a meal. The present study aimed to identify the potential risk factors for the development of first bite syndrome. METHODS: We retrospectively reviewed 30 consecutive patients with parapharyngeal space tumors who had been surgically treated between August 2003 and December 2015 at our department. RESULTS: The tumor site (prestyloid or retrostyloid) and surgical approach (transcervical-parotid, transparotid, or transcervical) were not correlated with the development of first bite syndrome. Ligation and mobilization of the external carotid artery was significantly correlated with the development of first bite syndrome. Moreover, patients with complete resection of the parotid gland did not experience first bite syndrome. DISCUSSION: The present findings suggest that concomitant surgical settings of 1) sympathetic denervation of the parotid gland with ligation of the external carotid artery or injury of the sympathetic nerve plexus around the external carotid artery during its mobilization, and 2) residual parotid gland tissue are risk factors for the development of first bite syndrome after surgical resection of parapharyngeal space tumors. J. Med. Invest. 70 : 150-153, February, 2023.

Outpatient ablation treatment with two doses of 30 mCi of radioactive iodine for non-low-risk papillary thyroid cancer.

Outpatient ablation therapy with low-dose radioactive iodine (RAI) is applied to non-low-risk papillary thyroid cancer patients due to a chronic shortage of inpatient RAI treatment wards in Japan. We used the maximum dosage available for outpatient therapy of 30 mCi of RAI for ablation and diagnostic (Dx) whole-body scintigraphy (WBS). This study aimed to examine the significance of the second dose of 30 mCi. DxWBS was performed 6 months after ablation, and assessment of success or failure was performed 12 months after ablation. A second WBS was performed in the remaining RAI accumulation cases in the neck on DxWBS. The criteria for successful ablation was negative cervical accumulation on WBS, thyroid stimulating hormone-suppressed thyroglobulin (sup-Tg) below 1.0 ng?/?mL, and no increase in thyroglobulin antibody (TgAb) level. At the time of DxWBS, 35?/?68 cases met the successful criteria, and 45 cases achieved success at assessment. Sup-Tg values decreased significantly after ablation and decreased further after DxWBS in successful ablation cases, whereas those were not changed in ablation failure cases. Findings indicated that RAI used in DxWBS had therapeutic effects. It makes sense to use 30 mCi for DxWBS, given the current difficulty of inpatient ablation therapy with high-dose RAI. J. Med. Invest. 70 : 17-21, February, 2023.

Comparison of the efficacy of the Epley maneuver and repeated Dix-Hallpike tests for eliminating positional nystagmus: A multicenter randomized study.

Background and objectives: Patients with benign paroxysmal positional vertigo of the posterior canal (pc-BPPV) exhibit BPPV fatigue, where the positional nystagmus diminishes with the repeated performance of the Dix-Hallpike test (DHt). BPPV fatigue is thought to be caused by the disintegration of lumps of otoconial debris into smaller parts and can eliminate positional nystagmus within a few minutes [similar to the immediate effect of the Epley maneuver (EM)]. In this study, we aimed to show the non-inferiority of the repeated DHt to the EM for eliminating positional nystagmus after 1 week. Methods: This multicenter, randomized controlled clinical trial was designed based on the CONSORT 2010 guidelines. Patients who had pc-BPPV were recruited and randomly allocated to Group A or Group B. Patients in Group A were treated using the EM, and patients in Group B were treated using repeated DHt. For both groups, head movements were repeated until the positional nystagmus had been eliminated (a maximum of three repetitions). After 1 week, the patients were examined to determine whether the positional nystagmus was still present. The groups were compared in terms of the percentage of patients whose positional nystagmus had been eliminated, with the non-inferiority margin set at 15%. Results: Data for a total of 180 patients were analyzed (90 patients per group). Positional nystagmus had been eliminated in 50.0% of the patients in Group A compared with 47.8% in Group B. The upper limit of the 95% confidence interval for the difference was 14.5%, which was lower than the non-inferiority margin. Discussion: This study showed the non-inferiority of repeated DHt to the EM for eliminating positional nystagmus after 1 week in patients with pc-BPPV and that even the disintegration of otoconial debris alone has a therapeutic effect for pc-BPPV. Disintegrated otoconial debris disappears from the posterior canal because it can be dissolved in the endolymph or returned to the vestibule via activities of daily living. Classification of evidence: This study provides Class II evidence of the non-inferiority of repeated DHt to the EM for eliminating positional nystagmus after 1 week. Registration number: UMIN000016421.

Muscle mass, quality, and strength; physical function and activity; and metabolic status in cachectic patients with head and neck cancer.

BACKGROUND & AIMS: Cancer cachexia is commonly associated with poor prognosis in patients with head and neck cancer (HNC). However, its pathophysiology and treatment are not well established. The current study aimed to assess the muscle mass/quality/strength, physical function and activity, resting energy expenditure (REE), and respiratory quotient (RQ) in cachectic patients with HNC. METHODS: This prospective cross-sectional study analyzed 64 patients with HNC. Body composition was measured via direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity on ultrasonography images. Muscle strength was investigated utilizing handgrip strength and isometric knee extension force (IKEF). Physical function was evaluated using the 10-m walking speed test and the five times sit-to-stand (5-STS) test. Physical activity was examined using a wearable triaxial accelerometer. REE and RQ were measured via indirect calorimetry. These parameters were compared between the cachectic and noncachectic groups. RESULTS: In total, 23 (36%) patients were diagnosed with cachexia. The cachectic group had a significantly lower muscle mass than the noncachectic group. Nevertheless, there was no significant difference in terms of fat between the two groups. The cachectic group had a higher quadriceps echo intensity and a lower handgrip strength and IKEF than the noncachectic group. Moreover, they had a significantly slower normal and maximum walking speed and 5-STS speed. The number of steps, total activity time, and time of activity (<3 Mets) did not significantly differ between the two groups. The cachectic group had a shorter time of activity (≥3 Mets) than the noncachectic group. Furthermore, the cachectic group had a significantly higher REE/body weight and REE/fat free mass and a significantly lower RQ than the noncachectic group. CONCLUSIONS: The cachectic group had a lower muscle mass/quality/strength and physical function and activity and a higher REE than the noncachectic group. Thus, REE and physical activity should be evaluated to determine energy requirements. The RQ was lower in the cachectic group than that in the noncachectic group, indicating changes in energy substrate. Further studies must be conducted to examine effective nutritional and exercise interventions for patients with cancer cachexia.

Assessment of inner ear morphology and function in response to local positive pressure for Ménière's disease: a nonrandomized controlled trial.

Ménière's disease (MD) is an inner ear disorder in which the main pathological feature is endolymphatic hydrops (EH). Positive pressure therapy (PPT) using a portable device is now a second-line therapy for intractable MD when initial medical treatment fails. However, it remains unknown whether PPT causes the morphological and functional changes of inner ear in patients with active MD in accordance with reduction of vertigo attacks. In this nonrandomized controlled trial of 52 patients with MD, the volume of EH significantly decreased with reduction of vertigo attacks during 8 months of PPT combined with medications while the volume of that significantly increased with medications alone. There was no difference between Control group (n = 26) and PPT group (n = 26) regarding the vertigo control, however, PPT group achieved a significant functional improvement of vertical semicircular canals. The effect of volume reduction by PPT has been firstly demonstrated and the functional changes of all semicircular canals during PPT have been firstly examined. Morphological and functional changes in the inner ear by administrating local positive pressure are quite different from those caused by medications alone.Clinical trial registration: UMIN-CTR UMIN000041164 (registered on July 20, 2020).

Diagnostic and therapeutic strategies for vestibular neuritis of the Japan society for equilibrium research.

OBJECTIVE: To provide diagnostic and therapeutic strategies for vestibular neuritis in accordance with the Japanese Clinical Practice Guidelines for Vestibular Neuritis 2021. METHODS: The Committee for Clinical Practice Guidelines for Vestibular Neuritis was entrusted with a review of the relevant scientific literature on the above topic. Clinical Questions (CQs) concerning the treatment of vestibular neuritis were produced, and a search of the literature was conducted to identify studies related to the CQs. The recommendations were based on the literature review and the expert opinion of a subcommittee. RESULTS: We proposed the diagnostic criteria for vestibular neuritis, as well as answers to CQs, recommendations, and evidence levels for the treatment of vestibular neuritis. CONCLUSION: The diagnostic criteria for vestibular neuritis were based on clinical history and examination findings after completing the differential diagnosis process. The treatment of vestibular neuritis was divided into acute, subacute, and chronic stages. The Japanese Clinical Practice Guidelines for Vestibular Neuritis 2021 should be used as a reference in the diagnosis and treatment of vestibular neuritis.

Betuletol, a Propolis Component, Suppresses IL-33 Gene Expression and Effective against Eosinophilia.

Propolis, a resinous substance produced by honeybees, has been used in folk medicine since ancient times due to its many biological benefits such as antitumor, antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory effects. Propolis contains flavonoids, terpenoids, aromatic aldehydes, and alcohols, which vary with different climate and environmental conditions. In our study, we examined the antiallergic activity of Brazilian green propolis (BGP) and isolated the active compound that can suppress an allergy-sensitive gene, IL-33, expression and eosinophilia. Ethanolic extract of BGP freeze-dried powder was fractionated with several solvent systems, and the active fractions were collected based on activity measurement. The single active compound was found by thin-layer chromatography. Using column chromatography and NMR, the active compound was isolated and identified as 3,5,7-trihydroxy-6,4'-dimethoxyflavone, also known as betuletol. Further, the antiallergic activity of that has been examined in PMA-induced up-regulation of IL-33 gene expression in Swiss 3T3 cells. Our data showed the IL-33 gene suppression both by BGP and the isolated active compound, betuletol. We also found that betuletol suppressed ERK phosphorylation, suggesting it could be effective in suppressing IL-33 mediated eosinophilic chronic inflammation and will provide new insights to develop potent therapeutics against allergic inflammations.

A 14-year nationwide epidemiological analysis of delayed endolymphatic hydrops in Japan.

BACKGROUND: Delayed endolymphatic hydrops (DEH) is an inner ear disease that causes recurrent vertigo in the ipsilateral ear or fluctuating hearing in the contralateral ear due to endolymphatic hydrops secondary to preceding deafness. There are few reports of large, multicentre studies investigating the clinical-epidemiological characteristics of DEH. OBJECTIVE: This study aimed to clarify the characteristics of DEH in Japan. METHODS: Clinical data on 662 patients with DEH were analysed by nationwide, multicentre surveys conducted by the Peripheral Vestibular Disorders Research Group of Japan. RESULTS: The proportion of ipsilateral DEH (IDEH) was slightly higher than that of contralateral DEH (CDEH) at 55.4%. The time delay between onset of precedent deafness and onset of DEH was significantly longer for CDEH than for IDEH. The most common cause of precedent deafness was a disease of unknown cause with onset in early childhood (33.1%). Epidemiological characteristics were not significantly different between CDEH with and without vertigo. CONCLUSION: DEH appearing to be caused by viral labyrinthitis has a high rate of onset within 40 years of precedent deafness. Clinical and epidemiological characteristics of IDEH, CDEH with vertigo, and CDEH without vertigo were very similar. SIGNIFICANCE: The clinical-epidemiological characteristics of DEH in Japan were clarified.

Association of phase angle with muscle function and prognosis in patients with head and neck cancer undergoing chemoradiotherapy.

OBJECTIVES: The aims of this study were to investigate the correlation of phase angle (PhA) with other parameters (e.g., muscle mass/quality/strength and physical function), assess the prognostic relevance of prechemoradiotherapy (CRT) PhA, and suggest a reference value of PhA in Asian patients with head and neck cancer (HNC). METHODS: Ninety-six patients with HNC who underwent CRT were divided into two groups- maintained-PhA group and low-PhA group-according to the PhA 25th percentile values by sex. Pretreatment PhA was measured using direct segmental multifrequency bioelectrical impedance analysis, and muscle quality was assessed using echo intensity in ultrasound images. Correlation of PhA with other parameters was investigated, and between-group differences with respect to adverse events, treatment interruption, and 3-y survival were assessed. RESULTS: PhA showed a positive correlation with isometric knee extension force (R = 0.710), handgrip strength (R = 0.649), skeletal muscle mass index (R = 0.620), and maximum gait speed (R = 0.543; P < 0.001). PhA showed a negative correlation with echo intensity (R = -0.439) and five times sit-to-stand test (R = -0.505; P < 0.01). The low-PhA group had a higher incidence of severe anemia (52% in low-PhA versus 17% in maintained-PhA), aspiration (17 versus 1%), radiotherapy interruption (17 versus 3%), and poor 3-y survival (47 versus 81%) than the maintained-PhA group (P < 0.05). CONCLUSION: PhA was correlated with muscle mass/quality/strength, and physical function. Low PhA was associated with severe adverse events, treatment interruption, and shorter survival. These findings suggested that 4.6° for men and 4° for women may be useful as prognostic reference values in Asian patients with HNC.

12-month effect of middle ear pressure therapy with the EFET01 device for intractable definite Meniere's disease and delayed endolymphatic hydrops after certification by the public health insurance system in Japan.

BACKGROUND: Middle ear pressure therapy (MEPT) is effective for intractable vertigo in patients with definite Meniere's disease (MD) and treatment-refractory delayed endolymphatic hydrops (DEH). Four-month MEPT with the EFET01®, an MEPT device developed in Japan and covered by national health insurance since September 2018, has shown efficacy. However, efficacy and safety after 12 months of treatment, which is appropriate for determining the therapeutic effect of MEPT devices, is unclear. OBJECTIVES: Examine the therapeutic effect of 12-month MEPT using the ETET01®. MATERIAL AND METHODS: Patients underwent MEPT using the EFET01® from September 2018 to July 2021. Thirty-three patients followed for >12 months were enrolled in this retrospective study. Clinical data were evaluated in the first and second 6-month treatment periods. Data from the second 6-month period were compared with data from an MEPT study using a different device. RESULTS: MEPT with the EFET01® significantly improved vertigo in the first period, with further improvement in the second period. The efficacy and safety were comparable to MEPT with other devices. CONCLUSIONS: MEPT with the EFET01® is effective for intractable vertigo in patients with definite MD and DEH, and 12-month follow-up is recommended. SIGNIFICANCE: The efficacy of 12-month MEPT with the EFET01® was demonstrated.

Efficiency of a novel middle ear pressure device for intractable definite Meniere's disease and delayed endolymphatic hydrops after certification by the public health insurance system in Japan.

BACKGROUND: Middle ear pressure therapy (MEPT) is effective in treating intractable vertigo in patients with definite Meniere's disease (MD) and delayed endolymphatic hydrops (DEH) refractory to conservative treatment. A novel middle ear pressure device, the EFET01®, which requires no transtympanic ventilation tubes, was developed in Japan, approved by the Japanese Ministry of Health, Labour and Welfare, and has been used under Japanese national health insurance since September 2018. OBJECTIVES: To examine short-term therapeutic effect of MEPT using the ETET01® compared with previous clinical trial results. METHODS: Patients selected according to Japan Society for Equilibrium Research (JSER) guidelines underwent MEPT using the EFET01 from September 2018 to July 2021, and 44 patients were enrolled in this retrospective study. Clinical data analysed at 4 months after the start of MEPT were compared with those of the previous clinical trial for the EFET01. RESULTS: MEPT using the EFET01 showed the same therapeutic efficacy as that of the previous clinical trial, i.e. improvement in the intensity and frequency of vertigo with no effect on hearing, even under JSER guidelines for proper use of MEPT. CONCLUSION: MEPT using the EFET01 provided an effective treatment option for intractable vertigo in patients with definite MD and DEH.

Effects of sublingual immunotherapy with tablets or drops containing Japanese cedar pollen antigens on nasal symptoms and sleep disturbance in patients with Japanese cedar pollinosis.

OBJECTIVE: We examined the effects of SLIT with tablets containing JCP antigens on nasal symptoms and sleep disturbance in patients with Japanese cedar pollinosis during pollen dispersal season. METHODS: A total of 128 patients with Japanese cedar pollinosis were categorized into four groups:19 one-year SLIT with tablets group, 16 two-year SLIT with drops group, 19 antihistamine group, and 74 untreated group. The scores of nasal symptoms and sleep disturbance were evaluated based on the Japanese guidelines for allergic rhinitis and the Athens Insomnia Scale. RESULTS: The scores of nasal symptoms and sleep disturbance at the peak cedar pollen period in the two-year SLIT with drop group and the one-year SLIT with tablets group were significantly lower than those in untreated group. Additionally, these scores were significantly lower in the one-year SLIT with tablets group than those in the antihistamine group. CONCLUSION: It is suggested that SLIT with JCP tablets improved both nasal symptoms and sleep disturbances at peak pollen period in patients with Japanese cedar pollinosis. SLIT with JCP tablets for one year was more effective than SLIT with JCP drops for two years and prophylactic treatment with antihistamines. J. Med. Invest. 69 : 97-100, February, 2022.

New method to evaluate sequelae of static facial asymmetry in patients with facial palsy using three-dimensional scanning analysis.

OBJECTIVE: During the process of neural recovery after facial palsy, distressing sequelae of static and dynamic facial asymmetry develop in patients with facial palsy. A pronounced nasolabial fold is mainly responsible for static facial asymmetry, which leads to many psychological and social problems in patients. Objective and qualitative assessment of facial appearance is critical to determine the severity of sequelae of static facial asymmetry and whether an intervention is effective for treatment. In the present study, an attempt was made to develop three-dimensional analysis method to assess sequelae of static facial asymmetry after facial palsy. METHODS: Eight patients with sequelae of facial asymmetry after facial palsy and ten healthy volunteers were enrolled. We used three-dimensional scanning analysis with a portable non-contact optical scanner to obtain three-dimensional surface data from a patient's face and produced a three-dimensional digital model of the face. We then identified a reference plane fixed with the patient's face, and measured the depth of the nasolabial fold of the face. RESULTS: The nasolabial fold of the face on the affected side was significantly deeper than that on the unaffected side in patients with sequelae of static facial asymmetry after facial palsy. However, the depth of the facial nasolabial fold on the right side was not different from that on the left side in healthy volunteers. Affected-unaffected side differences in the depth of the nasolabial fold in patients with sequelae of static facial asymmetry after facial palsy were significantly larger than left-right differences in the depth of the nasolabial fold in healthy volunteers. Two weeks after treatment with botulinum toxin injection to the affected zygomaticus muscles, affected-unaffected side differences in the depth of the nasolabial fold were significantly decreased in the patients. In the patients who received botulinum toxin, the absolute values of affected-unaffected side differences in the depth of the nasolabial fold measured using the three-dimensional scanning analysis showed a significant positive correlation with the visual analog scale scores of facial asymmetry marked by independent doctors. CONCLUSION: The present findings suggest that affected-unaffected side differences in the depth of the nasolabial fold of the measured using three-dimensional scanning analysis can be used as an index of sequelae of static facial asymmetry. It is also suggested that the index can evaluate whether interventions are effective for the treatment of sequelae.

Efficacy of dual sublingual immunotherapy with Japanese cedar pollen and house dust mite allergens in patients with allergic rhinitis sensitized to multiple allergens.

OBJECTIVE: In the present study, we examined the effects of dual sublingual immunotherapy (SLIT) with Japanese cedar pollen (JCP) and house dust mite (HDM) allergens on nasal symptoms during the peak pollen period (PPP) and in late fall (LF) in patients with allergic rhinitis (AR) sensitized to both JCP and HDM. We then compared the efficacy of dual-SLIT with JCP and HDM to that of mono-SLIT with JCP at PPP. METHODS: Twenty-five bisensitized patients with AR who showed positive serum specific immunoglobulin E (IgE) against both JCP and HDM were enrolled. In dual-SLIT, 16 patients received JCP drops/tablets and HDM tablets concurrently. In mono-SLIT with JCP, nine patients received JCP drops/tablets. Nasal symptoms were scored on a 0-4 point scale. RESULTS: The nasal scores at PPP and in LF in the bisensitized patients with AR who received dual-SLIT with JCP and HDM in 2019 were significantly lower than those in the same patients who received antihistamines only in 2018. The decrease in scores of nasal obstruction at PPP from 2018 to 2019 in patients who received dual-SLIT was significantly greater than those in patients who received mono-SLIT with JCP. Dual-SLIT was well tolerated and only had mild adverse effects. CONCLUSION: These findings suggest that dual-SLIT suppressed both JCP-induced seasonal and HDM-induced perennial nasal symptoms in bisensitized patients with AR. Dual-SLIT was more effective in suppressing nasal obstruction at PPP than mono-SLIT with JCP with limitation of baseline characteristics not to be controlled between the two groups, suggesting that dual-SLIT suppressed HDM-induced priming effects, thus resulting in further suppression of nasal obstruction at PPP. LEVEL OF EVIDENCE: 3b, a case-controlled study.

Long-term changes in serum squamous cell carcinoma antigen levels after surgery in patients with sinonasal inverted papilloma.

OBJECTIVES: This study aimed to examine whether serum SCCA levels can be used as clinical markers for monitoring recurrence of sinonasal inverted papilloma (IP) during the follow-up period after surgery. We measured long-term changes in serum levels of SCCA after surgery in patients with IP and examined whether postoperative SCCA levels were associated with IP recurrence. METHODS: Twenty-five consecutive patients (13 with primary IPs and 12 with recurrent IPs after their previous surgery) were included in this study. All patients underwent endoscopic or external surgery. Postoperative serum SCCA levels were measured 3 months after surgery and every 3 - 12months during the follow-up. The optimal cut-off values of postoperative SCCA levels to predict subsequent recurrence of IP were evaluated using ROC analysis. RESULTS: Preoperative serum levels of SCCA were higher than the upper limit of normal range in most patients with both primary and recurrent IP, and significantly decreased after surgery. Thus, the presence of IP was closely associated with elevated serum SCCA levels. Moreover, postoperative elevation of SCCA levels was closely associated with subsequent recurrence of IP. Postoperative SCCA levels in 5 patients with recurrence were significantly higher than those in 20 patients without recurrence. The optimum cut-off value of SCCA levels to predict subsequent recurrence of IP 3 months after surgery was 1.85 ng/ml, with a sensitivity of 100.0 % and a specificity of 90.0 %. CONCLUSIONS: These findings suggest that SCCA can be a tumor marker of IP. It is also suggested that postoperative elevation of SCCA levels is a clinical marker for monitoring the recurrence of IP during the follow-up period. A SCCA cut-off value of 1.85 ng/ml postoperatively may predict the subsequent recurrence of IP with high sensitivity and specificity.

Clinical trials of Cry j 1 and Cry j 2 T-cell epitope peptide-expressing rice in patients with Japanese cedar pollinosis.

BACKGROUND: In allergic models, administration of rice that expresses a hybrid peptide consisting of 7 major T cell epitopes of Cry j 1 and Cry j 2 (7Crp), suppressed allergic symptoms, IgE elevation and specific T cell response to Japanese cedar pollen. OBJECTIVE: To evaluate the efficacy and safety of 7Crp-expressing rice in patients with Japanese cedar pollinosis. METHODS: A 24-week randomized, double-blind, placebo-controlled study was performed to see the efficacy of 7Crp on allergic symptoms using scoring systems, in which 45 patients were assigned to take either 5 g, 20 g test rice, or placebo daily. A 96-week open study was also conducted to determine its inhibitory effect on serum IgE and T cell proliferative response for Japanese cedar pollen, in which 10 patients consumed 5 g test rice daily. RESULTS: No adverse events associated with the test rice occurred, and the intake rate was more than 96%. The test rice did not show suppression of symptoms related to Japanese cedar pollinosis within 24 weeks. However, intake of 5 g test rice led to a significant decrease in T cell response to Japanese cedar pollen during and after the second disperse season in a 96-week open trial, whereas the specific IgE titer remained unchanged. CONCLUSIONS: Tolerability and safety of 7Crp-expressing rice was accepted. Daily intake of up to 20 g transgenic rice did not provide beneficial effects on Japanese cedar pollinosis within 24 weeks, however, continuous intake of 5 g rice might reduce allergen specific T cell response.