Chronic intranasal corticosteroid treatment induces degeneration of olfactory sensory neurons in normal and allergic rhinitis mice.

BACKGROUND: Nasal eosinophilic inflammation is the therapeutic target for olfactory dysfunction in allergic rhinitis (AR). Intranasal corticosteroids are commonly considered to offer targetable benefit given their immunosuppressive property. However, experimental evidence suggests that continuous corticosteroid exposure may directly cause olfactory damage by disrupting the turnover of olfactory sensory neurons (OSNs). This potentially deleterious effect of corticosteroids calls into question their long-term topical use for treating olfactory loss related to AR. The aim of this study was to assess the impacts of chronic intranasal corticosteroid treatment on olfactory function and OSN population in mice under normal and pathological conditions. METHODS: BALB/c mice were intranasally treated with fluticasone propionate (FP, 0.3 mg/kg) for up to 8 weeks. Additional mice were used to establish an ovalbumin-induced mouse model of AR, followed by nasal challenge with ovalbumin for 8 weeks in the presence or absence of intranasal FP treatment. The authors examined olfactory function, OSN existence, neuronal turnover, and nasal inflammation using behavioral test, histological analyses, Western blotting, and enzyme-linked immunosorbent assay. RESULTS: Intranasal treatment with FP for 8 weeks (FP-wk8) reduced odor sensitivity in normal mice. This reduction was concomitant with loss of OSNs and the axons projecting to the olfactory bulb, primarily resulting from increased neuronal apoptosis. In FP-wk8 AR mice, intranasal FP treatment attenuated olfactory impairment and eosinophilic inflammation but failed to reconstitute OSN population and axonal projections. CONCLUSION: These results suggest that chronic intranasal corticosteroid treatment contributes to OSN degeneration that may reduce the therapeutic effectiveness for AR-related olfactory loss.

Research Status and Future Development of Cochlear Reimplantation.

Cochlear implants are the most successful sensory prostheses worldwide, and they can be useful for patients with severe and profound hearing impairment. However, various complications, including infection, pain, and device failure which is mainly due to falls and trauma, are associated with the use of cochlear implants. Reimplantation is required to replace the initial device in severe complications. Nevertheless, reimplantation can present certain surgical risks and may impose a significant economic and psychological burden on patients and their families; therefore, it requires greater attention and focus. This article presents a review of the literature on cochlear reimplantation and summarizes the current status, knowledge gaps, and future research directions on cochlear reimplantation. Since 1980s, cochlear reimplantation techniques can be considered to be relatively mature; however, some clinical and scientific problems remain unresolved, including the lack of a unified definition of cochlear reimplantation, non-standardized calculation of the reimplantation rat, and insufficient effect assessment. This review highlights the urgent need to establish an international consensus statement on cochlear reimplantation research to standardize the definition, calculation formulas of reimplantation rate, and follow-up systems.

A Four-Gene Signature Model Improves the Prediction of Distant Metastasis in Patients with Nasopharyngeal Carcinoma: A Retrospective, Three-Center Observational Study.

Background: Similar to that in other malignant tumors, distant metastasis is one of the most important causes of poor prognosis in nasopharyngeal carcinoma (NPC). However, the genetic hallmarks and networks that regulate the distant metastasis of NPC are not fully understood. Methods: In this study, we performed high-throughput screening of mRNA expression profiles in 92 NPC samples collected from 3hospitals and detected the mRNA expression levels of 31,503 genes in these samples. Gene functional enrichment analyses were performed using gene set enrichment analysis (GSEA). Least absolute shrinkage and selection operator (LASSO) was applied to select prognostic genes and a Cox proportional hazards regression model including these genes was constructed to predict prognosis. The Kaplan-Meier curve and time-dependent receiver operating characteristic (ROC) curve were plotted to assess the performance of this model. Univariate and multivariate analyses were performed using the Cox proportion hazard model to test the independence of prognostic effect of gene model and other clinical features. Results: A total of 1837 differentially expressed genes between patients with and without distant metastasis were identified in the training cohort, including 869 upregulated genes and 968 downregulated genes. Six gene sets, including the Wnt/ß catenin signaling pathway, hedgehog (Hh) signaling pathway, Notch signaling pathway, mitotic spindle, apical surface, and estrogen response late, were enriched in patients with distant metastasis. A four-gene signature model was constructed in the training cohort, and according to the time-dependent ROC curve, this model had certain accuracy in predicting distant metastasis-free survival (DMFS) in both the training and validation cohorts. Conclusion: We developed a four-gene signature model that can evaluate the distant metastasis risk of NPC patients and may also provide novel therapeutic targets for NPC treatment in the near future.

Traumatic Stapediovestibular Dislocation With Intact Stapes: Report and Review.

Stapediovestibular dislocation is a rare disorder as a result of traumatic injury to the structures in the middle ear. We described a case of a 60-year-old female with stapediovestibular dislocation with associated perilymph fistula. She presented with symptoms including hearing loss, vertigo, and tinnitus after a penetrating injury by an ear pick. After 4 months of conservative management, her symptoms failed to improve. Therefore, she underwent surgery which resolved completely her vestibular symptoms and her hearing loss had partially improved. The restoration of the stapes to its normal anatomical position coupled with ossiculoplasty and closure of the tympanic membrane are effective in patients with stapediovestibular dislocation.

Comparison of whole exome sequencing in circulating tumor cells of primitive and metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common cancers. To investigate the gene mutation profile of NPC patients, we performed whole exome sequencing (WES) in tumor cells, peripheral blood cells, and circulating tumor cells (CTCs) of primitive and metastatic NPC patients, and explored its clinical significance. METHODS: Primitive tumor cells, white blood cells, and CTCs of patients were collected and hybridized with probes targeting whole exons. Mutational signatures, signaling pathways, and cancer associated genes from CTCs cells of two primitive and two metastatic patients were analyzed using gene ontology (GO) method. RESULTS: The mutational landscape of four primitive tumors showed that there were more MSH2 alterations in more non-silent mutation number patients Additionally, BAP1 gene mutation only occurred in metastatic patients. The most frequently mutated genes among the primitive tumor and CTC samples were CFAP74, MOB3C, PDE4DIP, IGFN1, CYFIP2, NOP16, SLC22A1, ZNF117, and SSPO. Interestingly, only PMS1, BRIP1, DEE, OR2T12, CPN2, MLXIPL, BAIAP3, IGSF3, SIN3B, and ZNF880 alterations occurred in primary tumors of metastatic patients. Primitive and metastatic NPC had significantly distinct mutational signatures. GO analysis revealed that each patient had his own mutational signaling pathways. Non-silent single nucleotide variations (non-silent SNVs) and insertion-deletion mutations (INDELs) in CTCs were more dramatic than in primitive tumor cells. CONCLUSIONS: These changes are strongly relevant to their clinical characteristics and therapeutic strategy.

A study on the value of narrow-band imaging (NBI) for the general investigation of a high-risk population of nasopharyngeal carcinoma (NPC).

BACKGROUND: This study aims to explore the feasibility of narrow-band imaging (NBI) applied for the diagnostic screening of a high-risk population of nasopharyngeal carcinoma (NPC) and increase the accuracy rate of nasopharyngeal biopsy and the diagnosis rate of early-stage patients. METHODS: The positive high-risk population of NPC to EB virus antibody was followed up. At the same time, serological screening and pharyngorhinoscopy were carried out. The specific methods were as follows: (1) all subjects received nasopharyngeal examinations through both the HD endoscopic white light mode (WL) and NBI mode, (2) nasopharyngeal biopsy was conducted on positive subjects with microscopic examination, and, finally, (3) a comparative analysis was conducted between the biopsy pathology results and microscopy results. In addition, the following comparative indicators were recorded under different modes: sensitivity, specificity, accuracy, positive likelihood ratio, and negative likelihood ratio. Then, the area under the ROC curve and the kappa coefficient were calculated. RESULTS: A total of 115 subjects were detected to be positive by microscopic examination under the WL mode. Among these subjects, 19 subjects were diagnosed with NPC. In addition, 24 subjects were detected to be positive by microscopic examination under the NBI mode. Among these subjects, 23 subjects were diagnosed with NPC. Under the WL mode, the specific values of the comparative indicators were as follows: sensitivity, 82.61%; specificity, 0%; and area under the ROC curve, 0.413. Furthermore, the WL mode in the diagnosis on the high-risk population of NPC exhibited poor consistency with the biopsy pathology results (kappa coefficient = - 0.069). Under the NBI mode, the specific values of the comparative indicators were as follows: sensitivity, 100%; specificity, 98.96%; and area under the ROC curve, 0.995. Furthermore, the NBI mode in the diagnosis on the high-risk population of NPC exhibited relatively satisfactory consistency with the biopsy pathology results (kappa coefficient = 0.973). Therefore, the NBI mode is significantly superior to the WL mode. CONCLUSION: NBI endoscopic examinations should be conducted on a routine basis for high-risk populations of NPC. This can decrease the frequency of biopsies and enhance diagnostic effects.

Correlation of metastasis-associated protein expression with prognosis and chemotherapy in nasopharyngeal carcinoma.

The aim of this study was to elaborate the correlation between metastasis-associated protein (MTA) family and the occurrence, progression, prognosis and chemotherapy efficiency in nasopharyngeal carcinoma (NPC).The expression of MTA1, MTA2 and MTA3 protein were detected by immunohistochemistry in a tissue microarray (TMAs) which contains tissue samples of 152 NPC patients embedded by formalin-fixed paraffin. The MTA proteins were mainly expressed in the nuclei of NPC tissues and the correlations between MTAs expression and clinical parameters as well as prognosis of NPC patients showed ethnical differences according to statistically analysis. The results showed that in Han ethnic group, MTA1 expression was positively correlated with N staging, while the expression of MTA2 was negatively correlated with age, and the expression of MTA3 was positively correlated with gender. Patients with high MTA1 expression had poorprognosis. In Zhuang ethnic group, only MTA3 expression was positively correlated with age, recurrence and metastasis of NPC patients; neither MTA1 nor MTA2 expression had any correlation with clinical indexes. Patients with high MTA3 expression had unfavorable prognosis. In addition, our results showed that overall survival among Zhuang NPC patients with low expression of MTA2 increased significantly owing to "carboplatin + fluorouracil" chemotherapy. This therapeutic success, however, did not translate to longer overall survival among Han NPC patients. The biological function of MTA protein family in NPC patients was different among different ethnic groups. In conclusion, we demonstrated that MTAs had a certain tumor promoting function in patients with NPC, and the biological functions of MTAs might be ethnic differences, which suggesting MTAs to be important markers for guiding clinical treatment of NPC.

Up-regulation of the IRX2 gene predicts poor prognosis in nasopharyngeal carcinoma.

Aberrant expression of the IRX2 gene contributes to the oncogenesis and progression of various cancers. In this study, we analyzed the clinical significance and the prognostic value of mRNA expression level of the IRX2 gene in nasopharyngeal carcinoma (NPC) patients, with the goal to find a novel prognostic biomarker for NPC. Tissue samples were collected prior to treatment from 71 NPC patients for the detection of mRNA expression level of a total of 31503 genes, with high throughput screening of the mRNA expression profile. The Kaplan-Meier curves and log-rank test were used for univariate analyses to determine if the mRNA expression level of IRX2 and other 31502 genes, as well as clinical characteristics were of prognostic value for overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS). Regularized Cox regression was performed to test the contribution of prognostic factors to OS, DMFS, and DFS of NPC patients. The Cox proportional hazard model was used to test the independence of prognostic effect of IRX2 and other clinical features. The receiver operator characteristic curve was drawn and the area under the curve (AUC) was calculated to evaluate the predictive power of IRX2 gene. Univariate analyses showed a higher mRNA expression level of the IRX2 gene correlated with shorter OS (P = 0.001), DMFS (P = 0.003), and DFS (P = 0.007). Regularized Cox regression and Cox proportional hazard model analyses further showed that ahigher mRNA expression level of the IRX2 gene in the primary NPC was an independent prognostic factor for OS (Coxnet beta = 0.03, Cox proportion hazard model P = 0.038), DMFS (Coxnet beta = 0.018, Cox proportion hazard model P = 0.01) and DFS (Coxnet beta = 0.008, Cox proportion hazard model P = 0.029). The AUC showed that the mRNA expression level of the IRX2 gene is a significant predictor for predicting the OS (AUC value = 0.7105) and DMFS (AUC value = 0.7027) of NPC patients. Our results demonstrated that the IRX2 gene may be a novel independent unfavorable prognostic factor for NPC patients.

Clinical outcomes of residual or recurrent nasopharyngeal carcinoma treated with endoscopic nasopharyngectomy plus chemoradiotherapy or with chemoradiotherapy alone: a retrospective study.

BACKGROUND: Local residual and recurrent nasopharyngeal carcinoma (NPC) generally shows treatment failure after standard radiotherapy with or without concurrent chemotherapy. Whether endoscopic nasopharyngectomy might provide an additional therapeutic advantage remains controversial. Therefore, we retrospectively compared the clinical prognoses of patients with residual or recurrent NPC treated with endoscopic nasopharyngectomy combined with chemoradiotherapy (CRT) with those of patients treated with CRT alone. METHODS AND MATERIALS: A total of sixty-two patients with local residual or recurrent NPC were studied retrospectively: 36 patients received endoscopic nasopharyngectomy combined with CRT, whereas 26 patients who refused the surgery or had surgical contraindications received CRT alone. Serum Epstein-Barr virus (EBV) DNA levels were measured pre- and post-treatment. The differences in prognosis between the two treatment regimens and the pre- and post-treatment changes in EBV-DNA levels were analyzed. RESULTS: The median follow-up time was 31 months, with a 3-year overall survival (OS) of 51.40% and a 3-year disease-free survival (DFS) of 46.86%. The surgery + CRT group had a better OS than the CRT alone group did (χ2 = 4.054, P = 0.044). The pretreatment EBV-DNA levels showed a positive correlation with the clinical staging of recurrent NPC (χ2 = 11.674, P = 0.009). Patients with negative pretreatment serum EBV-DNA levels showed a superior OS to those of patients who tested positive for EBV-DNA (>0 copy/mL) (χ2 = 9.833, P = 0.002). The post-treatment EBV-DNA levels, compared with the pretreatment levels, decreased significantly in the surgery + CRT group (Z =  - 3.484, P = 0.000). In contrast, the EBV-DNA levels after CRT alone did not decrease significantly (Z =  - 1.956, P = 0.051). Multivariate analysis indicated that local staging, pretreatment EBV-DNA load, and the treatment method were independent risk factors for OS. Subgroup analysis indicated that the patients who tested negative for EBV-DNA before the treatment and those who received surgery + CRT showed a better OS than those who received CRT alone. CONCLUSIONS: The pretreatment serum EBV-DNA level was associated with disease prognosis. The combination therapy preceded by surgery can effectively decrease the copy number of EBV-DNA. Patients with local intermediate- and late-stage NPC, especially those negative for EBV-DNA, may consider opting for surgery followed by post-operative adjuvant radiotherapy or chemotherapy.

Influence of endoscopic sinus surgery on the quality of life of patients with early nasopharyngeal carcinoma and the analysis of prognosis-related factors.

The aim of this study is investigate the influence of endoscopic sinus surgery on the quality of life and prognosis of patients with early nasopharyngeal carcinoma. Patients initially diagnosed with early nasopharyngeal carcinoma and received surgical treatment were matched with nasopharyngeal carcinoma patients who received chemoradiotherapy at a ratio of 1:1, according to the following seven factors: gender, age, T staging, N staging, clinical staging, radiotherapy options, and chemotherapy options. Patients in the surgery group received endoscopic sinus surgery plus chemoradiotherapy, while subjects in the control group received chemoradiotherapy. The quality of life of patients before and after treatment was evaluated based on the FACT-H&N (Functional Assessment of Cancer Therapy-Head and Neck) and QLQ-H&N35 (Head and Neck Cancer Specific Module) questionnaires. In addition, overall survival and disease-free survival were compared between these two groups. The results showed overall survival was superior in the surgery group compared with the control group ( p = 0.007). However, the difference in disease-free survival between these two groups was not statistically significant ( p = 0.128). Furthermore, subgroup analysis revealed that for N0 patients, the effect of surgery combined with chemoradiotherapy on overall survival was superior to that of chemoradiotherapy ( p = 0.048); while for N1 patients, the difference in overall survival between these two groups was not statistically significant ( p = 0.065). For early nasopharyngeal carcinoma patients without lymph node metastasis, overall survival and disease-free survival in T1 patients were superior to those in T2 patients (χ2 = 4.403, p = 0.036; χ2 = 4.542, p = 0.033). At the end of treatment, the pain score was found to be significantly lower in the surgery group than in the chemoradiotherapy group ( p = 0.027). At 3 months and 1 year after treatment, dry mouth scores were significantly lower in the surgery group than in the chemoradiotherapy group ( p = 0.002, p = 0.026). These results demonstrated that the curative effect of surgery combined with chemoradiotherapy in the treatment of nasopharyngeal carcinoma was satisfactory and was particularly suitable for N0 patients.

The Safety and Immunological Effects of rAd5-EBV-LMP2 Vaccine in Nasopharyngeal Carcinoma Patients: A Phase I Clinical Trial and Two-Year Follow-Up.

Epstein-Barr virus (EBV)-encoded latent membrane protein 2 (LMP2) promotes nasopharyngeal carcinoma (NPC) progression. Previously, we reported that the dendritic cells (DCs) transfected with EBV-LMP2 recombinant serotype 5 adenoviruses (rAd5) induced anti-tumor effect by eliciting cytotoxic T lymphocytes (CTLs)-mediated immune response in vitro and the adenoviral vaccine of EBV-LMP2 (rAd5-EBV-LMP2) stimulated antigen-specific cellular immunity in mice. However, the safety and immunological effect of rAd5-EBV-LMP2 vaccine in human still remained unknown. Here we conducted a single-center, non-randomized, open-label, single-arm phase I clinical trial to clarify this unsolved issue. A total of 24 patients with regional advanced NPC were sequentially enrolled into three dose level groups (2×10(9), 2×10(10), 2×10(11) vp). The rAd5-EBV-LMP2 vaccines were intramuscularly injected for four times within 28 d (D0, D7, D14, D28). Blood samples were harvested immediately before every vaccination, one week and one month after the last vaccination (D0, D7, D14, D28, D35, D58). All the vaccine inoculation-related toxicities presented as grade I/II adverse events. The most frequent systemic adverse reactions were fatigue (33.0%, 8/24), myalgia (29.2%, 7/24) and cough (29.2%, 7/24), while the most common regional adverse reaction was tenderness in the inoculation site (54.2%, 13/24). In addition, proportion of CD(3+)CD(4+) cells in peripheral blood was significantly increased in the high dose group (2×10(11) vp). The rAd5-EBV-LMP2 vaccine was generally well-tolerated and the high dose (2×10(11) vp) is recommended to be adopted in phase II studies. The long-term outcome of rAd5-EBV-LMP2 vaccine inoculation is required to be determined in following placebo-controlled trials.

Interleukin-1ß regulates the expression of glucocorticoid receptor isoforms in nasal polyps in vitro via p38 MAPK and JNK signal transduction pathways.

BACKGROUND: To explore the upstream signal transduction mechanisms responsible for the imbalanced expression of glucocorticoid receptor (GR) isoforms in chronic rhinosinusitis (CRS) mucosa. METHODS: An in vitro model of Glucocorticoid resistance was established by inducing nasal polyp tissue with IL-1ß. Changes in the protein and mRNA expression of GRα, GRß and the key enzymes in the p38 MAPK and JNK signal pathways were measured, respectively, before and after being induced with different doses of IL-1ß and specific inhibitors of p38 MAPK, JNK, ERK, PI3K and PKC. The Glucocorticoid sensitivity was measured using in vitro Glucocorticoid binding assay. Analysis of variance (ANOVA) was used to analyze the data. RESULTS: The mRNA and protein expression levels of GRα, GRß and key enzymes of the p38 MAPK and JNK pathways increased both in time- and concentration-dependent manners in IL-1ß-induced nasal polyp tissue. The expression of GRß increased more significantly than that of GRα, and the GRα/GRß ratio decreased in time- and concentration-dependent manners. Statistically significant differences were found in the GRα/GRß ratio and the mRNA expression of phospho-p38 MAPK and phospho-JNK between the IL-1ß-induced groups and the control groups (P < 0.05). Either a specific inhibitor of the p38 MAPK pathway or a specific inhibitor of the JNK pathway increased the GRα/GRß ratio and the Glucocorticoid affinity. None of the specific inhibitors of ERK, PI3K or PKC had any influence on the expression of GR isoforms. CONCLUSION: Our results demonstrated that the imbalanced expression of GR isoforms in nasal polyp tissue induced by IL-1ß in vitro is mediated through the p38 MAPK and JNK signal pathways.