Peritumoral SPARC expression induced by exosomes from nasopharyngeal carcinoma infected Epstein-Barr virus: A poor prognostic marker.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) cells have high metastatic potential. Recent research has revealed that the interaction of between tumor cells and the surrounding stroma plays an important role in tumor invasion and metastasis. In this study, we showed the prognostic value of expression of SPARC, an extracellular matrix protein with multiple cellular functions, in normal adjacent tissues (NAT) surrounding NPC. In the immunohistochemical analysis of 51 NPC biopsy specimens, SPARC expression levels were significantly elevated in the NAT of EBER (EBV-encoded small RNA)-positive NPC compared to that in the NAT of EBER-negative NPC. Moreover, increased SPARC expression in NAT was associated with a worsening of overall survival. The enrichment analysis of RNA-seq of publicly available NPC and NAT surrounding NPC data showed that high SPARC expression in NPC was associated with epithelial mesenchymal transition promotion, and there was a dynamic change in the gene expression profile associated with interference of cellular proliferation in NAT, including SPARC expression. Furthermore, EBV-positive NPC cells induce SPARC expression in normal nasopharyngeal cells via exosomes. Induction of SPARC in cancer-surrounding NAT cells reduced intercellular adhesion in normal nasopharyngeal structures and promoted cell competition between cancer cells and normal epithelial cells. These results suggest that epithelial cells loosen their own binding with the extracellular matrix as well as stromal cells, facilitating the invasion of tumor cells into the adjacent stroma by activating cell competition. Our findings reveal a new mechanism by which EBV creates a pro-metastatic microenvironment by upregulating SPARC expression in NPC.

Identification rate of Legionella species in non-purulent sputum culture is comparable to that in purulent sputum culture in Legionella pneumonia.

Many Legionella pneumonia patients do not produce sputum, and it is unknown whether purulent sputum is required for the identification of Legionella species. This study aimed to evaluate the identification rate of Legionella species based on sputum quality and the factors predictive of Legionella infection. This study included Legionella pneumonia patients at Kurashiki Central Hospital from November 2000 to December 2022. Sputum quality, based on gram staining, was classified as the following: Geckler 1/2, 3/6 and 4/5. Geckler 4/5 was defined as purulent sputum. The sputa of 104 of 124 Legionella pneumonia patients were cultured. Fifty-four patients (51.9%) were identified with Legionella species, most of which were Legionella pneumophila serogroup 1 (81.5%). The identification rates of Legionella species according to sputum quality were 57.1% (16/28) in Geckler 1/2 sputum, 50.0% (34/68) in Geckler 3/6 sputum, and 50.0% (4/8) in Geckler 4/5 sputum, which were not significantly different (P = 0.86). On multivariate analysis, pre-culture treatment with anti-Legionella antimicrobials (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.06-0.91), Pneumonia Severity Index class ≥IV (OR 2.57 [95% CI 1.02-6.71]), and intensive care unit admission (OR 3.08, 95% CI 1.06-10.09) correlated with the ability to identify Legionella species, but sputum quality did not (OR 0.88, 95% CI 0.17-4.41). The identification rate of Legionella species in non-purulent sputum was similar to that in purulent sputum. For the diagnosis of Legionella pneumonia, sputum should be collected before administering anti-Legionella antibiotics and cultured regardless of sputum quality.

Immune-Related Gene Expression Profile at Peritumoral Tonsillar Tissue Is Modified by Oropharyngeal Cancer Nodal Status.

Secondary lymphoid organs, such as lymph nodes and tonsils, serve as an interface between the immune system and tumor cells as an initial antigen-presentation site, crucial in antitumor immune response and disease progression. In oropharyngeal cancers originating from palatine tonsils, it was hypothesized that characterizing the immunologic process occurring in the peritumoral tonsil tissue would elucidate immune mechanisms of the lymphatic spread of the disease. A total of 33 patients were enrolled and divided into two cohorts. In Cohort 1 (6 patients), gene expression profiles at the peritumoral lymph regions and tumor regions were analyzed using the whole-transcriptome atlas. In the peritumoral lymph regions, 237 genes were up-regulated in metastasis-negative cases compared with metastasis-positive ones, but only 1 gene was up-regulated in tumor regions. In Cohort 2 (27 patients), microarray analysis of peritumoral tonsil tissue revealed 192 up-regulated genes. Gene ontology analysis revealed the significantly enriched Gene Ontology terms associated with T-cell activation; top 10 hub genes, as ranked by degree, were PTPRC, TLR4, CD80, CD40, STAT3, CD28, CD40LG, CD44, CCR7, and IL7R. Gene set enrichment analysis combined with principal component analysis were used to effectively classify patients as lymph node metastasis positive or negative. These findings suggest peritumoral tonsils as a potential target for investigating the immune mechanisms associated with the lymphatic spread of the disease in oropharyngeal cancers.

Three cases of hospitalized Legionella pneumonia patients successfully treated with lascufloxacin.

Legionella pneumonia is one of the major causes of severe pneumonia, in which treatment delay might lead to a poor prognosis. Therefore, as far as possible, early diagnosis and treatment of Legionella pneumonia is essential. Regarding the antimicrobials for Legionella pneumonia, fluoroquinolones, such as levofloxacin, or macrolides, such as azithromycin (AZM), are recommended in Japan and other countries. Lascufloxacin (LSFX), the newest fluoroquinolone developed in Japan, has been in use in daily clinical practice since January 2020. However, there are only few reports of Legionella pneumonia cases treated with LSFX. Here, we report three cases of hospitalized Legionella pneumonia patients that were successfully treated using LSFX. All three patients were admitted to the medical ward on admission, although one patient was subsequently transferred to the ICU for mechanical ventilatory management due to worsening of the pneumonia on day 3. All patients improved and were discharged following LSFX treatment (the patient admitted to the ICU was treated using LSFX + AZM combination therapy) without any severe adverse events. LSFX might be considered to be the first antibiotic choice for Legionella pneumonia, similar to levofloxacin. However, further data regarding the treatment of Legionella pneumonia cases using LSFX are needed to evaluate its efficacy and safety.

EBV genome variations enhance clinicopathological features of nasopharyngeal carcinoma in a non-endemic region.

Nasopharyngeal carcinoma (NPC) is caused by infection with Epstein-Barr virus (EBV) and endemic in certain geographic regions. EBV lytic gene, BALF2, closely associates with viral reactivation and BALF2 gene variation, the H-H-H strain, causes NPC in endemic region, southern China. Here, we investigate whether such EBV variations also affect NPC in a non-endemic region, Japan. Viral genome sequencing with 47 EBV isolates of Japanese NPC were performed and compared with those of other EBV-associated diseases from Japan or NPC in Southern China. EBV genomes of Japanese NPC are different from those of other diseases in Japan or endemic NPC; Japanese NPC was not affected by the endemic strain (the BALF2 H-H-H) but frequently carried the type 2 EBV or the strain with intermediate risk of endemic NPC (the BALF2 H-H-L). Seven single nucleotide variations were specifically associated with Japanese NPC, of which six were present in both type 1 and 2 EBV genomes, suggesting the contribution of the type 2 EBV-derived haplotype. This observation was supported by a higher viral titer and stronger viral reactivation in NPC with either type 2 or H-H-L strains. Our results highlight the importance of viral strains and viral reactivation in the pathogenesis of non-endemic NPC.

Estrogen induces the expression of EBV lytic protein ZEBRA, a marker of poor prognosis in nasopharyngeal carcinoma.

Several epidemiological studies have suggested that Epstein-Barr virus (EBV) lytic infection is essential for the development of nasopharyngeal carcinoma (NPC), as the elevation of antibody titers against EBV lytic proteins is a common feature of NPC. Although ZEBRA protein is a key trigger for the initiation of lytic infection, whether its expression affects the prognosis and pathogenesis of NPC remains unclear. In this study, 64 NPC biopsy specimens were analyzed using immunohistochemistry. We found that ZEBRA was significantly associated with a worsening of progression-free survival in NPC (adjusted hazard ratio, 3.58; 95% confidence interval, 1.08-11.87; p = 0.037). Moreover, ZEBRA expression positively correlated with key endocrinological proteins, estrogen receptor α, and aromatase. The transcriptional level of ZEBRA is activated by estrogen in an estrogen receptor α-dependent manner, resulting in an increase in structural gene expression levels and extracellular virus DNA copy number in NPC cell lines, reminiscent of lytic infection. Interestingly, it did not suppress cellular proliferation or increase apoptosis, in contrast with cells treated with 12-O-tetradecanoylphorbol-13-acetate and sodium butyrate, indicating that viral production induced by estrogen is not a cell lytic phenomenon. Our results suggest that intratumoral estrogen overproduced by aromatase could induce ZEBRA expression and EBV reactivation, contributing to the progression of NPC.

Inflammatory biomarkers are not useful for predicting prognosis in nursing and healthcare-associated pneumonia: A prospective, cohort study.

INTRODUCTION: Whether inflammatory biomarkers including procalcitonin (PCT) and C-reactive protein (CRP) are useful for predicting prognosis in nursing and healthcare-associated pneumonia (NHCAP) is unknown. The aim of the present study was to investigate the utility of serial PCT and CRP measurements for predicting prognosis and treatment efficacy for hospitalized NHCAP patients. METHODS: This prospective, observational, cohort study enrolled consecutive NHCAP patients hospitalized at Kurashiki Central Hospital from October 2010 to September 2017. PCT and CRP were measured twice, once on admission and again within 48-72 h after admission. The primary outcome was 30-day all-cause mortality, and the secondary outcome was initial treatment failure. RESULTS: A total of 299 patients were included. The 30-day mortality rate was 8.4% (25/299), and the initial treatment failure rate was 15.4% (46/299). On multivariate analysis, performance status [odds ratio (OR) (95% confidence interval (CI)): 2.25 (1.34-3.77), P = 0.002], temperature [OR (95%CI): 0.53 (0.32-0.88), P = 0.02], heart rate [OR (95%CI): 1.03 (1.01-1.06), P = 0.007], albumin [OR (95%CI): 0.42 (0.18-0.95), P = 0.04], and blood urea nitrogen [OR (95%CI): 1.02 (1.00-1.05), P = 0.04] were significant prognostic factors, and CRP D3 [OR (95%CI): 1.07 (1.02-1.11), P = 0.003] and PSI [OR (95%CI): 1.01 (1.00-1.02), P = 0.01] were the predictors of initial treatment failure. Consecutive measurements of PCT and CRP were not significant predictors of 30-day mortality. CONCLUSIONS: Inflammatory biomarkers including PCT and CRP were not useful for predicting prognosis and treatment efficacy in NHCAP patients. We should carefully evaluate the patients' vital signs and comorbidities when managing NHCAP patients.

Increased risk of Legionella pneumonia as community-acquired pneumonia after heavy rainfall in 2018 in west Japan.

INTRODUCTION: Japan experienced a heavy rainfall event from June 28 to July 8, 2018, and many casualties were caused by both heavy rainfall and flooding. Few studies have investigated patients' characteristics and the causative pathogens of community-acquired pneumonia before and after heavy rainfall events. The aim of the present study was to evaluate the causative pathogens and clinical characteristics of hospitalized patients with community-acquired pneumonia before and after the heavy rainfall event using prospective cohort data. METHODS: The study was divided into two periods: July to November 2013-2017 (before heavy rainfall) and July to November 2018 (after heavy rainfall). The patients' clinical characteristics and causative pathogens before and after the heavy rainfall were investigated. Regarding the causative pathogens, adjustments were made for precipitation and seasonal patterns. RESULTS: There were no significant differences in the number and clinical characteristics of patients before and after heavy rainfall. However, the frequency of Legionella pneumonia was significantly higher after than before the heavy rainfall event (8.9% vs 3.0%, P = 0.02) and remained significant after adjusting for precipitation and season. Three of 7 Legionella pneumonia patients engaged in reconstruction work and 2 Legionella pneumonia patients had soil exposure. CONCLUSIONS: An increased risk of Legionella pneumonia after not only rainfall and serious flooding, but also following recovery work or soil exposure should be considered.

Usefulness of ß-lactam and macrolide combination therapy for treating community-acquired pneumonia patients hospitalized in the intensive care unit: Propensity score analysis of a prospective cohort study.

INTRODUCTION: Whether ß-lactam and macrolide combination therapy reduces mortality in severe community-acquired pneumonia (SCAP) patients hospitalized in the intensive care unit (ICU) is controversial. The aim of the present study was to evaluate the usefulness of ß-lactam and macrolide combination therapy for SCAP patients hospitalized in the ICU. METHODS: A prospective, observational, cohort study of hospitalized pneumonia patients was performed. Hospitalized SCAP patients admitted to the ICU within 24 h between October 2010 and October 2017 were included for analysis. The primary outcome was 30-day mortality, and secondary outcomes were 14-day mortality and ICU mortality. Inverse probability of treatment weighting (IPTW) analysis as a propensity score analysis was used to reduce biases, including six covariates: age, sex, C-reactive protein, albumin, Pneumonia Severity Index score, and APACHE II score. RESULTS: A total of 78 patients were included, with 48 patients in the non-macrolide-containing ß-lactam therapy group and 30 patients in the macrolide combination therapy group. ß-lactam and macrolide combination therapy significantly decreased 30-day mortality (16.7% vs. 43.8%; P = 0.015) and 14-day mortality (6.7% vs. 31.3%; P = 0.020), but not ICU mortality (10% vs 27.1%, P = 0.08) compared with non-macrolide-containing ß-lactam therapy. After adjusting by IPTW, macrolide combination therapy also decreased 30-day mortality (odds ratio, 0.29; 95%CI, 0.09-0.96; P = 0.04) and 14-day mortality (odds ratio, 0.19; 95%CI, 0.04-0.92; P = 0.04), but not ICU mortality (odds ratio, 0.34; 95%CI, 0.08-1.36; P = 0.13). CONCLUSIONS: Combination therapy with ß-lactam and macrolides significantly improved the prognosis of SCAP patients hospitalized in the ICU compared with a non-macrolide-containing ß-lactam regimen.

Prognostic factors in nursing and healthcare-associated pneumonia.

BACKGROUND AND OBJECTIVE: Nursing and healthcare-associated pneumonia (NHCAP) is a category of healthcare-associated pneumonia modified for the healthcare system in Japan. To date, only a few studies have examined the prognostic factors of NHCAP in a prospective cohort. This study aimed to investigate the prognostic factors related to 30-day mortality in patients with NHCAP by analyzing prospective data. METHODS: We analyzed patients hospitalized for NHCAP who were enrolled between October 2010 and February 2017. Age, sex, comorbidities, vital signs and laboratory findings were used as prognostic variables. The primary outcome was 30-day mortality. RESULTS: Of 817 NHCAP patients identified, the mean age was 78.0 ± 11.1 years, 580 (71.0%) were men and 30-day mortality was 13.1% (107/817). On multivariate analysis, male sex (odds ratio [OR]: 2.07, 95% confidence interval [CI]: 1.18-3.63), malignancy (OR: 2.35, 95%CI: 1.38-4.01), performance status (PS) (OR: 1.55, 95%CI: 1.23-1.96), body temperature (OR: 0.77, 95%CI: 0.61-0.97), heart rate (OR: 1.02, 95%CI: 1.01-1.03), respiratory rate (OR: 1.04, 95%CI: 1.01-1.08), serum albumin (Alb) (OR: 0.45, 95%CI: 0.30-0.66) and blood urea nitrogen (BUN) (OR: 1.02, 95%CI: 1.01-1.03) were significantly related to 30-day mortality. On the other hand, the risk factors for involvement by drug-resistant pathogens predicted a better prognosis (OR: 0.39, 95%CI: 0.19-0.82). CONCLUSIONS: Male sex, malignancy, poor PS, hypothermia, tachycardia, tachypnea, low serum Alb and high BUN are worse prognostic factors. Thus, the risk of drug-resistant pathogens is not necessarily related to poor prognosis.

Expression of estrogen receptor alpha is associated with pathogenesis and prognosis of human papillomavirus-positive oropharyngeal cancer.

Human papillomavirus (HPV) has been identified as a causative agent of cervical cancer and oropharyngeal cancer (OPC). Intriguingly, estrogen and HPV were shown to play synergistic roles in cervical carcinogenesis. We recently demonstrated that the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which is inducible by estrogen, could lead to HPV DNA hypermutation and cause viral DNA integration. In the present study, we examined the relationships between estrogen-estrogen receptor α (ERα) and A3s in HPV-positive OPC. ERα expression was associated with HPV positivity in OPC biopsy samples using immunohistochemical analysis and reverse-transcription quantitative polymerase chain reaction. In addition, ERα was significantly associated with improved overall survival in HPV-positive OPC (hazard ratio, 0.26; p = 0.029). APOBEC3A (A3A) mRNA was induced by estrogen in HPV and ERα-positive OPC cells. Furthermore, A3A mRNA and protein expression were significantly higher in ERα-positive cases than in ERα-negative ones, among HPV-positive biopsy samples (p = 0.037 and 0.047). These findings suggest that A3A is associated with a good prognosis in ERα-positive OPC, and indicate the prognostic significance of ERα in HPV-positive OPC. This is the first study to demonstrate the prognostic role of ERα in HPV-positive OPC.

Progression of understanding for the role of Epstein-Barr virus and management of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is very common in southern China and Southeast Asia. In regions where NPC is endemic, undifferentiated subtypes constitute most cases and are invariably associated with Epstein-Barr virus (EBV) infection, whereas the differentiated subtype is more common in other parts of the world. Undifferentiated NPC is a unique malignancy with regard to its epidemiology, etiology, and clinical presentation. Clinically, NPC is highly invasive and metastatic, but sensitive to both chemotherapy and radiotherapy (RT). Overall prognosis has dramatically improved over the past three decades because of advances in management, including the improvement of RT technology, the broader application of chemotherapy, and more accurate disease staging. Despite the excellent local control with modern RT, distant failure remains a challenging problem. Advances in molecular technology have helped to elucidate the molecular pathogenesis of NPC. This article reviews the contribution of EBV gene products to NPC pathogenesis and the current management of NPC.

Modulation of the tumor microenvironment by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma.

Latent membrane protein 1 (LMP1) is a primary oncogene encoded by the Epstein-Barr virus, and various portions of LMP1 are detected in nasopharyngeal carcinoma (NPC) tumor cells. LMP1 has been extensively studied since the discovery of its transforming property in 1985. LMP1 promotes cancer cell growth during NPC development and facilitates the interaction of cancer cells with surrounding stromal cells for invasion, angiogenesis, and immune modulation. LMP1 is detected in 100% of pre-invasive NPC tumors and in approximately 50% of advanced NPC tumors. Moreover, a small population of LMP1-expressing cells in advanced NPC tumor tissue is proposed to orchestrate NPC tumor tissue maintenance and development through cancer stem cells and progenitor cells. Recent studies suggest that LMP1 activity shifts according to tumor development stage, but it still has a pivotal role during all stages of NPC development.

EBV infection is prevalent in the adenoid and palatine tonsils in adults.

Epstein-Barr virus (EBV) is associated with the pathogenesis of several diseases in both adults and children. However, there have been no reports on the prevalence and amount of EBV in the adenoids of adults; thus, it is important to investigate these in the adenoids and tonsils of adults and children. In this study, 67 patients who underwent tonsillectomy or adenotonsillectomy were included and divided into two groups: adults aged ≥ 16 years (n = 35) and children aged <16 years (n = 32). Patients' adenoid and tonsil tissues were analyzed using quantitative polymerase chain reaction for EBV DNA. EBV was detected in 26 (74%) adenoids and 25 (71%) tonsils among the adult group and was detected 21 (66%) adenoids and 20 (63%) tonsils in the child group. There was no significant difference in EBV DNA prevalence between the adenoids and tonsils for each group. However, there was a significant correlation between EBV DNA load in the adenoids and tonsils of the same individual in both groups (r = 0.579, P < 0.01, adult group; r = 0.919, P < 0.01, child group). In conclusion, EBV infection is prevalent in the adenoids and tonsils in adults and children. These results indicate that EBV continuously reside in the nasopharyngeal region after primal infection and may develop several diseases.

Expression of interferon regulatory factor 7 correlates with the expression of Epstein-Barr Virus latent membrane protein 1 and cervical lymph node metastasis in nasopharyngeal cancer.

Interferon regulatory factor 7 (IRF7) has oncogenic properties in several malignancies such as Epstein-Barr virus (EBV)-associated lymphoma. However, there is no evidence whether IRF7 is associated with the oncogenesis of nasopharyngeal cancer (NPC), the pathogenesis of which is closely associated with EBV. Herein, we report that expression of IRF7 was increased in normal nasopharyngeal cells that expressed the EBV principal oncoprotein, latent membrane protein 1 (LMP1). In addition, IRF7 was mainly expressed in the nucleus in both normal nasopharyngeal cells and nasopharyngeal cancer cells that expresses LMP1. On immunohistochemical analysis, IRF7 was predominantly localized in the nucleus in biopsy samples of NPC tissues. In total, IRF7 expression was detected with 36 of 49 specimens of these tissues. Furthermore, the expression score of IRF7 correlated with the expression score of LMP1. Moreover, the expression score of IRF7 is associated with cervical lymph-node metastasis, which reflects the highly metastatic nature of this cancer. Taken together, our results suggest that expression of IRF7 is one of the metastatic effectors of LMP1 signalling in EBV-associated NPC.

Factors Affecting Resumption of Oral Intake of Food in Patients Undergoing Swallowing Rehabilitation.

In this study, we investigated for a period of 8 years, 884 patients who underwent swallowing rehabilitation in our hospital, and evaluated the factors affecting resumption of oral intake of food. We found that the number of patients undergoing swallowing rehabilitation in our hospital increased over time. Of the included patients, 82.8% were ≥70 years of age and men were more frequent than women (p=0.004). At the end of the rehabilitation, 56.3% patients' main nutrition route was oral. Most (60.5%) patients required <30 days of rehabilitation. We evaluated correlation between the states of patients at starting point of swallowing rehabilitation and the result of the rehabilitation. The patients having a desire for eating were significantly more successful in regaining oral intake of food than those without the desire (p<0.001) and those with desire unknown (p<0.001). We classified the patients as per the Japan Coma Scale into four groups: alert, 1 digit, 2 digits, and 3 digits; the 3-digit group was significantly less successful in resumption of oral ingestion compared to all other groups (p<0.001). Based on the activities of daily living (ADL), we classified the patients into four groups: supine position, possible to semi-sitting group (get-up more than 30°), possible to sit-up group, and possible more than transferring by oneself group. It was proved that the supine position group was significantly less successful in regaining oral intake of food compared to all other groups (p<0.001). Multivariate analysis showed that the strongest correlation for regaining oral ingestion was desire for eating (p<0.001), followed by ADL and level of consciousness. In conclusion, we found that the number of patients undertaking swallowing rehabilitation in our hospital is increasing, and that factors such as desire for eating, ADL, and level of consciousness significantly influence the resumption of oral intake of food.

[Pharyngoesophageal Reconstruction Using a Laryngotracheal Flap Following Resection for Hypopharyngeal Cancer].

We used hemilaryngotracheal tissue without tumor involvement as a laryngotracheal flap (LTF) for immediate repair of a pharyngoesophageal defect following resection for hypopharyngeal cancer. Five cases of lateralized advanced hypopharyngeal cancer were treated in our department. The median age was 82 years, ranging from 64 to 90 years. Four tumors were T3 stage, and the other was T2. A pharyngocutaneous fistula developed in one patient. The postoperative swallowing function was satisfactory, but one patient developed difficulty in eating a normal diet, because of pharyngoesophageal stenosis at 7 months after chemoradiotherapy. During the follow-up period, there was no locoregional recurrence. One patient had lung metastasis, and died of the disease. One patient died of another cause. Three patients are alive without evidence of the disease. Reconstruction of the hypopharynx with an LTF is a minimally invasive method compared with the radial forearm free flap and free jejunal flap. For selected cases of advanced hypopharyngeal cancer, this method would be one of the choices to reconstruct the pharyngoesophageal defect.

Progress and controversy for the role of chemotherapy in nasopharyngeal carcinoma.

Since the publication of Intergroup Study 0099, representing a superiority of concurrent chemoradiotherapy with cisplatin followed by adjuvant chemotherapy to radiotherapy alone for the treatment of locoregionally advanced nasopharyngeal carcinoma, an efficacy of concurrent setting of cisplatin-based chemotherapy with radiotherapy has been repeatedly validated. In meanwhile, the role of adjuvant part of the protocol has been controversial. There is an increasing evidence for the positive role of neoadjuvant chemotherapy with following concurrent chemoradiotherapy whereas favorable contribution was not proven in the last century. This article reviews the role of chemotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

[Pursed Lips Inspiration for Vocal Cord Dysfunction].

Paradoxical vocal cord motion (PVCM) during vocal cord dysfunction (VCD) generally occurs spasmodically and transiently. After we had experienced 36 cases of VCD and successfully treated with conservative treatment including "pursed lips inspiration" method, we experienced a boy who had persistent PVCM. It was observed his PVCM vanished when he breathed in through pursed lips, while it appeared again when he stopped pursed lips inspiration. An airway reflex has been reported where the negative pressure in the subglottic space resulting from the inspiratory effort against a narrowed glottis activates the vocal cord adductor. VCD is considered to have both acceleration of laryngeal closure reflex against airway stimuli and active adductive movement of vocal cords against negative pressure in the subglottic space as underlying factors. The pursed lips inspiration method enables VCD patients not only to accomplish slow and light breathing but also to decrease the difference in the pressure between the supra--and subglottic space by occluding the nasal cavity and voluntary puckering up of the mouth which generate negative pressure in the supraglottic space. This is the first report of the pursed lips inspiration method as a treatment for VCD. Pursed lips inspiration is a simple method which is easy to perform anytime, anywhere without any special equipment, and is considered to be worth trying for VCD.