Effect of anti-reflux treatment on gastroesophageal reflux-associated chronic cough: Implications of neurogenic and neutrophilic inflammation.

Objective: Gastroesophageal reflux disease (GERD) is an important cause of chronic cough. Substance P (SP) has been implicated in the pathophysiology of cough. Proton pump inhibitors (PPIs) and prokinetic agents are the current treatment for GER-associated cough. The aim was to evaluate the effects of anti-reflux treatment and its associations with cellular and neurogenic inflammation.Methods: Thirty-seven patients with GER-associated cough suspected based on characteristic symptoms such as heartburn and worsening of cough by phonation and rising were recruited. A PPI, rabeprazole 20 mg daily, and a prokinetic agent, itopride 50 mg t.i.d., were administered for 4 weeks in a prospective, observational manner. Before and after treatment, subjective cough measures [visual analog scale (VAS) and the Japanese version of the Leicester Cough Questionnaire (J-LCQ)], the modified frequency scale for the symptoms of GERD [FSSG, consisting of 2 domains: acid-reflux (AR) and functional dyspepsia symptoms], sputum and plasma SP levels, and sputum cell differentials were examined. Patients with good response to treatment [Δ (decrease of) VAS >15 mm; n = 21) were compared with poor responders (ΔVAS ≤15 mm).Results: Anti-reflux treatment significantly improved the cough VAS, J-LCQ, and AR symptoms, and ΔVAS and ΔAR were significantly correlated. Decreases of plasma and sputum SP levels and sputum neutrophil counts were significantly greater in responders than in poor responders. Both baseline values and post-treatment changes of plasma SP and sputum neutrophils were significantly correlated for all patients.Conclusions: Successful treatment of GER-associated cough may be associated with the attenuation of neurogenic and neutrophilic inflammation.

Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients.

BACKGROUND: Despite the close linkage between rhinitis, chronic rhinosinusitis (CRS) and asthma, relevant biomarkers of both upper and lower airway inflammation are rare. METHODS: Patients with asthma (without upper airway disease [UAD; n = 24], with rhinitis [n = 25], CRS [n = 24], and nasal polyps [n = 2]), isolated rhinitis (n = 13), isolated CRS (n = 13), and 10 healthy controls were prospectively recruited. Fractional exhaled nitric oxide (NO) levels at 50 mL/s (FeNO50), nasal NO levels, Lund-Macay-scores of sinus computed tomography and an asthma control questionnaire (ACQ) were evaluated. RESULTS: Asthma was associated with higher FeNO50 levels irrespective of the UAD category. FeNO50 levels were higher in asthmatics with CRS (median: 54.0 ppb) than those with rhinitis (35.2 ppb, p = 0.02) and those without UAD (34.3 ppb, p = 0.002). Nasal NO levels were higher in rhinitis patients than other UAD categories, irrespective of the asthma concomitance. Nasal NO levels were higher in asthmatics with rhinitis (112.8 ppb) than those without UAD (67.2 ppb, p = 0.001) and those with CRS (57.6 ppb, p < 0.0001). A receiver-operating-characteristic curve analysis for detecting comorbid allergic rhinitis (AR) in asthmatics showed a high area under the curve (0.87). Nasal NO levels were positively correlated with FeNO50 levels (ρ = 0.56, p = 0.003) in asthmatics with rhinitis. In contrast, they were negatively correlated with the Lund-Macay (ρ = -0.46, p = 0.03) and ACQ scores (ρ = -0.52, p = 0.009) in asthmatics with CRS. CONCLUSIONS: Higher nasal NO levels reflect the presence of AR, irrespective of asthma concomitance. Higher FeNO50 levels reflect the presence of CRS and asthma. These NO measurements are useful for assessing comorbid UAD in asthmatics.

Diagnostic utility of fractional exhaled nitric oxide in prolonged and chronic cough according to atopic status.

BACKGROUND: Cough-variant asthma (CVA) and cough-predominant asthma (CPA) are the major causes of persistent cough in Japan. The utility of fractional exhaled nitric oxide (FeNO) measurement in the differential diagnosis of persistent cough has been reported, but the influence of atopic status, which is associated with higher FeNO levels, on the diagnostic utility of FeNO has been unknown. METHODS: We retrospectively analyzed 105 non-smoking patients with prolonged and chronic cough that were not treated with corticosteroids and anti-leukotrienes. RESULTS: CPA was diagnosed in 37 patients, CVA in 40, and non-asthmatic cough (NAC) in 28. FeNO levels were significantly higher in the CPA [35.8 (7.0-317.9) ppb] and CVA [24.9 (3.1-156.0) ppb] groups than in the NAC group [18.2 (6.9-49.0) ppb] (p < 0.01 by Kruskal-Wallis test). The optimal cut-off for distinguishing asthmatic cough (AC; CPA and CVA) from NAC was 29.2 ppb [area under the curve (AUC) 0.74, p < 0.01]. Ninety-one percent of subjects with FeNO levels ≥29.2 ppb had AC. Meanwhile, 40% of AC patients had FeNO levels <29.2 ppb. Stratified cut-off levels were 31.1 ppb (AUC 0.83) in atopic subjects vs. 19.9 ppb (AUC 0.65) in non-atopic subjects (p = 0.03 for AUC). CONCLUSIONS: Although high FeNO levels suggested the existence of AC, lower FeNO levels had limited diagnostic significance. Atopic status affects the utility of FeNO levels in the differential diagnosis of prolonged and chronic cough.

ABCB1 polymorphism as a predictive biomarker for amrubicin-induced neutropenia.

BACKGROUND: Amrubicin is a promising therapy for lung cancer, but is associated with a high incidence of severe neutropenia. The present study assessed the utility of ABCB1 and NAD(P)H quinone oxidoreductase 1 (NQO1) polymorphism as a predictor of amrubicin-induced neutropenia. MATERIALS AND METHODS: Fifty-four Japanese lung cancer patients who received amrubicin chemotherapy were consecutively recruited and toxicities and SNPs (MDR1; C1236T, C3435T and G2677T/A, NQO1; C609T) were evaluated. RESULTS: The incidence of neutropenia was higher in patients treated with 40 mg/m2 of amrubicin (n=32) compared to patients treated with 35 mg/m2 of amrubicin (n=22) (53.1% vs. 22.7%). Patients who were homogenous for the wild-type allele of C3435T were at significantly higher risk of neutropenia compared to patients with other genotypes. By contrast, the C609T genotype of NQO1 was not related to neutropenia. CONCLUSION: C3435T polymorphisms of ABCB1 might be able to predict severe amrubicin-induced neutropenia.

Esophagitis resulting from treatment with crizotinib for anaplastic lymphoma kinase rearrangement-positive lung adenocarcinoma: A case report.

Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed type of cancer and is a leading cause of cancer-related mortality worldwide. Treatment is currently focused on individualization according to the molecular profile of the disease. Here we present the case of a 41-year-old patient who presented with multiple pulmonary nodules, a left pleural effusion and an ovarian tumor. Adenocarcinoma of the lung was diagnosed from pathological examination of the pleural effusion and the surgically resected ovarian tumor, and chemotherapy was initiated. Relapse was experienced following third-line chemotherapy with pemetrexed and anaplastic lymphoma kinase (ALK)-positive adenocarcinoma was diagnosed using a specimen from the resected ovarian tumor. Subsequently, crizotinib therapy was initiated. Eight days later the patient developed severe nausea and vomiting and esophagitis was diagnosed by gastrointestinal endoscopic examination. Following the interruption of crizotinib treatment by treatment with a proton pump inhibitor (PPI), crizotinib treatment was re-initiated and was effective for a minimum of 6 months. Clinicians should be aware that treatment with crizotinib may result in severe esophagitis.

Transformed lymphoplasmacytic lymphoma involving the main carina: A case report.

A 41-year-old male was admitted to Nagoya City University Hospital subsequent to experiencing a cough with bloody sputum for a few days. The patient had a 4-year history of lymphoplasmacytic lymphoma (LPL) and had achieved a good partial response to anticancer chemotherapy. Chest computed tomography (CT) showed an endobronchial tumor of the main carina. A bronchoscopy revealed an exophytic tumor at the main carina, and autofluorescence imaging bronchovideoscopy showed that the tumor and surrounding area were magenta in color. The biopsy specimens demonstrated that the endobronchial tumor was composed of large atypical lymphoid cells. The patient was diagnosed with a high-grade transformation of LPL. In addition to describing a rare case of transformed LPL involving the main carina, the present study also summarizes and discusses endobronchial lymphomas, with a brief review of a number of published studies.

Involvement of intermediate filament nestin in cell growth of small-cell lung cancer.

BACKGROUND: Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during the development of the central nervous system. Nestin is detected in various types of tumors and is involved in malignant processes. This study investigated the expression and function of nestin in small-cell lung cancer (SCLC). METHODS: Expression of nestin and achaete-scute homolog 1 (ASH1) was studied in 21 lung cancer cell lines. To assess the function of nestin, a short hairpin RNA (shRNA) targeting nestin was transfected into two SCLC cell lines (DMS53 and SBC3), and cloned cells that showed apparent down-regulation of nestin were obtained. Nestin expression was also studied immunohistochemically in surgically resected SCLC primary tumors and metastatic SCLC tumors obtained from autopsy cases. RESULT: Nestin was expressed in nine of 10 SCLC cell lines. The nestin expression level was significantly higher in SCLC cell lines than in NSCLC cell lines (P < 0.01). There was a statistically significant positive correlation between the expression levels of nestin and ASH1 in SCLC cell lines. Nestin knock-down cells created by transfection with shRNA exhibited decreased invasion and cell proliferation capabilities. Furthermore, nestin was detected in SCLC tumor cells and tumor vessels in all clinical tumor specimens. CONCLUSION: Nestin is expressed in SCLC in association with neuroendocrine features and participates in malignant phenotypes, including cell growth. Therefore, nestin may be a novel therapeutic target for SCLC.

Analgesic effect of switching from oral opioids to a once-a-day fentanyl citrate transdermal patch in patients with lung cancer.

A new once-a-day fentanyl citrate transdermal patch was developed in Japan. We retrospectively investigated analgesic and adverse effects of this drug in 24 patients with lung cancer. All patients were started on this patch by switching from an oral opioid. The mean pain score before switching was 2.45 (0-5); 48 hours after switching, 15 of the 24 patients showed a decreased pain score and the mean score (2.00) was significantly lower than that before switching. Of the 16 patients who had adverse effects of oral opioids, 7 patients showed improvement in their symptoms after switching. Two patients showed adverse effects of the drug but their symptoms were mild, and no patient required dose decrease. This new transdermal patch could be a useful treatment option for cancer pain.