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Introduction Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. Methods We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. Results Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation – or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). Conclusions Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Background Asthma and rhinitis are common diseases that often occur concomitantly. However, in patients with asthma, the concurrent assessment of seasonal variation in rhinitis and asthma symptoms has not been comprehensively addressed. We prospectively evaluated seasonal changes in rhinitis and asthma symptoms over one year. Methods Fifty-six patients with asthma were enrolled. Asthma and rhinitis symptoms were assessed by using the State of the Impact of Allergic Rhinitis on Asthma Control (SACRA) questionnaire, developed and validated in Japan by the committee of Global Initiative for Asthma and the committee of Allergic Rhinitis for asthma and its impact on Asthma. Results Fifty-three patients completed the study. Forty-five patients (85%) had nasal symptoms during at least one or more seasons and 15 patients (28%) had perennial rhinitis. The association between asthma symptoms and rhinitis symptoms, assessed by a visual analogue scale (VAS), was significant during each season; seasonal variations of symptoms were synchronous. Uncontrolled asthma was more prevalent in patients with moderate-to-severe rhinitis compared to those with mild rhinitis. The VAS score of asthma symptoms in patients with asthma and perennial rhinitis was significantly higher than that in patients with non-perennial rhinitis or without rhinitis, across every season, except for spring. Correlations were more significantn patients less than 65 years of age than in older patients. Conclusion Rhinitis is common in patients with asthma. Symptoms of rhinitis and asthma often co-exist, and the association between these symptoms may be stronger n younger patients with asthma than older.

Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression.We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death.Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001).Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression.

Background and objective: Septic pulmonary embolism due to periodontal disease (SPE-PD) is rarely reported and little is known about its clinical features. The purpose of this study was to evaluate the clinical and radiological features, as well as outcome, in SPE-PD. Methods: Patients' records were retrospectively reviewed and 12 patients with SPE-PD were identified (10 men, mean age 60.5 years). The patients' demographic features, laboratory data, physical and radiological findings, and clinical outcomes were evaluated. Results: All but one patient were smokers. Eight of the 12 patients had comorbidities including hypertension (58%) and/or diabetes mellitus (17%). Prevalent symptoms were fever (67%) and chest pain (58%). Only two patients fulfilled the criteria of systemic inflammatory response syndrome; most of the subjects were not clinically severely ill. Blood cultures were negative in all cases. Contrast-enhanced chest computed tomography (CT) showed multiple peripheral nodules in all 12 patients, wedge-shaped peripheral lesions abutting on the pleura in 10 (83%) and a feeding-vessel sign in 9 (75%). All patients recovered from their illness after antimicrobial therapy concomitant with tooth extraction or periodontal care. The median duration of antibiotic administration was 51 days. Conclusions: Most patients with SPE-PD were not seriously ill. Contrast-enhanced chest CT appeared to be useful to diagnose SPE-PD.

The availability of many types of inhalers in the treatment of asthma has resulted in a wide range of prescription choices for clinicians. With so many devices available, however, there is some confusion regarding their proper use among both medical staff and patients. Since 2007, Kitano Hospital and Kita-ku Pharmaceutical Association, Osaka, Japan, have provided a network system for delivering instruction on correct inhalation technique through community pharmacists. We examined the clinical effects of this network system.Our measurements included the manner in which community pharmacists instruct patients with asthma, the frequency of asthma exacerbations, patients' adherence to inhalation therapy using a 5-point Likert scale questionnaire, and patients' health status both prior to this system and at 4 years after.Usable information was obtained from 53 community pharmacists and 146 patients with asthma at baseline and from 60 community pharmacists and 148 patients at 4 years. When compared with baseline values, significant improvement was found in pharmacists' instruction and significant decreases were observed in the frequency of asthma exacerbations (1.4 ± 1.6 vs. 1.0 ± 1.4 times/yr, p = .042) and emergency room visits (0.5 ± 1.0 vs. 0.2 ± 0.5 times/yr, p = .004). Adherence to the inhalation regimen significantly increased (4.0 ± 0.7 vs. 4.2 ± 0.8, p = .041), but health status was unchanged.Our network system may improve asthma control and adherence to inhalation regimens.

Masaya Takemura1, Katsumi Mitsui2, Ryo Itotani1, Manabu Ishitoko1, Shinko Suzuki1, Masataka Matsumoto1, Kensaku Aihara1, Tsuyoshi Oguma1, Tetsuya Ueda1, Hitoshi Kagioka1, Motonari Fukui11Division of Respiratory Medicine, 2Division of Pharmacy, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, JapanPurpose: Adherence to inhalation therapy is a critical determinant of the success of chronic obstructive pulmonary disease (COPD) management. However, in practice, nonadherence to inhalation therapy is very common in COPD patients. The effects of adherence to inhalation therapy in COPD have not been fully studied, and less is known about the relationship between medication adherence and quality of life in COPD. Our aim is to assess the factors that contribute to adherence to inhalation therapy and examine their correlation with quality of life.Patients and methods: A cross-sectional analysis of 88 COPD patients was performed using a self-reported adherence questionnaire with responses on a 5-point Likert scale.Results: Of the 88 patients who were potential participants, 55 (63%) responded with usable information. The only significant factor associated with the overall mean adherence score was receiving repeated instruction about inhalation techniques (P = 0.032). Of the 55 respondents, 22 (40.0%) were given repeated verbal instruction and/or demonstrations of inhalation technique by a respiratory physician. Significant correlations were found between the overall mean adherence score and the health-related quality of life score (St George’s Respiratory Questionnaire: total, r = −0.35, P = 0.023; symptoms, r = −0.43, P = 0.002; impacts, r = −0.35, P = 0.011). Furthermore, patients with repeated instruction showed better quality of life scores than those who did not receive instruction (total, P = 0.030; symptoms, P = 0.038; impacts, P = 0.019).Conclusions: Repeated instruction for inhalation techniques may contribute to adherence to therapeutic regimens, which relates to better health status in COPD.Keywords: COPD, adherence, quality of life, repeated instruction

Adherence to inhalation therapy is a critical determinant of the success of asthma management. Reasons for nonadherence have been well studied, but reasons for good adherence are poorly understood. Understanding the mechanisms of adherence to inhalation therapy is important in developing strategies to promote adherence. The objective of this study was to assess the factors and mechanisms that contribute to and the clinical outcomes relating to adherence to inhalation therapy.The factors and outcomes related to adherence to inhalation therapy were examined cross-sectionally in 176 adults with asthma using a self-reported adherence questionnaire that consisted of four items dealing with the use of inhaled controller medications. A 5-point Likert scale was used for the responses to each item. Adherence was assessed based on the overall mean adherence score.Of the 176 patients who were potential participants, 146 (83%) responded with usable information. Significant factors associated with the overall mean adherence score were older age (r = .18, p = .032) and receiving repeated instruction on inhalation techniques (p = .0016). Of the 146 respondents, 25 (17.1%) patients were given repeated verbal instruction or demonstrations of inhalation technique by a respiratory physician. On logistic regression analysis, good adherence to inhalation therapy was significantly related to the receiving of repeated instruction on inhalation technique, with an odds ratio of 2.90 (95% confidence interval 1.07-7.88; p = .037). Furthermore, less intentional nonadherent behavior was reported in patients with repeated instruction on inhalation technique compared to those without it. A significant correlation was found between the overall mean adherence score and the frequency of asthma exacerbations (r = -.19, p = .021), emergency room visits (r = -.19, p = .042), and the health-related quality of life score (St. George's Respiratory Questionnaire: Total, r = -.22, p = .024; Symptoms, r = -.21, p = .022; Impacts, r = -.20, p = .035).Repeated instruction on inhalation techniques may contribute to adherence to inhalation therapy through decreasing intentional nonadherence. Furthermore, good adherence to the therapeutic regimen may offer good asthma-related outcomes.

Septic pulmonary embolism due to periodontal disease (SPE-PD) is rarely reported and little is known about its clinical features. The purpose of this study was to evaluate the clinical and radiological features, as well as outcome, in SPE-PD.Patients' records were retrospectively reviewed and 12 patients with SPE-PD were identified (10 men, mean age 60.5 years). The patients' demographic features, laboratory data, physical and radiological findings, and clinical outcomes were evaluated.All but one patient were smokers. Eight of the 12 patients had comorbidities including hypertension (58%) and/or diabetes mellitus (17%). Prevalent symptoms were fever (67%) and chest pain (58%). Only two patients fulfilled the criteria of systemic inflammatory response syndrome; most of the subjects were not clinically severely ill. Blood cultures were negative in all cases. Contrast-enhanced chest computed tomography (CT) showed multiple peripheral nodules in all 12 patients, wedge-shaped peripheral lesions abutting on the pleura in 10 (83%) and a feeding-vessel sign in 9 (75%). All patients recovered from their illness after antimicrobial therapy concomitant with tooth extraction or periodontal care. The median duration of antibiotic administration was 51 days.Most patients with SPE-PD were not seriously ill. Contrast-enhanced chest CT appeared to be useful to diagnose SPE-PD.

Background Dyspnea on exertion (DOE) is a major symptom of chronic obstructive pulmonary disease (COPD) and is difficult to control. This study was performed to determine whether acupuncture is superior to placebo needling in improving DOE in patients with COPD who are receiving standard medication. Methods Sixty-eight of 111 patients from the Kansai region of Japan who were diagnosed as having COPD and were receiving standard medication participated in a randomized, parallel-group, placebo-controlled trial (July 1, 2006, through March 31, 2009) in which the patients, evaluators, and statistician were unaware of the random allocation. Participants were randomly assigned to traditional acupuncture (real acupuncture group, n = 34) or placebo needling (placebo acupuncture group, n = 34). Both groups received real or placebo needling at the same acupoints once a week for 12 weeks. The primary end point was the modified Borg scale score evaluated immediately after the 6-minute walk test. Measurements were obtained at baseline and after 12 weeks of treatment. Result After 12 weeks, the Borg scale score after the 6-minute walk test was significantly better in the real acupuncture group compared with the placebo acupuncture group (mean [SD] difference from baseline by analysis of covariance, −3.6 [1.9] vs 0.4 [1.2]; mean difference between groups by analysis of covariance, −3.58; 95% CI, −4.27 to −2.90). Patients with COPD who received real acupuncture also experienced improvement in the 6-minute walk distance during exercise, indicating better exercise tolerance and reduced DOE. Conclusion This study clearly demonstrates that acupuncture is a useful adjunctive therapy in reducing DOE in patients with COPD. Trial Registration umin.ac.jp/ctr Identifier: UMIN000001277

Optimal oxygen delivery is an essential component of therapy for patients with respiratory failure. Reservoir masks or air entrainment nebulizers have often been used for patients who require highly concentrated oxygen, but these may not actually deliver a sufficient fraction of inspired oxygen if there is a marked increase in the patient's ventilatory demands, or if oxygen flow becomes limited due to high resistance in the nebulizer nozzles. The HighFO nebulizer is a novel air entrainment nebulizer equipped with unique structures which reduce nozzle resistance, and as a result, it is possible to supply a sufficient flow of highly concentrated-oxygen. The purpose of this study was to evaluate the effectiveness and usefulness of the HighFO nebulizer in 10 respiratory failure patients with severe hypoxemia who used a reservoir mask and required more than 10 L/min of oxygen supply. In each case, the reservoir mask was replaced with the HighFO nebulizer, and changes in percutaneous oxygen saturation (SpO2) were monitored using pulse oximetry. Oxygenation improved promptly after the reservoir mask was substituted for the HighFO nebulizer (SpO2 : 83.7% +/- 8.5%-94.2% +/- 3.2%, p = 0.007). This finding suggests that the HighFO nebulizer was reasonably effective in delivering highly concentrated oxygen, sufficient for patient demands. The HighFO nebulizer may be the beginning of a new strategy for oxygen therapy.

A 56-year-old man with allergic bronchopulmonary aspergillosis (ABPA) was admitted due to the appearance of nodular opacities in the right upper lung field on chest radiography, after discontinuing itraconazole and clarithromycin on the suspicion of possible hepatic adverse effects. Chest CT scans on admission revealed nodular opacities in the right S3 and lingula bronchus, and bilateral bronchiectasis with mucoid impactions. A specimen obtained by transbronchial lung biopsy showed complete replacement of bronchioles by necrotizing granulomatous inflammation, containing the diagnosis of bronchocentric granulomatosis. Treatment with corticosteroids and micafungin sodium resulted in marked resolution of nodular opacities and mucoid impacts. This case suggests that abrupt cessation of antifungal agents and macrolides may provoke acute exacerbation of ABPA and development of bronchocentric granulomatosis.

A 77-year-old woman presented with hoarseness and hemoptysis. Chest CT scan revealed a mediastinal tumor in the lumen of the left pulmonary artery. A definitive diagnosis could not be made based on mediastinoscopy and thoracotomy. Eight months later, multiple nodular shadows appeared in both lung fields.Video-assisted lung biopsy showed that these nodules were lung metastases of a spindle cell sarcoma. Based on the pathological and radiological findings, a pulmonary artery sarcoma was eventually diagnosed. Interestingly, on immunohistological staining, the tumor cells were diffusely positive for KIT, which is an immunohistochemical marker of gastrointestinal stromal tumors. The patient was treated with imatinib, a KIT tyrosine kinase inhibitor; however, the tumors progressed. The relationship between pulmonary artery sarcoma and KIT requires further study.

The introduction of second-generation QuantiFERON-TB (QFT) enables the diagnosis of Mycobacterium tuberculosis (TB) infection with high specificity and sensitivity. This in vitro diagnostic test uses 2 TB-specific proteins (ESAT-6 and CFP-10) to stimulate cells in heparinized whole blood and detects interferon-gamma (IFN-gamma) produced from blood cells. When QFT is done in laboratories outside of the hospital, several hours may be required to transport blood samples. We studied the relationship between QFT results and the time taken from collection of blood to incubation (preincubation time).Heparinized whole blood drawn from TB suspects was immediately transported to a laboratory. We started to incubate 4 aliquots of blood with ESAT-6, CFP-10, mitogen (phytohemagglutinin), and nil control, at 1, 3, 6, 9, and 12 h after blood was drawn. After incubation, the concentration of IFN-gamma in each plasma sample was determined by ELISA, and values E and C were expressed as the concentration of IFN-gamma with ESAT-6 or CFP-10, minus the concentration of IFN-gamma in the nil control. Value E or Cor =0.35IU/mL was considered positive,or =0.10 and0.35IU/mL as equivocal (gray zone), and0.10IU/mL as negative. We analyzed 8 patients with value E or Cor =0.10IU/mL at a preincubation time of 1 h.Value E and C decreased especially for preincubation time6 h. As a result, the interpretation of value E changed from "positive" to "equivocal" in 2 cases and from "equivocal" to "negative" in 2 cases. Interpretation of value C also changed from "positive" to "equivocal" or "negative" in 2 cases and from "equivocal "to "negative" in 1 case. Even if the higher of value E or C were used for analysis, QFT results changed in half of patients when preincubation time was6 h.Since QFT results in half of patients changed when preincubation time was6 h, incubation of whole blood should startor =6 h after blood drawing.

Masaya Takemura,1 Katsumi Mitsui,2 Masako Ido,2 Masataka Matsumoto,1 Misuzu Koyama,3 Daiki Inoue,1 Kazufumi Takamatsu,1 Ryo Itotani,1 Manabu Ishitoko,1 Shinko Suzuki,1 Kensaku Aihara,1 Minoru Sakuramoto,1 Hitoshi Kagioka,1 Motonari Fukui11Respiratory Disease Center, Kitano-Hospital, the Tazuke Kofukai Medical Research Institute, Osaka, Japan; 2Division of Pharmacy, Kitano-Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan; 3Kita-ku Pharmaceutical Association, Osaka, JapanIntroduction: Nonadherence to inhalation therapy is very common in patients with chronic obstructive pulmonary disease (COPD). Few data are available to support the role of community pharmacists in optimizing inhalation therapy in COPD patients. Since 2007, the Kitano Hospital and the Kita-ku Pharmaceutical Association have provided a network system for delivering correct inhalation techniques through certified community pharmacists. The effects of this network system on clinical outcomes in COPD patients were examined.Methods: A total of 88 consecutive outpatients with COPD at baseline and 82 of those 4 years later were recruited from the respiratory clinic of Kitano Hospital Medical Research Institute. Measurements included the frequency of COPD exacerbations, patients’ adherence to inhalation therapy using a five-point Likert scale questionnaire, and patients’ health status both prior to this system and 4 years later.Results: Usable information was obtained from 55 patients with COPD at baseline, and from 51 patients 4 years later. Compared with baseline values, a significant decrease was observed in the frequency of COPD exacerbations (1.5 ± 1.6 versus 0.8 ± 1.4 times/year, P = 0.017). Adherence to the inhalation regimen increased significantly (4.1 ± 0.7 versus 4.4 ± 0.8, P = 0.024), but health status was unchanged. At 4 years, of 51 COPD patients, 39 (76%) patients who visited the certified pharmacies showed significantly higher medication adherence than those who did not (4.6 ± 0.6 versus 3.9 ± 1.0, P = 0.022).Conclusion: The network system may improve COPD control and adherence to inhalation regimens.Keywords: COPD, adherence, community pharmacist, exacerbation, quality of life

Background Lung cancer cells have been reported to produce cytokines, resulting in systemic reactions. There have been few reports showing that these cytokines induced the formation of an inflammatory mass around lung cancers. Case presentation We encountered a patient with a pleomorphic carcinoma of the lung. This tumor produced interleukin (IL)-8, granulocyte colony-stimulating factor and IL-6, which in turn recruited inflammatory cells, such as CD8 positive lymphocytes, around the tumor, resulting in a rapidly growing tumor shadow. Conclusion 18 F-fluoro-deoxy-glucose positron emission tomography, in addition to a conventional radiological approach such as computed tomography, may detect immunological responses around a tumor.