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Background: This prospective, post-marketing observational study in Japanese patients aimed to evaluate the safety and effectiveness of daily afatinib use in general practice. Methods: This non-interventional study (NCT02131259) enrolled treatment-naïve and pre-treated patients with inoperable/recurrent EGFR mutation-positive NSCLC, eligible for afatinib treatment as per the afatinib label in Japan. Patients received afatinib at the approved dose (20, 30, 40, or 50 mg/day; physician decision), and were observed following treatment initiation for 52 weeks or until premature discontinuation. Primary endpoint was the incidence of adverse drug reactions (ADRs). Secondary endpoints included ADRs of special interest, and objective response rate (ORR). Post hoc Cox multivariate analyses were used to assess prognostic factors associated with the incidence of ADRs. Results: 1602 patients, at 374 sites (April 2014–March 2015), were included in the analysis; 307 (19%) were aged ≥ 75 years. The most frequently reported ADRs (all/grade 3–4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and nail effects (38%/4%). Serious ADRs resulting in death occurred in 18 patients (1%). 762 patients (48%) had ≥ 1 afatinib dose reduction and 366 (23%) discontinued due to ADRs; the most common reason for both was diarrhea (8.2% and 6.7%, respectively). ORR was 40.1%. Conclusions: Real-world treatment of 1602 Japanese patients with afatinib was associated with a predictable ADR profile. Afatinib showed effectiveness in inoperable/recurrent EGFR mutation-positive NSCLC, especially as first-line treatment. As with other EGFR TKIs, prompt management of adverse events is needed in the Japanese population, to reduce serious events and outcomes, including interstitial lung disease. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed. [ABSTRACT FROM AUTHOR]

Aim Pneumonia is the third largest cause of death in Japan. Pneumonia continues to be one of the most common causes of morbidity, hospitalization and mortality, especially in the elderly. The aim of the present study was to evaluate the factors related to the development of pneumonia acquired outside hospitals among the Japanese elderly. Methods We carried out a hospital-based, case-control study. Cases were patients who had been newly diagnosed with pneumonia acquired outside hospitals. For each case, one to three controls were defined as outpatients with other diseases (not pneumonia) at the same hospitals. All participants (i.e. 50 cases and 110 controls) were aged 65 years and older. Results Compared with control participants, hypoalbuminemia (<3.5 g/dL) and low body mass index (<18.0) were more common in pneumonia patients, whereas the proportion of those who could go out by themselves (i.e. self-support in activities of daily living) and the vaccination rate of seasonal influenza were lower in patients with pneumonia than control participants. Even after controlling for age, sex, hospital and aforementioned four factors, hypoalbuminemia ( OR 9.19, 95% CI 3.70-22.81) increased the risk of pneumonia, whereas seasonal influenza vaccination ( OR 0.37, 95% CI 0.16-0.85) reduced the risk. Even after excluding those who lived in a nursing home, hypoalbuminemina ( OR 12.19, 95% CI 4.29-34.63) increased the risk of pneumonia. Conclusions Hypoalbuminemia might be a risk factor for pneumonia among the elderly living in the community. Geriatr Gerontol Int 2016; 16: 223-229. [ABSTRACT FROM AUTHOR]

In spite of recent advances in chemotherapy, the treatment of pulmonary aspergilloma remains unsatisfactory. To evaluate the clinical efficacy and safety of combination therapy for pulmonary aspergilloma, we conducted a multi-institutional prospective study using micafungin (MCFG) and itraconazole (ITCZ). Adult patients who fulfilled the criteria for pulmonary aspergilloma were enrolled in this study. After patient consent had been obtained, intravenous MCFG 150 mg/day and an oral capsule of ITCZ 200 mg/day were administered for at least 1 month. The primary endpoint was the response assessed using an algorithm that incorporated the levels of improvement by evaluating clinical symptoms and signs, mycological and serological tests, and diagnostic imaging. A total of 17 patients were enrolled from three facilities. The response rate to the combination therapy was 58.8% (10/17). The long-term control in the group of patients who responded to treatment was better than that in the group of patients who did not respond. Adverse events occurred in 6 of the 17 patients (35.3%), but there were no severe adverse events. MCFG-ITCZ combination therapy appeared to be relatively safe and effective in patients with pulmonary aspergilloma. [ABSTRACT FROM AUTHOR]

Background and objective: A multi-institutional phase II trial combining uracil-tegafur (UFT) and cisplatin (CDDP) was conducted in patients with previously untreated advanced non-small cell lung cancer (NSCLC) to evaluate the safety and efficacy of this combined treatment regimen. Methods: The entry criteria for this study were previously untreated NSCLC, measurable disease, age <80 years, performance status <2, and adequate haematological, hepatic and renal function. Patients were treated with 400 mg/m2 oral UFT from day 1 to day 14 and 80 mg/m2 cisplatin on day 15. The treatment course was repeated every 3 weeks. Results: Of the 68 patients enrolled, 64 (27 with stage IIIB and 37 with stage IV disease) were eligible for treatment. Twenty of the 64 patients responded to the chemotherapy (response rate 31.3%; 95% CI 21.2–43.4%). The median survival time was 8.6 months, and the 1-year survival was 41.5%. Haematological toxicity ≥WHO grade 3 was seen in 3 (4.7%) patients. For non-haematological toxicities, anorexia with WHO grade 3 was seen in 8 (12.5%) patients, nausea and vomiting with WHO grade 3 in 4 (6.3%), diarrhoea with WHO grade 4 in 1 (1.6%), and liver dysfunction with WHO grade 4 in 1 (1.6%) patient. Conclusions: The combination of oral UFT plus cisplatin was found to be a safe and active treatment against advanced NSCLC. The observed low toxicity of this combined regimen may warrant its application to the treatment of elderly patients. [ABSTRACT FROM AUTHOR]

Background: Patients with severe asthma require multiple therapies to improve lung function and reduce symptoms. The use of long-acting inhaled β2-agonists plus theophylline in addition to high doses of inhaled corticosteroids (ICSs) for the treatment of severe asthma has not been extensively studied. Objective: The purpose of this study was to investigate the efficacy and safety of salmeterol combined with high-dose ICSs plus theophylline in severe asthma. Methods: We undertook a randomized, placebo-controlled, crossover study to compare the effect of a single dose of inhaled salmeterol (50 μg) or a placebo in patients with severe asthma whose conditions were not being adequately controlled by therapies with high-dose ICSs plus oral theophylline with or without leukotriene receptor antagonists. Results: Twenty patients took part in the trial. Compared with the placebo, the inhalation of salmeterol significantly increased the FEV1. Even in the 9 patients treated with high-dose ICSs plus theophylline plus a leukotriene receptor antagonist, the FEV1 increased significantly more after salmeterol than after the placebo. Conclusion: Patients with severe asthma receiving high-dose ICSs plus theophylline may benefit from the addition of salmeterol. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Crizotinib is the first clinically available tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and is associated with the development of complex renal cysts. We now describe a 39-year-old woman who developed infected complex renal cysts during crizotinib treatment. After 10 months of such treatment, she presented with a high fever and low back pain. Computed tomography findings were consistent with complex renal cysts and perilesional inflammation. Interventions including cyst drainage and antibiotic administration contributed to diagnosis and management of the infected cysts. [ABSTRACT FROM AUTHOR]

To determine the predictive value of the expression of p53 and glutathione S-transferase-π (GST-π) with respect to chemotherapy response, immunostaining was performed on transbronchial biopsy specimens from previously untreated patients with non-small cell lung cancer. Of the 54 patients, 34 patients (63%) and 37 patients (69%) were positive for p53 and GST-π, respectively. The response rates in the p53-positive and p53-negative group were 15 and 45%, and those in GST-π-positive and GST-π-negative groups were 16 and 47%, respectively. A multiple logistic regression analysis revealed that positive immunostaining for GST-π was a significant risk factor for clinical chemotherapy resistance. The combination of these two markers was the most important independent factor in predicting a response to chemotherapy in multiple logistic regression analysis. Immunohistochemical expression of p53 and GST-π was independently related to clinical chemoresistance in patients with non-small cell lung cancer. Combined use of these two biomarkers may be a useful predictor of clinical chemoresistance.Copyright © 1999 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives Drug-induced interstitial lung disease (ILD) is often associated with high mortality; however it is difficult to predict and manage. we examined the clinical findings and imaging characteristics of nivolumab induced ILD reported in the two phase II studies patients with recurrent or advanced non-small-cell lung cancer. Materials and methods We examined the clinical findings and imaging characteristics of all cases of ILD reported in two phase II trials of nivolumab, an anti-programmed death-1 antibody, in Japanese patients with recurrent or advanced non-small-cell lung cancer. These studies are registered with the Japan Pharmaceutical Information Center, numbers JapicCTI-132072, JapicCTI-132073. Results Eight (7.2%; two with squamous cell carcinoma, six with non-squamous cell carcinoma) of the 111 patients included in these two studies experienced ILD, and a causal relationship with nivolumab could not be ruled out in any of them. ILD of ≥grade 3 severity was found in four patients (3.6%), and ILD was considered a serious treatment-related adverse event in seven patients (6.3%). All of the patients who experienced ILD were male and had a history of smoking, with a median age of 65 years (range 52–78 years). In seven of the eight patients who experienced ILD, their events were rapidly resolving or resolved spontaneously or with steroid therapy; one patient died of respiratory failure without resolution of ILD, after docetaxel treatment was initiated following nivolumab discontinuation. Chest computed tomography images for the seven patients with resolving or resolution of ILD showed a pattern of organizing pneumonia or nonspecific interstitial pneumonia without traction bronchiectasis, while the patient who died had traction bronchiectasis. Conclusion Although the risk factors for nivolumab-induced ILD were not identified, careful monitoring including imaging examinations is important in preventing the worsening of ILD in patients receiving nivolumab. [ABSTRACT FROM AUTHOR]

Background: The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival.Methods: We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants.Findings: Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6-15·6) than in the cisplatin group (11·4 months,10·2-12·2; hazard ratio 0·81, 95% CI 0·65-1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively.Interpretation: Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.Funding: West Japan Oncology Group and Sanofi. [ABSTRACT FROM AUTHOR]

Objectives The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. Materials and methods Our analysis compared the ‘EGFR testing strategy’, in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the ‘no-testing strategy,’ in which genetic testing was not conducted and all patients were treated with standard chemotherapy. A three-state Markov model was constructed to predict expected costs and outcomes for each strategy. We included only direct medical costs from the healthcare payer's perspective. Outcomes in the model were based on those reported in the Iressa Pan-Asia Study (IPASS). The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life-years (QALYs) gained. Sensitivity and scenario analyses were conducted. Results The incremental cost and effectiveness per patient of the ‘EGFR testing strategy’ compared to the ‘no-testing strategy’ was estimated to be approximately JP¥122,000 (US$1180; US$1 = JP¥104 as of February 2014) and 0.036 QALYs. The ICER was then calculated to be around JP¥3.38 million (US$32,500) per QALY gained. These results suggest that the ‘EGFR testing strategy’ is cost-effective compared with the ‘no-testing strategy’ when JP¥5.0 million to 6.0 million per QALY gained is considered an acceptable threshold. These results were supported by the sensitivity and scenario analyses. Conclusion The combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin–paclitaxel for the treatment for NSCLC in Japan. [ABSTRACT FROM AUTHOR]

Crizotinib was the first clinically available inhibitor of the tyrosine kinase ALK, and next-generation ALK inhibitors, such as alectinib, are now under development. Although crizotinib is generally well tolerated, severe esophageal injury has been reported as a rare but serious adverse event of crizotinib therapy. We now describe the successful treatment with alectinib of a patient who developed crizotinib-induced esophageal ulceration. [ABSTRACT FROM AUTHOR]