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Background and Objective Although older patients with coronavirus disease 2019 (COVID-19) are at the high risk of exacerbation that requires treatment with remdesivir, the safety of this medication is unclear in clinical practice, especially among older patients. We aimed to retrospectively evaluate the safety of remdesivir in older patients with COVID-19 who required hospitalization in our institute. Methods We reviewed patients with COVID-19 who were treated with remdesivir at our institute between July 2020 and May 2021. We defined older patients as those aged 80 years or older at admission; all other patients were defined as younger patients. We evaluated the safety of remdesivir by examining the incidence of discontinuation of remdesivir treatment because of adverse events and the incidence of any adverse events. Results A total of 80 patients were included in this study. Compared with younger patients, fewer older patients were treated with remdesivir for more than 5 days: 4 (15.4%) vs 23 (42.6%). Discontinuation of remdesivir because of adverse events occurred in one older patient (3.9%) and four younger patients (7.4%) [p > 0.99]. Remdesivir-induced liver dysfunction was the most frequent adverse event, which occurred in 29 (36.3%) patients. There were no significant differences in the incidence of remdesivir-induced liver dysfunction, renal dysfunction, and fatigue. Conclusions The safety of remdesivir was suggested to be comparable between patients older than 80 years of age and patients younger than 80 years of age. The results of this study may encourage the administration of remdesivir to this older patient group.

In advanced lung cancer treatment, immunotherapy provides durable responses in some patients. However, other patients experience progressive disease and the resistance mechanisms to immunotherapy have yet been fully elucidated. Small cell transformation of non‐small cell lung cancer (NSCLC) is commonly recognized as one of the resistance mechanisms to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors in EGFR‐mutant NSCLC treatment. As a resistant mechanism for immunotherapy, we report the first case of small cell transformation in 2017. Since then, eight similar cases have been reported and the concept of small cell transformation is now becoming more prevalent as a mechanism of immunotherapy resistance. In our facility, we have experienced four cases of small cell transformation after immunotherapy (including the reported case in 2017). The histology of each primary tumor was squamous cell carcinoma, large cell type neuroendocrine carcinoma, or poorly differentiated NSCLC. None had driver gene mutations. Nivolumab was administered in all four cases and atezolizumab was administered as a next line to nivolumab treatment in one case. The best response to immunotherapy was partial response or stable disease. There was a wide range of periods from the start of immunotherapy to confirmation of small cell transformation (from 2 weeks to almost 3 years). In conclusion, small cell transformation is an important resistance mechanism in cancer immunotherapy. When NSCLC progresses after immunotherapy, the possibility of small cell transformation and rebiopsy should always be encouraged, as it leads to clarification of the resistance mechanisms and frequency., Small cell transformation is an important resistance mechanism in cancer immunotherapy. When non‐small cell lung cancers progress after immunotherapy, we should always consider the possibility of small cell transformation and rebiopsy should be encouraged. Herein, we report four cases of tumor transformation from non‐small cell lung cancer to small cell cancer under immunotherapy.

Recent advancements in cancer immunotherapy using immune checkpoint inhibitors (ICIs) have received considerable attention. Although advantageous, ICI therapies cause unique immune-related adverse events (irAEs) in some patients. Moreover, infectious diseases, such as tuberculosis, have been recognized as emerging concerns during immunotherapy. We aimed to evaluate the interferon-gamma release assay (IGRA) conversion rate and active tuberculosis incidence during immunotherapy to elucidate the incidence of tuberculosis reactivation after ICI therapy induction. We prospectively assessed IGRA results in lung cancer patients who received ICI monotherapy before ICI treatment and at 6 and 12 months after ICI treatment. We also assessed computed tomography findings to determine the presence of active tuberculosis when positive IGRA results were obtained. The ICIs used were nivolumab, pembrolizumab, atezolizumab, and durvalumab. In all, 178 patients were prospectively recruited between March 2017 and March 2020. Of these, 123 completed serial IGRAs, of whom 18, 101, and 4, respectively, had positive, negative, and indeterminate IGRAs at baseline. Three and four patients, respectively, showed IGRA reversion and conversion during immunotherapy. One patient with a sustained, stable positive IGRA and one with IGRA conversion developed active pulmonary tuberculosis during immunotherapy. We found that 3.3% and 1.6% of the patients developed IGRA conversion and active tuberculosis, respectively. Of the four patients who developed IGRA conversion, one developed active pulmonary tuberculosis during immunotherapy. Another patient with sustained, stable positive IGRA developed active tuberculosis. Physicians should be alert to tuberculosis development during ICI therapy, and IGRA testing is a useful tool to assess the risk of developing active tuberculosis.

Background The incidence of nontuberculous mycobacterial lung disease (NTM-LD) peaks in middle- and old age groups, coinciding with senescence; thus, chronic infectious diseases can accelerate frailty and worsen mental health in the elderly. In this study, we aimed to compare the prevalence of physical and psychiatric frailty between patients with NTM-LD and bronchiectasis (BE). Methods The Kihon Checklist Questionnaire (KCQ) was used to assess physical and psychiatric frailties and identify those at risk of requiring care among patients with newly diagnosed NTM-LD and BE. Additionally, the Hospital Anxiety and Depression Scale (HADS) scores and chronic inflammatory biomarkers of the alveolar region (surfactant protein [SP]-A, SP-D, and human cationic antibacterial protein [hCAP]/LL-37) were assessed and compared between NTM-LD and BE patients. Results There were no significant differences in the background characteristics between the 33 NTM and 36 BE patients recruited. The KCQ revealed that the proportion of frail NTM patients at diagnosis was higher than that of frail BE patients (48.5% vs. 22.2%, p = 0.026). HADS scores were significantly higher in the NTM group than in the BE group (p p = 0.001), but serum hCAP/LL-37 levels were significantly lower in the NTM group than in the BE group (p = 0.023). However, there were no significant differences in the BALF and serum SP-D levels between the two groups. Conclusions The number of frail NTM patients at diagnosis was significantly higher than that of frail BE patients. Biomarker analysis suggested that the former had more localized lung inflammation than the latter. Trial registration This trial was prospectively registered in the Clinical Trials Registry (UMIN 000027652).

The current coronavirus disease 2019 (COVID‐19) pandemic is associated with a heavy burden on the mental and physical health of patients, regional healthcare resources, and global economic activity. Many patients with lung cancer are thought to be affected by this situation. Therefore, in this study, we aimed to evaluate the impact of COVID‐19 pandemic on lung cancer treatment scheduling. We retrospectively reviewed the medical records of lung cancer patients who were undergoing anticancer treatment at the National Hospital Organization Kyoto Medical Center (600 beds) in Kyoto, Japan, between 1 March 2020 and 31 May 2020. After the medical records were reviewed, the patients were assigned to one of two groups, depending on whether their lung cancer treatment schedule was delayed. We assessed the characteristics, types of histopathology and treatment, and the reason for the delay. A total 15 (9.1%) patients experienced a delay in lung cancer treatment during the COVID‐19 pandemic. Patients with a treatment delay received significantly more immune checkpoint inhibitor (ICI) monotherapy than patients without a treatment delay (P = 0.0057). On the contrary, no patients receiving molecular targeted agents experienced a treatment delay during the COVID‐19 pandemic period (P = 0.0027). The treatments of most of the patients were delayed at their request. We determined that 9.1% lung cancer patients suffered anxiety and requested a treatment delay during the COVID‐19 pandemic. Oncologists should bear in mind that patients with cancer have more anxiety than expected under unprecedented circumstances such as the COVID‐19 pandemic., We found that the lung cancer treatments of 9.1% of patients included in the study were delayed during the COVID‐19 pandemic. However, the treatments of most of these patients were delayed at their request. Oncologists should bear in mind that cancer patients tend to have more anxiety than expected under special circumstances such as the COVID‐19 pandemic.

There are limited real‐world data on the treatment practices, outcomes, and safety of chemoradiotherapy (CRT) alone in potential candidates for immune checkpoint inhibitors (ICI) for unresectable non‐small cell lung cancer (NSCLC). In this study, we analyzed the safety and efficacy of CRT in patients who underwent CRT and would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real‐world settings (m‐sub) for unresectable Stage III NSCLC between 1 January 2013 and 31 December 2015 at 12 sites in Japan. The m‐sub comprised 214 patients with a median follow‐up of 31.6 months (range 1.9‐65.8 months). Median overall survival (OS) and progression‐free survival (PFS) from completing CRT were 36.4 months (95% confidence interval [CI] 28.1 months to not reached) and 9.5 months (95% CI 7.7‐11.7 months), respectively. Consolidation chemotherapy did not influence OS or PFS. Median PFS was 16.9 vs 9.1 months in patients with vs without epidermal growth factor receptor (EGFR) mutations, with PFS rates of ~20% at 3‐4 years. Pneumonitis was the most common adverse event (according to MedDRA version 21.0J), and about half of events were grade 1. Pneumonitis mostly occurred 10‐24 weeks after starting CRT, peaking at 18‐20 weeks. Esophagitis and dermatitis generally occurred from 0 to 4 weeks, peaking at 2‐4 weeks after starting CRT. Pericarditis was rare and occurred sporadically. In conclusion, the results of the m‐sub provide real‐world insight into the outcomes of CRT, and will be useful for future evaluations of ICI maintenance therapy after CRT., We analyzed the efficacy and safety of chemoradiotherapy (CRT) for unresectable Stage III non‐small cell lung cancer in patients who would satisfy the key eligibility criteria for maintenance therapy with durvalumab (eg, no progression after CRT) in real‐world settings (m‐sub). Our results provide real‐world insight into the outcomes of CRT, and will be useful for future evaluations of immune checkpoint inhibitor (ICI) maintenance therapy after CRT.

Background Spirometry is useful for evaluating respiratory health status and predicting health-related outcomes. As spirometry requires skilled technician and takes time, it is useful to find simple way for predicting lung function impairment. The aim of this study was to investigate which tests could predict lung function impairment among workers. Methods This prospective study included workers of manufacturing industry who underwent health check-ups in 2017. Subjects underwent the chronic obstructive pulmonary disease (COPD) assessment test (CAT), spirometry, and physical fitness assessments, including handgrip strength (HGS). Lung function impairment was defined as a decline in any of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), or a FEV1/FVC ratio less than the lower limit of normal (LLN). Results Complete data on 475 workers (366 men, 50.4% ever smokers) were available. Lung function impairment was observed in 99 subjects (64 men). Men with lung function impairment had significantly higher rate of ever-smoking, passive smoking at home in childhood, high CAT scores, and decreased HGS, compared with those without. On multivariate analyses, ever-smoking (odds ratio [OR], 2.50; 95% confidence intervals [CI], 1.25–4.97), passive smoking at home in childhood (OR, 2.71; 95% CI, 1.16–6.32), CAT scores (OR, 1.06; 95% CI, 1.01–1.12), and HGS (OR, 0.73; 95% CI, 0.57–0.92) were independently associated with lung function impairment in men. Conclusions Ever-smoking, passive smoking at home in childhood, high CAT scores, and decreased HGS are significantly associated with lung function impairment in men. Trial registration Registration number: UMIN000028011. Date of registration: July 1, 2017.

Aim To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients. Patients and methods We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed. Results Nine patients a had high (≥50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9±1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab. Conclusion Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.

Background In Japan, over 25% of the population is elderly. As the risk of lung cancer increases with age, the number of elderly patients with lung cancer also increases. Given the challenges of an aging society, it is critical that elderly patients receive safe therapies. Aim We assessed the safety and efficacy of immune checkpoint inhibitors (ICIs) in patients with non‐small cell lung cancer (NSCLC) aged ≥80 years. Methods We retrospectively reviewed NSCLC patients aged ≥80 years old who received ICIs in the National Hospital Organization Kyoto Medical Center. We collected data on patient characteristics, prior treatments, number of cycles, response, and immune‐related adverse events (irAEs) during ICI monotherapy. Results A total of 45 patients were reviewed. The patients' median age was 85 years. Twenty‐one, 17, and 7 patients received nivolumab, pembrolizumab, and atezolizumab, respectively. The disease control rate (partial response [PR] + stable disease [SD]) was 60.0%, and the progression‐free survival was 3.4 months. In patients with nivolumab, seven patients (33.3%) achieved SD, and three patients (14.2%) achieved PR. In patients treated with pembrolizumab, seven patients (41.2%) achieved SD, and six patients (35.3%) achieved PR. In patients with atezolizumab, three patients (42.9%) achieved SD, and one patient (14.2%) achieved PR. Sixteen (36%) patients presented with a poor performance status. Three patients treated with pembrolizumab experienced grade 3 pneumonia, while one patient treated with nivolumab experienced grade 5 pneumonia. Conclusion This study suggested that ICIs are an acceptable treatment option for NSCLC patients aged ≥80 years. Oncologists should pay attention to severe irAEs.

Background and Objectives: Immune-checitors have been established as a novel standard treatment for non-small cell lung cancer (NSCLC). The aim of this study was to identify factors associated with efficacy and nivolumab-related interstitial pneumonia in NSCLC by evaluating clinical data at the initiation of and during treatment. Methods: We retrospectively reviewed the medical records of patients who underwent treatment with nivolumab between October 2015 and December 2017. Using pretreatment patient data, we investigated factors associated with overall survival (OS) and the onset of nivolumab-related pneumonitis. We investigated serum biochemistry during treatment to identify the determinants associated with progressive disease (PD) and the onset of nivolumab-related pneumonitis. Results: A total of 94 patients were included. Eleven patients continued treatment, and 54 patients were diagnosed with progressive disease. Nivolumab-related pneumonitis occurred in 15 patients. A pretreatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0 was linked to significantly longer OS than ECOG PS = 1 (median: 20.1 vs. 6.5 months, respectively; p < 0.001). There was a higher incidence of nivolumab-related pneumonitis in patients with a history of interstitial pneumonia than in those without it ( p = 0.008). During treatment, the level of albumin gradually decreased prior to PD and onset of nivolumab-related pneumonitis. Conclusion: These results suggest that the pretreatment ECOG PS is the determining factor that is associated with OS, whereas history of interstitial pneumonia is the factor associated with nivolumab-related pneumonitis. A decrease in albumin during treatment may be associated with both PD and nivolumab-related pneumonitis.

Background A synergistic effect of cyclooxygenase inhibitors (COX‐I) and immune checkpoint inhibitors (ICIs) has been suggested. However, the impact of COX‐I on the efficacy of ICIs is unclear. Here, we aimed to evaluate the relationship between COX‐I use and the efficacy of ICI in patients with non‐small cell lung cancer (NSCLC). Methods We retrospectively reviewed NSCLC patients who received ICI monotherapy. We defined COX‐I use as regular use of COX‐I other than low‐dose aspirin during the initiation of ICIs to the first evaluation of efficacy. The efficacy of ICIs was evaluated with response rate (RR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Differences in baseline characteristics by COX‐I use were controlled by using an inverse probability of treatment weighting (IPW) adjusted analysis. Results A total of 198 patients with NSCLC received ICIs; 128, 50, and 20 patients received nivolumab, pembrolizumab, and atezolizumab, respectively; there were 65 (32.8%) COX‐I users. While there was no significant difference in RR (15.4% vs. 13.5%; p = 0.828), DCR (41.5% vs. 49.6%; p = 0.294), PFS (median, 2.69 vs. 3.68 months; 95% confidence intervals [CI], 1.77–5.19 vs. 2.20–4.60 months; p = 0.630), COX‐I users had significantly shorter OS than non‐COX‐I users (median, 6.08 vs. 16.10 months; 95% CI: 3.78–11.66 vs. 9.49–19.68 months; p = 0.003). On IPW adjusted analysis, there was no significant difference in OS (median, 7.85 vs. 15.11 months; 95% CI: 5.03–14.92 vs. 9.49–19.32 months; p = 0.081). Conclusions There was no additional or negative impact of COX‐I use on the efficacy of ICIs in NSCLC., We retrospectively evaluated the relationship between cyclooxygenase inhibitor (COX‐I) use and the efficacy of immune‐checkpoint inhibitors (ICIs) in patients with non‐small cell lung cancer (NSCLC). We adjusted with as many factors as possible by inverse probability weighting estimated by propensity score. After adjustment, there was no additional or negative impact of COX‐I use on the efficacy of ICIs in NSCLC.

BACKGROUND Over the past two decades, antiresorptive agent-related osteonecrosis of the jaw (ARONJ) has become a growing concern. We examined the incidence of ARONJ and identified its risk factors in lung cancer patients in the real-world clinical setting. To our knowledge, we are the first to do so. PATIENTS AND METHODS We retrospectively analyzed lung cancer patients with bone metastases who had received anti-resorptive agents (zoledronate or denosumab) at the National Hospital Organization Kyoto Medical Center from October 2012 to September 2018. All ARONJ cases were diagnosed by the dentists according to the established diagnostic criteria. RESULTS A total of 171 patients were reviewed, 13 (7.6%) of whom experienced ARONJ. Among the 13 patients, six (46.2%), four (30.8%) and three (23.1%) had adenocarcinoma, squamous carcinoma and not otherwise specified, respectively. ARONJ was stage 2 in three (23.1%) patients and stage 3 in 10 (76.9%). More cycles of antiresorptive agents (odds ratio [OR] = 11.54; 95% confidence interval [CI], 2.47-53.99; P

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.

After approval of anti-programmed cell death (PD)-1 antibodies, treatment for non-small cell lung cancer (NSCLC) has drastically changed. However, even in patients with favorable effects, therapeutic efficacy does not last long. Recently, retreatment with anti-PD-1 antibody has received attention. The aim of this study was to evaluate the efficacy and safety of retreatment with pembrolizumab in NSCLC patients previously treated with nivolumab. We retrospectively reviewed NSCLC patients retreated with pembrolizumab who were previously treated with nivolumab. We collected the following data: patient characteristics, number of cycles of nivolumab and pembrolizumab, treatment interval between nivolumab and pembrolizumab, best response, and immune-related adverse events. Twelve patients were reviewed. The median number of cycles of nivolumab was 12.5 (range 2–32 cycles). Seven patients (58.3%) achieved a partial response (PR) and two patients (16.7%) achieved stable disease (SD). Eight patients (66.7%) received cytotoxic chemotherapy between nivolumab and pembrolizumab. The median number of cycles of chemotherapy treatment was 4 (range 1–9 cycles). The median number of cycles of pembrolizumab was 3.5 (range 1–17 cycles). One patient (8.3%) achieved PR and four patients (33.3%) achieved SD as their best response to pembrolizumab. All patients showing response to pembrolizumab had very high (≥ 80%) tumor PD-Ligand 1 expression. This study suggested that retreatment with anti-PD-1 antibody is a reasonable option for selected NSCLC patients.

Background:Brain metastases (BM) are one of the strongest negative prognostic factors in patients with non-small cell lung cancer (NSCLC). Molecularly targeted agents are standard of care for NSCLC patients with a driver mutation; however, their efficacy in patients with BM is not fully understood because patients with BM are usually excluded from clinical studies. This study investigated the current management and outcomes of newly diagnosed NSCLC patients with BM in Japanese clinical practice, focusing on their driver mutation status. Patients and Methods:We enrolled newly diagnosed, treatment-naïve NSCLC patients with BM between January 2012 and December 2015 from 4 institutions in Japan. The medical records of each patient were retrospectively reviewed, and the treatment details and outcomes were evaluated. Results:In total, 203 patients with BM were enrolled in this study and 73 (36%) were neurologically symptomatic. Regarding initial treatment, 110 patients (54%) received local therapy, including radiotherapy and surgery, whereas 77 (38%) received systemic therapy. The median overall survival (OS) was 14.3 months for all patients, and it was significantly longer among patients with a driver mutation (28.9 months; 95% confidence interval [CI], 20.9–41.0) than among patients without a driver mutation (9.9 months; 95% CI, 7.0–13.4) (hazard ratio [HR] 0.39; 95% CI, 0.27–0.57; p < 0.001). Multivariate analysis identified performance status (HR 1.78; 95% CI, 1.16–2.72; p = 0.009) and driver mutation status (HR 0.27; 95% CI, 0.17–0.44; p < 0.001) as significant prognostic factors. No significant difference in OS was noted according to the type of initial treatment, i.e., local versus systemic. Conclusion:The median OS of patients with a driver mutation was longer than 2 years, even of patients with BM, and it was significantly longer than that of patients without a driver mutation. Driver mutation status, in addition to performance status, was a significant prognostic factor in NSCLC patients with BM.

Disseminated nontuberculous mycobacterial (NTM) infections usually occur in severely immunosuppressed patients. These infections may also occur in previously immunocompetent patients with acquired anti–interferon-gamma antibodies (anti–IFN-γ Abs). A previously healthy 33-year-old man presented with a 3-week history of cough and fever. Chest computed tomography showed air-space consolidation in the middle lobe of the right lung and enlargement of the supraclavicular, mediastinal, and hilar lymph nodes. Tissue samples obtained via mediastinoscopy showed granuloma formation with acid-fast bacteria; cultures from the tissue revealed Mycobacterium kansasii. Accordingly, a diagnosis of disseminated M. kansasii disease was made. The positive control tested negative in the QuantiFERON-TB Gold In-tube test, suggesting the presence of anti–IFN-γ Abs. The ELISA test for anti–IFN-γ Abs demonstrated an increased titer. Antimycobacterial drug treatments were initiated after diagnosis. His symptoms improved over 2 months, and he remains well on outpatient management. Disseminated M. kansasii disease is a very rare condition suggestive of immunosuppression. Testing for anti–IFN-γ antibodies might be important in all cases of disseminated M. kansasii disease.

Background This study evaluated the efficacy and safety of retreatment with anti-programmed death 1 (anti-PD-1) antibodies in patients with advanced non-small cell lung cancer (NSCLC) after prior treatment with anti-programmed death-ligand 1 (anti-PD-L1) antibodies. Methods Data (N = 15) on patients' characteristics, number of cycles, regimens, their best response and immune-related adverse events (irAEs) were recorded retrospectively. Results NSCLC was initially treated with anti-PD-L1 antibody atezolizumab (N = 14) or durvalumab (N = 1). No patients had a high (≥50%) tumor expression of PD-L1. The median cycles for atezolizumab were five (range 1-15), and median progression-free survival was 2.8 and 6.0 months for atezolizumab and durvalumab, respectively. Five (33.3%) and nine (60.0%) patients showed stable and progressive disease as their best response, respectively. No differences in irAEs between anti-PD-L1 and anti-PD-1 antibodies occurred. Conclusion Patients treated with anti-PD-L1 antibodies for NSCLC received limited benefits from retreatment with anti-PD-1 antibodies.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. Since patients with severe COPD may experience exacerbations and eventually face mortality, advanced care planning (ACP) has been increasingly emphasized in the recent COPD guidelines. We conducted a multicenter, cross-sectional study to survey the current perspectives of Japanese COPD patients toward ACP. "High-risk" COPD patients and their attending physicians were consecutively recruited. The patients' family configurations, understanding of COPD pathophysiology, current end-of-life care communication with physicians and family members, and preferences for invasive life-sustaining treatments including mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) were evaluated using a custom-made, structured, self-administered questionnaire. Attending physicians were also interviewed, and we evaluated the patient-physician agreement. Among the 224 eligible "high-risk" patients, 162 participated. Half of the physicians (54.4%) thought they had communicated detailed information; however, only 19.4% of the COPD patients thought the physicians did so (κ score = 0.16). Less than 10% of patients wanted to receive invasive treatment (MV, 6.3% and CPR, 9.4%); interestingly, more than half marked their decision as "refer to the physician" (MV 42.5% and CPR 44.4%) or "refer to family" (MV, 13.8% and CPR, 14.4%). Patients with less knowledge of COPD were less likely to indicate that they had already made a decision. Although ACP is necessary to cope with severe COPD, Japanese "high-risk" COPD patients were unable to make a decision on their preferences for invasive treatments. Lack of disease knowledge and communication gaps between patients and physicians should be addressed as part of these patients' care.

Objective/background The prevalence of pulmonary nontuberculous mycobacterial (pNTM) disease, including Mycobacterium avium complex (MAC), varies widely according to geographic region. However, the factors that influence regional variations in pNTM disease prevalence remain unknown. This study was undertaken to examine whether environmental or occupational factors or host traits could influence regional variations in pNTM disease prevalence. Methods We collected laboratory data on pulmonary tuberculosis (pTB) and pNTM from two hospitals in the West Harima area of Japan and five hospitals in Kyoto City, Japan from 2012 to 2013. We estimated microbiological pNTM disease prevalence by multiplying all pTB cases in each area with the ratio of pNTM cases and pTB cases at the survey hospitals in each area. We administered a standardized questionnaire to 52 patients and 120 patients with pulmonary MAC (pMAC) disease at Ako City Hospital and Kyoto University Hospital, respectively. Results The estimated prevalence of microbiological pNTM disease in the West Harima area (85.4/100,000 population-years) was significantly higher than that observed in Kyoto City (23.6/100,000 population-years; p

Vitamin D maintains calcium balance and has immunomodulatory effects. Only few studies have revealed the relationship between vitamin D and its associated factors in Mycobacterium avium complex (MAC) infection. This study aimed to investigate the effects of MAC infection on serum vitamin D, human cationic antimicrobial protein 18, its C-terminal 37 amino acid fragment (hCAP18/LL-37) levels, and bone mineral density (BMD). We enrolled 58 patients with MAC lung disease and 15 control participants. Serum 25-hydroxyvitamin D and hCAP18/LL-37 levels were measured via enzyme-linked immunosorbent assay. Lastly, computed tomography scan density readings of the BMD of the thoracic and lumbar vertebral bones (Th4, Th7, Th10, and L1) were assessed. No significant differences in patient characteristics and serum vitamin D levels were observed. Patients with MAC lung disease had significantly low serum hCAP18/LL-37 levels (P = .049). Moreover, low BMD of the mean thoracic and lumbar vertebrae was observed (mean Th, P = .012; L1, P = .48, respectively). A higher prevalence of scoliosis (P = .031) was observed in the participants with low BMD compared with the control participants. Based on a multivariate analysis, patients with MAC lung disease had significantly lower body mass index [odds ratio (OR), 19.1; 95% confidence interval (CI), 2.0–419.0; P

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.

Recently, cancer immunotherapy by immune checkpoint inhibitors has been considered one of the pillars for the treatment of cancer. Nivolumab is the first immune checkpoint inhibitor approved for lung cancer treatment in Japan. Although nivolumab has superior survival benefits and fewer adverse events than cytotoxic agents, it can generate dysimmune toxicities, known as immune-related adverse events. Although autoimmune manifestations are well-known immune-related adverse events, the development of infectious diseases is rare. Here, we report on a patient with advanced NSCLC in whom pulmonary tuberculosis developed rapidly during nivolumab treatment and discuss the potential mechanisms as well as what is known about infections during checkpoint inhibitor therapy.

Backgrounds Cancer immunotherapy using immune checkpoint inhibitors has received a remarkable amount of attention in patients with non-small cell lung cancer (NSCLC). The unique adverse effects known as immune-related adverse events (irAEs) associated with immune checkpoint inhibitors are not known however, and neither is the incidence of infectious disease among patients receiving immune checkpoint inhibitors. The aims of this study were to investigate the incidence of infections during nivolumab treatment, and the risk factors associated with infections. Methods We retrospectively reviewed NSCLC patients who received nivolumab in two teaching hospitals (National Hospital Organization Kyoto Medical Center and Kyoto University Hospital, Kyoto, Japan) between December 2015 and June 2017. We counted any infectious diseases occurring at any time after the initiation of nivolumab until 3 months after its discontinuation. In the current study, “infectious disease” was defined as any infection requiring the administration of any antimicrobial agent. Results Of a total of 167 NSCLC patients reviewed, 32 (19.2%) experienced infectious diseases. Of the 33 infections in 32 patients, 25 were bacterial, 2 were fungal, and 6 were viral. Twenty-seven of the patients with infections used corticosteroids during their treatment course. There was no statistically significant difference in the use of immunosuppressive agents between patients with and without infections. A history of diabetes mellitus was significantly associated with infection (odds ratio 3.61, 95% confidence interval 1.14–11.4, p = 0.028). Conclusions Lung cancer patients receiving nivolumab have a certain level of risk for developing infectious diseases. In the current study, a history of diabetes mellitus was an independent risk factor for infectious disease development. Clinicians should pay attention to occult infectious diseases in patients receiving lung cancer treatment with immune checkpoint inhibitors, especially those with the history of diabetes mellitus.

Lessons Learned Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients. In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population. Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. Background Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. Methods This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. Results A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%–72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1–82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. Conclusion Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420.A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236CT, 2677GT/A, 3435CT), ABCG2 (421CA), and CYP3A5 (6986AG) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated.The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62).ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.

Objective: We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease smallcell lung cancer. Methods: Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m 2 )w ere administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if .45 responses were observed in the 55 patients. Results: Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6‐87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8‐18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9‐7.4). Conclusions: This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial.

Background: Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non–small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). Patients and Methods: We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. Results: The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. Conclusions: There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects.

A study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and serum hepatocyte growth factor (HGF) for their associations with response to gefitinib therapy and prognostic impact. An enzyme-linked immunosorbent assay was used to determine levels of HGF in serum from 96 Japanese patients with advanced non-squamous NSCLC. The peptic nucleic acid-locked nucleic acid clamp method was used to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and risk factors associated with prognosis. HGF-positive serum status (hazard ratio, 1.536; 95% confidence interval, 1.042-2.400; P = 0.0295) had a significant and independent negative effect on progression-free survival among patients with wild-type EGFR. We demonstrate that having HGF-positive serum is predictive of a negative response to gefitinib therapy in patients with advanced NSCLC who harbor wild-type EGFR.

Cancer-associated retinopathy is a rare paraneoplastic syndrome that is often associated with small-cell lung cancer. It is caused by an autoantibody to the 23 kDa photoreceptor protein, recoverin. A small number of reports have described effective treatment for the disease. We report two cases of cancer-associated retinopathy with small-cell lung cancer whose visual symptom preceded the diagnosis of cancer. Their visual acuity and visual field were slightly improved after steroid and anticancer therapy. Steroid therapy was effective, although the period from visual symptom onset to therapy was comparative longer. When cancer-associated retinopathy is suspected, a comparatively large quantity of steroids and anticancer treatment should be combined immediately.

The aim of this study was to analyze the factors independent of epidermal growth factor (EGFR) gene mutations that affect the progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) after gefitinib therapy.Eighty patients with advanced NSCLC between January 2003 and April 2010 at Kyoto University Hospital were analyzed for EGFR somatic mutations and treated with gefitinib. We adopted the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method for determination of EGFR mutation status. To evaluate risk factors associated with PFS, Cox proportional hazards regression model with a step-down procedure was used. Proportional hazards assumptions were checked and satisfied; only those variables with statistically significant results in univariate analysis were included in a multivariate analysis.The median PFS of patients with EGFR mutations were significantly longer than in patients with wild-type EGFR. The median PFS of patients after first-line gefitinib therapy was significantly longer than those who received treatment as a second-line therapy. The median PFS of patients over 75 years of age was significantly longer than in younger patients. Based on multivariate analysis, wild-type EGFR status and age75 years were significant and independent negative factors that affect PFS after gefitinib therapy.In this study, we showed the EGFR mutants and age75 years were good predictive factors for PFS after gefitinib therapy, suggesting that first-line gefitinib treatment for older patients is efficacious regardless of EGFR mutational status.

A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome.

BACKGROUND: Although the association of multiple pulmonary metastases, and particularly miliary metastases, with response to gefitinib treatment in patients with nonsmall cell lung cancer has been reported, the association of miliary pulmonary metastases with epidermal growth factor receptor gene (EGFR) mutations remains unclear. METHODS: The authors retrospectively investigated the association of diffuse, random pulmonary metastases in patients with lung adenocarcinoma. The study included 163 Japanese patients who had unresectable, advanced lung adenocarcinoma diagnosed between April 2003 and March 2010. Computed tomography scans that were obtained at the time of diagnosis were analyzed by 2 investigators. For the purposes of this study, diffuse, random pulmonary metastases were defined as multiple nodules (n = 50; ≤3 cm in greatest dimension) distributed diffusely and randomly throughout the lungs. RESULTS: Of 163 patients, 55 had pulmonary metastases, and EGFR mutations were detected in 22 of those 55 patients. The mutations were identified preferentially among women (P = .15) and were identified significantly among patients who had a smoking history of

Recently, two small-molecule kinase inhibitors targeting epidermal growth factor receptor have proven effective in the treatment of non-small cell lung cancer. There are specific activating mutations within the tyrosine kinase domain of epidermal growth factor receptor related to the sensitivity of tyrosine kinase inhibitors. However, it is unknown whether rare mutations in the N-lobe (exons 18‐20) and the C-lobe (exon 21) of the epidermal growth factor receptor kinase domain other than L858R in exon 21 and the in-frame deletion in exon 19 may predict the effectiveness of epidermal growth factor receptor—tyrosine kinase inhibitors. We reported a case of non-small cell lung cancer harboring a rare epidermal growth factor somatic mutation, codon 768 AGC . ATC in exon 20 (S768I), who showed ag ood clinical response to gefitinib. Therefore, we may suggest that this rare mutation (S768I in exon 20) may not be an insensitive epidermal growth factor receptor somatic mutation in vivo.

Introduction Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). Method We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. Results In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. Conclusion Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Cutaneous lymphangitis carcinomatosa (CLC) is a rare form of cutaneous metastasis that causes lymphoedema and various eruptions. We report a case of lung cancer with CLC that caused both superior vena cava (SVC) stenosis and cervicofacial oedema, suggestive of SVC syndrome. A 64-year-old woman with lung adenocarcinoma presented with cervicofacial oedema and erythema, followed by severe dyspnoea 2 months after four cycles of carboplatin, pemetrexed and bevacizumab triplet therapy. Although chest CT indicated SVC stenosis, cervicofacial oedema remained despite treating the SVC stenosis via balloon dilation. A skin biopsy of the erythematic sample confirmed CLC as the cause of the patient's symptoms. CLC should be considered as a differential diagnosis of cervicofacial oedema in addition to SVC syndrome, especially when it is observed in combination with skin erythema and induration. Moreover, a skin biopsy should be performed promptly for accurate diagnosis of CLC and to decide on appropriate treatment.

The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin-antithrombin complex (TAT), and plasmin-α2-plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future.

The importance of an epidermal growth factor receptor (EGFR) gene mutation has been recognized in patients with non-small cell lung cancer (NSCLC), and many reports have indicated that the presence of somatic mutations in the EGFR gene is a strong predictor of both clinical and in vitro sensitivity to EGFR tyrosine kinase inhibitors; thus necessitating the standardization of a mutation screening system based on the sources of tissue samples.In this study, we compared the results of EGFR mutation analyses in 19 small biopsy specimens with results obtained in surgical materials from the same patients with NSCLC. We used a laser microdissection method and a direct sequencing method, and we confirmed the accuracy of EGFR mutation analysis with small biopsy specimens.The results obtained from the biopsy specimens were identical to those obtained from the surgical materials in 18 of the 19 patients analyzed. For the 1 patient in whom the results obtained from the two sets of materials were not identical, the number of cancer cells in one bronchoscopic specimen was insufficient to perform analyses of all three exons of interest (i.e., exons 18, 19, and 21), and so only exon 19 was sequenced, and no mutation was demonstrated.We conclude that satisfactory accuracy can be achieved by the genomic analysis of a small biopsy specimen from a patient with NSCLC and we note that it is possible to conduct prospective clinical trials that include patient assignment for treatment based on the results obtained.

Circulating amphiregulin and transforming growth factor-alpha (TGF-alpha) have been found to be correlated with an unfavorable response to gefitinib based on the identification of patients with a higher probability of resistance to the drug. However, the association between an epidermal growth factor receptor (EGFR) somatic mutation and the overexpression of its ligands has not been determined. To verify the clinical significance of the two serum markers and EGFR mutation status, we determined serum amphiregulin and TGF-alpha levels by enzyme-linked immunosorbent assay in 93 patients with advanced non-squamous, non-small cell lung cancer and EGFR somatic mutation status using the peptic nucleic acid-locked nucleic acid clamp method in 46 cases. The relationship between each independent clinicopathological variable and the response to gefitinib therapy was examined. We also evaluated the risk factors associated with prognosis. Fourteen (41.0%) of 34 progressive disease cases were positive for amphiregulin (P = 0.007). Eleven (32.4%) of 34 progressive disease cases were positive for TGF-alpha (P = 0.005). The median survival time of patients with the EGFR somatic mutation was significantly longer (P = 0.01). The same was true of amphiregulin- (P = 0.046) and TGF-alpha-negative patients (P < 0.01). In multivariate analysis, serum TGF-alpha positivity (hazard ratio, 2.558; P = 0.005) and the wild type EGFR gene (hazard ratio, 1.894; P = 0.003) were significant independent prognostic factors. Our study demonstrates that the status of the serum EGFR ligand, in addition to EGFR activating mutation, is a predictive factor for response to gefitinib therapy.

Background and objective: Chest CT has been widely used for the evaluation of structural changes in lung parenchyma and airways in cross-sectional studies. There has been no report on the annual changes in airway dimensions as assessed by CT in COPD patients. The objective of this study was to investigate the annual changes in airway dimensions and lung attenuation using CT in patients with COPD and to evaluate the correlations among annual changes in CT measurements and pulmonary function. Methods: Eighty-three men with COPD had completed five annual assessments of CT scans and pulmonary function tests over 4 years. Airway dimensions of the basal segment bronchi and lung attenuation on CT images were analysed in 38 subjects in whom the same airway could be measured at least three times, including at entry and at the end of the study. Results: Mean annual decline in FEV1 was 21 mL/year. Annual changes in the percentage of low attenuation areas were not significantly correlated with decline in FEV1. On the other hand, annual changes in the percentage of wall area (WA%/year) were significantly inversely correlated with annual changes in FEV1 (r = −0.363, P = 0.025), whereas WA%/year did not differ among severity stages at entry and did not correlate with baseline FEV1. Conclusions: The results showing that annual changes in airway thickening correlated with annual decline in air flow limitation suggests the importance of treatment of airway inflammation in COPD. CT is a useful tool for quantitative estimation not only of emphysema but also of airway lesions in longitudinal studies.

Objective Interstitial lung disease (ILD) is a severe adverse event of gefitinib therapy. However, the mechanism still remains unclear. The objective of this study was to examine whether or not oxidative stress, one of the common factors in drug-associated ILD, is involved in the pathogenesis of gefitinib-induced ILD. Patients and Methods Using an enzyme-linked immunosorbent assay (ELISA), we measured the concentration of serum thioredoxin (Trx), a redox-active protein with antioxidative effects, in 44 patients treated with gefitinib, including three patients who had ILD. Results In patients who had gefitinib-induced ILD, serum Trx levels were significantly elevated. They decreased after cessation of gefitinib therapy accompanying clinical improvement of ILD. Conclusion It was suggested that oxidative stress may be involved as a part of mechanisms causing or worsening gefitinib-induced ILD.

A 73-year-old man with a known history of asthma presented with dyspnea, worsening wheezing and a productive cough complicated by chronic sinusitis. Chest computed tomography showed bronchial wall thickening with centrilobular nodules and ground-glass opacity in the right lower lobe. Features meeting the diagnostic criteria for diffuse panbronchiolitis (DPB) were identified, and lobectomy confirmed the presence of lung cancer. Over the subsequent four years, the patient's symptoms worsened. We reevaluated a lung lobe specimen, which showed hypereosinophilic obliterative bronchiolitis (HOB). A transbronchial lung biopsy also indicated bronchitis with eosinophilic infiltration. Our initial diagnosis of DPB was subsequently changed to HOB after four years. We herein describe this case of HOB, which was initially diagnosed as DPB primarily based on high-resolution computed tomography, with a focus on the histopathology and long-term clinical course. This is the first report to document the long-term clinical course of HOB.

Objective This study evaluates the risks of postoperative complications in 124 patients with non-small-cell lung cancer who received pre-operative induction chemoradiotherapy and surgery. Methods All patients with non-small-cell lung cancer who underwent surgery after induction therapy between January 1990 and December 2003 were reviewed. We adopted univariate and multiple logistic regression models to identify predictors that increased the incidence of postoperative complications. Results Of 124 patients, 59 received carboplatin and docetaxel, 53 received cisplatin and etoposide, and 12 received other platinum-based combinations. Pre-operative thoracic radiotherapy was performed concurrently with chemotherapy. The median dose to the primary tumor was 40 Gy, and 29 patients (23.4%) received radiotherapy of more than 45 Gy before surgery. There were 25 pneumonectomies (20.2%). The overall postoperative mortality was 9 of 124 patients (7.3%), and complications developed in 54 patients (43.5%). Multivariate analysis demonstrated that only thoracic radiotherapy of more than 45 Gy predicted postoperative complications (P = 0.021; odds ratio, 3.620; 95% confidence interval, 1.214-10.797). Conclusions Thoracic radiotherapy of more than 45 Gy, in combination with chemotherapy, was a significant risk factor for postoperative complications.

N-Glycan structures on the surface of cancer cells have diverse structures and play significant roles in metastatic process. However, little is known about their roles in organ-selective metastasis. Our study revealed that an alpha1,6-fucosylated biantennary N-glycan structure designated A2G2F is characteristic of lungs, with far more abundant expression in normal human and murine lungs than in other organs. In this study, we further examined the role of A2G2F in pulmonary metastasis. We stained metastatic cancers by alpha1,6-fucose-specific Lens culinaris agglutinin lectin and revealed that pulmonary metastatic nodules more abundantly expressed alpha1,6-fucosylated N-glycans than hepatic metastatic nodules from common primary cancers. The most specific alpha1,6-fucosylated N-glycan structure in pulmonary metastatic cancer was identified to be A2G2F. Using a B16 melanoma cell metastasis model, we showed that A2G2F-rich B16 cells formed more pulmonary metastatic nodules than A2G2F-poor cells. Our results suggest that A2G2F plays a critical role in pulmonary metastasis.

Background: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. Methods: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by √BSA of a segmental bronchus (T/√BSA), was examined. Results: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/√BSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/√BSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. Conclusion: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

Radiation exposure is known to impair healing in irradiated areas. Fibroblasts play a major role in the production and modification of extracellular matrix in wound repair. Since one important aspect of wound repair is the contraction of the wound, this study investigated the effects of radiation on the ability of fibroblasts to mediate collagen gel contraction in an in vitro model of wound retraction. After irradiation, the cells were detached and suspended in a solution of rat tail tendon collagen. Radiation exposure decreased retraction, and this effect was dose dependent. In order to define the mechanism of reduced gel retraction, we investigated alpha2beta1 cell surface integrin and fibronectin, which are thought to mediate contraction, and prostaglandin E2 (PGE2), which is known to inhibit this process. PGE2 release increased dose responsively following radiation. The cyclooxygenase inhibitor indomethacin could partially restore the contractile activity of irradiated fibroblasts. Fibronectin production in gel culture showed a significant decrease. In contrast, there was no decrease in alpha2beta1 integrin expression in radiated cells. In conclusion, radiation decreases fibroblast-mediated gel contraction. Increased PGE2 production and decreased fibronectin production by irradiated fibroblasts may contribute to this effect and may be in part responsible for poor healing of radiated tissue.

A 54-year-old man presented to our emergency department with fever and dyspnoea. He required vigorous haemodynamic support and mechanical ventilation for hypotensive distributive shock with hypoalbuminaemia, haemoconcentration, rhabdomyolysis and acute renal failure, consistent with idiopathic systemic capillary leak syndrome. Left lung consolidation and hypoxaemia were observed 6 days after admission. Sputum smear revealed the presence of acute angled branching hyphae, consistent with a diagnosis of invasive pulmonary aspergillosis. Antifungal therapy was administered and mechanical ventilation discontinued on day 66. The patient recovered and was discharged from the hospital on day 185.

We report a case of life-threatening haemoptysis after administration of dabigatran in a patient with bronchiectasis. A 72-year-old woman had received dabigatran at a dose of 110 mg twice daily for chronic atrial fibrillation. She was admitted to our hospital for cerebral infarction after a few days of self-interruption of dabigatran. After the diagnosis of cerebral infarction, administration of dabigatran was restarted. Seven days later, she suffered acute-onset massive haemoptysis and required mechanical ventilation. Dabigatran treatment was discontinued, and bronchial artery embolisation (BAE) was performed twice. The bleeding continued for 11 days, but she recovered and was discharged on day 58 after admission.

Bradykinin is a multifunctional mediator of inflammation believed to have a role in asthma, a disorder associated with remodeling of extracellular connective tissue. Using contraction of collagen gels as an in vitro model of wound contraction, we assessed the effects of bradykinin tissue on remodeling. Human fetal lung fibroblasts were embedded in type I collagen gels and cultured for 5 days. After release, the floating gels were cultured in the presence of bradykinin. Bradykinin significantly stimulated contraction in a concentration- and time-dependent manner. Coincubation with phosphoramidon augmented the effect of 10−9and 10−8M bradykinin. A B2receptor antagonist attenuated the effect of bradykinin, whereas a B1receptor antagonist had no effect, suggesting that the effect is mediated by the B2receptor. An inhibitor of intracellular Ca2+mobilization abolished the response; addition of EGTA to the culture medium attenuated the contraction of control gels but did not modulate the response to bradykinin. In contrast, the phospholipase C inhibitor U-73122 and the protein kinase C inhibitors staurosporine and GF-109203X attenuated the responses. These data suggest that by augmenting the contractility of fibroblasts, bradykinin may have an important role in remodeling of extracellular matrix that may result in tissue dysfunction in chronic inflammatory diseases, such as asthma.

Background: Imbalance between proteinases and their inhibitors released from alveolar type II pneumocytes may cause development of inflammatory lung diseases. Objectives and Methods: We examined mRNA expressions of matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in a cell line (A549) and in primary culture of normal adult human type II pneumocytes using reverse transcription-competitive polymerase chain reaction. Results: Interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) increased MMP-3 and TIMP-3 expressions in A549 cells in a time- and concentration-dependent manner. IL-1β mainly augmented MMP-3 expression, while TGF-β1 mainly augmented TIMP-3 expression. Dexamethasone attenuated both IL-1β- and TGF-β1-stimulated expressions of MMP-3 and TIMP-3. Interleukin-10 had no significant effect. Hepatocyte growth factor alone had no effect on constitutive MMP-3 expression or TIMP-3 expression, but it augmented TGF-β1-stimulated MMP-3 expression. The constitutive expressions were higher in normal type II pneumocytes than in A549 cells, but the regulations were similar. Conclusions: These data indicated that the matrix degradation is enhanced by IL-1β and suppressed by TGF-β1 via regulations in the balance between MMP-3 and TIMP-3. Further, these regulations were shown to be modulated by glucocorticoids and growth factors.