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Purpose The purpose of this study was to investigate the impact of social isolation and loneliness on the overall survival and death at home in patients with lung cancer. Methods This prospective cohort study was conducted in a Japanese tertiary hospital. The enrollment period was from April 2018 to March 2020. Patients with pathologically diagnosed advanced lung cancer were included in this study. The primary outcome was overall survival, whereas the secondary outcome was death at home. The exposures were social isolation and loneliness. Results A total of 211 patients were enrolled and divided into two groups and further into quartiles according to their social isolation and loneliness level, respectively. The hazard ratios of social isolation were 1.65 (95% confidence interval; 1.12 to 2.44) and 1.87 (95% confidence interval; 1.15 to 3.03) in the univariate analysis, while 1.40 (95% confidence interval; 0.92 to 2.13) in the multivariate analysis with complete case and multiple imputation. The odds ratio of death at home with social isolation was 3.47 (95% confidence interval; 1.08 to 11.1) in the multivariate analysis with multiple imputation. Loneliness was not associated with overall survival or death at home. Conclusions Our study suggests that social isolation may be related to overall survival and death at home among patients with advanced lung cancer. More attention should be given to such patients at the time of diagnosis.

The gut microbiome plays an important role in the immune system and has attracted attention as a biomarker of several diseases, including cancer. In this study, we examined the relationship between the gut microbiome and lung cancer progression.Female never-smokers diagnosed with lung adenocarcinoma were consecutively enrolled between May 2018 and August 2019, and fecal samples were collected. Principal coordinate analyses were performed using Bray-Curtis distance matrices to investigate the effects of clinical variables (age, body mass index, Tumor-Node-Metastasis stage, T category, N category, M category, primary tumor size, performance status, and EGFR mutation status) on the gut microbial community.A total of 37 patients were enrolled. T category and primary tumor size were significantly correlated with the gut microbial community (p=0.018 and 0.041, respectively).This study identified the gut microbiome as a promising biomarker of lung cancer progression.

Background Social determinants of health (SDHs) are social factors that affect human health; loneliness and social isolation are core SDH factors. There is a possibility that SDHs are related to passive decisionmaking. However, few studies have evaluated SDHs, especially social isolation and loneliness, among lung cancer patients. This study aims to investigate the effects of social isolation and loneliness on the diagnosis and treatment of Japanese lung cancer patients. Methods This is a prospective cohort study that was conducted in a tertiary referral hospital in Japan (University Hospital Medical Information Network registration: UMIN000031810). The enrollment period was between April 2018 and March 2020. Patients with clinical and/or pathological diagnosis of lung cancer were enrolled in this study. Exposures were social isolation and loneliness, and main outcomes were diagnosis methods and whether the initial treatment involved active therapy or best supportive care (BSC). The confounding factors were defined as sex, age, smoking status, respiratory symptoms, weight loss, presentation with any symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, tumor nodes metastasis (TNM) classification, driver gene mutations [i.e., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)], and programmed death-ligand 1 (PD-L1) tumor proportion score. Results The study enrolled 264 patients who were divided into quartiles according to their loneliness scores and into two groups according to the social isolation level. Univariate analysis, complete case analysis, and multivariate analysis with multiple imputation failed to detect significant differences in diagnostic method or initial treatment strategy according to loneliness or social isolation level. Conclusions Physicians may not need to consider a patient's loneliness and/or social isolation when diagnosing lung cancer and selecting treatment under universal health insurance coverage. Further studies are needed to understand the influences of loneliness and social isolation on the prognosis of lung cancer patients.

BackgroundObjective evaluations of cough frequency are considered important for assessing the clinical state of patients with respiratory diseases. While cough monitors with audio recordings are used in research settings, they are rarely used in clinical settings. Issues regarding privacy and background noise (especially the sounds of someone else’s cough) with audio recordings are barriers to the wide use of these monitors in clinical settings; to solve these problems, we developed a novel automatic cough frequency monitoring system combining a triaxial accelerator and a stretchable strain sensor.MethodsEleven healthy adult volunteers and 10 adult patients with cough were enrolled. The participants sat in a chair and wore two devices for 30 minutes for the cough measurements. An accelerator was attached to the epigastric region, and a stretchable strain sensor was worn around their neck. When the subjects coughed, these devices displayed specific waveforms. For the development of the algorithm, the participants’ measurement data from both devices were divided into consecutive small “units” lasting 5 seconds each. Whether each unit corresponded to a “cough unit” was determined by the observer who manually counted the cough records. Then, the data from all the participants were categorized into a training dataset and a test dataset. Using a variational autoencoder, a machine learning algorithm with deep learning, the components of the test dataset were automatically judged as being a “cough unit” or “non-cough unit”.ResultsThe sensitivity and specificity in detecting coughs among 21 participants were 92% and 96%, respectively. The triaxial accelerometer only yielded a sensitivity of 91% and specificity of 95%. Therefore, the diagnostic accuracy improved slightly when the accelerometer was combined with a stretchable strain sensor.Conclusions According to the results of the current study, a cough frequency monitor with good performance can be created by combining an accelerometer and another biometric sensor. Our cough monitor is suitable for ambulatory settings because the devices are small and light. Our cough monitoring system, which does not require audio recordings, has the potential to be widely used in clinical settings without any concerns regarding privacy or background noise.

Background/aim Previous reviews of Social determinants of health in lung cancer patients have not examined essential factors such as social isolation and loneliness. This study aimed to explore the factors affecting social isolation and loneliness among lung cancer patients. Patients and methods A cross-sectional study was conducted. Social isolation, loneliness, and the presence of dementia were measured using Japanese adaptations of the Lubben Social Network Scale, UCLA Loneliness Scale, and Life Function Evaluation for Care Provision, respectively. Results From March 2019 to March 2020, 264 patients were included. Social isolation was significantly higher for patients receiving welfare (adjusted OR=5.28, 95% CI=2.24-12.4). Loneliness was significantly higher for patients receiving welfare (beta coefficient=0.52, 95% Cl=0.13-0.90) with symptoms of dementia (beta coefficient=0.28, 95% Cl=0.03-0.54). Conclusion Results showed that receiving welfare was associated with experiencing social isolation. Receiving welfare and symptoms of dementia were associated with experiencing loneliness.

In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.

Background: The gut microbiome plays an important role in the immune system and has attracted attention as a biomarker of various diseases, including cancer. As such, we examined the relationship between the gut microbiome and lung cancer progression. In addition, we assessed the correlation between the gut microbiome and epidermal growth factor receptor (EGFR) mutation status.Methods: Female never-smokers diagnosed with lung adenocarcinoma were consecutively and prospectively enrolled between May 2018 and August 2019. Fecal samples were collected within 1 month before or after diagnosis and before administration of any lung cancer treatment. Principal coordinate analyses were retrospectively performed using Bray-Curtis distance matrices to investigate the effects of clinical variables (age, body mass index, Tumor-Node-Metastasis stage, T category, N category, M category, primary tumor size, performance status, and EGFR mutation status) on the gut microbial community. A correlation analysis was also performed to determine the strength of association between the dominant taxonomy (comprising ≥1% of the relative abundance of bacterial DNA sequences) and clinical variables.Results: A total of 37 patients were enrolled. T category and primary tumor size were significantly correlated with the gut microbial community (p=0.018 and 0.041, respectively). At the genus level, a significant positive correlation was observed between the relative abundance of Faecalibacterium and both T category (correlation coefficient, R=0.51, p=0.0013) and primary tumor size (R=0.37, p=0.024), whereas a significant negative correlation was observed between the relative abundances of Fusicatenibacter and Bacteroides and T category (R=−0.35, p=0.034 and R=−0.32, p=0.05, respectively) and primary tumor size (R=−0.36, p=0.029 and R=−0.41, p=0.012, respectively). EGFR mutation status had no statistically significant effect on the gut microbial community (p=0.11). However, the relative abundances of Bifidobacterium and Faecalibacterium were significantly higher in EGFR mutation–negative patients than EGFR mutation–positive patients (p=0.012 and 0.041), whereas the relative abundance of Blautia was significantly lower in EGFR mutation–negative patients (p=0.036).Conclusions: This is the first study identifying the gut microbiome as a promising biomarker of lung cancer progression. Further elucidation of the role of the gut microbiome in lung cancer progression could facilitate development of new treatments for lung cancer.

Background Adequate tumor tissue is required to make the best treatment choice for non-small cell lung cancer (NSCLC). Transbronchial biopsy (TBB) by endobronchial ultrasonography with a guide sheath (EBUS-GS) is useful to diagnose peripheral lung lesions. The data of tumor cell numbers obtained by two different sizes of GSs is limited. We conducted this study to investigate the utility of a large GS kit to obtain many tumor cells in patients with NSCLC. Methods Patients with a peripheral lung lesion and suspected of NSCLC were prospectively enrolled. They underwent TBB with a 5.9-mm diameter bronchoscope with a large GS. When the lesion was invisible in EBUS, we changed to a thinner bronchoscope and TBB was performed with a small GS. We compared the tumor cell number prospectively obtained with a large GS (prospective large GS group) and those previously obtained with a small GS (small GS cohort). The primary endpoint was the tumor cell number per sample, and we assessed characteristics of lesions that could be obtained by TBB with large GS. Results Biopsy with large GS was performed in 55 of 87 patients (63.2%), and 37 were diagnosed with NSCLC based on histological samples. The number of tumor cells per sample was not different between two groups (658±553 vs. 532±526, estimated difference between two groups with 95% confidence interval (CI); 125 (-125–376), p = 0.32). The sample size of the large GS group was significantly larger than that of the small GS cohort (1.75 mm2 vs. 0.83 mm2, estimated difference with 95% CI; 0.92 (0.60–1.23) mm2, p = 0.00000019). The lesion involving a third or less bronchus generation was predictive factors using large GS. Conclusions The sample size obtained with large GS was significantly larger compared to that obtained with small GS, but there was no significant difference in tumor cell number. The 5.9-mm diameter bronchoscope with large GS can be used for lesions involving a third or less bronchus generation.

Parathyroid crisis, which might occur during the natural history of primary hyperparathyroidism, presents fatal hypercalcemia. Although hyperparathyroidism is known to cause metastatic pulmonary calcification, parathyroid crisis with respiratory failure is rarely reported. Here, we present a case of parathyroid crisis with respiratory failure due to parathyroid adenoma. For the first 2 weeks after admission to our hospital, the patient was treated with hydration, calcium-lowering agents, dialysis and extracorporeal membrane oxygenation, with gradual improvement in her respiratory condition as blood calcium levels decreased. However, she still needed oxygen even after that. Therefore, parathyroidectomy was performed on day 48, and she no longer needed oxygen after the surgery. Chest computed tomography scan also demonstrated improvement in pulmonary calcification, although it did not completely disappear even 4 months after parathyroidectomy. Parathyroid crisis is an endocrine emergency, and its possibility should be considered in patients with respiratory failure with hypercalcemia.

Introduction : When using portable oxygen, a demand oxygen delivery system (DODS), which senses the beginning of inhalation and delivers a bolus of oxygen, is often used. However, conventional DODS may not supply sufficient oxygen when reduced tidal flow fails to trigger the flow sensor. Recently, “auto-DODS,” which detects the negative pressure of inhalation and switches among 3 trigger sensitivity levels (standard, high, and extra high), has been developed to improve the efficacy of oxygenation. An auto-DODS can also supply pulsed-flow oxygen when it detects apnea, whereas a conventional DODS has only standard sensitivity. This randomized, open-label, crossover pilot study compared the performance of an auto-DODS with that of a conventional DODS. Methods : We recruited patients with chronic obstructive pulmonary disease (COPD) or interstitial pneumonia receiving long-term oxygen therapy. Interventions were performed on 2 different days for each participant. On each day, an auto-DODS or a conventional DODS were tested at rest for 30 minutes and during the 6-minute walk test. The primary outcome was mean oxygen saturation (SpO2). Secondary outcomes were the ratios of time for each sensitivity level and pulsed-flow oxygen when using the auto-DODS, total time desaturated below SpO2 90%, percentage of time desaturated below SpO2 90%, minimum SpO2, mean and maximum pulse rate, six-minute walk distance, recovery time after 6-minute walk test, modified Borg scale, comfort, and discomfort index. Results : When using the auto-DODS at rest, a high or extra high sensitivity level was observed in addition to standard sensitivity in 6 of 8 participants. During the 6-minute walk test, only standard sensitivity was observed in 6 participants. Mean SpO2 differences between the auto-DODS and conventional DODS at rest and during the 6-minute walk test were −0.6 [−4.5, 3.4] and 0.0 [−2.5, 2.5] ([95% confidence interval]), respectively, neither of which were significant (P = .73 and P = .99). There were no significant differences in secondary outcomes. There were no adverse events when using the auto-DODS. Conclusions : This study showed that the auto-DODS did not show superiority in oxygenation either at rest or during exercise compared to a conventional DODS. The auto-DODS was shown to supply oxygen safely and detect inhalations with various trigger sensitivities.

Background/aim Immune checkpoint inhibitors (ICI) are a novel medication for non-small cell lung cancer (NSCLC). Recent reports indicated that baseline tumor size (BTS) relates to the efficacy of ICI therapy for melanoma, but no study exists for NSCLC. This study aimed to evaluate the utility of BTS for ICI therapy. Patients and methods Data from 58 patients diagnosed with NSCLC who underwent ICI monotherapy, were retrospectively analyzed. Patients were divided into two groups according to BTS (below 101 mm, above 101 mm). The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS). Results PFS of patients with a large BTS was significantly shorter than that of those with a small BTS (median; 2.07 [95% confidence interval [CI]=0.99-6.77] months versus 6.39 [95%CI=4.17-11.50] months) (p=0.044). OS of patients with large BTS was also significantly shorter (p Conclusion BTS is a predictive and prognostic negative factor of ICI therapy for NSCLC.

Aim The aim of this study was to identify factors affecting the final diagnosis of cough. Materials and methods This study recruited 463 consecutive patients who visited five Japanese general hospitals due to cough from October 2006 to September 2007. Of these, 418 patients (90%) who completed a questionnaire designed to acquire data regarding clinical manifestations of cough were included. Results Most patients with bronchial asthma had cough with seasonal variation and wheezing. Patients with gastro esophageal reflux disease suffered from heartburn and cough without daily or seasonal variation. Cough associated with sinobronchial syndrome was only observed in females and was linked to increased sputum. Patients with whooping cough were bothered by cough interrupting sleep and talking. Patients with cardiogenic cough had exertional dyspnea. Conclusion The specific items on our questionnaire relating to patient characteristics, complications, and triggers of cough, represent useful tools for diagnosing the primary disease producing cough.

Background: It has not been determined that demand valve oxygen therapy is effective for nocturnal hypoxia. A portable oxygen concentrator with an auto-demand oxygen delivery system (auto-DODS; standard, high, and extra high) has recently been developed to improve oxygenation and comfort. This oxygen concentrator can supply a pulsed flow when it detects apnoea. The aim of this study is to demonstrate that this newly developed portable oxygen concentrator with an auto-demand function is non-inferior to a continuous-flow oxygen concentrator for nocturnal hypoxemia. Methods: Twenty patients with chronic obstructive pulmonary disease or interstitial pneumonia will be randomized to receive a portable oxygen concentrator with an auto-DODS or a continuous-flow oxygen concentrator during sleep. The primary endpoint is mean oxygen saturation (SpO2) during the total sleep time. The secondary endpoints are the ratios of time that the oxygen concentrator spends in each sensitivity mode (standard, high, and extra-high) and at a constant pulse rate to the total sleep time, the total time and ratio of time for which SpO2 is less than 90% during the total sleep time, the lowest value of SpO2 during the total sleep time, the mean and highest pulse rate during the total sleep time, the apnoea index during the total sleep time, the total sleep duration itself, and comfort and reliability as measured by numerical rating scale and questionnaires. Discussion: If the auto-DODS demonstrates non-inferiority to continuous flow in oxygenation during sleep, the auto-DODS can be used even at night, and the patient will need only 1 device. Trial Registration: The study was registered on Aug 23, 2019 (jRCTs052190042).

Introduction: Long-term oxygen therapy is reported to improve hypoxemia and survival in patients with respiratory failure. The demand oxygen delivery system (DODS) saves oxygen and extends the usable time of an oxygen cylinder 2- to 3-fold. A portable oxygen concentrator with an auto-DODS has been developed to switch its sensitivity among 3 levels (standard, high, and extra high) and to supply pulsed-flow oxygen when it detects apnea. The aim of this study is to evaluate the efficacy of this newly developed portable oxygen concentrator with auto-DODS compared to the efficacy of conventional DODS in oxygenation. Methods and analysis: Twenty-six patients with chronic obstructive pulmonary disease or interstitial pneumonia will be randomized to use auto-DODS or conventional DODS at rest and during a 6-minute walk test. Primary endpoints are mean oxygen saturation (SpO2) at rest and during the 6-minute walk test. Secondary endpoints are the ratios of the times during which the oxygen concentrator operates at each sensitivity mode (standard, high, and extra high) and at a constant pulse rate to the examination time, the ratio of the times during which SpO2 fall below 90% to the examination time, the lowest value of SpO2 during the examination time, the mean and highest pulse rates during the examination time, 6-minute walking distance, recovery time, Borg scale, comfort, and reliability, which are measured by a numerical rating scale and a questionnaire, respectively. Ethics and dissemination: The study was conducted in accordance with the Declaration of Helsinki and was registered on Aug 23, 2019 (https://jrct.niph.go.jp/en-latest-detail/jRCTs052190041). The results of the study will be presented at academic conferences and submitted to a peer-reviewed journal. Trial registration number: jRCTs052190041

IntroductionSocioeconomic factors with an influence on human health are known as social determinants of health (SDH). There are some SDH studies in patients with lung cancer, but important exposures such as social isolation and loneliness have not been adequately investigated. This study will assess the influence of SDH, particularly social isolation and loneliness, on patients with advanced lung cancer in Japan.Methods and analysisThe inclusion criteria for this prospective cohort study will be as follows: a diagnosis of advanced lung cancer; unsuitability for curative surgery; and willingness to participate. The primary outcome will be the initial choice of treatment and the secondary outcomes will be overall survival, changes in disease staging or performance status, route to diagnosis and place of death. The exposures will be social isolation, loneliness, employment, insurance type, education and dementia. The study enrolment period will be 1 year and the follow-up duration will be 2 years. The log-rank test will be used to compare overall survival between patients when grouped according to the study exposures and multivariate analysis will be performed using Cox proportional hazards regression. The Χ2test will be used to compare the initial treatment, changes in disease stage and place of death, and logistic regression will be used for multivariate analysis of these factors. A p value Ethics and disseminationThis study has been approved by the Institutional Review Board at Hyogo Prefectural Amagasaki General Medical Center (No 29-164). A manuscript summarising the outcome of this study will be submitted to a peer-reviewed journal and the data will be presented at conferences.Trial registration numberUMIN000031810.

Aim The aim of the present study was to assess the prognostic utility of the pretreatment blood neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein-to-albumin ratio (CAR) in patients with inoperable malignant pleural mesothelioma (MPM). Materials and methods The medical records of consecutive patients with histologically confirmed MPM from our hospital between January 2007 and August 2017 were retrospectively reviewed. The primary outcome was overall survival (OS). Univariate and multivariate analyses for the prognostic factors were performed using a Cox proportional hazards model. Results A total of 143 patients with inoperable MPM were included. On multivariate analysis, pretreatment CAR was an independent factor associated with worse OS (hazard ratio(HR)=1.72; 95% confidence interval(CI)=1.11-2.67; p=0.016). However, NLR was not associated with OS in any of the analyses. Conclusion CAR appears to be a prognostic factor in patients with inoperable MPM.

Patients frequently experience great discomfort during a bronchoscopy for the diagnosis of lung neoplasms. Sedation is generally recommended during bronchoscopy; however, few studies have evaluated the discomfort and tolerability of patients to a bronchoscopy with regard to the administration procedures. The aim of the present study was to evaluate the discomfort and tolerability of patients undergoing a bronchoscopy using different sedation procedures with midazolam. The retrospective survey of sedation during bronchoscopy involved the comparison of two periods: January-March 2012 (first period) and July-September 2012 (second period). A numerical rating score, which ranged between 1 (best) and 5 (worst) according to the subjective view of the patients, was used to rate patient discomfort, pain, sensation, time and tolerability to the bronchoscopy. In the first period, 2.5 mg midazolam was administered prior to the initiation of surgery, and additional doses of midazolam was added in 2.5-mg increments whenever the patient deviated from the target sedation level. In the second period, 2.0 or 3.0 mg midazolam was administered prior to the initiation of surgery, and additional midazolam doses were administered in 1.0-mg increments until the patients were sedated to the target sedation level. In total, 60 and 68 valid responses were obtained in the first and second periods, respectively. The patients in the second period exhibited significantly improved discomfort and pain scores during the bronchoscopy and higher rates of consent to re-examination, as compared with the patients in the first period (1.89±1.40 vs. 2.78±1.52, P

In this study, we aimed to examine the clinical value of the pleural effusion (PE) biomarkers, soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA), and the utility of combining chest computed tomography (CT) findings with these biomarkers, in diagnosing malignant pleural mesothelioma (MPM). We conducted a retrospective cohort study in a single center. Consecutive patients with undiagnosed pleural effusions who underwent PE analysis between September 2014 and August 2016 were reviewed. This study included 240 patients (32 with MPM and 208 non-MPM). SMRP and the CYFRA 21-1/CEA ratio had a sensitivity and specificity for diagnosing MPM of 56.3% and 86.5%, and 87.5% and 74.0%, respectively. Using receiver operating characteristics (ROC) curve analysis of the ability of these markers to distinguish MPM from all other PE causes, the area under the ROC curve (AUC) for SMRP and the CYFRA 21-1/CEA ratio was 0.804 and 0.874, respectively. The sensitivity and specificity of SMRP combined with the CYFRA 21-1/CEA ratio were 93.8% and 64.9%, respectively. The sensitivity of the combination of SMRP, the CYFRA 21-1/CEA ratio, and the presence of Leung's criteria (a chest CT finding that is suggestive of malignant pleural disease) was 93.8%. In conclusion, the combined PE biomarkers had a high sensitivity for diagnosing MPM, although the addition of chest CT findings did not improve the sensitivity of SMRP combined with the CYFRA 21-1/CEA ratio. Combination of these biomarkers helped to rule out MPM effectively among patients at high risk of suffering MPM and would be valuable especially for old frail patients who have difficulty in undergoing invasive procedures such as thoracoscopy.

Optimal chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is established for paclitaxel and carboplatin, but is otherwise controversial. Therefore, we assessed the efficacy and safety of paclitaxel and carboplatin with or without bevacizumab for treating these patients. We analyzed the outcomes of 21 patients with advanced nonsquamous NSCLC with ILD who received paclitaxel and carboplatin without (paclitaxel–carboplatin group; n = 11) or with bevacizumab (paclitaxel–carboplatin–bevacizumab group; n = 10) between April 2008 and October 2013. The median progression-free survival time of the paclitaxel–carboplatin–bevacizumab group was 5.3 months (95 % CI 0.4–11.6 months) compared with 4.4 months (95 % CI 0.9–6.3 months) for the paclitaxel–carboplatin group (p = 0.060). Their respective median overall survival times were 16.1 months (range 0.4–34.8 months) and 9.7 months (range 2.6–37.0 months) (p = 0.772) with corresponding overall response rates of 40 and 27 % (p = 0.659), respectively. One patient in the paclitaxel–carboplatin–bevacizumab group experienced chemotherapy-related exacerbation of ILD (0/11 vs. 1/10; p = 0.476). The addition of bevacizumab to paclitaxel and carboplatin may provide an effective and safe treatment option for patients with advanced nonsquamous NSCLC with ILD.

Mutated epidermal growth factor receptor (EGFR) and signaling pathways were associated with multiple brain and intra-pulmonary metastases, oncogenic progression and metastasis. However, features of metastasis to other organs and the independent prognostic influence of metastatic lesions were not elucidated in patients with lung cancer harboring EGFR mutations. Between January 2007 and April 2012, we treated 277 patients diagnosed with stage IV lung adenocarcinoma. Studied were 246 patients with available tumor EGFR mutation data who also underwent radiographic evaluation of lung, abdominal, brain, and bone metastases. The EGFR mutated group (N = 98) had significantly more metastatic lesions in the brain and bone than the wild-type group (N = 148): brain, 3 (1–93) versus 2 (1–32) median (range), P = 0.023; bone, 3 (1–43) versus 2 (1–27), P = 0.035, respectively. In addition, EGFR mutations were significantly more frequent in patients with multiple than non-multiple lung metastases (24/40 vs. 12/42, P = 0.004). Multivariate analysis showed that bone metastasis was a significant independent negative predictive factor of overall survival (OS) in patients with mutated [hazard ratio (HR) 2.04; 95 % confidence interval (CI) 1.17–3.64; P = 0.011] and wild-type EGFR (HR 2.09; 95 % CI 1.37–3.20; P

Immune checkpoint inhibitors (ICIs) have drastically changed the clinical care of cancer. Although cancer immunotherapy has shown promise in various types of malignancies, thus far, the proportion of patients who can benefit from ICIs is relatively small. Immune-related adverse events and high cost are unavoidable problems. Therefore, biomarkers defining patients that are most likely to benefit from ICIs are urgently needed. The expression of programmed cell death-ligand 1 (PD-L1) is a logical biomarker for the prediction of response to anti-PD1/PD-L1 immunotherapies. However, its usefulness is currently debatable because of its varied definition, threshold, and spatial/temporal heterogeneity. Recently, it was reported that the tumor mutational burden, expression of neoantigens, mismatch repair status, and specific gene mutations may be markers for the success of treatment with ICIs. Moreover, it was suggested that the fecal microbiota prior to immunotherapy may play an important role in predicting the efficacy of ICIs. In this review, we focused on these potential biomarkers for cancer immunotherapy reported in recent clinical articles. Further studies are warranted to develop a predictive model using these biomarkers, with the aim of practicing precision medicine in cancer immunotherapy.

BackgroundEGFR gene mutation is independently associated with a favorable response in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs), regardless of sex or smoking history. Squamous cell carcinoma patients harboring EGFR mutations show a significantly worse response to EGFR-TKIs compared with adenocarcinoma patients. We hypothesized that the serum cytokeratin 19 fragment (CYFRA 21-1) is associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients.MethodsWe retrospectively screened 160 NSCLC patients harboring EGFR mutations, who had received either gefitinib, or erlotinib between 1992 and 2011. Patients were screened for clinical characteristics, the efficacy of EGFR-TKI, and tumor markers (carcinoembryonic antigen [CEA]/CYFRA 21-1) at the initial diagnosis.ResultsOf 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA 21-1 level (>2 ng/ml) showed significantly shorter progression-free survival (PFS) than the 83 patients with normal CYFRA 21-1 level (median PFS, 7.5 versus 13.3 months; p < 0.001). No significant difference in PFS was observed between the high-CEA group (>5 ng/ml) and the normal-CEA group (median PFS, 8.6 versus 11.2 months; p = 0.242). A multivariate analysis revealed that high CYFRA 21-1 level is independently associated with PFS (hazard ratio, 1.27; p = 0.002). No significant difference in overall survival was observed between the high- and the normal-CYFRA 21-1 groups (median overall survival, 24.8 versus 39.1 months; p = 0.104).ConclusionsPatients with a high CYFRA 21-1 level have significantly shorter PFS. CYFRA 21-1 is not a prognostic but a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.

Interstitial lung disease (ILD), especially idiopathic pulmonary fibrosis, has been shown to be associated with lung carcinogenesis. However, an association between epidermal growth factor receptor (EGFR) mutation status and preexisting ILD in patients with lung adenocarcinoma is unknown.Between January 2008 and April 2012, we analyzed 602 patients with lung adenocarcinoma. EGFR mutation status was analyzed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, and preexisting ILD was diagnosed based on clinical features, chest high-resolution computed tomography (HRCT) findings, and histological findings.There were 555 patients with pulmonary adenocarcinoma with tumor EGFR mutation data available for analysis. Of them, 31 patients (6%) had preexisting ILD, and EGFR mutations were detected in 246 of the 555 patients (46%). In the comparison between patients with EGFR mutations and those with wild-type EGFR, there was a significant inverse association between occurrence of tumors with EGFR mutations and ILD (1/246 vs. 30/309, P0.001). Based on the multivariate analysis of age, gender, smoking status, Eastern Cooperative Oncology Group Performance Status, stage, and ILD, EGFR mutations were found to be independently associated with females (OR, 1.58; 95% CI, 1.01-2.46; P=0.048), never-smokers (OR, 3.31; 95% CI, 2.12-5.20; P0.001), and the absence of ILD (OR, 17.41; 95% CI, 3.54-315.34; P0.001).This study showed that patients with pulmonary adenocarcinoma and ILD had a lower probability of carrying tumor EGFR mutations.

The safety and efficacy of second-line chemotherapy for treating patients with small cell lung cancer (SCLC) and interstitial lung disease (ILD) have not been elucidated to date.Between January 2005 and September 2013, we analyzed 23 patients with SCLC and ILD who received second-line chemotherapy. Pre-existing ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography results.The overall objective response rates and disease control rates were 22% and 52%, respectively. The median respective durations of progression-free survival and overall survival were 2.1 months (95% confidence interval (CI)=2.0-3.0 months) and 7.1 months (95% CI=3.6-11.3 months), respectively. Three patients with unusual interstitial pneumonia pattern (13%) developed chemotherapy-related pneumonitis.Second-line treatment may be an effective and safe option for SCLC patients with ILD after sufficient evaluation of risks and benefits.

BACKGROUND: We evaluated the efficacy of high-flow nasal cannula (HFNC) therapy, a promising respiratory support method for acute hypoxemic respiratory failure (AHRF). METHODS: We conducted a retrospective single-center cohort study comparing the periods before (June 2010 to May 2012) and after (June 2012 to May 2014) HFNC introduction (pre- and post-HFNC periods). During these periods, we retrieved cases of AHRF treated with any respiratory support (invasive ventilation, noninvasive ventilation [NIV], and HFNC) and compared in-hospital mortality, ICU/intermediate care unit/hospital stay, and need for mechanical ventilation. RESULTS: Eighty-three subjects (65 treated with NIV, and 18 treated with invasive ventilation) and 89 subjects (33 treated with HFNC, 43 treated with NIV, and 13 treated with invasive ventilation) identified from 782 pre-HFNC and 930 post-HFNC records of acute respiratory failure who required emergent admissions to the respiratory care department were analyzed. Overall, the in-hospital mortality rate was similar, although there was a non-significant and slight decrease from 35 to 27% ( P = .26). There was no significant difference among ICU, intermediate care unit ( P = .80), and hospital ( P = .33) stay. In the post-HFNC period, significantly fewer subjects required mechanical ventilation (NIV or invasive ventilation) (100% vs 63%, P < .01). Additionally, there were significantly fewer ventilator days (median [interquartile range] of 5 [2–11] vs 2 [1–5] d, P < .05) and more ventilator-free days (median [interquartile range] of 18 [0–25] vs 26 [20–27] d, P < .01). CONCLUSIONS: HFNC might be an alternative for AHRF subjects with NIV intolerance.

Background: Early nutrition appears to be effective for acute respiratory failure; however, airway problems such as mucus plug and vomiting could be serious complications of noninvasive ventilation (NIV). The safety of early enteral nutrition among patients receiving noninvasive ventilation is not well known. Methods: Of 85 patients who admitted in our respiratory department for acute respiratory failure and received NIV more than 48 hours, data on 70 who were incapable of eating themselves were retrospectively examined. Comparing the patients with and without enteral nutrition, we investigated their clinical background and complications. Result: 49 (70%) of the 70 patients incapable of eating themselves who received NIV had enteral nutrition. Patients with normal PaCO2 level, low albumin level tend to receive enteral nutrition (p=0.049, Conclusion: Among patients receiving NIV, enteral nutrition didn9t improve in-hospital mortality, but was associated with an increased risk of airway problems and longer duration of NIV. This result could call attention to enteral nutrition in patients on NIV for acute respiratory failure.

Data on prognosis and predictors of overall survival in advanced lung cancer patients diagnosed following emergency admission (DFEA) are currently lacking.We retrospectively analysed data from 771 patients with advanced nonsmall cell lung cancer between April 2004 and April 2012.Of the 771 patients, 103 (13%) were DFEA. DFEA was not an independent predictor of overall survival by multivariate Cox proportional hazard models, whereas good performance status (PS), epidermal growth factor receptor gene mutation, stage IIIB, adenocarcinoma and chemotherapy were independent predictors of overall survival (hazard ratio (95% CI) 0.36 (0.29–0.44), pDFEA is relatively common. DFEA and PS at emergency admission were not independent predictors of overall survival, but good PS just prior to opting for chemotherapy was an independent predictor of longer overall survival. Efforts to improve patient PS after admission should be considered vital in such circumstances.

OBJECTIVE Non-HIV patients with pneumocystis pneumonia (PCP) have a poor prognosis. We aimed to evaluate the prognostic factors for in-hospital mortality in terms of the clinical findings, including the results of bronchoalveolar lavage fluid (BALF)-analyses, in non-HIV PCP patients. METHODS We retrospectively reviewed non-HIV PCP patients diagnosed using bronchoalveolar lavage between April 2006 and July 2012. For patients with a poor respiratory status, noninvasive positive pressure ventilation (NPPV) was used during the bronchoalveolar lavage (BAL) procedure. Data regarding demographics, laboratory findings and the prognosis were evaluated. RESULTS A total of 29 non-HIV PCP patients were analyzed. NPPV was carried out safely and successfully in 12 patients during the BAL procedure. Twelve patients (41%) died. The multivariate logistic regression analysis identified only BALF neutrophilia to be a significant prognostic factor determining in-hospital mortality. The log-rank test showed that the patients with BALF neutrophilia (≥ 31%) had a significantly lower survival rate than the other patients (p=0.001). CONCLUSION Only BALF neutrophilia was found to be a significant predictor of survival in patients with non-HIV PCP. Our data also emphasize the significance of performing BAL in such patients, as it provides both diagnostic and prognostic information.

8098 Background: EGFR-TKIs, gefitinib and erlotinib can demonstrate dramatic and durable response in patients with EGFR-mutant non-small cell lung cancer. Approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM) after initial response to EGFR-TKIs. Pharmacokinetic failure due to insufficient penetration of EGFR-TKIs is suggested as a cause of CNS failure. Therefore, high-dose EGFR-TKIs are considered reasonable therapeutic options for refractory CNS metastases after failure of standard dose EGFR-TKIs, but there is little present evidence of high-dose EGFR-TKI’s efficacy and tolerability. Methods: Between 2007 and 2012, we screened 279 patients harboring EGFR sensitive mutations, and identified 31 patients with LM. Ten of 31 patients received high-dose erlotinib, and the other 21 underwent only standard dose EGFR-TKIs (gefitinib and/or erlotinib). In these 10 patients, erlotinib was administered at 200 mg on alternating days (n=2), 300 mg on alternating days (n=6), 300 mg every 3 days (n=1), or 600 mg every 4 days (n=1). We retrospectively investigated the efficacy and tolerability of high-dose erlotinib. Additionally, survivals from the diagnosis of LM to death were compared in patients with or without high-dose erlotinib. Results: Regarding high-dose erlotinib, five of 10 patients were radiologically evaluable, and partial response was observed in 60% (3/5), stable disease in 20% (1/5), and progressive diasease 20% (1/5). Median time to CNS progression was 3.4 months (range, 0.3-6.6 months). Improvement of neurological symptoms was observed in 9 (90%) of 10 patients. No severe adverse events (≥ grade 3) associated with high-dose erlotinib were confirmed. Median survival from the diagnosis of LM in patients with high-dose erlotinib was 6.5 months (95% CI: 2.5-12.3 months), and that in those without was 5.8 months (95% CI: 1.1-7.8 months) (p =0.51). Conclusions: The efficacy and tolerability of high-dose erlotinib were suggested for refractory LM. It can be a therapeutic option in patients after failure of standard dose erlotinib. Optimal dose and schedule are unclear, and further investigations are warranted.