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Background: Lung transplantation is the last treatment option for end-stage lung disease, and the number of lung transplantations has been steadily increasing. Hyperbilirubinemia is a rare complication after lung transplantation. The aim of this study was to review rare causes of hyperbilirubinemia after lung transplantation at our center. Methods: In this single-center study, we retrospectively reviewed the records of 116 consecutive lung transplantation patients who underwent lung transplantation at Severance Hospital and Gangnam Severance Hospital of Yonsei University College of Medicine in South Korea between December 22, 2010 and January 1, 2016. Hyperbilirubinemia was defined as a total bilirubin level exceeding 5 mg/dL for at least 3 days after lung transplantation. Results: Hyperbilirubinemia occurred in 33 patients (28.4%) who received lung transplants at our institution. Twenty-four cases involved common causes such as drug toxicity, biliary tract stone, sepsis, and bleeding. However, rare causes of hyperbilirubinemia including hemophagocytic lymphohistiocytosis (HLH), thrombotic microangiopathy (TMA), and ischemic cholangiopathy were observed in 9 (7.8%) patients during the study period. All patients with hyperbilirubinemia due to a rare cause died despite aggressive treatment. Conclusion: Causes of hyperbilirubinemia after lung transplantation are varied, and the prognosis of patients with hyperbilirubinemia arising from rare causes was poor. Therefore, early evaluation and management of hyperbilirubinemia after lung transplantation is important to improve patient outcomes.

Objectives Programmed death-ligand 1 (PD-L1) is a widely used biomarker for predicting immune checkpoint inhibitors, but is of limited usefulness in the prediction of drug response. MYC, a transcription factor that is overexpressed in cancers, is involved in preventing immune cells from attacking tumor cells through inducing PD-L1 expression. This study evaluated the relationship between MYC and PD-L1 expression in 84 non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection. Materials and Methods The relationship between MYC and PD-L1 was investigated by introducing pcDNA3-cMYC into A549 and H1299 cells with low PD-L1 expression and siRNA against MYC into H60 and H2009 cells with high PD-L1 expression. Expression of PD-L1 in NSCLC tissues was analyzed by immunostaining using a PD-L1 (22C3) PharmDx protocol using the Dako Automated Link 48 platform and expression of MYC was determined using anti-c-MYC (Y69) (ab320720). Results Of 84 patients, PD-L1 was expressed in 14 (16.7%) and MYC was overexpressed in 30 (35.7%). We investigated the relationship between PD-L1 and MYC expression. There were 49 (58.3%) double-negative patients and 9 (10.7%) double-positive patients. Significant positive correlation was observed between PD-L1 and MYC expression (γ=0.210, P=0.029). Double-negative patients showed better disease free (31.1 vs. 7.1 months, P=0.011) and overall survival (56.1 vs. 14.4 months, P=0.032) than double-positive patients. Conclusion Taken together, MYC expression significantly correlated with PD-L1 expression in NSCLC. The usefulness of MYC expression as a surrogate marker of treatment response assessment is worth evaluating for immune checkpoint inhibitor therapy and special interest are required for the subgroup of NSCLC patients, whose tumor expresses PD-L1 and MYC double positive.

This study aimed to determine the incidence and characteristics of active tuberculosis (TB) in patients treated with tumor necrosis factor (TNF) antagonists according to baseline latent tuberculosis infection (LTBI). Data were retrospectively obtained from 702 patients aged ≥20 years treated with TNF antagonists between November 2005 and June 2016 at Severance Hospital, a tertiary referral hospital in Seoul, South Korea. The interferon-gamma release assay (IGRA) with or without a tuberculin skin test (TST) was used to diagnose LTBI. Of the total of 702 patients, LTBI was diagnosed in 255 (36.3%) patients. 23.9% (168/702) had positive IGRA results, and 32.2% (165/512) had positive TST results. Five patients developed active TB after LTBI treatment, and 6 developed TB despite baseline negative LTBI results. After adjustment for age and sex, the standardized TB incidence ratio was 6.01 (95% CI 1.94–14.04) in the LTBI group and 5.14 (95% CI 1.88–11.18) in the baseline negative LTBI group. Clinicians should be aware of the risk of active TB in patients treated with TNF antagonists despite baseline negative LTBI screening results. Regular monitoring and serial tests should be considered during long-term TNF antagonist therapy, especially in intermediate to high TB burden country.

Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that occurs in immunocompromised patients. The aim of this study was to evaluate risk factors for PJP in kidney transplantation recipients. We conducted a retrospective analysis of patient data from 500 consecutive kidney transplants performed at Severance Hospital between April 2011 and April 2014. Eighteen kidney transplantation recipients (3.6%) were diagnosed with PJP. In the univariate analysis, acute graft rejection, CMV infection, use of medication for diabetes mellitus, and lowest lymphocyte count were associated with PJP. Recipients who experienced acute graft rejection (odds ratio [OR] 11.81, 95% confidence interval [CI] 3.06–45.57, P P = 0.005) had high odds of PJP in multivariate analysis. In the acute graft rejection subgroup, patients treated with anti-thymocyte globulin (ATG) had significantly higher odds of PJP (OR 5.25, 95% CI 1.01–27.36, P = 0.006) than those who were not. Our data suggest that acute graft rejection and CMV infection may be risk factors for PJP in kidney transplant patients. The use of ATG for acute graft rejection may increase the risk of PJP.

Background: An automatic alarm system was developed was developed for unexpected vital sign instability in admitted patients to reduce staffing needs and costs related to rapid response teams. This was a pilot study of the automatic alarm system, the medical emergency system (MES), and the aim of this study was to determine the effectiveness of the MES before expanding this system to all departments. Methods: This retrospective, observational study compared the performance of patients admitted to the pulmonary department at a single center using patient data from three 3-month periods (before implementation of the MES, December 2013-February 2014; after implementation of the MES, December 2014-February 2015 and December 2015-February 2016). Results: A total of 571 patients were admitted to the pulmonary department during the three observation periods. During this pilot study, the MES automatically issued 568 alarms for 415 admitted patients. There was no significant difference in the rate of cardiopulmonary resuscitation (CPR) before and after application of the MES. The mortality rate also did not change. However, it appeared that CPR was prevented in four patients admitted from the general ward to the intensive care unit (ICU) during MES implementation. The median length of hospital stay and median length of ICU stay were not significantly different before and after MES implementation. Conclusions: Although we did not find a significant improvement in outcomes upon MES implementation, the CPR rate and mortality rate did not increase despite increased comorbidities. This was a small pilot study and, based on these results, we believe that the MES may have significant effects in longer-term and larger-scale studies.

Background Sarcopenia and osteoporosis are systemic features of COPD. The present study investigated the association between sarcopenia and osteopenia/osteoporosis and the factors associated with low bone mineral density (BMD) in men with COPD. Methods Data from 777 men with COPD who underwent both pulmonary function test and dual-energy x-ray absorptiometry were extracted from the Korean National Health and Nutritional Examination Survey database between 2008 and 2011. Sarcopenia was assessed with the appendicular skeletal mass index (ASMI) and osteopenia/osteoporosis with the T-score. Results As the severity of airflow limitation increased, the prevalence of sarcopenia increased ( P trend P trend r = 0.408; P P Conclusions Sarcopenia is closely correlated with osteopenia/osteoporosis in men with COPD. Moreover, different factors are associated with low BMD according to the presence/absence of sarcopenia in that population.

A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models. The synergism of this combination was evaluated by the Chou-Talalay Combination Index method. In vivo activity was evaluated by micro-CT. In NSCLC cells, there was a time and dose-dependent phosphorylation of SRC-JAK2-STAT3 by cisplatin, followed by increased expression of anti-apoptotic molecules. When the expression of the BCL-2 protein family members was evaluated in clinical samples, BCL-xL was most frequently overexpressed. Dominant negative STAT3 suppressed their expression, suggesting that STAT3 mediates cisplatin mediated overexpression of the anti-apoptotic molecules. ABT-737 displaced BCL-xL from mitochondria and induced oligomerization of BAK. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a murine lung cancer model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in preclinical models, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC.

South Korea has an increasing prevalence of diabetes and a relatively high burden of tuberculosis. We aimed to determine the prevalence of diabetes in patients with active pulmonary tuberculosis (PTB) and examine the effect of diabetes on tuberculosis treatment outcomes. Data from patients ≥30 years diagnosed with and treated for PTB between January 2010 and December 2012 at Severance Hospital, a 2000-bed tertiary referral hospital in Seoul, South Korea, were analyzed and compared with data from a contemporaneous general population sample extracted from KNHANES V. Diabetes prevalence was 24.2% (252/1044) among patients with PTB and 11.6% (1700/14,655) among controls. Diabetes [odds ratios (OR) 2.56, 95% confidence interval (CI) 1.56–4.21, P

Background: Despite many ongoing, prospective studies on the topic, sepsis still remains one of the main causes of death in hospital. The hormone insulin-like growth factor 1 (IGF-1) has a similar molecular structure to that of insulin. IGF-1 exerts anabolic effects and plays important roles in both normal physiology and pathologic processes. Previous studies have observed low serum IGF-1 level in patients with critical illnesses. Here, we evaluated changes in IGF-1 level based on survival of septic patients. Methods: We evaluated 140 patients with sepsis and septic shock (21 with sepsis and 119 with septic shock) admitted to the intensive care unit of a university-affiliated hospital in Korea. Serum IGF-1 level was measured on days 0, 1, 3, and 7. Patients with liver disease were excluded from this study. All data were analyzed using SPSS version 20 (SPSS Inc., Chicago, IL, USA). Results: Patients with septic shock had significantly lower serum IGF-1 level on days 1 and 3 than patients without septic shock (p = 0.002 and p = 0.007, respectively). Generally, there was a negative relationship between IGF-1 and serum cortisol levels; however, this relationship was only significant on day 3 (p = 0.029). Furthermore, renin showed significantly negative correlation with IGF-1 on day 3 (p = 0.038). IGF-1 level did not show significant difference between survivors and non-survivors. Conclusions: Our results showed that IGF-1 was associated with septic shock, and that the IGF-1 axis is severely disrupted in septic patients. Additionally, serum cortisol and renin levels were associated with IGF-1 level.

Background: Primary graft dysfunction (PGD) is a severe, acute and post-transplantation lung injury associated with early morbidity and mortality. We aimed to identify clinical risk factors for PGD, as well as the outcome of PGD after lung transplantation in Korea. Methods: We retrospectively analyzed lung transplant patients in a South Korean Hospital. The primary outcome was grade 3 PGD, defined according to the International Society for Heart and Lung Transplantation criteria. We compared grade 0–2 PGD group to grade 3 PGD group to identify the risk factors and outcome of grade 3 PGD. Results: Sixty-one patients were enrolled; 16 (26.2%) developed grade 3 PGD. Univariate analysis revealed higher body mass index (BMI) and history of smoking, extracorporeal membrane oxygenation (ECMO) before transplantation in recipients, and an extended intraoperative ischemic time as risk factors for grade 3 PGD. In multivariate analysis, independent risk factors for PGD were higher BMI in recipients [odds ratio (OR), 1.286; P=0.043] and total intraoperative ischemic time (OR, 1.028; P=0.007). As compared to grade 0–2 PGD, grade 3 PGD was significantly associated with a higher re-operation rate (grade 0–2 PGD vs. grade 3 PGD, 22.2% vs. 50.0%; P=0.036), prolonged ventilator apply (median: 6.0 vs. 14.5 days; P=0.044), a longer intensive care unit stay (median: 9.0 vs. 17.0 days; P=0.041), and a higher rate of renal replacement therapy (RRT) (17.8% vs. 62.5%; P=0.002) after transplantation. Conclusions: Patients who developed grade 3 PGD had higher re-operation rate, longer ventilator apply, longer intensive care unit stay, higher rate of RRT, with higher BMI and total intraoperative ischemic time being the significant risk factor. These findings may allow physicians to modify risk factors before development of PGD.

Eph-Ephrin signalling mediates various cellular processes, including vasculogenesis, angiogenesis, cell migration, axon guidance, fluid homoeostasis and repair after injury. Although previous studies have demonstrated that stimulation of the EphA receptor induces increased vascular permeability and inflammatory response in lung injury, the detailed mechanisms of EphA2 signalling are unknown. In the present study, we evaluated the role of EphA2 signalling in mice with lipopolysaccharide (LPS)-induced lung injury. Acute LPS exposure significantly up-regulated EphA2 and EphrinA1 expression. Compared with LPS+IgG mice (IgG instillation after LPS exposure), LPS+EphA2 mAb mice [EphA2 monoclonal antibody (mAb) instillation posttreatment after LPS exposure] had attenuated lung injury and reduced cell counts and protein concentration of bronchoalveolar lavage fluid (BALF). EphA2 mAb posttreatment down-regulated the expression of phosphoinositide 3-kinases (PI3K) 110γ, phospho-Akt, phospho-NF-κB p65, phospho-Src and phospho-S6K in lung lysates. In addition, inhibiting the EphA2 receptor augmented the expression of E-cadherin, which is involved in cell–cell adhesion. Our study identified EphA2 receptor as an unrecognized modulator of several signalling pathways–including PI3K-Akt-NF-kB, Src-NF-κB, E-cadherin and mTOR–in LPS-induced lung injury. These results suggest that EphA2 receptor inhibitors may function as novel therapeutic agents for LPS-induced lung injury.

BACKGROUND Forced expiratory volume in 1 second (FEV1)/forced expiratory volume in 6 seconds (FEV6) has been proposed as an alternative to FEV1/forced vital capacity (FVC) for detecting airway obstruction. A fixed cut-off value for FEV1/FEV6 in a Korean population is lacking. We investigated a fixed cut-off for FEV1/FEV6 as a surrogate for FEV1/FVC for detecting airway obstruction. MATERIALS AND METHODS We used data obtained in the 5 years of the Fifth and Sixth Korean National Health and Nutrition Examination Survey. A total of 14,978 participants aged ≥40 years who underwent spirometry adequately were the study cohort. "Airway obstruction" was a fixed cut-off FEV1/FVC

Chronic obstructive pulmonary disease (COPD) is increasing in prevalence and mortality. This study evaluated the prevalence, risk factors, characteristics, and health-related quality of life (HRQoL) of COPD among nonsmokers in Korea. This was a population-based cross-sectional study using data obtained from the Fourth and Fifth Korean National Health and Nutrition Examination Survey, which was conducted from 2007 to 2011. A total of 15,063 participants completely answered the questionnaire and performed the spirometry. Among them, 59.6 % were nonsmokers and 40.4 % were smokers. The prevalence of nonsmoker COPD was 7.1 %. On multivariate analysis, age ≥65 years (OR, 2.93; 95 % CI, 2.44–3.51), male sex (OR, 2.98; 95 % CI, 2.40–3.71), living in rural area (OR, 1.26; 95 % CI, 1.05–1.51), lower body mass index (BMI) (

Increased serum CA 19-9 levels in patients with nonmalignant diseases have been investigated in previous reports. This study evaluates the clinical significance of serum CA 19-9 elevation in pulmonary nontuberculous mycobacterial disease and pulmonary tuberculosis. The median CA 19-9 level was higher in patients with pulmonary nontuberculous mycobacterial disease than in patients with pulmonary tuberculosis (pulmonary nontuberculous mycobacterial disease: 13.80, tuberculosis: 5.85, p

A 55-year-old woman was referred to the division of pulmonology at Severance Hospital for the investigation of uncontrolled asthma with recurrent cough at night, blood-tinged sputum, malaise, and wheezing since 3 months. Chest computed tomography revealed bronchiectasis and broncholithiasis in the lateral segmental bronchus of the right middle lobe and the anterobasal segmental bronchus of the right lower lobe. Bronchoscopic broncholith removal was performed because of recurrent blood-tinged sputum and the outflow of purulent exudate behind the broncholith in the lateral segmental bronchus of the right middle lobe. The extracted material presenting amorphous eosinophilic necrotic materials with calcification was compatible with broncholithiasis. Following decalcification, histopathology revealed degenerated septate fungal hyphae and spores that were morphologically consistent with Aspergillus spp. A final diagnosis was allergic bronchopulmonary aspergillosis (ABPA) forming broncholith. The results from this case suggest that the early recognition of ABPA should be considered in patients with uncontrolled asthma accompanied by broncholithiasis.

Ah Young Leem, Se Kyu Kim, Joon Chang, Young Ae Kang, Young Sam Kim, Moo Suk Park, Song Yee Kim, Eun Young Kim, Kyung Soo Chung, Ji Ye Jung Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Background: Heavy metal exposure may contribute to inflammation in the lungs via increased oxidative stress, resulting in tissue destruction and obstructive lung function (OLF). In this study, we evaluated the relationship between lead and cadmium levels in blood, and lung function in the Korean population.Methods: Pooled cross-sectional data from 5,972 subjects who participated in the Korean National Health and Nutrition Examination Survey 2008–2012 were used for this study. OLF was defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC)

PURPOSE Few studies on plasma glucagon levels in patients with sepsis have been performed. We aimed to assess clinical value of glucagon levels in comparison with clinical parameters and severity scores in patients with severe sepsis or septic shock. METHODS A total of 112 patients who were admitted to intensive care unit with severe sepsis or septic shock were included. Plasma levels of glucagon on days 0, 1, 3, and 7 were serially measured in 112 patients with severe sepsis or septic shock. RESULTS Compared with survivors, patients who died within 28 days had significantly higher glucagon levels on every day of examination. Glucagon levels were positively correlated with and Acute Physiology and Chronic Health Evaluation II score (day 0, r = 0.288, P < 0.01) and Sequential Organ Failure Assessment (day 0, r = 0.482, P< 0.01; day 1, r = 0.588, P < 0.01; day 3, r = 0.480, P < 0.01; day 7, r = 0.454, P < 0.01). Receiver operating characteristic analysis showed that the area under the curve of glucagon levels to predict 28-day survival was 0.65 (95% confidence interval [CI], 0.55-0.75; P = 0.005), similar to the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. Multivariate analysis revealed that glucagon levels of greater than 70 pg/mL (hazard ratio, 1.85; 95% CI, 1.03-3.29) and chronic liver disease (hazard ratio, 1.97; 95% CI, 1.02-3.79) were associated with mortality. CONCLUSIONS Glucagon levels might reflect disease severity and clinical outcomes in patients with severe sepsis or septic shock.

We conducted drug susceptibility testing (DST) against various antimicrobial agents, including new candidate drugs, and investigated the relationship between inducible resistance (IR) to macrolides and erm(41) gene in Mycobacterium abscessus complex. Sixty-two isolates of M. abscessus complex from 2 tertiary care hospitals in South Korea were tested against 10 antimicrobial agents. Thirty-five isolates were M. abscessus, and 27 were Mycobacterium massiliense. Amikacin, moxifloxacin, linezolid, clofazimine, and tigecycline were active against most isolates and cefoxitin and ciprofloxacin against moderate number of isolates. M. massiliense remained susceptible to macrolides; in contrast, M. abscessus became highly resistant on day 14 after incubation. DST pattern did not differ between clarithromycin and azithromycin. IR to clarithromycin was correlated with erm(41) genotype in M. abscessus. Variations in susceptibility to antimicrobial agents within species and the difference in DST patterns between M. abscessus and M. massiliense suggest that DST and identification of M. abscessus complex are significant before treatment.

This study was conducted to assess the prognostic value of a simplified mortality score (SMS) using the delta neutrophil index (DNI) and thrombotic microangiopathy (TMA) score, both easily obtained from the complete blood count, to identify critically ill patients at high risk of death.This was a retrospective study performed in the medical ICU at Yonsei University College of Medicine from June 2015 to February 2016. The primary end point was 28-day all-cause mortality. Participants were divided into two groups: a training (n = 232) and a test (n = 57) set. We used Cox proportional-hazards analysis, Harrell's C index, and Kaplan-Meier survival analysis to derive the SMS and test its internal validity.We enrolled 289 patients. The 28-day mortality rate was 31.1% (n = 90). Nonsurvivors had higher APACHE II, SOFA, and TMA scores, and DNI. The SMS, derived by Cox proportional-hazards analysis, consisted of age, sex, DNI, and TMA score. We assigned a weighted point to each variable in the SMS, as follows: age + 11 if male + (2 × DNI) + (61 [TMA = 1], 76 [TMA = 2], 74 [TMA = 3], 26 [TMA = 4], 99 [TMA = 5]). Nonsurvivors had a higher median SMS than survivors, and the Harrell's C index was 0.660. Analysis of survival by risk group according to SMS (low, intermediate, high risk) showed a significant difference among these three groups (P 0.001). We then investigated this SMS in the test set to determine internal validity; the results were similar to those of the training set.The SMS is a more rapid, simple prognostic score for predicting 28-day mortality and stratifying risk than the APACHE II or SOFA scores. However, external validation using a larger sample is needed.

Objectives Among non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations, ∼20–30% exhibit de novo resistance to EGFR-tyrosine kinase inhibitor (TKI). The aim of this study was to examine whether mutations in the EGFR -downstream genes may be associated with de novo resistance to EGFR-TKIs in EGFR mutation-positive patients. Materials and methods Sixty-eight never-smoker adenocarcinoma patients with an activating EGFR mutation were included in the mutational analysis and 55 patients treated with EGFR-TKIs were analyzed for the treatment outcomes to EGFR-TKIs. We concurrently analyzed mutations in PIK3CA , PTEN , AKT and STK11 , which are all EGFR -downstream genes. Mutations in PIK3CA , PTEN , AKT , and STK11 were analyzed by polymerase chain reaction-based sequencing. Results PIK3CA mutations were detected in 4.4% (3/68) of patients, PTEN mutations in 16.1% (11/68), AKT mutations in 5.9% (4/68), and STK11 mutations in 13.2% (9/68). One patient with an activating exon 21 L858R mutation concomitantly had an exon 20 T790M mutation in EGFR . The proportion of patients who had mutations in EGFR -downstream genes was 32.4% (22/68). When we analyzed the treatment outcome of 55 patients treated with EGFR-TKI, the presence of mutations in EGFR -downstream genes correlated with a poor overall response rate to EGFR-TKIs (63.6 vs .14.5% in patients with mutation in EGFR -downstream gene, P vs . 3.0 months, P =0.060), and shorter median overall survival (18.9 vs . 25.0 months, P =0.048). Conclusion Mutations in the EGFR -downstream genes may confer resistance to EGFR-TKIs and result in poor treatment outcomes in never-smoker adenocarcinoma patients with activating EGFR mutations.

Treatment of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) is difficult because the mortality rate after surgery or chemotherapy is high for these patients. Spontaneous regression of cancer is rare, especially in lung cancer. A 62-year-old man, previously diagnosed with IPF, presented with stage IIIC (T2N3M0) non-small cell lung cancer. About 4 months later, spontaneous regression of the primary tumor was observed without treatment. To the best of our knowledge, this is the first report of spontaneous regression of lung cancer in a patient with IPF.

A 52-year-old man was referred to our clinic for an 11.3 mm nodule in the left lower lobe that was discovered on a chest computed tomography (CT) scan. Eleven small nodules were subsequently found in both lungs. Initially, we performed a transthoracic needle aspiration using CT scan guidance. The pathologic report showed a few clusters of atypical cells that were suspicious for malignancy. The positron emission tomography images revealed multiple lung nodules scattered throughout both lungs. The largest nodule (11.3 mm) in the left lower lobe did not have any discernible fludeoxyglucose uptake. For pathologic confirmation, we consulted a thoracic surgeon to perform the video-assisted thoracoscopic surgery. The final diagnosis was minute pulmonary meningothelial-like nodules (MPMNs). MPMNs are benign in nature, and only a few cases require treatment. However, when clinicians are suspicious of potential malignancy, a pathological correlation is essential, even if the final diagnosis is MPMNs.

The aims of this study were to determine the incidence of tuberculosis (TB) and nontuberculous mycobacteria (NTM) lung disease in patients who were treated with tumor necrosis factor (TNF) antagonists in South Korea and to evaluate their clinical characteristics.We surveyed all patients (N = 509) who were treated with TNF antagonists at Severance Hospital, South Korea, between January 2002 and December 2011. We reviewed the patients' medical records and collected microbiological, radiographic, and clinical data, including the type of TNF blocker(s) used and the results of tuberculin skin tests and interferon-gamma release assays.Rheumatoid arthritis (43.6 %) and ankylosing spondylitis (27.9 %) were the most common diseases in the patients treated with TNF antagonists. Patients received etanercept (33.4 %), infliximab (23.4 %), or adalimumab (13.2 %). The remaining patients received two or more TNF antagonists (30 %). Nine patients developed TB, and four patients developed NTM lung disease. After adjustment for age and sex, the standardized TB incidence ratio was 6.4 [95 % CI 3.1-11.7] compared with the general population. The estimated NTM incidence rate was 230.7 per 100,000 patients per year.Our results show that mycobacterial infections increase in patients treated with TNF antagonists. The identification of additional predictors of TB for the treatment of latent tuberculosis infection and the careful monitoring and timely diagnosis of NTM-related lung disease are needed for patients who receive long-term therapy with TNF antagonists.

Transforming growth factor-β1 (TGF-β1) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (IPF). The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease. We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 (T → C) of the TGF-β1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. The IPF patients consisted of 55 men and 30 women. The mean age was 61 ± 8 years. Fifty-one (60 %) of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different (IPF: TT 43.5 % and TC or CC 56.5 %; controls: TT 27.1 % and TC or CC 72.9 %, p = 0.037). TT genotype was significantly associated with decreased PaO2 and increased D(A–a)O2 upon initial diagnosis (p = 0.006 and 0.009, respectively). There was a positive association between TT genotype and IPF development (odds ratio [OR] = 2.1, 95 % confidence interval [CI] = 1.1–4.0, p = 0.028). This study suggests that the TGF-β1 gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-β1 gene polymorphism and IPF.

Chan Ho Lee, Eun Kyung Goag, Su Hwan Lee, Kyung Soo Chung, Ji Ye Jung, Moo Suk Park, Young Sam Kim, Se Kyu Kim, Joon Chang, Joo Han Song Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Background: Iron-catalyzed oxidative stress contributes to lung injury after exposure to various toxins, including cigarette smoke. An oxidant/antioxidant imbalance is considered to play a critical role in the pathogenesis of COPD. Ferritin is a key protein in iron homeostasis, and its capacity to oxidize and sequester the metal preventing iron prooxidant activity implicates its possible role in the alteration of antioxidant imbalance. We investigated the relationship among cigarette smoking, lung function, and serum ferritin concentration in a large cohort representative of the Korean adult population. Materials and methods: Among 50,405 participants of the Korean National Health and Nutrition Examination Survey from 2010 to 2014, 15,239 adult subjects older than 40years with serum ferritin levels and spirometric data were selected for this study. Results: The mean age was 56.5years for men (43%) and 56.9years for women (57%). The prevalence of airway obstruction was 13.4%, which was significantly higher in men than in women, and increased in former or current smokers. The median levels of serum ferritin were highest in the airway obstruction group, followed by the restrictive pattern group, and lowest in the normal lung function group. The median ferritin levels were increased by smoking status and amounts in each spirometric subgroup. In multivariable regression analysis, serum ferritin was positively associated with forced expiratory volume in 1second and forced expiratory volume in 1second/forced vital capacity, whereas the smoking amount was negatively associated with the adjustment with age, sex, height, and weight. Conclusion: Serum ferritin levels were increased in former or current smokers and were increased with smoking amount in all subgroups of participants categorized according to spirometric results. The result was also evident in the subgroups divided by obstructive severity. While smoking amount was inversely related to lung function, higher levels of serum ferritin were associated with enhanced spirometric results in a representative sample of the general Korean adult population. Future prospective studies will be needed to clarify the causality between serum ferritin and lung functions and their role in COPD morbidity. Keywords: airway obstruction, ferritin, smoking

PURPOSE Acute kidney injury (AKI) is common in critically ill patients. Serum cystatin C has emerged as a reliable marker of AKI. We sought to assess the value of serum cystatin C for early detection and prediction of renal function recovery in patients with sepsis. MATERIALS AND METHODS Sepsis patients (113 AKI patients and 49 non-AKI patients) admitted to the intensive care unit (ICU) were included. Serum creatinine and cystatin C levels and glomerular filtration rate were measured on days 0, 1, 3, and 7. RESULTS Serum cystatin C levels were significantly higher in AKI patients than in non-AKI patients at all time points. Multivariate analysis showed that only serum cystatin C levels on day 0 were associated with AKI development [odds ratio (OR)=19.30; 95% confidence interval (CI)= 2.58-144.50, p

Background Chronic obstructive pulmonary disease (COPD) is a serious public health problem. Understanding the longitudinal trend in prevalence is important for characterizing the burden of COPD and planning health services. Methods We analyzed the prevalence of airflow obstruction between 2001 and 2011 using data from Korean National Health and Nutritional Examination Surveys (2001, n = 2217; 2011, n = 3101). Participants >40 years of age with an FEV 1 /FVC Results The crude prevalence of COPD was not significantly different between 2001 and 2011 (2001, 13.0%; 2011, 13.2%), but the age-standardized prevalence of COPD decreased significantly over the 10-year period (2001, 15.7%; 2011, 12.4%). While significant decreases were observed for ex-smokers and current smokers, significant increases were noted for subjects who smoked 2 . The prevalence of mild and severe COPD decreased (2001, mild 8.5%, severe 1.4%; 2011, mild 5.4%, severe 0.5%), while the prevalence of moderate COPD increased (2001, 5.7%; 2011, 6.4%) after age standardization. Conclusions We report a reduction in the age-standardized prevalence of COPD in Korea from 2001 to 2011. Continued surveillance and early prevention are required because the socioeconomic burden of COPD remains substantial.

BACKGROUND: The antibodies to human leukocyte antigen (HLA) have been suggested to be associated with outcomes in lung transplantation. However, data is limited in Asia. OBJECTIVES: We were to investigate the prevalence of anti-HLA antibodies before transplantation and to assess their impact on outcomes in lung transplant recipients in Korea. METHODS: We conducted a single-center retrospective study including 76 patients who received lung transplant at tertiary hospital in South Korea between January 2010 and March 2015. RESULTS: Nine patients (11.8%) had class I or class II panel-reactive antibody that was elevated above 50%. Thirteen patients (17.1%) had anti-HLA antibodies with low mean fluorescent intensity (MFI, 1000-3000), 7 (9.2%) with moderate MFI (3000-5000), and 12 (15.8%) with high MFI (>5000). Ten (13.2%) had suspected donor-specific antibodies (DSA), and 60% (6/10) had antibodies with high MFI. In the analysis of outcomes, high-grade (grade≥2) primary graft dysfunction was more frequent in patients with anti-HLA antibodies of moderate to high MFI than in patients with low MFI (39.4% vs. 14.0%, p =0.011). Of the 20 patients who survived more than 2 years after transplant, bronchiolitis obliterans syndrome was more frequent in patients with anti-HLA antibodies of moderate to high MFI than in patients with low MFI, although this difference was not statistically significant (50.0% vs. 14.3%, p =0.091). CONCLUSIONS: The prevalence of anti-HLA antibodies with high MFI was not high. However, the MFI was relatively high in patients with DSA. Anti-HLA antibodies with moderate to high MFI could also be associated with outcomes in lung transplant recipients in Korea.

Objectives Disruption in the stability of respiratory microbiota is known to be associated with many chronic respiratory diseases. However, only few studies have examined microbiomes in lung cancer. Therefore, we characterized and compared the microbiomes of patients with lung cancer and those with benign mass-like lesions. Materials and methods Bronchoalveolar fluid was collected prospectively to evaluate lung masses in patients who had undergone bronchoscopies from May to September 2015. Twenty-eight patients (20 male, 8 female) were enrolled: 20 diagnosed with lung cancer and 8 diagnosed with benign diseases. Samples were analysed by 16S rRNA-based next-generation sequencing. Results The participants’ mean age was 64 ± 11 years. Bacterial operational taxonomic units were classified into 26 phyla, 44 classes, 81 orders, 153 families, 288 genera, and 797 species. The relative abundance of two phyla (Firmicutes and TM7) was significantly increased in patients with lung cancer (p = 0.037 and 0.035, respectively). Furthermore, two genera (Veillonella and Megasphaera) were relatively more abundant in lung cancer patients (p = 0.003 and 0.022, respectively). The area under the curve of a combination of these two genera used to predict lung cancer was 0.888 (sensitivity = 95.0%, specificity = 75.0% and sensitivity = 70.0%, specificity = 100.0%; p = 0.002). Conclusion The results indicate that differences exist in the bacterial communities of patients with lung cancer and those with benign mass-like lesions. The genera Veillonella and Megasphaera showed the potential to serve as biomarkers to predict lung cancer. Thus, the lung microbiota may change the environment in patients with lung cancer.

Background The ratio of the diameter of the main pulmonary artery (mPA) to the diameter of the aorta (Ao) on chest computed tomography is associated with diverse clinical conditions. Herein, we determined the functional and prognostic implications of the mPA/Ao ratio in Korean chronic obstructive pulmonary disease (COPD) patients. Methods The study population comprised 226 chronic obstructive pulmonary disease patients from the Korean Obstructive Lung Disease cohort who underwent chest computed tomography. We analyzed the relationships between the clinical characteristics, including pulmonary function, echocardiography findings, St. George's Respiratory Questionnaire, 6-minute walking (6MW) distance, and exacerbation with the mPA, Ao, and mPA/Ao ratio. Results The mean age was 65.8 years, and 219 (96.9%) patients were male. The mean FEV1% predicted and FEV1/FVC ratio were 61.2% and 47.3%, respectively. The mean mPA and Ao were 23.7 and 36.4 mm, respectively, and the mPA/Ao ratio was 0.66. The mPA/Ao ratio correlated negatively with the 6MW distance (G = -0.133, P = 0.025) and positively with the right ventricular pressure (G = 0.323, P = 0.001). After adjustment for potential confounders, the mPA/Ao ratio was significantly associated with 6MW distance (β = -107.7, P = 0.017). Moreover, an mPA/Ao ratio >0.8 was a significant predictor of exacerbation at the 1-year (odds ratio 2.12, 95% confidence interval 1.27–3.52) and 3-year follow-ups (odds ratio 2.04, 95% confidence interval 1.42–2.90). Conclusions The mPA/Ao ratio is an independent predictor of exercise capacity and an mPA/Ao ratio >0.8 is a significant risk factor of COPD exacerbation.

Summary Objective This study evaluated inducible protein 10 (IP-10) as a diagnostic biomarker for specific tuberculosis (TB) infection and evaluated the ability of IP-10 to distinguish between active TB and latent TB infection (LTBI). Methods Forty-six patients with active pulmonary TB, 22 participants with LTBI, and 32 non-TB controls were enrolled separately. We measured IP-10 in serum and in supernatants from whole blood stimulated with TB-specific antigens. Results TB antigen-dependent IP-10 secretion was significantly increased in the active TB patients and LTBI subjects compared with controls, but did not differ significantly between the active TB patients and LTBI subjects. Serum IP-10 levels were higher in active TB than in LTBI (174.9 vs. 102.7pg/ml, p =0.002). The respective rates of positive responders of TB antigen-dependent IP-10 were 97.8%, 90.9%, and 12.5% in active TB, LTBI, and non-TB controls, respectively. For serum IP-10, 87.5%, 45.5%, and 9.5% of responders were positive in the respective groups. Conclusions The IP-10 response to TB antigen may constitute a specific biomarker for TB infection, but does not by itself distinguish between active TB and LTBI. Serum IP-10 may enhance the diagnostic performance when used in combination with another marker.

Introduction Belotecan (Camtobell, CKD602) is a new camptothecin-derivative antitumor agent that belongsto the topoisomerase inhibitors. The aim of this study was to evaluate the efficacy and safetyof belotecan monotherapy as a second-line therapy in patients with relapsed or refractory small cell lung cancer (SCLC). Methods Between June 2008 and August 2011, a total of 50 patients with relapsed or refractory SCLC were treated with belotecan 0.5mg/m 2 for 5 consecutive days, every 3 weeks. We evaluated the overall response rate (ORR), the progression-free survival (PFS), and the overall survival (OS), and toxicity according to sensitivity to initial chemotherapy. Results The median age was 66 years (range, 43–84 years) and Eastern Cooperative Oncology Group performance was 0 or 1 in 34 patients (68%) and 2 in 16 patients (32%). Twenty patients (40%) had sensitive relapse and 30 patients (60%) had refractory disease. The ORR, PFS, and OS for sensitive patients were 20% (95% confidence interval [CI], 8–40), 2.8 months (95% CI, 0.53–5.06), and 6.5 months (95% CI, 1.58–11.42), respectively. In the refractory group, the ORR, PFS, and OS were 10% (95% CI, 1–21), 1.5 months (95% CI, 1.25–1.75), and 4.0 months (95% CI, 3.40–4.60), respectively. Most commonly reported grade-3 or -4 adverse events included neutropenia (54%), thrombocytopenia (38%), and anemia (32%). Conclusion Belotecan showed modest activity with an acceptable safety profile as a second-line therapy in patients with relapsed or refractory SCLC.

Summary Background The combination of tiotropium and fluticasone propionate/salmeterol (FSC) is commonly used to treat chronic obstructive pulmonary disease (COPD), but no study had evaluated the effectiveness of tiotropium plus FSC with 250 μg of fluticasone propionate. Our aim was to assess whether tiotropium (18 μg once daily) plus FSC (250/50 μg twice daily) provides better clinical outcomes compared to tiotropium monotherapy. Methods In this 24-week, randomized, open label, multicenter two-arm parallel study, 479 patients received tiotropium plus FSC ( n = 237) or tiotropium alone ( n = 242). Results After 24 weeks of treatment, the triple-inhaled treatment group had a significant improvement in pre-bronchodilator FEV 1 (L) compared to the tiotropium-only group (0.090 L vs. 0.038 L; P = 0.005). Regarding health-related quality of life, the mean change in total score on the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was −6.6 points in the tiotropium plus FSC group, but −1.5 points in the tiotropium-only group ( P = 0.001). In the subgroup of GOLD stage II patients with COPD, treatment with tiotropium plus FSC also improved FEV 1 compared to tiotropium alone (0.088 L vs. 0.030 L; P = 0.011) and improved the total SGRQ-C score than tiotropium alone (−4.5 points vs. −1.0 points, respectively). This triple-inhaled treatment approach did not induce more adverse events, such as pneumonia. Conclusion Over the course of 24 weeks, FSC (250/50 μg twice daily) added to tiotropium provided greater improvement in lung function and quality of life in patients with COPD (FEV 1 ≤ 65%) than tiotropium alone.

Limited information is available on the risk factors for false-negative results with the new generation of QuantiFERON-TB Gold In-Tube (QFT-GIT) tests in non-HIV-infected patients with tuberculosis (TB). We sought to identify risk factors for false-negative QFT-GIT results in culture-confirmed TB patients. We reviewed the microbiological, laboratory, radiographic, and clinical data of 362 patients with positive M. tuberculosis cultures who received QFT-GIT tests at a Korean tertiary hospital between September 2006 and March 2010. Of these, 311 (85.9%) had true-positive and 51 (14.1%) had false-negative results. The false-negative group was more likely to have immunosuppressant diseases and lower platelet, protein, and albumin levels than the true-positive group. An immunosuppressive condition was an independent risk factor for false-negative QFT-GIT results in non-HIV-infected patients with active TB (odds ratio, 2.98; 95% confidence interval, 1.38-6.47; P = .006). Careful interpretation of negative QFT-GIT results is thus necessary in immunocompromised patients suspected of having active TB.

The purpose of the study was to evaluate the utility of N-terminal pro-brain natriuretic peptide (NT-proBNP) as a marker of right ventricular (RV) dysfunction after open-lung approach (OLA) in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).Twenty-seven patients with ALI/ARDS underwent OLA (2-minute steps of fixed pressure-controlled ventilation with progressive positive end-expiratory pressure levels up to 30 cm H(2)O, followed by stepwise decrement of positive end-expiratory pressure level by 2 cm H(2)O). Patients who showed a PaO(2)/FiO(2) increase of more than 50% from baseline were defined as responders. Plasma NT-proBNP levels were taken immediately before OLA and 2 and 6 hours later. A minimum 30% increase in NT-proBNP level from baseline was considered significant.Right-over-left ventricular stroke work ratio and its percentage change did not differ between responders and nonresponders, whereas these values were higher in patients showing NT-proBNP increase (P.05). The NT-proBNP percentage change correlated with right-over-left ventricular stroke work ratio percentage change (r = 0.83), pulmonary vascular resistance (r = 0.81), and RV ejection fraction (r = -0.79) and correlated with plateau pressure in nonresponders only (r = 0.82).In patients with ALI/ARDS, intraindividual NT-proBNP changes correlated with RV afterload following OLA, thereby serving as a potential marker for RV dysfunction after OLA.

Background and objective: Because the mortality and social burden associated with COPD is increasing, repeated surveys of the prevalence of COPD have been used to assess risk factors, detect potential patients, and establish early diagnoses and management protocols. We report the prevalence of spirometrically detected COPD in Korea in 2008, using data from the fourth Korean National Health and Nutrition Survey. Methods: Using nationwide stratified random sampling, based on the Korean Statistical Office census, 6840 subjects aged ≥19 years underwent spirometry, which was performed by four trained technicians, during 2008. The place of residence, levels of education and income and smoking status, as well as other results from a COPD survey questionnaire were also assessed. Results: Airflow obstruction (FEV1/FVC

Background Belotecan is a topoisomerase I inhibitor. This phase II trial was conducted to evaluate the efficacy and toxicity of belotecan in relapsing small-cell lung cancer (SCLC) patients after irinotecan failure. Patients and methods SCLC patients, who had relapsed at least 3 months after achieving objective response to irinotecan plus platinum chemotherapy, were eligible. Belotecan was administered at a dose of 0.5 mg/m2/day for 5 consecutive days every 3 weeks. Results Twenty-seven patients were enrolled in this study. Twenty-five patients were evaluated for response, and 27 patients were evaluated for toxicity and survival. The overall response rate was 22%. The median time to progression was 4.7 months (95% CI, 3.6–5.8 months), and the median overall survival was 13.1 months (95% CI, 10.4–15.8 months). The most frequent grade 3/4 toxicities were neutropenia (93%) and thrombocytopenia (48%). There was one treatment-related death due to pneumonia. Conclusion Belotecan showed modest activity and manageable toxicities in relapsing SCLC patients in this study which was conducted in Asia. But further study in Caucasian patients is needed.

PurposeActive tobacco smoking has been associated with the incidence of epidermal growth factor receptor (EGFR) mutations. However, the impact of environmental tobacco smoke (ETS) on EGFR mutations has been unknown. We investigated an association between ETS exposure and EGFR mutations in never smokers with non–small-cell lung cancer (NSCLC).Patients and MethodsWe enrolled 179 consecutive never smokers who were newly diagnosed with NSCLC. The history of ETS exposure was obtained with a standardized questionnaire that included exposure period, place, and duration. The nucleotide sequences of exons 18 to 21 on EGFR gene were determined using nested polymerase chain reaction amplification.ResultsThe incidence of EGFR mutations was significantly lower in patients with ETS exposure than in those without (38.5% v 61.4%; P = .008). In a logistic regression model that adjusted for sex and histology, an adjusted odds ratio (AOR) for the risk of EGFR mutations with exposure to ETS was 0.40 (95% CI, 0.20 to 0.81; P = .011). In quartile groups based on total smoker-year, the AORs for the lowest- to highest-quartile groups were 0.59 (95% CI, 0.23 to 1.49), 0.50 (95% CI, 0.17 to 1.50), 0.48 (95% CI, 0.20 to 1.18), and 0.22 (95% CI, 0.08 to 0.62; Ptrend= .028). Among the types of ETS exposure, adulthood ETS and household ETS were significantly associated with the incidence of EGFR mutations. Patients with ETS exposure showed a lower response rate to EGFR tyrosine kinase inhibitors than did patients without ETS exposure (24.6% v 44.8%; P = .053).ConclusionETS exposure is negatively associated with EGFR mutations in never smokers with NSCLC.

Although epidermal growth factor receptor (EGFR) tyrosine kinase (TK) mutations are highly predictive of response to EGFR TK inhibitors in advanced non-small-cell lung cancer (NSCLC), a prognostic value of EGFR mutations in resected NSCLC has not been established.We retrospectively reviewed 117 patients with primary lung adenocarcinoma who underwent surgical resection between 1995 and 2005. Nucleotide sequencing of the kinase domain of EGFR (exons 18-21) was performed using nested PCR amplification of individual exons.Forty-eight patients (41.8%) harbored exon 19 deletion or exon 21 point mutations. EGFR mutations were more frequently found in never-smoker (P = 0.04) or in smaller-sized primary tumor (P = 0.001). A presence of EGFR mutations was significantly associated with longer disease-free survival (DFS) (20.1 vs. 34.4 months in mutated EGFR; P = 0.003). In multivariate analysis of DFS, wild-type EGFR was associated with a higher risk of recurrence, with an adjusted hazard ratio of 1.42 (95% CI, 1.1-2.41, P = 0.04), as compared to mutated EGFR. However, no significant association was observed between EGFR mutations and overall survival (P = 0.39). Isolated brain metastasis as the first recurrence after resection was found more frequently in those patients with tumors bearing EGFR mutations, although the difference was not statistically significant (9 vs. 24% in mutated EGFR, P = 0.15).Activating mutations within the EGFR TK domain can be used to predict the risk of recurrence in curatively resected pulmonary adenocarcinoma.

Purpose: We investigated the prognostic effect of incorporating metabolic assessment by 18F-fluoro-2-deoxyglucose uptake on positron emission tomography/computed tomography (18F-FDG-PET/CT) into a conventional staging system in small-cell lung cancer (SCLC). Experimental Design: Seventy-six consecutive patients with pathologically proven SCLC were enrolled. All patients underwent standard treatment after pretreatment 18F-FDG-PET/CT scanning. The mean values of maximal standardized uptake values (meanSUVmax) of the malignant lesions upon 18F-FDG-PET/CT were calculated. The Cox proportional hazards model was used with performance status, lactate dehydrogenase, stage, and meanSUVmax. Results: Patients with high meanSUVmax were significantly related with the established poor prognostic factors, such as higher lactate dehydrogenase (P = 0.04) and extensive disease (ED; P = 0.01). Furthermore, in multivariate analysis, patients with high meanSUVmax were associated with poor survival outcomes compared with patients with low meanSUVmax [adjusted hazard ratio, 3.74; 95% confidence interval (95% CI), 1.67-8.37; P = 0.001, for death and adjusted hazard ratio, 2.25; 95% CI, 1.21-4.17; P = 0.01 for recurrence/progression]. In subgroup analysis, limited disease (LD) with high meanSUVmax showed significantly shorter overall survival than LD with low meanSUVmax [high versus low meanSUVmax, 20.1 months (95% CI, 7.9-23.2) versus 35.3 months (95% CI, 27.6-42.9); P = 0.02]. ED with high meanSUVmax had significantly shorter overall survival than ED with low meanSUVmax [high versus low meanSUVmax, 9.5 months (95% CI, 4.9-13.9) versus 17.7 months (95% CI, 12.0-20.1); P = 0.007]. These findings were replicated in progression-free survival analysis. Conclusions: In SCLC, tumor metabolic activity as assessed by FDG-PET is a significant prognostic factor and identifies subgroups of patients at higher risk of death in both LD and ED SCLC.

Purpose To determine whether germ-line variations in BRCA1 affect outcome in non–small-cell lung cancer (NSCLC) patients treated with platinum combination chemotherapy. Patients and Methods We evaluated the associations of four tagging BRCA1 polymorphisms and their haplotypes with treatment outcome in 300 NSCLC patients at stages IIIA (16%), IIIB (31%), and IV (53%). Results The median age was 63 years (range, 28 to 89 years). Histologically, 139 (46.3%) of the patients had squamous cell carcinomas and 137 (45.7%) had adenocarcinomas. Patient median survival time (MST) was 13.0 months. We observed no significant association between any of the tagging polymorphisms [S1613G, IVS13-1893 (A>C), IVS12-1207 (C>T), and IVS12+112 (C>A)] and overall survival. Of the five haplotypes evaluated (AACC, AACA, GCTC, GATC, and AATC), the survival of patients with two copies of the AACC (wild-type) haplotype was significantly shorter than that of patients with zero to one copies (MST, 8.47 v 14.57 months; log-rank P = .0066), even after adjustment for body weight loss, performance status, stage, second-line treatment, and radiation therapy (hazard ratio = 2.097; 95% CI, 1.339 to 3.284). The survival of patients with squamous cell carcinoma and two copies was significantly shorter than that of other patients with squamous cell carcinoma (MST, 6.8 v 15.3 months; log-rank P = 3.6 × 10−5), whereas differences in survival between the two adenocarcinoma groups was not significant (log-rank P = .677). Conclusion These findings suggest that the AACC haplotype of the BRCA1 gene is an important prognostic marker in NSCLC patients treated with platinum combination chemotherapy.

The prognosis of patients with stage III non-small-cell lung cancer (NSCLC) who achieve a pathological complete response or downstaging following neoadjuvant therapies are better than the prognosis of patients with residual metastatic lymph nodes (LN). However, the prognostic significance of the number of residual metastatic LNs remains unclear. From January 2001 to January 2006, 42 consecutive patients with stage IIIAN2 (22 patients) and IIIB without pleural effusion (20 patients) were treated with neoadjuvant chemotherapy. Thirty-four (81.0%) of the 42 patients were pathologically staged by mediastinoscopy. Neoadjuvant chemotherapy consisted of 3 cycles of platinum-based doublet (21 patients with gemcitabine, 15 with paclitaxel, and 6 with docetaxel). After neoadjuvant chemotherapy, a pathological complete response was achieved in one patient and downstaging was achieved in 24 patients. Pathological LN metastasis was absent in 9 patients (21.4%) and present in 33 patients (78.6%). With a median follow-up of 23 months, the 2-year disease-free survival (DFS) rate of patients without residual LN metastasis was statistically better than that of patients with residual LN metastasis (46% vs. 18% respectively, P=0.03). Among 33 patients with residual LN metastasis, age (P=0.01), pathological downstaging (P=0.098) and the number of residual metastatic LNs (median 14 months in 1-4 LN vs. median 5 months in LN > or =5; P=0.011) were significant predictors of DFS in univariate analysis. In multivariate analysis, the number of residual metastatic LNs was an independent predictor of DFS among patients with residual LN metastasis, irrespective of pathological downstaging. The number of residual metastatic lymph nodes following neoadjuvant chemotherapy is an independent predictor of DFS in patients with stage III NSCLC.

The efficacy and safety of a combined regimen of topotecan and etoposide was tested in patients with relapsed or refractory small-cell lung cancer.From October 2003 to May 2005, 23 patients who have failed to the previous irinotecan and platinum chemotherapy received intravenous topotecan 1 mg/m2 (day 1-5) and etoposide 80 mg/m2 (day 1-3). Treatment was repeated every 21 days for a maximum of 6 cycles.Twelve patients were refractory to first-line chemotherapy. Seventeen patients (73.9%) were male and the median age was 63 years. ECOG performance status was 0-1 in 13 (56.5%) patients. The median cycles of chemotherapy was three. Twenty-one patients were assessable for response evaluation. The overall response rate was 17.4% (0 CR, 4 PR, 7 SD, 10 PD) under the intent-to-treat analysis. Two sensitive case patients and two refractory case patients achieved partial response. After a median follow-up of 20.8 months, median progression free survival was 4.7 months and median overall survival was 9.5 months. The estimated 1-year survival rate was 38.7%. All patients were assessable for toxicity and major toxicities were myelosuppression. Grade 3/4 neutropenia and thrombocytopenia occurred in 18 (78.3%) and 12 (52.2%) patients, respectively. Grade 3/4 febrile neutropenia occurred in two patients (8.7%) and infection in three patients (13.0%). There was one treatment-related death due to pneumonia.This salvage regimen showed modest efficacy and manageable toxicities. Further study will be required in recurrent SCLC patients pretreated irinotecan and platinum.

BACKGROUND. The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC). METHODS. The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC. RESULTS. Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P = .036), longer progression-free survival (P = .060), and longer overall survival (P = .025). CONCLUSIONS. Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups. Cancer 2007. © 2007 American Cancer Society.

PURPOSE Refractory small-cell lung cancer (SCLC) has a poor prognosis, and current salvage chemotherapy for refractory SCLC, such as CAV (cyclophosphamide, adriamycin, vincristine) or topotecan, has an unsatisfactory outcome, with a response rate and overall survival of less than 10% and 6 months, respectively. This phase II study evaluated the role of topotecan combined with etoposide in SCLC patients that have progressed, or relapsed, within 3 months following completion of the initial chemotherapy. MATERIALS AND METHODS Twenty-seven patients were entered into this study. Eligible patients had an ECOG performance status of less than, or equal to, 2, at least one bidimensionally measurable lesion and adequate end organ function. IV topotecan, 1.0 mg/m2/d for 5 consecutive days, and etoposide, 100 mg/m2/d through days 1 to 3, were administered every 3 weeks until disease progression or undue toxicity. RESULTS The major toxicity was myelosuppression. Grade 3/4 anemia, granulocytopenia, and thrombocy-topenia occurred in 14.2, 34.8, and 27.3% of cycles, respectively. There was no treatment-related death, and other non-hematologic toxicities were generally mild. Four patients achieved partial responses, with a response rate RR of 14.8%. The progression-free survival PFS ranged from 1 to 7 months, with a median of 2.0 months (95% confidence interval 1.22~2.78 months). Twenty-five patients died, with a median overall survival of 5.5 months (ranging from 1 to 21 months, 95% CI 4.32~6.68 months), and the 6-month survival rate was 32.1% (95% confidence interval 14.4~49.8%). CONCLUSION The combination of topotecan and etoposide chemotherapy showed a modest response rate, but failed to prolong survival of refractory SCLC patients compared to topotecan monotherapy.