Ying-Huang Tsai

The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

Prediction of fluid responsiveness in acute respiratory distress syndrome patients ventilated with low tidal volume and high positive end-expiratory pressure*

Objective:Dynamic preload indicators with pulse pressure variation and stroke volume variation are superior to static indicators for predicting fluid responsiveness in mechanically ventilated patients. However, they are influenced by tidal volume and the level of positive end-expiratory pressure. The present study was designed to evaluate the clinical applicability of pulse pressure variation and stroke volume variation in predicting fluid responsiveness on acute respiratory distress syndrome patients ventilated with protective strategy (low tidal volume and high positive end-expiratory pressure). Design:Prospective, observational study. Setting:A 20-bed medical intensive care unit of a tertiary medical center. Patients:Twenty-two sedated and paralyzed early acute respiratory distress syndrome patients. Interventions:After being enrolled, central venous pressure, pulmonary capillary wedge pressure, and cardiac output index were obtained from a pulmonary artery catheter (OptiQ SvO2/CCO catheter), and intrathoracic blood volume, global end-diastolic volume, stroke volume variation, and pulse pressure variation were recorded from a PiCCOplus monitor. The whole set of hemodynamic measurements was performed before and after volume expansion with 500 mL hydroxyethyl starch (10% pentastarch 200/0.5). Measurements and Main Results:Cardiac output index, central venous pressure, pulmonary capillary wedge pressure, global end-diastolic volume, and intrathoracic blood volume significantly increased, and pulse pressure variation and stroke volume variation significantly decreased after volume expansion. Baseline pulse pressure variation significantly correlated with volume expansion-induced absolute changes (r = .62), or percent changes in cardiac output index (r = .75) after volume expansion. The area under the receiver operating characteristic curve was the highest for pulse pressure variation (area under the receiver operating characteristic curve = 0.768) than other indicators. The threshold value for baseline pulse pressure variation greater than 11.8% predicted a significant positive response to volume expansion with a sensitivity of 68% and a specificity of 100%. Conclusions:Baseline pulse pressure variation accurately predicted the fluid responsiveness in early acute respiratory distress syndrome patients. Roughly, a baseline pulse pressure variation greater than the threshold value of 12% is associated with a significant increase in cardiac output index after the end of volume expansion.

Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy.

Lung cancer is the leading cause of cancer death worldwide as well as in Taiwan. Interleukin‐6 (IL‐6) is a multifunctional cytokine and has been implicated in tumor progression. This study recruited 245 patients with advanced (Stage 3B/4) nonsmall cell lung cancer (NSCLC) that had received chemotherapy, to evaluate associations between IL‐6 and lung cancer‐specific survival. Among these subjects, 112 gave blood samples before and 133 after the start of chemotherapy. Plasma IL‐6 was measured using an enzyme linked‐immunosorbent assay. The 33rd and 66th percentiles of IL‐6 concentrations were 2.01 and 25.16 for the 245 patients and were defined as the cutoff points for dividing the patients into low, intermediate and high groups. Kaplan‐Meier and Cox proportional‐hazard models were used to evaluate the relationship between the IL‐6 level and survival time. Results after adjusting for age, sex, smoking history, histologic type and stage of lung cancer revealed a significant relationship. For all patients, the hazard ratio with high IL‐6 levels for lung cancer‐specific survival was 2.10 [95% confidence interval (CI) = 1.49 − 2.96] compared with low IL‐6 levels. The hazard ratio for patients who were recruited before and after the start of chemotherapy was1.25 (95% CI = 0.73 − 2.13) and 3.66 (95% CI = 2.18 − 6.15), respectively. Patients with high circulating IL‐6 also responded poorly to chemotherapy. Therefore, a high level of circulating IL‐6 was associated with an inferior response and survival outcome in NSCLC patients treated with chemotherapy.

Importin subunit alpha-2 is identified as a potential biomarker for non-small cell lung cancer by integration of the cancer cell secretome and tissue transcriptome

The cancer cell secretome may contain potentially useful biomarkers. In this study, we integrated the profiles of secreted proteins in lung cancer cell lines with mRNA expression levels from pulmonary adenocarcinoma tissue, with a view to identify effective biomarkers for non‐small cell lung cancer (NSCLC). Among the novel candidates isolated, importin subunit alpha‐2 (also known as karyopherin subunit alpha [KPNA]‐2), was selected for further validation. Immunohistochemical staining revealed overexpression of KPNA2 in the nuclei of tumor cells, compared with adjacent normal cells. A sandwich ELISA assay developed to detect KPNA2 levels in serum samples showed significantly higher serum KPNA2 in NSCLC patients than in healthy controls. A combination of serum KPNA2 and carcinoembryonic antigen displayed higher diagnostic capacity than either marker alone. Importantly, protein levels of KPNA2 in pleural effusion from NSCLC patients were also significantly higher than those from non‐lung cancer. Moreover, knockdown of KPNA2 inhibited the migration ability and viability of lung cancer cells. Our results collectively suggest that integration of the cancer cell secretome and transcriptome datasets provides an efficient means of identifying novel biomarkers for NSCLC, such as KPNA2.

A Polymorphism in the APE1 Gene Promoter is Associated with Lung Cancer Risk

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the base excision repair pathway, which is the primary mechanism for the repair of DNA damage caused by oxidation and alkylation. We hypothesized that polymorphisms of APE1 are associated with risk for lung cancer. In the hospital-based matched case-control study, a total of 730 lung cancer cases and 730 cancer-free controls were genotyped for four APE1 haplotype-tagging polymorphisms (that is, -656T>G, 400A>G, 630T>C, and 1350T>G). Among them, the single-nucleotide polymorphism -656T>G located in the promoter region of APE1 was significantly associated with risk for lung cancer. We found that, compared with -656 TT homozygotes, the variant genotypes were associated with a significantly decreased risk [adjusted odds ratio, 0.51; 95% confidence interval (95% CI), 0.33-0.79 for -656 TG; adjusted odds ratio, 0.43; 95% CI, 0.25-0.76 for -656 GG, respectively]. Furthermore, we found a statistically significant reduced risk of -656T>G variants among heavy smokers (adjusted odds ratio, 0.52; 95% CI, 0.30-0.93 for -656 TG; adjusted odds ratio, 0.27; 95% CI, 0.13-0.57 for -656 GG, respectively), with a significant gene-smoking interaction (P = 0.013). A similar gene-smoking interaction in the context of APE1 haplotypes was also observed. The in vitro promoter assay revealed that the -656 G allele had a significantly higher transcriptional activity than that of the -656 T allele. Together, our results suggest that polymorphisms of the APE1 gene possibly interact with smoking and may contribute to the development of lung cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):223–9)

Early corticosteroid use in acute exacerbations of chronic airflow obstruction

To determine the benefit of early steroid use in acute exacerbations of chronic airflow obstruction in the ED, 113 patients with an average age of 66 years, acute or chronic dyspnea, an FEV1 of < 60% and FEV1/FVC ratio of < 60% were included in a randomized, double-blinded, interventional clinical trial. All patients received the same bronchodilator treatment. At 6 hours the steroid- treated group showed a 21.71 L/min improvement in PEFR (P < .05) and 0.14 L improvement in FEV1 (P < .05), while the nonsteroid group showed insignificant improvements of 5.52 L/min and 0.02 L, respectively. Of those patients receiving steroids, 22 achieved > 40% improvements in PEFR by 6 hours and 17 achieved similar results in FEV1, whereas of those not receiving steroids, 13 and 8, respectively, achieved improvements. Within 24 hours of observation in the ED, 16 patients receiving steroids were discharged and none relapsed within 2 weeks. Of those not receiving steroids, only 10 were discharged and 3 returned with exacerbations. Although early response to steroids in chronic airflow obstruction is variable, the overall medical and cost benefits justify their early use in acute exacerbations.

Discovery of Retinoblastoma-Associated Binding Protein 46 as a Novel Prognostic Marker for Distant Metastasis in Nonsmall Cell Lung Cancer by Combined Analysis of Cancer Cell Secretome and Pleural Effusion Proteome

Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, which is one of the most prominent causes of cancer-related mortality worldwide. Discovery of serum tumor markers could facilitate early NSCLC detection and metastatic prognosis. Here, we simultaneously analyzed the NSCLC cell secretome and proteomic profiles of pleural effusion from lung adenocarcinoma patients for NSCLC biomarker discovery. Retinoblastoma-associated binding protein 46 (RbAp46), one of the proteins detected both in NSCLC cell secretome and pleural effusion proteome, was chosen for further evaluation. Both of RbAp46 mRNA and protein levels were upregulated significantly in NSCLC cancer tissues. Serum levels of RbAp46 were markedly higher in NSCLC patients than in healthy controls, and a combination of RbAp46 and CEA could outperform CEA alone in discriminating NSCLC patients from healthy persons. Importantly, elevated serum RbAp46 level was highly correlated with NSCLC distant metastasis. Moreover, knockdown of RbAp46 inhibited the migration ability of lung cancer cells. Our data collectively suggest that RbAp46 serves as a novel biomarker and prognosticator for NSCLC, and is involved in lung cancer cell migration.

Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer

BACKGROUND The study compared the efficacy of a first-line treatment with day 1 i.v. vinorelbine (NVBiv) and day 8 oral vinorelbine (NVBo) versus docetaxel (DCT) in a cisplatin-based combination in advanced non-small-cell lung cancer, in terms of time to treatment failure (TTF), overall response, progression-free survival (PFS), overall survival (OS), tolerance and quality of life (QoL). METHODS Patients were randomly assigned to receive cisplatin 80 mg/m2 with NVBiv 30 mg/m2 on day 1 and NVBo 80 mg/m2 on day 8 every 3 weeks, after a first cycle of NVBiv 25 mg/m2 on day 1 and NVBo 60 mg/m2 on day 8 (arm A) or cisplatin 75 mg/m2 and DCT 75 mg/m2 on day 1 every 3 weeks (arm B), for a maximum of six cycles in both arms. RESULTS From 2 February 2004 to 1 January 2006, 390 patients were entered in a randomised study and 381 were treated. The patient characteristics are as follows (arms A/B): metastatic (%) 80.5/84.8; patients with three or more organs involved (%) 45.3/40.8; median age 59.4/62.1 years; male 139/146; squamous (%) 34.2/33.5; adenocarcinoma (%) 41.6/39.3; median TTF (arms A/B in months) [95% confidence interval (CI)]: 3.2 (3.0-4.2), 4.1 (3.4-4.5) (P = 0.19); overall response (arms A/B) (95% CI): 27.4% (21.2% to 34.2%), 27.2% (21.0% to 34.2%); median PFS (arms A/B in months) (95% CI): 4.9 (4.4-5.9), 5.1 (4.3-6.1) (P = 0.99) and median OS (arms A/B in months) (95% CI): 9.9 (8.4-11.6), 9.8 (8.8-11.5) (P = 0.58). The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B, respectively. Main haematological toxicity was grade 3-4 neutropenia: 24.4% (arm A) and 28.8% (arm B). QoL as measured by the Lung Cancer Symptom Scale was similar in both arms. CONCLUSIONS Both arms provided similar efficacy in terms of response, time-related parameters and QoL, with an acceptable tolerance profile. In the current Global Lung Oncology Branch trial 3, NVBo was shown to be effective as a substitute for the i.v. formulation. This can relieve the burden of the i.v. injection on day 8 and can optimise the hospitals resources and improve patient convenience.

Open lung biopsy in early-stage acute respiratory distress syndrome.

IntroductionAcute respiratory distress syndrome (ARDS) has heterogeneous etiologies, rapid progressive change and a high mortality rate. To improve the outcome of ARDS, accurate diagnosis is essential to the application of effective early treatment. The present study investigated the clinical effects and safety of open lung biopsy (OLB) in patients with early-stage ARDS of suspected non-infectious origin.MethodsWe undertook a retrospective study of 41 patients with early-stage ARDS (defined as one week or less after intubation) who underwent OLB in two medical intensive care units of a tertiary care hospital from 1999 to 2005. Data analyzed included baseline characteristics, complication rate, pathological diagnoses, treatment alterations, and hospital survival.ResultsThe age of patients was 55 ± 17 years (mean ± SD). The average ratio of arterial partial pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) was 116 ± 43 mmHg (mean ± SD) at biopsy. Seventeen patients (41%) were immunocompromised. Postoperative complications occurred in 20% of patients (8/41). All biopsies provided a pathological diagnosis with a diagnostic yield of 100%. Specific pathological diagnoses were made for 44% of patients (18/41). Biopsy findings led to an alteration of treatment modality in 73% of patients (30/41). The treatment alteration rate was higher in patients with nonspecific diagnoses than in patients with specific diagnoses (p = 0.0024). Overall mortality was 50% (21/41) and was not influenced by age, gender, pre-OLB oxygenation, complication rate, pathological results, and alteration of treatment. There was no surgery-related mortality. The survival rate for immunocompromised patients was better than that for immunocompetent patients (71% versus 33%; p = 0.0187) in this study.ConclusionOur retrospective study suggests that OLB was a useful and acceptably safe diagnostic procedure in some selected patients with early-stage ARDS.

Adequacy and complications of computed tomography-guided core needle biopsy on non-small cell lung cancers for epidermal growth factor receptor mutations demonstration: 18-gauge or 20-gauge biopsy needle

INTRODUCTION To compare adequacy of tissue acquisition for EGFR DNA mutation analysis and the resulting complications in CT-guided lung biopsy cases with either 18-gauge or 20-gauge core biopsy needle. METHODS Forty-seven patients with advanced staged non-small cell lung cancers who were failure-treated by conventional chemotherapy were retrospectively reviewed. All had received CT-guided core needle lung biopsy for histology diagnosis and freshly frozen for EGFR mutation analysis before targeted therapy. We compared the complications resulting from these CT-guided lung biopsies and the specimen assessment using 18-gauge (32 patients) or 20-gauge (15 patients) biopsy needle via 17-gauge or 19-gauge coaxial needle. RESULTS With an overall pneumothorax rate of 12.8%, pneumothorax occurred in 12.5% and 13.3% of patients by 17-gauge and 19-gauge coaxial needles respectively. The overall rate of hemoptysis was 6.4%, with 6.3% by 18-gauge biopsy needle and 6.6% by 20-gauge biopsy needle. Large peritumoral hemorrhage revealed only in 2 cases of those completed with 18-gauge biopsy needles. 18-gauge biopsy needle obtained larger specimens with heavier weight (average 10.15mg vs 9mg) and higher DNA concentration (average 47.13ng/ul vs 35.92ng/ul) than 20-gauge biopsy needle. Otherwise, the range of optical density (1.67-2.09) was more constant in the specimens by 20-gauge biopsy needles. Mutation demonstration was achieved for all samples. CONCLUSION CT-guided core needle biopsy is a feasible technique in acquisition of fresh cancer tissues for EGFR gene mutation analysis. The specimen is adequate for gene demonstration either using 18-gauge or 20-gauge tru-cut biopsy needles via 17-gauge or 19-gauge coaxial needles.