Chong-jen Yu - Academia.edu (original) (raw)

Papers by Chong-jen Yu

JAMA oncology, Jan 30, 2015

Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cance... more Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cancer (NSCLC) has appeared promising in retrospective analyses, highlighting the challenge to identify whether progression is the optimal time to switch treatment. To study the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and postprogression erlotinib therapy. ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) was a phase 2, open-label, single-arm study conducted from 2011 to 2012 in 23 centers in Hong Kong, Korea, Taiwan, and Thailand of adults with stage IV, EGFR mutation-positive NSCLC, with ECOG performance status 0 to 2. Patients received erlotinib 150 mg/d orally until disease progression, after which erlotinib therapy could be continued at patient and/or investigator discretion. The primary end point was progression-free survival (PFS1; time to Response Evaluation Criteria in Solid Tumours 1.1 progression or dea...

Thorax, 1998

BACKGROUNDThe clinical value of colour Doppler ultrasound and amplitude ultrasound angiography in... more BACKGROUNDThe clinical value of colour Doppler ultrasound and amplitude ultrasound angiography in the diagnosis and follow up of pulmonary arteriovenous malformations (PAVM) was investigated.METHODSSix consecutive patients suspected by clinical appearance and abnormal chest radiographic findings of having PAVM were included in the study. Ultrasonography was performed first by real time grey scale imaging then by colour Doppler imaging and amplitude

Pulmonary cryptococcosis causes significant morbidity and mortality in immunocompromised patients... more Pulmonary cryptococcosis causes significant morbidity and mortality in immunocompromised patients. Definitive diagnosis of pulmonary cryptococcosis is usually difficult. The use of direct determination of cryptococcal antigen in transthoracic needle aspirate to diagnose pulmonary cryptococcosis was investigated. Over a 2-year period, we studied a total of 41 patients with respiratory symptoms and pulmonary infiltrates of unknown etiology who were suspected of having pulmonary cryptococcosis. Twenty-two patients were immunocompetent patients and 19 patients were immunocompromised. A diagnosis of pulmonary cryptococcosis was based on cytological examination, culture for Cryptococcus neoformans, histopathologic examination, and clinical response to antifungal therapy. All patients underwent chest ultrasound and ultrasound-guided percutaneous transthoracic needle aspiration to obtain specimens for cryptococcal antigen determination. The presence of cryptococcal antigen was determined by the latex agglutination system (CALAS; Meridian Diagnostics, Cincinnati, Ohio). An antigen titer equal to or greater than 1:8 was considered positive. The specimens were also sent for cytological examination, fungal culture, and/or histopathologic examination. A final diagnosis of pulmonary cryptococcosis was made in eight patients. Direct determinations of cryptococcal antigen in lung aspirate were positive in all eight patients with pulmonary cryptococcosis (100% sensitivity, 97% specificity, a positive predictive value of 89%, and negative value of 100%), and there was only one false-positive in noncryptococcosis patients. The diagnostic accuracy was 97.5%. Serum cryptococcal antigen was positive in only three patients with pulmonary cryptococcosis (sensitivity, 37.5%). This study showed that direct measurement of cryptococcal antigen in lung aspirate can be a rapid and useful test for diagnosis of pulmonary cryptococcosis.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 8, 2015

Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk allele... more Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluate...

The Lancet Oncology, 2015

Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion muta... more Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393. Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1-84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8-42·8) in group 2 and two (8·7%, 1·1-28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6-14·7) in group 1, 2·9 months (1·2-8·3) in group 2; and 2·7 months (1·8-4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4-26·9) in group 1, 14·9 months (8·1-24·9) in group 2, and 9·2 months (4·1-14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4-93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9-80·2) with Leu861Gln, and eight (100·0%, 63·1-100·0) with Ser768Ile. Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. Boehringer Ingelheim.

PLOS ONE, 2015

The performance of the BluePoint MycoID plus kit (Bio Concept Corporation, Taichung, Taiwan), whi... more The performance of the BluePoint MycoID plus kit (Bio Concept Corporation, Taichung, Taiwan), which was designed to simultaneously detect Mycobacterium tuberculosis (MTB), rifampin- and isoniazid-resistant MTB, and nontuberculous mycobacteria (NTM) was first evaluated with 950 consecutive positive cultures in Mycobacterium Growth Indicator Tube (MGIT) system (BACTEC, MGIT 960 system, Becton-Dickinson, Sparks) from clinical respiratory specimens. The discrepant results between kit and culture-based identification were finally assessed by 16S rRNA gene sequencing and clinical diagnosis. The accuracy rate of this kit for identification of all Mycobacterium species was 96.3% (905/940). For MTB identification, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the kit were 99.7%, 99.3%, 99.0% and 99.8%, respectively. For rifampicin-resistant MTB identification, the sensitivity, specificity, PPV, and NPV of the kit were 100.0%, 99.4%, 91.3%, and 100.0%, respectively, while the corresponding values of isoniazid-resistant MTB identification were 82.6%, 99.4%, 95.0%, and 97.6%, respectively. In identifying specific NTM species, the kit correctly identified 99.3% of M. abscessus (147/148) complex, 100% of M. fortuitum (32/32), M. gordonae (38/38), M. avium (39/39), M. intracellulare (90/90), M. kansasii (36/36), and M. avium complex species other than M. avium and M. intracellulare (94/94). In conclusions, the diagnostic value of the BluePoint MycoID plus kit was superior to culture method for recoveries and identification of NTM to species level. In addition, the diagnostic accuracy of BluePoint MycoID plus kit in MTB identification was similar to conventional culture method with high accuracy rate of rifampicin-resistant M. tuberculosis identification.

PLOS ONE, 2015

Patients with renal failure are vulnerable to tuberculosis, a common worldwide infectious disease... more Patients with renal failure are vulnerable to tuberculosis, a common worldwide infectious disease. In the growing dialysis population, the risk for tuberculosis among the associated sub-groups is important but unclear. This study investigated latent tuberculosis infection (LTBI) in patients with severe chronic kidney disease (CKD) and among dialysis-unit staff caring for patients on dialysis. From January 2012 to June 2013, patients undergoing dialysis, those with severe CKD (estimated glomerular filtration rate <30ml/min/1.73 m2), and the dialysis-unit staff (nursing staff and doctors in hemodialysis units) in several Taiwan hospitals were prospectively enrolled. Interferon-gamma release assay (IGRA) through QuantiFERON-TB Gold In-tube was used to determine LTBI. Predictors for LTBI were analyzed. Of the 599 participants enrolled, 106 (25%) in the dialysis group were IGRA positive. This was higher than the seven (11%) among severe CKD patients and 12 (11%) in the dialysis-unit staff. Independent predictors of LTBI in patient with renal dysfunction were old age (odds ratio [OR]: 1.03 [1.01-1.04] per year increment), prior TB lesion on chest radiograph (OR: 2.90 [1.45-5.83]), serum albumin (OR: 2.59 [1.63-4.11] per 1 g/dl increment), and need for dialysis (OR: 2.47, [1.02-5.95]). The QFT-GIT response was similar among the three groups. Malignancy (OR: 4.91 [1.84-13.10]) and low serum albumin level (OR: 0.22 [0.10-0.51], per 1 g/dl decrease) were associated with indeterminate IGRA results. More patients on dialysis have LTBI compared to those with severe CKD and the dialysis-unit staff. Old age, prior radiographic TB lesion, high serum albumin, and need for dialysis are predictors of LTBI in patients with renal failure. Patients with severe CKD are a lower priority for LTBI screening. The hemodialysis environment is not a risk for LTBI and dialysis-unit staff may be treated as general healthcare workers.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 31, 2015

Blood-based circulating free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation t... more Blood-based circulating free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas(®) tissue test and the cobas(®) blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut+ cfDNA (HR 0.22, 95% CI 0.14-0.33, P < 0.0001) and 6.2 versus 6.1 months, respectiv...

Journal of critical care, Jan 8, 2015

The purpose of this study is to investigate the prognostic values of the serum levels of lipids i... more The purpose of this study is to investigate the prognostic values of the serum levels of lipids in patients with severe community-acquired pneumonia (CAP) that required intensive care unit (ICU) admission. Patients who had severe CAP that required ICU admission were included. Serum lipid level was collected on the days 1 and 7 of ICU stay. Clinical outcome, including length of ICU stay, hospital stay, and death, were monitored prospectively. A total of 40 patients were enrolled in this study. Lower high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were found in nonsurvival group on ICU admission day 7 (survivors vs nonsurvivors; mean HDL, 41.8 vs 13.0 mg/dL, P = .002; LDL, 62.3 vs 30.3 mg/dL, P = 0.006, respectively). High-density lipoprotein cholesterol level of less than or equal to 17 mg/dL on day 7 (odds ratio, 1.23) and LDL cholesterol level of less than or equal to 21 mg/dL on day 7 (odds ratio, 1.10) could be a predictor of hospital mortality. The mean change i...

PloS one, 2014

Natural history of chronic obstructive pulmonary disease (COPD) is punctuated by exacerbations; h... more Natural history of chronic obstructive pulmonary disease (COPD) is punctuated by exacerbations; however, little is known about prognosis of the first-ever COPD exacerbation and variables predicting its outcomes. A population-based cohort study among COPD patients with their first-ever exacerbations requiring hospitalizations was conducted. Main outcomes were in-hospital mortality and one-year mortality after discharge. Demographics, comorbidities, medications and in-hospital events were obtained to explore outcome predictors. The cohort comprised 4204 hospitalized COPD patients, of whom 175 (4%) died during the hospitalization. In-hospital mortality was related to higher age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.03-1.06) and Charlson comorbidity index score (OR: 1.08 per point; 95% CI: 1.01-1.15); angiotensin II receptor blockers (OR: 0.61; 95% CI: 0.38-0.98) and β blockers (OR: 0.63; 95% CI: 0.41-0.95) conferred a survival benefit. At one year after disch...

Lung cancer (Amsterdam, Netherlands), 2005

Sialyl Lewis antigens (sLe(x/a)) are cancer-associated carbohydrate determinants, serve as ligand... more Sialyl Lewis antigens (sLe(x/a)) are cancer-associated carbohydrate determinants, serve as ligands of the selectin family and are associated with hematogenous metastasis of cancer. So far, the clinicopathologic values of sialyl Lewis x (sLe(x)) and sialyl Lewis a (sLe(a)) in lung cancer have remained controversial. Using immunohistochemistry, the expressions of sLe(x) and sLe(a) antigens, and an airway mucin (MUC5AC) protein, which was supposed to be the major carrying protein of sialyl Lewis moieties, were studied in surgically resected tumor tissues of 61 patients with stages I or II NSCLC. Thirty-two (52.5%) of the 61 studied subjects were found to be positive for expression of sLe(a), 40 (65.6%) were positive for expression of sLe(x), and 16 (26.2%) were positive for MUC5AC protein. Both the expression of sLe(x) and MUC5AC were associated with adenocarcinoma subtype. Patients bearing tumors with MUC5AC and/or sLe(x) expression had a higher probability of post-operative distant m...

Lung Cancer, 2015

RET rearrangements represent one of the newest molecular targets in non-small cell lung cancer (N... more RET rearrangements represent one of the newest molecular targets in non-small cell lung cancer (NSCLC). However, the prevalence, clinical characteristics, and outcome of patients with RET-rearranged lung adenocarcinoma in metastatic disease remain uncertain. Multiplex reverse transcription-polymerase chain reaction (RT-PCR) was used to detect KIF5B-RET and CCDC6-RET fusions from specimens of malignant pleural effusion (MPE) in patients with metastatic lung adenocarcinoma. The demographic data and outcome of patients with RET-rearranged tumors were compared with those with EGFR-mutant, KRAS-mutant, EML4-ALK-rearranged, and quadri-negative tumors. Of the 722 patients with MPE of lung adenocarcinoma screened, 17 (2.4%) had RET-rearranged tumors. The detected RET rearrangements comprised 11 (65%) KIF5B-RET and 6 (35%) CCDC6-RET fusions, including 2 novel fusion variants identified. The presence of RET rearrangements was not associated with age at diagnosis, gender or smoking history, but predominantly seen in solid histological subtype. None of patients with RET-rearranged tumors had received kinase inhibitors with activity against RET kinase. The median overall survival was 22.4 months (95% CI, 8.8-36.0) for the 17 patients with RET-rearranged tumors, compared with 21.3 months (95% CI, 18.7-23.9; P=0.57) for the 451 patients with EGFR-mutant tumors, 5.4 months (95% CI, 2.7-8.1; P=0.002) for the 13 patients with KRAS-mutant tumors, 18.9 months (95% CI, 10.7-27.1; P=0.82) for the 51 patients with EML4-ALK-rearranged tumors, and 12.0 months (95% CI, 9.0-15.0; P=0.07) for the 190 patients with quadri-negative tumors. Multiplex RT-PCR from specimens of MPE is feasible for the screening of RET rearrangements in NSCLC. Metastatic RET-rearranged lung adenocarcinoma patients with MPE might have favorable survival comparable to those with metastatic EGFR-mutant tumors.

Respiratory Research, 2014

BackgroundChronic pulmonary obstructive disease (COPD) has become the fourth leading cause of dea... more BackgroundChronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide. Cigarette smoking induces neutrophil elastase (NE) and contributes to COPD, but the detailed mechanisms involved are not fully established. In an animal model of pulmonary emphysema, there are increased expressions of placenta growth factor (PlGF) and lung epithelial (LE) cell apoptosis. This study hypothesized that excessive NE may up-regulate PlGF and that PlGF-induced LE apoptosis mediates the pathogenesis of pulmonary emphysema.MethodsHuman bronchial epithelial cells, BEAS-2B, and primary mouse type II alveolar epithelial cells were treated with NE. The PlGF promoter activity was examined by luciferase activity assay, while PlGF expression and secretion were evaluated by RT-PCR, Western blotting, and ELISA. Both cell lines were treated with PlGF to evaluate its effects and the downstream signaling pathways leading to LE cell apoptosis. PlGF knockout and wild-type mice were instilled with NE to determine the roles of PlGF and its downstream molecules in NE-promoted mice pulmonary apoptosis and emphysema phenotype.ResultsThe transcriptional factor, early growth response gene-1, was involved in the NE-promoted PlGF promoter activity, and the expression and secretion of PlGF mRNA and protein in LE cells. PlGF-induced LE cell apoptosis and NE-induced mice pulmonary apoptosis and emphysema were mediated by the downstream c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)¿ signaling pathways.ConclusionThe NE-PlGF-JNK/PKC¿ pathway contributes to the pathogenesis of LE cell apoptosis and emphysema. PlGF and its downstream signaling molecules may be potential therapeutic targets for COPD.

PLOS ONE, 2015

It is important to select appropriate targeted therapies for subgroups of patients with lung aden... more It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations.

Clinical lung cancer, Jan 10, 2015

The purpose of this study was to explore the predictive factors of the effectiveness and treatmen... more The purpose of this study was to explore the predictive factors of the effectiveness and treatment toxicity for pemetrexed as continuation maintenance therapy in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Patients with advanced nonsquamous NSCLC treated with pemetrexed as continuation maintenance therapy were enrolled. The medical records were reviewed and analyzed, including data on basic characteristics, estimated creatinine clearance rate (Ccr), treatment responses, progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. A total of 124 patients were included and all had adenocarcinoma. Patients with an estimated Ccr < 60 mL/min had a significantly longer PFS and OS (P = .045, and P = .006, respectively). Each 10 mL/min increase in estimated Ccr was associated with an increase of 9.8% in the risk of disease progression, and an increase of 9.2% in the risk of death. In contrast, an increase of 10 mL/min in estimated C...

Diagnostic Microbiology and Infectious Disease, 2007

Because of the increasing numbers of nontuberculous mycobacterial isolates from clinical specimen... more Because of the increasing numbers of nontuberculous mycobacterial isolates from clinical specimens, rapid and accurate methods for culture confirmation of Mycobacterium tuberculosis are urgently needed. The study evaluated the performance of the Capilia TB immunochromatographic assay (TAUNS, Numazu, Japan) for culture confirmation of M. tuberculosis using 242 culture-positive liquid media in 2 mycobacterial laboratories from November 2005 to February 2006.

Objectives: We assessed the fluoroquinolone (FQ) susceptibility of clinical isolates of Mycobacte... more Objectives: We assessed the fluoroquinolone (FQ) susceptibility of clinical isolates of Mycobacterium tuberculosis in an endemic area. The genetic mutations responsible for FQ resistance were also evaluated. Methods: A total of 420 M. tuberculosis isolates during January 2004 to December 2005 were randomly selected. Data on the clinical characteristics of the patients were obtained from medical records. The MICs of

Journal of geriatric oncology, 2015

Data on the treatment modalities and prognostic factors for elderly patients with advanced non-sm... more Data on the treatment modalities and prognostic factors for elderly patients with advanced non-small cell lung cancer (NSCLC) remain limited. This study investigates the impact of age and comorbidities on treatment modalities and patient prognosis. From January 2004 to December 2008, patients aged ≥70years old and diagnosed with stage IIIB or IV NSCLC were included retrospectively. Their clinical characteristics were reviewed and analyzed. Comorbidity status was evaluated using Charlson comorbidity index (CCI) and simplified comorbidity score (SCS). A total of 576 patients were included in this analysis. Four hundred and nineteen patients (72.7%) received systemic therapy, including 182 (31.6%) patients who received chemotherapy, and 237 (41.1%) patients who received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) as initial treatment. Patients aged ≥80 were less likely to receive chemotherapy as initial treatment than those aged 70-79 (12.3% vs. 40.9%, p<0....

Oncotarget, Jan 10, 2015

Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth fac... more Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and ...

The Journal of pharmacology and experimental therapeutics, 2014

Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EG... more Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially p...

JAMA oncology, Jan 30, 2015

Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cance... more Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cancer (NSCLC) has appeared promising in retrospective analyses, highlighting the challenge to identify whether progression is the optimal time to switch treatment. To study the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and postprogression erlotinib therapy. ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) was a phase 2, open-label, single-arm study conducted from 2011 to 2012 in 23 centers in Hong Kong, Korea, Taiwan, and Thailand of adults with stage IV, EGFR mutation-positive NSCLC, with ECOG performance status 0 to 2. Patients received erlotinib 150 mg/d orally until disease progression, after which erlotinib therapy could be continued at patient and/or investigator discretion. The primary end point was progression-free survival (PFS1; time to Response Evaluation Criteria in Solid Tumours 1.1 progression or dea...

Thorax, 1998

BACKGROUNDThe clinical value of colour Doppler ultrasound and amplitude ultrasound angiography in... more BACKGROUNDThe clinical value of colour Doppler ultrasound and amplitude ultrasound angiography in the diagnosis and follow up of pulmonary arteriovenous malformations (PAVM) was investigated.METHODSSix consecutive patients suspected by clinical appearance and abnormal chest radiographic findings of having PAVM were included in the study. Ultrasonography was performed first by real time grey scale imaging then by colour Doppler imaging and amplitude

Pulmonary cryptococcosis causes significant morbidity and mortality in immunocompromised patients... more Pulmonary cryptococcosis causes significant morbidity and mortality in immunocompromised patients. Definitive diagnosis of pulmonary cryptococcosis is usually difficult. The use of direct determination of cryptococcal antigen in transthoracic needle aspirate to diagnose pulmonary cryptococcosis was investigated. Over a 2-year period, we studied a total of 41 patients with respiratory symptoms and pulmonary infiltrates of unknown etiology who were suspected of having pulmonary cryptococcosis. Twenty-two patients were immunocompetent patients and 19 patients were immunocompromised. A diagnosis of pulmonary cryptococcosis was based on cytological examination, culture for Cryptococcus neoformans, histopathologic examination, and clinical response to antifungal therapy. All patients underwent chest ultrasound and ultrasound-guided percutaneous transthoracic needle aspiration to obtain specimens for cryptococcal antigen determination. The presence of cryptococcal antigen was determined by the latex agglutination system (CALAS; Meridian Diagnostics, Cincinnati, Ohio). An antigen titer equal to or greater than 1:8 was considered positive. The specimens were also sent for cytological examination, fungal culture, and/or histopathologic examination. A final diagnosis of pulmonary cryptococcosis was made in eight patients. Direct determinations of cryptococcal antigen in lung aspirate were positive in all eight patients with pulmonary cryptococcosis (100% sensitivity, 97% specificity, a positive predictive value of 89%, and negative value of 100%), and there was only one false-positive in noncryptococcosis patients. The diagnostic accuracy was 97.5%. Serum cryptococcal antigen was positive in only three patients with pulmonary cryptococcosis (sensitivity, 37.5%). This study showed that direct measurement of cryptococcal antigen in lung aspirate can be a rapid and useful test for diagnosis of pulmonary cryptococcosis.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 8, 2015

Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk allele... more Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluate...

The Lancet Oncology, 2015

Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion muta... more Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393. Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1-84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8-42·8) in group 2 and two (8·7%, 1·1-28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6-14·7) in group 1, 2·9 months (1·2-8·3) in group 2; and 2·7 months (1·8-4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4-26·9) in group 1, 14·9 months (8·1-24·9) in group 2, and 9·2 months (4·1-14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4-93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9-80·2) with Leu861Gln, and eight (100·0%, 63·1-100·0) with Ser768Ile. Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. Boehringer Ingelheim.

PLOS ONE, 2015

The performance of the BluePoint MycoID plus kit (Bio Concept Corporation, Taichung, Taiwan), whi... more The performance of the BluePoint MycoID plus kit (Bio Concept Corporation, Taichung, Taiwan), which was designed to simultaneously detect Mycobacterium tuberculosis (MTB), rifampin- and isoniazid-resistant MTB, and nontuberculous mycobacteria (NTM) was first evaluated with 950 consecutive positive cultures in Mycobacterium Growth Indicator Tube (MGIT) system (BACTEC, MGIT 960 system, Becton-Dickinson, Sparks) from clinical respiratory specimens. The discrepant results between kit and culture-based identification were finally assessed by 16S rRNA gene sequencing and clinical diagnosis. The accuracy rate of this kit for identification of all Mycobacterium species was 96.3% (905/940). For MTB identification, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the kit were 99.7%, 99.3%, 99.0% and 99.8%, respectively. For rifampicin-resistant MTB identification, the sensitivity, specificity, PPV, and NPV of the kit were 100.0%, 99.4%, 91.3%, and 100.0%, respectively, while the corresponding values of isoniazid-resistant MTB identification were 82.6%, 99.4%, 95.0%, and 97.6%, respectively. In identifying specific NTM species, the kit correctly identified 99.3% of M. abscessus (147/148) complex, 100% of M. fortuitum (32/32), M. gordonae (38/38), M. avium (39/39), M. intracellulare (90/90), M. kansasii (36/36), and M. avium complex species other than M. avium and M. intracellulare (94/94). In conclusions, the diagnostic value of the BluePoint MycoID plus kit was superior to culture method for recoveries and identification of NTM to species level. In addition, the diagnostic accuracy of BluePoint MycoID plus kit in MTB identification was similar to conventional culture method with high accuracy rate of rifampicin-resistant M. tuberculosis identification.

PLOS ONE, 2015

Patients with renal failure are vulnerable to tuberculosis, a common worldwide infectious disease... more Patients with renal failure are vulnerable to tuberculosis, a common worldwide infectious disease. In the growing dialysis population, the risk for tuberculosis among the associated sub-groups is important but unclear. This study investigated latent tuberculosis infection (LTBI) in patients with severe chronic kidney disease (CKD) and among dialysis-unit staff caring for patients on dialysis. From January 2012 to June 2013, patients undergoing dialysis, those with severe CKD (estimated glomerular filtration rate &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;30ml/min/1.73 m2), and the dialysis-unit staff (nursing staff and doctors in hemodialysis units) in several Taiwan hospitals were prospectively enrolled. Interferon-gamma release assay (IGRA) through QuantiFERON-TB Gold In-tube was used to determine LTBI. Predictors for LTBI were analyzed. Of the 599 participants enrolled, 106 (25%) in the dialysis group were IGRA positive. This was higher than the seven (11%) among severe CKD patients and 12 (11%) in the dialysis-unit staff. Independent predictors of LTBI in patient with renal dysfunction were old age (odds ratio [OR]: 1.03 [1.01-1.04] per year increment), prior TB lesion on chest radiograph (OR: 2.90 [1.45-5.83]), serum albumin (OR: 2.59 [1.63-4.11] per 1 g/dl increment), and need for dialysis (OR: 2.47, [1.02-5.95]). The QFT-GIT response was similar among the three groups. Malignancy (OR: 4.91 [1.84-13.10]) and low serum albumin level (OR: 0.22 [0.10-0.51], per 1 g/dl decrease) were associated with indeterminate IGRA results. More patients on dialysis have LTBI compared to those with severe CKD and the dialysis-unit staff. Old age, prior radiographic TB lesion, high serum albumin, and need for dialysis are predictors of LTBI in patients with renal failure. Patients with severe CKD are a lower priority for LTBI screening. The hemodialysis environment is not a risk for LTBI and dialysis-unit staff may be treated as general healthcare workers.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 31, 2015

Blood-based circulating free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation t... more Blood-based circulating free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas(®) tissue test and the cobas(®) blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut+ cfDNA (HR 0.22, 95% CI 0.14-0.33, P < 0.0001) and 6.2 versus 6.1 months, respectiv...

Journal of critical care, Jan 8, 2015

The purpose of this study is to investigate the prognostic values of the serum levels of lipids i... more The purpose of this study is to investigate the prognostic values of the serum levels of lipids in patients with severe community-acquired pneumonia (CAP) that required intensive care unit (ICU) admission. Patients who had severe CAP that required ICU admission were included. Serum lipid level was collected on the days 1 and 7 of ICU stay. Clinical outcome, including length of ICU stay, hospital stay, and death, were monitored prospectively. A total of 40 patients were enrolled in this study. Lower high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were found in nonsurvival group on ICU admission day 7 (survivors vs nonsurvivors; mean HDL, 41.8 vs 13.0 mg/dL, P = .002; LDL, 62.3 vs 30.3 mg/dL, P = 0.006, respectively). High-density lipoprotein cholesterol level of less than or equal to 17 mg/dL on day 7 (odds ratio, 1.23) and LDL cholesterol level of less than or equal to 21 mg/dL on day 7 (odds ratio, 1.10) could be a predictor of hospital mortality. The mean change i...

PloS one, 2014

Natural history of chronic obstructive pulmonary disease (COPD) is punctuated by exacerbations; h... more Natural history of chronic obstructive pulmonary disease (COPD) is punctuated by exacerbations; however, little is known about prognosis of the first-ever COPD exacerbation and variables predicting its outcomes. A population-based cohort study among COPD patients with their first-ever exacerbations requiring hospitalizations was conducted. Main outcomes were in-hospital mortality and one-year mortality after discharge. Demographics, comorbidities, medications and in-hospital events were obtained to explore outcome predictors. The cohort comprised 4204 hospitalized COPD patients, of whom 175 (4%) died during the hospitalization. In-hospital mortality was related to higher age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.03-1.06) and Charlson comorbidity index score (OR: 1.08 per point; 95% CI: 1.01-1.15); angiotensin II receptor blockers (OR: 0.61; 95% CI: 0.38-0.98) and β blockers (OR: 0.63; 95% CI: 0.41-0.95) conferred a survival benefit. At one year after disch...

Lung cancer (Amsterdam, Netherlands), 2005

Sialyl Lewis antigens (sLe(x/a)) are cancer-associated carbohydrate determinants, serve as ligand... more Sialyl Lewis antigens (sLe(x/a)) are cancer-associated carbohydrate determinants, serve as ligands of the selectin family and are associated with hematogenous metastasis of cancer. So far, the clinicopathologic values of sialyl Lewis x (sLe(x)) and sialyl Lewis a (sLe(a)) in lung cancer have remained controversial. Using immunohistochemistry, the expressions of sLe(x) and sLe(a) antigens, and an airway mucin (MUC5AC) protein, which was supposed to be the major carrying protein of sialyl Lewis moieties, were studied in surgically resected tumor tissues of 61 patients with stages I or II NSCLC. Thirty-two (52.5%) of the 61 studied subjects were found to be positive for expression of sLe(a), 40 (65.6%) were positive for expression of sLe(x), and 16 (26.2%) were positive for MUC5AC protein. Both the expression of sLe(x) and MUC5AC were associated with adenocarcinoma subtype. Patients bearing tumors with MUC5AC and/or sLe(x) expression had a higher probability of post-operative distant m...

Lung Cancer, 2015

RET rearrangements represent one of the newest molecular targets in non-small cell lung cancer (N... more RET rearrangements represent one of the newest molecular targets in non-small cell lung cancer (NSCLC). However, the prevalence, clinical characteristics, and outcome of patients with RET-rearranged lung adenocarcinoma in metastatic disease remain uncertain. Multiplex reverse transcription-polymerase chain reaction (RT-PCR) was used to detect KIF5B-RET and CCDC6-RET fusions from specimens of malignant pleural effusion (MPE) in patients with metastatic lung adenocarcinoma. The demographic data and outcome of patients with RET-rearranged tumors were compared with those with EGFR-mutant, KRAS-mutant, EML4-ALK-rearranged, and quadri-negative tumors. Of the 722 patients with MPE of lung adenocarcinoma screened, 17 (2.4%) had RET-rearranged tumors. The detected RET rearrangements comprised 11 (65%) KIF5B-RET and 6 (35%) CCDC6-RET fusions, including 2 novel fusion variants identified. The presence of RET rearrangements was not associated with age at diagnosis, gender or smoking history, but predominantly seen in solid histological subtype. None of patients with RET-rearranged tumors had received kinase inhibitors with activity against RET kinase. The median overall survival was 22.4 months (95% CI, 8.8-36.0) for the 17 patients with RET-rearranged tumors, compared with 21.3 months (95% CI, 18.7-23.9; P=0.57) for the 451 patients with EGFR-mutant tumors, 5.4 months (95% CI, 2.7-8.1; P=0.002) for the 13 patients with KRAS-mutant tumors, 18.9 months (95% CI, 10.7-27.1; P=0.82) for the 51 patients with EML4-ALK-rearranged tumors, and 12.0 months (95% CI, 9.0-15.0; P=0.07) for the 190 patients with quadri-negative tumors. Multiplex RT-PCR from specimens of MPE is feasible for the screening of RET rearrangements in NSCLC. Metastatic RET-rearranged lung adenocarcinoma patients with MPE might have favorable survival comparable to those with metastatic EGFR-mutant tumors.

Respiratory Research, 2014

BackgroundChronic pulmonary obstructive disease (COPD) has become the fourth leading cause of dea... more BackgroundChronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide. Cigarette smoking induces neutrophil elastase (NE) and contributes to COPD, but the detailed mechanisms involved are not fully established. In an animal model of pulmonary emphysema, there are increased expressions of placenta growth factor (PlGF) and lung epithelial (LE) cell apoptosis. This study hypothesized that excessive NE may up-regulate PlGF and that PlGF-induced LE apoptosis mediates the pathogenesis of pulmonary emphysema.MethodsHuman bronchial epithelial cells, BEAS-2B, and primary mouse type II alveolar epithelial cells were treated with NE. The PlGF promoter activity was examined by luciferase activity assay, while PlGF expression and secretion were evaluated by RT-PCR, Western blotting, and ELISA. Both cell lines were treated with PlGF to evaluate its effects and the downstream signaling pathways leading to LE cell apoptosis. PlGF knockout and wild-type mice were instilled with NE to determine the roles of PlGF and its downstream molecules in NE-promoted mice pulmonary apoptosis and emphysema phenotype.ResultsThe transcriptional factor, early growth response gene-1, was involved in the NE-promoted PlGF promoter activity, and the expression and secretion of PlGF mRNA and protein in LE cells. PlGF-induced LE cell apoptosis and NE-induced mice pulmonary apoptosis and emphysema were mediated by the downstream c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)¿ signaling pathways.ConclusionThe NE-PlGF-JNK/PKC¿ pathway contributes to the pathogenesis of LE cell apoptosis and emphysema. PlGF and its downstream signaling molecules may be potential therapeutic targets for COPD.

PLOS ONE, 2015

It is important to select appropriate targeted therapies for subgroups of patients with lung aden... more It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations.

Clinical lung cancer, Jan 10, 2015

The purpose of this study was to explore the predictive factors of the effectiveness and treatmen... more The purpose of this study was to explore the predictive factors of the effectiveness and treatment toxicity for pemetrexed as continuation maintenance therapy in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Patients with advanced nonsquamous NSCLC treated with pemetrexed as continuation maintenance therapy were enrolled. The medical records were reviewed and analyzed, including data on basic characteristics, estimated creatinine clearance rate (Ccr), treatment responses, progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. A total of 124 patients were included and all had adenocarcinoma. Patients with an estimated Ccr < 60 mL/min had a significantly longer PFS and OS (P = .045, and P = .006, respectively). Each 10 mL/min increase in estimated Ccr was associated with an increase of 9.8% in the risk of disease progression, and an increase of 9.2% in the risk of death. In contrast, an increase of 10 mL/min in estimated C...

Diagnostic Microbiology and Infectious Disease, 2007

Because of the increasing numbers of nontuberculous mycobacterial isolates from clinical specimen... more Because of the increasing numbers of nontuberculous mycobacterial isolates from clinical specimens, rapid and accurate methods for culture confirmation of Mycobacterium tuberculosis are urgently needed. The study evaluated the performance of the Capilia TB immunochromatographic assay (TAUNS, Numazu, Japan) for culture confirmation of M. tuberculosis using 242 culture-positive liquid media in 2 mycobacterial laboratories from November 2005 to February 2006.

Objectives: We assessed the fluoroquinolone (FQ) susceptibility of clinical isolates of Mycobacte... more Objectives: We assessed the fluoroquinolone (FQ) susceptibility of clinical isolates of Mycobacterium tuberculosis in an endemic area. The genetic mutations responsible for FQ resistance were also evaluated. Methods: A total of 420 M. tuberculosis isolates during January 2004 to December 2005 were randomly selected. Data on the clinical characteristics of the patients were obtained from medical records. The MICs of

Journal of geriatric oncology, 2015

Data on the treatment modalities and prognostic factors for elderly patients with advanced non-sm... more Data on the treatment modalities and prognostic factors for elderly patients with advanced non-small cell lung cancer (NSCLC) remain limited. This study investigates the impact of age and comorbidities on treatment modalities and patient prognosis. From January 2004 to December 2008, patients aged ≥70years old and diagnosed with stage IIIB or IV NSCLC were included retrospectively. Their clinical characteristics were reviewed and analyzed. Comorbidity status was evaluated using Charlson comorbidity index (CCI) and simplified comorbidity score (SCS). A total of 576 patients were included in this analysis. Four hundred and nineteen patients (72.7%) received systemic therapy, including 182 (31.6%) patients who received chemotherapy, and 237 (41.1%) patients who received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) as initial treatment. Patients aged ≥80 were less likely to receive chemotherapy as initial treatment than those aged 70-79 (12.3% vs. 40.9%, p<0....

Oncotarget, Jan 10, 2015

Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth fac... more Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and ...

The Journal of pharmacology and experimental therapeutics, 2014

Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EG... more Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially p...