Yoon Soo Chang

Capecitabine combined with gemcitabine (CapGem) as first‐line treatment in patients with advanced/metastatic biliary tract carcinoma

Biliary tract carcinoma is an aggressive cancer, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A Phase II trial was conducted to study a combination of oral capecitabine and gemcitabine (CapGem) as first‐line therapy in patients with advanced and/or metastatic biliary carcinoma.

The Clinical Utility of Polymerase Chain Reaction for the Diagnosis of Pleural Tuberculosis

BACKGROUND There is no exact consensus about the usefulness of the Mycobacterium tuberculosis polymerase chain reaction (PCR) testing for the diagnosis of tuberculous pleural effusion because of the diverse PCR methods and the different diagnostic criteria that are described in other studies. METHODS We analyzed pleural effusion specimens obtained from 111 patients for whom the exclusion of the possibility of tuberculous pleural effusion was necessary. We performed M. tuberculosis PCR testing using the Cobas Amplicor MTB test (Roche Diagnostic Systems), which is fully automated and commercially available. RESULTS Results of the M. tuberculosis PCR test of pleural effusion specimens were positive for 7 (17.1%) of the 41 patients with confirmed pleural tuberculosis and for 3 (18.8%) of the 16 patients with probable pleural tuberculosis. The overall sensitivity and specificity of M. tuberculosis PCR testing of pleural effusion were 17.5% and 98.1%, respectively. The sensitivity of M. tuberculosis PCR testing for each group of patients with tuberculous pleural effusion detected by smear-positive results, smear-negative and culture-positive results, and culture-negative and pleural biopsy-positive results, was 100.0%, 33.3%, and 3.7%, respectively. Of the 57 patients with pleural tuberculosis, only 3 (5.3%) had positive results of M. tuberculosis PCR testing along with negative results of smearing, negative results of pleural pathological analysis, and a low level of adenosine deaminase. CONCLUSION For specimens such as pleural effusion, in which the bacillary load is very low, the clinical utility of PCR testing seems highly limited.

Promoter −202 A/C polymorphism of insulin-like growth factor binding protein-3 gene and non-small cell lung cancer risk

Insulin‐like growth factor binding protein‐3 (IGFBP‐3) inhibits the mitogenic and antiapoptotic activity of insulin‐like growth factor (IGF) by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP‐3 can enhance the activity of IGF by protecting IGF from degradation. More than half of the interindividual variations in IGFBP‐3 levels are known to be genetically determined by the polymorphism at −202 locus of IGFBP‐3 gene. Therefore, we attempted to ascertain whether the A−202C polymorphic variation of IGFBP‐3 gene constitutes a risk factor for non‐small cell lung cancer (NSCLC). Our study included 209 NSCLC patients and 209 age‐, gender‐ and smoking status‐matched control subjects. The frequencies of each polymorphic variation in the control population were as follows: AA = 95 (45.5%), AC = 91 (43.5%) and CC = 23 (11.0%). In the NSCLC subjects, the genotypic frequencies were as follows: AA = 131 (62.7%), AC = 73 (34.9%) and CC = 5 (2.4%). We detected statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p < 0.05, Pearsons chi‐square test). The NSCLC risk correlated significantly with AA genotype. Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 2.45 (95% CI = 1.17–5.40) and that for the ones with AA genotype was 4.58 (95% CI = 2.17–10.30). These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC and a potential target for novel antineoplastic therapies and/or preventative strategies in high‐risk groups.

Clinical significance of insulin-like growth factor-1 receptor expression in stage I non-small-cell lung cancer: immunohistochemical analysis.

Background/Aims The insulin-like growth factor (IGF) system has been implicated in tumor growth, invasion, and metastasis. However, reports on the IGF-1 receptor (IGF-1R) based on radioimmunoassays are conflicting, and its prognostic implications in non-small-cell lung cancer (NSCLC) are still controversial. Methods Seventy-one paraffin-embedded tissue sections from stage I NSCLC patients were stained using a mouse monoclonal antibody against human IGF-1R. Results The intensity and frequency of IGF-1R expression on the membrane and cytoplasm of cancer cells was evaluated and scored using a semiquantitative system. IGF-1R expression was detected in nine of 71 (12.7%) cases. No significant relationship was found between clinical/histopathological parameters and IGF-1R expression. None of the patients whose tumor expressed IGF-1R had experienced distant metastasis or cancer-related death, although the difference did not reach statistical significance. Conclusions We conclude that IGF-1R expression may not be a major prognostic factor for stage I NSCLC.

Clinical Outcomes of Tigecycline in the Treatment of Multidrug-Resistant Acinetobacter baumannii Infection

PURPOSE Acinetobacter baumannii (A. baumannii) has emerged as a major cause of nosocomial pneumonia and sepsis in seriously ill patients. Multidrug-resistant A. baumannii (MDRAB) is increasing in frequency, and the management of its infections is consequently difficult. Therefore, tigecycline is considered to be the drug of choice for MDRAB treatment. The aim of our study was to evaluate the microbiological eradication and clinical effectiveness of tigecycline against MDRAB in seriously ill patients, including patients with ventilator-associated pneumonia (VAP). MATERIALS AND METHODS We conducted a retrospective study including patients with A. baumannii infections who were treated with tigecycline between April 1, 2009 and March 31, 2010. We treated 27 patients with tigecycline for MDRAB infections. RESULTS The mean age of patients was 66.2 years, and 20 (74.1%) patients were male. The median length of stay at hospital was 74.6 days. MDRAB was eradicated from the site of infection in 23 cases (85.2%), however, only 17 cases (63.0%) showed positive clinical responses. Overall, an in-hospital mortality rate of 51.9% was observed, and 4 cases of death were attributable to sepsis. The combination therapy showed better clinical and microbial success rates than the monotherapy without significant difference. CONCLUSION We observed the relatively low clinical success rate although the microbial eradication rate was high, probably due to superinfections in VAP and bacteremia. We suggest that clinicians should limit tigecycline monotherapy for MDRAB infection in critically ill patients, until large controlled clinical trials should be conducted.

Lipid raft modulation inhibits NSCLC cell migration through delocalization of the focal adhesion complex

Lipid raft, a specialized membrane structure enriched with cholesterol and glycosphingolipid, contains molecules that convey environmental stimuli to the intracellular systems. Authors investigated the effects of raft cholesterol depletion on non-small cell lung cancer (NSCLC) cell migration. Incubation of NSCLC cells in media containing lovastatin resulted in inhibition of cell migration by 63.1-83.3%, whereas raft cholesterol depletion with successive treatment using methyl-beta cyclodextrin (MbetaCD) followed by lovastatin further suppressed their migration by 35.0-57.8%. Raft cholesterol depletion partially inhibited EGF-induced phosphorylation of EGFR and FAK, however, no change was observed in other molecules comprising focal adhesion complex. It resulted in disappearance of filopodia, inhibition of EGF-induced pY397 FAK aggregation, and its destabilization. Cholesterol depletion inhibited phosphorylation of Src on Y416 in the detergent-insoluble fraction followed by decreased localization of total and pY397 FAK in the detergent-insoluble fraction. Minimal changes in these molecules were observed in the detergent-soluble fraction and interactions between FAK and other molecules of the focal adhesion complex were not influenced. Immunocytochemical analysis confirmed translocation of Src from the raft into cytoplasm and disappearance of EGF-induced membrane ruffling by raft cholesterol depletion. In cholesterol-depleted cells, EGF-induced phosphorylation of Src, Akt, and p44/42 in the detergent-insoluble fraction were inhibited whereas phosphorylation of GSK-3beta was unaffected. We conclude that raft cholesterol depletion inhibited NSCLC migration through inhibition of phosphorylation of raft associated Src and dislocation of molecules comprising focal adhesion complexes from raft rather than by inhibiting their recruitment to Src and interaction.

Inhibition of mTORC1 induces loss of E-cadherin through AKT/GSK-3β signaling-mediated upregulation of E-cadherin repressor complexes in non-small cell lung cancer cells

BackgroundmTOR, which can form mTOR Complex 1 (mTORC1) or mTOR Complex 2 (mTORC2) depending on its binding partners, is frequently deregulated in the pulmonary neoplastic conditions and interstitial lung diseases of the patients treated with rapalogs. In this study, we investigated the relationship between mTOR signaling and epithelial mesenchymal transition (EMT) by dissecting mTOR pathways.MethodsComponents of mTOR signaling pathway were silenced by shRNA in a panel of non-small cell lung cancer cell lines and protein expression of epithelial and mesenchymal markers were evaluated by immunoblotting and immunocytochemistry. mRNA level of the E-cadherin repressor complexes were evaluated by qRT-PCR.ResultsIGF-1 treatment decreased expression of the E-cadherin and rapamycin increased its expression, suggesting hyperactivation of mTOR signaling relates to the loss of E-cadherin. Genetic ablation of rapamycin-insensitive companion of mTOR (Rictor), a component of mTORC2, did not influence E-cadherin expression, whereas genetic ablation of regulatory-associated protein of mTOR (Raptor), a component of mTORC1, led to a decrease in E-cadherin expression at the mRNA level. Increased phosphorylation of AKT at Ser473 and GSK-3β at Ser9 were observed in the Raptor-silenced NSCLC cells. Of the E-cadherin repressor complexes tested, Snail, Zeb2, and Twist1 mRNAs were elevated in raptor-silenced A549 cells, and Zeb2 and Twist1 mRNAs were elevated in Raptor-silenced H2009 cells. These findings were recapitulated by treatment with the GSK-3β inhibitor, LiCl. Raptor knockdown A549 cells showed increased expression of N-cadherin and vimentin with mesenchymal phenotypic changes.ConclusionsIn conclusion, selective inhibition of mTORC1 leads to hyperactivation of the AKT/GSK-3β pathway, inducing E-cadherin repressor complexes and EMT. These findings imply the existence of a feedback inhibition loop of mTORC1 onto mTORC2 that plays a role in the homeostasis of E-cadherin expression and EMT, requiring caution in the clinical use of rapalog and selective mTORC1 inhibitors.

Notch1 destabilizes the adherens junction complex through upregulation of the Snail family of E-cadherin repressors in non-small cell lung cancer.

One of the critical steps driving cancer cell migration and metastasis is the repression of cell adhesion molecules resulting in loss of cell‑to-cell adhesion. Although interactions between Notch1 and components of the adherens junction complex have been suggested, little is known concerning the consequence of their interactions. In this study, we investigated the interaction between the Notch1 and the E‑cadherin/β‑catenin complex, its effect on the expression of adherens junction complex components and its influence on non-small cell lung cancer (NSCLC) cell proliferation. With progression of lung neoplastic lesions in LSL K-ras G12D mice, the expression of E‑cadherin was inhibited whereas that of Notch1 was increased with frequent nuclear localization, suggesting an inverse relationship between E‑cadherin and Notch1 expression with tumor progression. Transduction of the human Notch1 intracellular domain (N1ICD) into NSCLC cells inhibited expression of E‑cadherin and β‑catenin and induced changes in the localization of adherens junction molecules. The loss of E‑cadherin was mediated through upregulation of the Snail family of transcription factors, Snail and Slug. Experiments in which siRNA against E-cadherin was introduced into NSCLC cells revealed that N1ICD decreased the expression of β‑catenin in an E‑cadherin‑independent manner, leading to inhibition of markers of Wnt/β‑catenin signaling activation. Despite inhibition of Wnt/β‑catenin signaling in the N1ICD‑transduced cells, cells transduced with N1ICD showed no difference in cell cycle progression when compared with that of the control vector-transduced cells. In conclusion, Notch1 inhibited the expression of E‑cadherin through upregulation of the Snail family of transcriptional factors, resulting in inhibition of expression of β‑catenin and destabilization of adherens junctions.

Insulin-like growth factor-1 attenuates cisplatin-induced γH2AX formation and DNA double-strand breaks repair pathway in non-small cell lung cancer

Because insulin-like growth factor-1 (IGF-1) counteracts the anti-neoplastic effect of cisplatin that induces DNA damage and cell death through the formation of platinum-DNA adducts, we investigated the effects of IGF-1 on the DNA double-strand breaks (DSBs) repair system induced by cisplatin. NCI-H1299 and H460 non-small cell lung cancer (NSCLC) cells treated with IGF-1 recovered from cisplatin-derived inhibited proliferation and apoptosis. Decreased tail length in comet assay and suppressed phosphorylation of histone H2AX at Ser139 with IGF-1 cotreatment indicates that IGF-1 attenuates cisplatin-induced DNA damage. Cotreatment with IGF-1 attenuates phosphorylation of ataxia-telangiectasia mutated (ATM) at Ser1981, and ATM-Rad3-related (ATR) at Ser428 and subsequent phosphorylation of Chk2, Chk1, and p53 also dwindled by IGF-1. On the other hand, suppression of the IGF system with AG1024 or siRNA of insulin receptor substrate-1 (IRS-1), a major adaptor molecule of the IGF system, augmented cisplatin-induced gammaH2AX, Ser1981-pATM, and Ser428-pATR generation. ATM, which plays an important role in the phosphorylation of histone H2AX and Chk2 at Thr68, strongly binds with IRS-1 under the influence of cisplatin, and the interaction was partially inhibited by IGF-1. Immunocytochemistry revealed that cisplatin induces nuclear translocation of IRS-1 with Ser1981-pATM, which is suppressed by cotreatment with IGF-1. In conclusion, cisplatin-induced gammaH2AX formation, DNA DSBs repair, and damage checkpoint pathway is inhibited by IGF-1. Cisplatin derives interaction between ATM and IRS-1, which is suppressed by IGF-1. Modulation of biologic activity of the IGF-1 system could be a promising modality that raises the response rate of conventional chemotherapy.

Fiberoptic bronchoscopy for the rapid diagnosis of smear-negative pulmonary tuberculosis

BackgroundThis study was aimed to investigate the diagnostic value of fiberoptic bronchoscopy (FOB) with chest high-resolution computed tomography (HRCT) for the rapid diagnosis of active pulmonary tuberculosis (PTB) in patients suspected of PTB but found to have a negative sputum acid-fast bacilli (AFB) smear.MethodsWe evaluated the diagnostic accuracy of results from FOB and HRCT in 126 patients at Gangnam Severance Hospital (Seoul, Korea) who were suspected of having PTB.ResultsOf 126 patients who had negative sputum AFB smears but were suspected of having PTB, 54 patients were confirmed as having active PTB. Hemoptysis was negatively correlated with active PTB. Tree-in-bud appearance on HRCT was significantly associated with active PTB. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FOB alone was 75.9%, 97.2%, 95.3%, and 84.3%, respectively, for the rapid diagnosis of active PTB. The combination of FOB and HRCT improved the sensitivity to 96.3% and the NPV to 96.2%.ConclusionsFOB is a useful tool in the rapid diagnosis of active PTB with a high sensitivity, specificity, PPV and NPV in sputum smear-negative PTB-suspected patients. HRCT improves the sensitivity of FOB when used in combination with FOB in sputum smear-negative patients suspected of having PTB.