Budesonide/Formoterol Anti-Inflammatory Reliever and Maintenance or Fluticasone Propionate/Salmeterol Plus As-Needed, Short-Acting ß2 Agonist: Real-World Effectiveness in pAtients without Optimally Controlled asThma (REACT) Study.

INTRODUCTION: In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide®) plus as-needed, short-acting ß2 agonists (SABAs) in Taiwanese patients with inadequate asthma control. METHODS: Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4-5 and 12-16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3±1.3 µg/d, n=551; fluticasone/salmeterol, 1013.8±1.4 µg/d, n=172). RESULTS: At baseline, 72.5% and 27.5% of all patients had "partly" and "uncontrolled" asthma, respectively. Mean±SD ACQ-5 scores were 1.54±1.06 and 1.46±1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (-0.91±1.11) than the fluticasone/salmeterol group (-0.69±1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups. CONCLUSION: Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT00784953.

PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition.

Epigenetic regulation is important for cancer progression; however, the underlying mechanisms, particularly those involving protein acetylation, remain to be fully understood. Here, we show that p300/CBP-associated factor (PCAF)-dependent acetylation of the transcription factor intestine-specific homeobox (ISX) regulates epithelial-mesenchymal transition (EMT) and promotes cancer metastasis. Mechanistically, PCAF acetylation of ISX at lysine 69 promotes the interaction with acetylated bromodomain-containing protein 4 (BRD4) at lysine 332 in tumor cells, and the translocation of the resulting complex into the nucleus. There, it binds to promoters of EMT genes, where acetylation of histone 3 at lysines 9, 14, and 18 initiates chromatin remodeling and subsequent transcriptional activation. Ectopic ISX expression enhances EMT marker expression, including TWIST1, Snail1, and VEGF, induces cancer metastasis, but suppresses E-cadherin expression. In lung cancer, ectopic expression of PCAF-ISX-BRD4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF-ISX-BRD4 axis mediates EMT signaling and regulates tumor initiation and metastasis.

The MyoD family inhibitor domain-containing protein enhances the chemoresistance of cancer stem cells in the epithelial state by increasing ß-catenin activity.

Cancer cells with mesenchymal attributes potentially display chemoresistance. Cancer stem cells (CSCs), which are intrinsically resistant to most chemotherapy agents, exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal states. However, the drug response of CSCs in the epithelial and mesenchymal states has not been completely investigated. In this study, we found that epithelial-type (E-cadherinhigh/CD133high) CSCs displayed a higher sphere formation ability and chemoresistance than mesenchymal-type (E-cadherinlowCD133high) CSCs. Gene expression profiling of the CSC and non-CSC subpopulations with distinct epithelial-to-mesenchymal transition (EMT) states showed that MyoD family inhibitor domain-containing (MDFIC) was selectively upregulated in epithelial-type CSCs. Knockdown of MDFIC sensitized epithelial-type CSCs to chemotherapy agents. Ectopic expression of MDFIC increased the chemoresistance of mesenchymal-type CSCs. In a tissue microarray, high MDFIC expression was associated with poor prognosis of non-small cell lung cancer (NSCLC) patients. A mechanistic study showed that the MDFIC p32 isoform, which is located in the cytoplasm, interacted with the destruction complex, Axin/GSK-3/ß-catenin. This interaction stabilized ß-catenin by inhibiting ß-catenin phosphorylation at S33/37 and increased the nuclear translocation and transcriptional activity of ß-catenin. Knockdown of ß-catenin decreased MDFIC-enhanced chemoresistance. These results suggested that the upregulation of MDFIC enhanced the chemoresistance of epithelial-type CSCs by elevating ß-catenin activity. Thus, targeting MDFIC-regulated ß-catenin signaling of epithelial-type CSCs may be a potential strategy to overcome chemoresistance in NSCLC.

Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells.

Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.

Id1 promotes lung cancer cell proliferation and tumor growth through Akt-related pathway.

Overexpression of Id family proteins inhibits cell differentiation and enhances cell proliferation and invasiveness. Although Id1 is the Id family member mostly linked to tumorigenesis, its role in lung cancer is unclear. An elevated Id1 expression was observed in lung cancer cell lines as well as lung cancer tissues. Id1 overexpression increased cell proliferation while Id1 knockdown decreased cell proliferation, mostly through Akt-related pathway. Nude mice study further confirmed an increased tumor growth in Id1-overexpressing cells and a decreased tumor growth in Id1-knockdowned cells. In conclusion, inactivation of Id1 may provide a novel strategy for treatment of lung cancer patients.

Gefitinib as first-line therapy for advanced or metastatic non-small cell lung cancer patients in southern Taiwan.

Gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, is effective in treating patients with non-small cell lung cancer (NSCLC) after unsuccessful chemotherapy. However, survival outcomes and predictors for its effectiveness in chemotherapy-naive NSCLC patients are still not clear. The goal of this study was to investigate the response and survival rates and identify the predictive factors for patients with advanced or metastatic disease receiving gefitinib as first-line therapy. We retrospectively analyzed the response and survival rates of patients with advanced or metastatic NSCLC who had received gefitinib as first-line therapy across six medical institutes in Southern Taiwan between May 2004 and April 2006. The relationship between the response and survival rates to the known predictive factors for gefitinib response and survival was also investigated. A total of 97 patients (65 females and 32 males) were enrolled in this study. Seventy-four patients (76%) had never smoked. Eighty-eight patients (91%) had adenocarcinoma or bronchioloalveolar cell carcinoma. The objective response rate was 56% and the disease control rate (partial response plus stable disease) was 76%. Only poor performance status (Eastern Cooperative Oncology Group score, 3-4) was statistically significantly associated with overall response in this study. The 1-year survival rate was 77%. We suggest that first-line gefitinib monotherapy is promising in some subgroups of Asian patients with NSCLC. Further randomized controlled studies are needed to validate the effectiveness of first-line gefitinib therapy.

Successful weaning predictors in a respiratory care center in Taiwan.

Respiratory care centers (RCCs) provide effective care for patients who have been in intensive care and have undergone prolonged mechanical ventilation. Between February 2002 and December 2005, 891 patients who met the admission criteria of RCCs were referred to our RCC at Kaohsiung Medical University Hospital in southern Taiwan for attempted weaning. We recorded demographic and clinical data, including variables identified previously as predictive of weaning success among highly selected populations. The common causes of respiratory failure at RCC admission were neuromuscular disease (29.2%), pneumonia (27.5%), cancer (18.0%), cardiovascular disease (10.1%), sepsis (5.7%) and post-surgery (1.6%). The percentage of patients successfully weaned was 40.2%, while 59.8% remained dependent on ventilators. In a stepwise multivariate logistic regression analysis, significant predictors of weaning success included neuromuscular disease (odds ratio [OR], 2.64), APACHE II score (OR, 0.93) and blood urea nitrogen level at RCC admission (OR, 0.99). The results could be helpful in the accreditation of medical care quality and may provide guidelines for future research and education programs.

Organophosphate poisoning: 10 years of experience in southern Taiwan.

Poisoning due to organophosphate pesticides is an important cause of morbidity and mortality worldwide. Although standard treatments involving the administration of atropine and oximes have been used, there remain many controversial areas concerning organophosphate poisoning (OPP). Herein, we present our 10 years of experience in assessing the severity of OPP in southern Taiwan. A retrospective study was performed on patients admitted with OPP. A total of 75 patients (50 males and 25 females) were studied between January 1996 and December 2005. Diagnosis was based on a clinical assessment and serum acetylcholinesterase (AChE) level at the time of hospital admission. The severity of OPP was assessed using the grading system of Bardin et al. The duration and dosage of atropine and palidroxime were recorded. All the biochemical data were analyzed. Sixty-one of the patients had attempted suicide and 14 patients had accidental exposure. The overall mortality rate was 8%. Muscarinic effects were observed in 66 (88%) of the OPP patients and the most frequent symptom was bronchial hypersecretion (52%). Among these three different severity groups, prolonged length of stay, higher infection rates, and higher mortality were found in the life-threatened group. The initial serum C-reactive protein (CRP) level was strongly correlated to the severity grading of the OPP. Nearly half of the patients were admitted to the intensive care unit (ICU) and, of this, 21 patients developed respiratory failure within 72 hours. Low serum AChE levels support the diagnosis of OPP, but no significant association was found between the severity of OPP and serum AChE levels. The grading system of Bardin et al is very helpful for physicians to facilitate the recognition of seriously poisoned subjects, and to permit their early admission to an ICU. Initial serum CRP, an acute phase reactant, had significant value in assessing the severity of the OPP. Although the management of acute OPP is supportive and the recovery rate is high, anti-cholinergic therapy should be used as soon as possible to counteract muscarinic effects. Physicians must be aware of the potential dangers of respiratory failure, which could occur within 72 hours of OPP.

Do pulmonary hemodynamics change after effective lung volume reduction surgery for emphysema?

The improvement in lung function, exercise test, blood gas levels, and symptoms in emphysema patients after volume reduction surgery is a result of improvements in breathing mechanics. The question is, is the improvement in the condition related to pulmonary hemodynamics? Few studies have examined pre- and postoperative pulmonary pressure. This paper examines whether there is any significant change in systolic and diastolic pulmonary pressure after effective volume reduction surgery. From October 1999 to October 2002, 12 emphysema patients who underwent volume reduction surgery were studied. Systolic and diastolic pulmonary pressures were measured 2 days before surgery through cardiac catheterization and 2 days after removal of the chest tubes through Swan Ganz catheters placed in the operating room just before surgery. Patients were stable and breathed without assistance during the postoperative pressure measurement. Blood gas analysis, lung function tests, and a 6-minute walk test were performed preoperatively and 3 months postoperatively. The two sets of data were compared using the Wilcoxon signed rank test. There was no significant change in pulmonary hemodynamics, although pulmonary function improved. The improvement in pulmonary function after volume reduction surgery is not related to pulmonary hemodynamics.