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Year of Publication
1.  The Impact of Sequence of Chemotherapy and EGFR-TKI Treatment on Different EGFR Mutation Lung Adenocarcinoma 
BioMed Research International  2015;2015:948267.
Objectives. Chemotherapy as first-/second-line treatment in different epidermal growth factor receptor (EGFR) mutation lung adenocarcinoma remains controversial. Methods. Consecutive patients were collected between 2009 and 2012. Patients were divided into two groups (1st-line chemotherapy: n = 56 and 2nd-line chemotherapy: n = 55). Their outcomes profiles were analyzed. Results. The overall survival (OS) of all patients (390 versus 662 days, p < 0.0001), as well as both progression-free survival (PFS, 151 versus 252 days, p = 0.0001) and OS (308 versus 704 days, p = 0.0001) of patients with L858R mutation (n = 63), who received 2nd-line chemotherapy, was significantly poor. By univariate and multivariate analysis, 2nd-line chemotherapy, and L858R mutation were significantly related to poor PFS and OS. Conclusion. In advanced lung adenocarcinoma, L858R mutation and 2nd-line chemotherapy caused a poor outcome. It is a consideration to choice of 1st-line chemotherapy in these subjects. A prospective design is warranted to confirm this finding.
doi:10.1155/2015/948267
PMCID: PMC4644829  PMID: 26609535
2.  Afatinib in Treatment-Naive Patients With EGFR-Mutated Lung Adenocarcinoma With Brain Metastasis 
Medicine  2015;94(41):e1739.
Abstract
Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) were previously the standard first-line treatments for lung cancers with activating EGFR mutations. The first-generation reversible EGFR TKIs, gefitinib and erlotinib, demonstrated substantial efficacy in the treatment of brain metastases from EGFR-mutated lung adenocarcinoma. However, the efficacy of afatinib, the second-generation irreversible EGFR TKI, as the first-line treatment in lung adenocarcinoma patients with brain metastasis has yet to be evaluated.
Here, we report cases of 3 patients who received afatinib alone as the first-line treatment in combination with whole-brain radiotherapy or following surgical resection of brain metastases. All 3 patients had EGFR L858R mutation. The first patient had lung adenocarcinoma with brain metastasis and no neurologic symptoms. After consultation, she received afatinib as a first-line treatment. Chest computed tomography and brain magnetic resonance imaging (MRI) showed partial response. The second patient had lung adenocarcinoma accompanied with a metastatic brain lesion associated with seizures. This patient received whole-brain radiotherapy and afatinib treatment following brain MRI and subsequently showed significant regression of the brain metastasis. The third patient had strabismus of the right eye, and brain MRI showed a single tumor at the cerebellar pontine angle. This patient underwent surgical resection of the tumor followed by afatinib treatment. He refused adjuvant radiotherapy after surgery for brain metastasis. The brain MRI showed no recurrent brain metastasis, and the patient had relatively less neurologic deficiency.
This series of 3 cases indicate that afatinib may be an appropriate first-line treatment alternative in patients having lung adenocarcinoma with EGFR mutations. Further retrospective analyses and prospective clinical trials are required to substantiate the efficacy of afatinib in the treatment of brain metastases of lung adenocarcinoma.
doi:10.1097/MD.0000000000001739
PMCID: PMC4616807  PMID: 26469914
3.  Flexible Bronchoscopy with Multiple Modalities for Foreign Body Removal in Adults 
PLoS ONE  2015;10(3):e0118993.
Objectives
Aspiration of the lower airways due to foreign body is rare in adults. This study aimed to determine the outcome of patients who received flexible bronchoscopy with different modalities for foreign body removal in the lower airways.
Patients and Methods
Between January 2003 and January 2014, 94 patients diagnosed with foreign body in the lower airways underwent flexible bronchoscopy with different modalities, which included forceps, loop, basket, knife, electromagnet, and cryotherapy. The clinical presentation, foreign body location and characteristics, and applications of flexible bronchoscopy were analyzed.
Results
Forty (43%) patients had acute aspiration, which developed within one week of foreign body entry and 54 (57%) had chronic aspiration. The most common foreign bodies were teeth or bone. More patients with chronic aspiration than those with acute aspiration were referred from the out-patient clinic (48% vs. 28%), but more patients with acute aspiration were referred from the emergency room (35% vs. 6%) and intensive care unit (18% vs. 2%). Flexible bronchoscopy with different modalities was used to remove the foreign bodies (85/94, 90%). Electromagnet or cryotherapy was used in nine patients to eliminate the surrounding granulation tissue before foreign body removal. In the nine patients with failed flexible bronchoscopy, eight underwent rigid bronchoscopy instead and one had right lower lung lobectomy for lung abscess.
Conclusions
Flexible bronchoscopy with multiple modalities is effective for diagnosing and removing foreign bodies in the lower respiratory airways in adults, with a high success rate (90%) and no difference between acute and chronic aspirations.
doi:10.1371/journal.pone.0118993
PMCID: PMC4358882  PMID: 25768933
4.  Removal of Endobronchial Malignant Mass by Cryotherapy Improved Performance Status to Receive Chemotherapy 
The Scientific World Journal  2014;2014:369739.
Although malignant endobronchial mass (MEM) has poor prognosis, cryotherapy is reportedly a palliative treatment. Clinical data on postcryotherapy MEM patients in a university-affiliated hospital between 2007 and 2011 were evaluated. Survival curve with or without postcryotherapy chemotherapy and performance status (PS) improvement of these subjects were analyzed using the Kaplan-Meier method. There were 59 patients (42 males), with median age of 64 years (range, 51–76, and median performance status of 2 (interquartile range [IQR], 2-3). Postcryotherapy complications included minor bleeding (n = 12) and need for multiple procedures (n = 10), while outcomes were relief of symptoms (n = 51), improved PS (n = 45), and ability to receive chemotherapy (n = 40). The survival of patients with chemotherapy postcryotherapy was longer than that of patients without such chemotherapy (median, 534 versus 106 days; log-rank test, P = 0.007; hazard ratio, 0.25; 95% confidence interval, 0.10–0.69). The survival of patients with PS improvement postcryotherapy was longer than that of patients without PS improvement (median, 406 versus 106 days; log-rank test, P = 0.02; hazard ratio, 0.28; 95% confidence interval, 0.10–0.81). Cryotherapy is a feasible treatment for MEM. With better PS after cryotherapy, further chemotherapy becomes possible for patients to improve survival when MEM caused dyspnea and poor PS.
doi:10.1155/2014/369739
PMCID: PMC4212536  PMID: 25383370
5.  PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response 
The Journal of Clinical Investigation  null;125(12):4529-4543.
Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.
doi:10.1172/JCI82826
PMCID: PMC4665782  PMID: 26571401
6.  Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer 
Cancer research  2014;74(17):4822-4835.
Triple-negative breast cancer (TNBC) is a highly heterogeneous and recurrent subtype of breast cancer that lacks an effective targeted therapy. To identify candidate therapeutic targets, we profiled global gene expression in TNBC and breast tumor-initiating cells with a patient survival dataset. Eight TNBC-related kinases were found to be overexpressed in TNBC cells with stem-like properties. Among them, expression of PKC-α, MET and CDK6 correlated with poorer survival outcomes. In cases co-expressing two of these three kinases, survival rates were lower than in cases where only one of these kinases was expressed. In functional tests, two-drug combinations targeting these three kinases inhibited TNBC cell proliferation and tumorigenic potential in a cooperative manner. A combination of PKC-α−MET inhibitors also attenuated tumor growth in a cooperative manner in vivo. Our findings define three kinases critical for TNBC growth and offer a preclinical rationale for their candidacy as effective therapeutic targets in treating TNBC.
doi:10.1158/0008-5472.CAN-14-0584
PMCID: PMC4154991  PMID: 24970481
Triple-negative breast cancer; breast tumor-initiating cells; bioinformatics; cancer-related kinases; combinatorial therapy; synergism
7.  EGFR potentiates MCM7-mediated DNA replication through tyrosine phosphorylation of Lyn kinase in human cancers 
Cancer cell  2013;23(6):796-810.
Summary
EGFR initiates a signaling cascade that leads to DNA synthesis and cell proliferation, but its role in regulating DNA replication licensing is unclear. Here, we show that activated EGFR phosphorylates the p56 isoform of Lyn, p56Lyn, at Y32, which then phosphorylates MCM7, a licensing factor critical for DNA replication, at Y600 to increase its association with other MCM complex proteins, thereby promoting DNA synthesis complex assembly and cell proliferation. Both p56Lyn Y32 and MCM7 Y600 phosphorylation are enhanced in proliferating cells and correlated with poor survival of breast cancer patients. These results establish a signaling cascade in which EGFR enhances MCM7 phosphorylation and DNA replication through Lyn phosphorylation in human cancer cells.
doi:10.1016/j.ccr.2013.04.027
PMCID: PMC3703149  PMID: 23764002
8.  The Role of the High-Sensitivity C-Reactive Protein in Patients with Stable Non-Cystic Fibrosis Bronchiectasis 
Pulmonary Medicine  2013;2013:795140.
Study Objectives. The aim of this study is to investigate the correlation between serum high-sensitivity C-reactive protein (hs-CRP) and other clinical tools including high-resolution computed tomography (HRCT) in patients with stable non-CF bronchiectasis. Design. A within-subject correlational study of a group of patients with stable non-CF bronchiectasis, who were recruited from our outpatient clinic, was done over a two-year period. Measurements. Sixty-nine stable non-CF bronchiectasis patients were evaluated in terms of hs-CRP, 6-minute walk test, pulmonary function tests, and HRCT. Results. Circulating hs-CRP levels were significantly correlated with HRCT scores (n = 69, r = 0.473, P < 0.001) and resting oxygenation saturation (r = −0.269, P = 0.025). HRCT severity scores significantly increased in patients with hs-CRP level of 4.26 mg/L or higher (mean ± SD 28.1 ± 13.1) compared to those with hs-CRP level less than 4.26 mg/L (31.7 ± 9.8, P = 0.004). Oxygenation saturation at rest was lower in those with hs-CRP level of 4.26 mg/L or higher (93.5 ± 4.4%) compared to those with hs-CRP level less than 4.26 mg/L (96.4 ± 1.6%, P = 0.001). Conclusion. There was a good correlation between serum hs-CRP and HRCT scores in the patients with stable non-CF bronchiectasis.
doi:10.1155/2013/795140
PMCID: PMC3870862  PMID: 24381758
9.  Feasibility of Bispectral Index-Guided Propofol Infusion for Flexible Bronchoscopy Sedation: A Randomized Controlled Trial 
PLoS ONE  2011;6(11):e27769.
Objectives
There are safety issues associated with propofol use for flexible bronchoscopy (FB). The bispectral index (BIS) correlates well with the level of consciousness. The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation, benefiting the patients and bronchoscopists.
Methods
After administering alfentanil bolus, 500 patients were randomized to either propofol infusion titrated to a BIS level of 65-75 (study group) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation. The primary endpoint was safety, while the secondary endpoints were recovery time, patient tolerance, and cooperation.
Results
The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups (study vs. control groups: 39.9% vs. 35.7%, p = 0.340; 7.4% vs. 4.4%, p = 0.159, respectively). The mean lowest blood pressure was lower in the study group. Logistic regression revealed male gender, higher American Society of Anesthesiologists physical status, and electrocautery were associated with hypoxemia, whereas lower propofol dose for induction was associated with hypotension in the study group. The study group had better global tolerance (p<0.001), less procedural interference by movement or cough (13.6% vs. 36.1%, p<0.001; 30.0% vs. 44.2%, p = 0.001, respectively), and shorter time to orientation and ambulation (11.7±10.2 min vs. 29.7±26.8 min, p<0.001; 30.0±18.2 min vs. 55.7±40.6 min, p<0.001, respectively) compared to the control group.
Conclusions
BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance, with fast recovery and less procedure interference.
Trial Registration
ClinicalTrials. gov NCT00789815
doi:10.1371/journal.pone.0027769
PMCID: PMC3223212  PMID: 22132138

Results 1-9 (9)