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Ku G.Y.,Johns Hopkins Singapore International Medical Center | Haaland B.A.,National University of Singapore | de Lima Lopes G.,Johns Hopkins Singapore International Medical Center
Lung Cancer | Year: 2011

Background: Gefitinib is an oral tyrosine kinase inhibitor against the epidermal growth factor receptor (EGFR). It has been shown to be active in patients with advanced non-small cell lung cancer (NSCLC) whose tumors contain EGFR mutations. Methods: We performed a meta-analysis of four randomized studies that compared gefitinib with chemotherapy in the first-line treatment of patients with advanced NSCLC: IPASS, North-East Japan, West Japan and first-SIGNAL studies. Patients were selected either on the basis of known EGFR mutations or based on clinicopathologic criteria - non-smokers with adenocarcinomas - associated with increased likelihood of EGFR mutations. Results: Nearly 2000 patients were enrolled on these four trials. Median ages ranged from 57 to 64years. Seventy-six percent were women and 86% were non-smokers. Overall, gefitinib was associated with significantly less toxicity than chemotherapy and improved quality-of-life. Gefitinib also produced higher response rates in the EGFR mutation-positive patients (72% vs. 38%, odds ratio 4.04, p<10 -15), as well as improved progression-free survival (PFS; hazard ratio 0.45, p<10 -16). Overall survival (OS) was not significantly different between treatment groups (p=0.35). Conclusions: This meta-analysis confirms the results of each individual study and narrows the confidence intervals of these results. In patients with known EGFR mutations or whose tumors are likely to harbor a mutation, upfront gefitinib or chemotherapy are associated with similar OS. Gefitinib is associated with less fatigue, myelosuppression and nausea than chemotherapy (but produces more skin rash, diarrhea and pneumonitis). Patients receiving gefitinib have improved quality-of-life compared to those receiving chemotherapy, making it an appropriate first-line choice. © 2011 Elsevier Ireland Ltd.


Ku G.,Sloan Kettering Cancer Center | Tan I.B.,National Cancer Center Singapore | Yau T.,University of Hong Kong | Boku N.,Kanagawa University | And 5 more authors.
The Lancet Oncology | Year: 2012

Colon cancer is seen with increasing frequency in the Asia-Pacific region, and it is one of the most important causes of cancer mortality worldwide. This article reviews the available evidence for optimum management of colon cancer-in particular, with respect to screening and early detection of colon cancer, laparoscopic surgical treatment, adjuvant treatment of individuals with high-risk stage II and stage III cancer, palliative treatment of patients with metastatic disease, and management of resectable and potentially resectable metastases-and how these strategies can be applied in Asian countries with different levels of health-care resources and economic development, stratified by basic, limited, enhanced, and maximum resource levels. © 2012 Elsevier Ltd.


De Lima Lopes Jr. G.,Johns Hopkins Singapore International Medical Center | De Lima Lopes Jr. G.,Johns Hopkins University | Segel J.E.,National University of Singapore | Tan D.S.W.,National Cancer Center | And 3 more authors.
Cancer | Year: 2012

Background: Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach. Methods: A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted. Results: EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations. Conclusions: This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs. © 2011 American Cancer Society.


Yang Z.-C.,National University of Singapore | Wang M.,Johns Hopkins Singapore International Medical Center | Yong A.M.,Institute of Materials Research and Engineering of Singapore | Wong S.Y.,Institute of Materials Research and Engineering of Singapore | And 5 more authors.
Chemical Communications | Year: 2011

A facile method is developed to synthesize intrinsically fluorescent carbon dots by hydrothermal treatment of glucose in the presence of monopotassium phosphate. The fluorescence emission of the carbon dots thus produced is tunable by simply adjusting the concentration of monopotassium phosphate. © 2011 The Royal Society of Chemistry.


Chang A.Y.,Johns Hopkins University | Chang A.Y.,Johns Hopkins Singapore International Medical Center | Wang M.,Johns Hopkins University
BMC Cancer | Year: 2013

Background: Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.Methods: Growth inhibition was assessed by MTS assay. EGFR, Src and downstream proteins FAK, Akt, MAPK42/44, Stat3 expressions were measured by western blot. Cell adhesion, migration and invasion were performed with and without dasatinib treatment.Results: The IC50 of 9 cell lines ranged from 0.7 μM ~ 14.2 μM. In general the growth inhibition by dasatinib was related to total Src (t-Src) and the ratio of activated Src (p-Src) to t-Src. There was good correlation of the sensitivity to dasatinib and the inhibition level of p-Src, p-FAK576/577 and p-Akt. No inhibition was found on Stat3 and MAPK42/44 in all cell lines. The inhibition of cell adhesion, migration and invasion were correlated with p-FAK inhibition.Conclusion: Dasatinib inhibits the proliferation, adhesion, migration and invasion of HCC cells in vitro via inhibiting of Src tyrosine kinase and affecting SFK/FAK and PI3K/PTEN/Akt, but not Ras/Raf/MEK/ERK and JAK/Stat pathways. T-Src and p-Src/t-Src may be useful biomarkers to select HCC patients for dasatinib treatment. © 2013 Chang and Wang; licensee BioMed Central Ltd.


Ku G.Y.,Johns Hopkins Singapore International Medical Center | Ku G.Y.,Johns Hopkins University | Haaland B.A.,Quantitative Medicine | De Lima Lopes Jr. G.,Johns Hopkins Singapore International Medical Center | De Lima Lopes Jr. G.,Johns Hopkins University
Cancer Chemotherapy and Pharmacology | Year: 2012

Background Cetuximab, a monoclonal antibody against the epidermal growth factor receptor, inconsistently improves response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced colorectal cancer patients with K-ras wildtype (WT) tumors. Methods We performed a meta-analysis of four trials where K-ras WT Pts received a fluoropyrimidine (infusional vs. bolus 5-fluorouracil (5-FU) vs. capecitabine) and oxaliplatin or irinotecan with and without cetuximab (CRYSTAL, OPUS, COIN and NORDIC VII trials) and two trials, where K-ras WT and mutant patients received cetuximab and a fluoropyrimidine (capecitabine in a German AIO study and infusional 5-FU in the CECOG study) with oxaliplatin versus irinotecan. We sought to determine whether the choice of fluoropyrimidine or of oxaliplatin versus irinotecan affects the response to cetuximab. Meta-analysis was performed in the context of a mixed effects model with a random effect for each study. Results Only patients treated with infusional 5-FU-based chemotherapy derived benefit from cetuximab. Relative to infusional 5-FU, patients treated with capecitabine/bolus 5-FU-based doublet chemotherapy had a 42 % (95 % CI 21-58 %; p<0.001) decrease in response probability and a 52 % (95 % CI 20-93 %; p<0.001) and 33 % (95 % CI 7-65 %; p = 0.012) increase, respectively, in risk of progression and death. The choice of oxaliplatin or irinotecan did not affect benefit from cetuximab. Conclusion The lack of benefit for cetuximab with capecitabine/bolus 5-FU regimens is unexpected. Cetuximab should only be used with infusional 5-FU regimens in the first-line treatment of K-ras WT colorectal cancer patients. Further study is urgently needed to elucidate the basis of this observation. © Springer-Verlag 2012.


Chang A.Y.,Johns Hopkins University | Chang A.Y.,Johns Hopkins Singapore International Medical Center | Wang M.,Johns Hopkins Singapore International Medical Center
Anti-Cancer Drugs | Year: 2013

Hepatocellular carcinoma (HCC) is one of the most common and challenging malignant disease. The prognosis is poor in patients with advanced disease. Although sorafenib prolongs survival in these patients, improvement remains modest. We used doxorubicin and sorafenib as controls and screened eight new agents including ixabepilone, gefitinib, cetuximab, brivanib, dasatinib, sunitinib, BMS-690514, and BMS-536924 against nine HCC cell lines and evaluated their interactions. We studied growth inhibition of 10 drugs against nine HCC cell lines. Single-agent activity was tested using an MTS assay. Combination studies were carried out in both resistant and sensitive cells to determine the combination index. The IC50 of each agent varied widely among nine cell lines. Ixabepilone was more potent than doxorubicin. HT-17 cells were more sensitive to gefitinib and cetuximab than the other eight cell lines. BMS-536924 showed good efficacy (IC50≤1 μmol/l) on all three α-fetoprotein (AFP)-producing cell lines (HepG2, Hep3B, Huh-7). Three cell lines showed moderate sensitivity to dasatinib (IC50≤1 μmol/l). Dasatinib showed the most frequent and strongest synergism with ixabepilone, gefitinib, brivanib, BMS-690514, or BMS-536924. Ixabepilone, sorafenib, brivanib, dasatinib, and BMS-536924 are active against HCC cell lines. The heterogeneity of the sensitivity of each cell line emphasizes the need for individualized treatment. The sensitivity to BMS-536924 is closely associated with the production of AFP. AFP may be a biomarker predicting response to the insulin-like growth factor-1 receptor inhibitor in HCC patients. Additional studies are warranted. The synergism between dasatinib and other agents also provides future research directions to understand drug resistance and improve outcome. © 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.


Lopes G.,Johns Hopkins Singapore International Medical Center | Lopes G.,University of Miami | Gluck S.,University of Miami | Avancha K.,University of Miami | Montero A.J.,University of Miami
Breast Cancer Research and Treatment | Year: 2013

Eribulin was FDA approved in 2012 as a treatment for patients with MBC who have previously received at least two prior chemotherapy regimens. The aim of this analysis was to assess the cost effectiveness of eribulin versus the three most commonly utilized drugs (TPC) in the EMBRACE trial: vinorelbine, gemcitabine, and capecitabine (X); and to other branded FDA approved drugs: ixabepilone (I), liposomal-doxorubicin (D), and nab-paclitaxel. We created a decision-analytical and a Markov model using clinical data from the EMBRACE trial. Health utilities were derived from the published literature. Costs for drug acquisition, physician visits, and laboratory tests were obtained from Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2012 USD. Life-years saved (LY), quality-adjusted life years (QALY), and incremental cost effectiveness ratio (ICER) were calculated. Eribulin added 0.208 LY and 0.119 QALY with an incremental cost over TPC of $25,458, and therefore an ICER of $213,742 per QALY. The main drivers of the model were drug cost, PFS, OS, and health utility values. The results of the model were robust in sensitivity analyses. Relative to I, D, A, and X, the ICER for eribulin was $76,823, $109,283, $129,773, and $167,267, respectively. Even with a more contemporary willingness-to-pay threshold of approximately $120,000 per QALY, eribulin was not found to be cost effective in the treatment of MBC relative to TPC; relative to some more expensive branded drugs, eribulin appears to be cost effective. © 2012 Springer Science+Business Media New York.


De Souza J.A.,University of Chicago | Santana I.A.,Instituto Do Cancer Do Estado Of Sao Paulo | De Castro Jr. G.,Instituto Do Cancer Do Estado Of Sao Paulo | De Lima Lopes Jr. G.,Johns Hopkins Singapore International Medical Center | Tina Shih Y.-C.,University of Chicago
International Journal of Radiation Oncology Biology Physics | Year: 2014

The purpose of this review was to describe cost-effectiveness and cost analysis studies across treatment modalities for squamous cell carcinoma of the head and neck (SCCHN), while placing their results in context of the current clinical practice. We performed a literature search in PubMed for English-language studies addressing economic analyses of treatment modalities for SCCHN published from January 2000 to March 2013. We also performed an additional search for related studies published by the National Institute for Health and Clinical Excellence in the United Kingdom. Identified articles were classified into 3 clinical approaches (organ preservation, radiation therapy modalities, and chemotherapy regimens) and into 2 types of economic studies (cost analysis and cost-effectiveness/cost-utility studies). All cost estimates were normalized to US dollars, year 2013 values. Our search yielded 23 articles: 13 related to organ preservation approaches, 5 to radiation therapy modalities, and 5 to chemotherapy regimens. In general, studies analyzed different questions and modalities, making it difficult to reach a conclusion. Even when restricted to comparisons of modalities within the same clinical approach, studies often yielded conflicting findings. The heterogeneity across economic studies of SCCHN should be carefully understood in light of the modeling assumptions and limitations of each study and placed in context with relevant settings of clinical practices and study perspectives. Furthermore, the scarcity of comparative effectiveness and quality-of-life data poses unique challenges for conducting economic analyses for a resource-intensive disease, such as SCCHN, that requires a multimodal care. Future research is needed to better understand how to compare the costs and cost-effectiveness of different modalities for SCCHN. © 2014 Elsevier Inc. All rights reserved.


Yu T.,Nanyang Technological University | Zhou Z.,Nanyang Technological University | Mu Y.,Nanyang Technological University | De Lima Lopes G.,Johns Hopkins Singapore International Medical Center | Luo K.Q.,Nanyang Technological University
Cancer Letters | Year: 2014

In this paper we show that acetyltanshinone IIA (ATA), a novel anti-cancer agent, preferentially inhibits cell growth of oestrogen receptor positive (ER+) breast cancer cells and that it is more potent than the commonly used anti-breast cancer agent, tamoxifen. The metabolic product of ATA, hydroquinone tanshinone IIA (HTA) binds to the ERα and causes its degradation mainly in the nucleus via an ubiquitin-mediated proteasome-dependent pathway. In addition, ATA also reduced the mRNA levels of the ERα encoding gene, ESR1, distinguishing ATA from another anti-breast cancer drug, fulvestrant. Finally, ATA reduced the transcription of an ER-responsive gene, GREB1. © 2013 Elsevier Ireland Ltd.

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