Showing papers by "Scott M. Lippman published in 2008"
TL;DR: From the Departments of Thoracic/Head and Neck Medical Oncology and Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston.
Abstract: From the Departments of Thoracic/Head and Neck Medical Oncology (R.S.H., J.V.H., S.M.L.), Cancer Biology (R.S.H., J.V.H.), and Clinical Cancer Prevention (S.M.L.), University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr. Lippman at the Department of Thoracic/Head and Neck Medical Oncology, Unit 432, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at slippman@ mdanderson.org.
1,910 citations
TL;DR: Non-inferior survival of gefitinib compared with docetaxel is established, suggesting that gef itinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.
1,231 citations
TL;DR: The expressions of several factors associated with the induction of EMT in HNSC cell lines and tumor specimens were investigated to define their functional and pathologic role in HnSC.
Abstract: BACKGROUND
Epithelial–mesenchymal transformations (EMT) are critical for the invasion, progression, and metastasis of epithelial carcinogenesis. The role of EMT in head and neck squamous carcinoma (HNSC) tumorigenesis remains unexplored. In the current study, the expressions of several factors associated with the induction of EMT in HNSC cell lines and tumor specimens were investigated to define their functional and pathologic role in HNSC.
METHODS
Eleven HNSC cell lines and 50 primary tumor tissue specimens formed the materials of this study. Western blot analysis as well as immunohistochemical, and functional techniques were used to assess the status of activated Src (p-Src), E-cadherin, and vimentin in both cell lines and tumor tissues and the results were correlated with patients' clinicopathologic parameters.
RESULTS
The results demonstrated the inverse expression of p-Src and E-cadherin in the majority of cell lines and in primary tumor tissues compared with normal squamous mucosa. Elevated levels of p-Src were accompanied by down-regulation of E-cadherin and the expression of vimentin in epithelial tumor cells. In vitro inhibition of Src led to E-cadherin reexpression and increased cell contact in squamous carcinoma cell lines. Immunophenotypic analysis of these markers in primary tumor tissues demonstrated a significant correlation between increased p-Src, decreased E-cadherin, and vimentin expression and aggressive tumor features including penetrating invasive fronts, high-grade sarcomatoid transformation, and lymph node metastasis.
CONCLUSIONS
The results of the current study indicate that Src and E-cadherin may play an important role in EMT, invasion, and aggressive clinicopathologic features of HNSC. These proteins may be targeted for the therapeutic intervention of patients with HNSC. Cancer 2008. © 2008 American Cancer Society.
208 citations
TL;DR: It is shown that podoplanin, a lymphatic endothelial marker, is highly expressed in oral cancer and some oral premalignancies and may serve as a powerful biomarker to predict the risk for oral cancer development in patients with OPL.
Abstract: Purpose Oral leukoplakia (OPL) is a heterogeneous oral lesion with an increased oral cancer risk. Current clinical parameters cannot predict the potential of malignant transformation in patients with OPL. We have shown that podoplanin, a lymphatic endothelial marker, is highly expressed in oral cancer and some oral premalignancies. The purpose of this study is to determine a role of podoplanin in predicting oral cancer development in patients with OPL. Patients and Methods Podoplanin expression was determined in 150 OPL patients with long-term follow-up using immunohistochemistry. Association between the protein expression patterns and clinicopathologic parameters including oral cancer development during the follow-up were analyzed. Results Fifty-six (37%) of the 150 OPL patients exhibited podoplanin expression in the basal and suprabasal layers and were classified as podoplanin positive. Podoplanin positivity was more frequent in older patients (P = .016), females (P = .020), and dysplastic lesions (P = ...
191 citations
TL;DR: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention.
Abstract: Purpose: Cyclooxygenase-2 (COX-2)–specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL). Experimental Design: Patients were randomly assigned to placebo ( n = 18), celecoxib 100 mg twice daily ( n = 17), or celecoxib 200 mg twice daily ( n = 15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL. Results: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months. Conclusions: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.
99 citations
TL;DR: These are the first reported results illustrating the potential of CREB as a molecular target for the prevention and treatment of NSCLC, especially in never smokers.
Abstract: Lung cancer is the leading cause of cancer deaths worldwide. Recent advances in targeted therapies hold promise for the development of new treatments for certain subsets of cancer patients by targeting specific signaling molecule. Based on the identification of the transcription factor cyclic AMP response element-binding protein (CREB) as an important regulator of growth of several types of cancers and our recent findings of its importance in normal differentiation of bronchial epithelial cells, we hypothesized that CREB plays an important pathobiologic role in lung carcinogenesis. We conducted this initial study to determine whether the expression and activation status of CREB are altered in non-small cell lung cancer (NSCLC) and of any prognostic importance in NSCLC patients. We found that the expression levels of mRNA and protein of CREB and phosphorylated CREB (p-CREB) were significantly higher in most of the NSCLC cell lines and tumor specimens than in the normal human tracheobronchial epithelial cells and adjacent normal lung tissue, respectively. Analysis of CREB mRNA expression and the CREB gene copy number showed that CREB overexpression occurred mainly at the transcriptional level. Immunohistochemical analysis of tissue microarray slides containing sections of NSCLC specimens obtained from 310 patients showed that a decreased survival duration was significantly associated with overexpression of CREB or p-CREB in never smokers but not in current or former smokers with NSCLC. These are the first reported results illustrating the potential of CREB as a molecular target for the prevention and treatment of NSCLC, especially in never smokers.
91 citations
TL;DR: Although well tolerated, fenretinide did not reduce the time-to-recurrence in patients with Ta, T1, or Tis TCC of the bladder.
Abstract: Purpose: The study aims to evaluate the efficacy and toxicity of fenretinide in preventing tumor recurrence in patients with transitional cell carcinoma (TCC) of the bladder. Experimental Design: We conducted a multicenter phase III, randomized, placebo-controlled trial of fenretinide (200 mg/day orally for 12 months) in patients with non–muscle-invasive bladder TCC (stages Ta, Tis, or T1) after transurethral resection with or without adjuvant intravesical Bacillus Calmette-Guerin (BCG). Patients received cystoscopic evaluation and bladder cytology every 3 months during the 1-year on study drug and a final evaluation at 15 months. The primary endpoint was time to recurrence. Results: A total of 149 patients were enrolled; 137 were evaluable for recurrence. The risk of recurrence was considered to be “low” in 72% (no prior BCG) and intermediate or high in 32% (prior BCG) of the evaluable patients. Of the lower-risk group, 68% had solitary tumors and 32% had multifocal, low-grade papillary (Ta, grade 1 or grade 2) tumors. The 1-year recurrence rates by Kaplan-Meier estimate were 32.3% (placebo) versus 31.5% (fenretinide; P = 0.88 log-rank test). Fenretinide was well tolerated and had no unexpected toxic effects; only elevated serum triglyceride levels were significantly more frequent on fenretinide (versus placebo). The Data Safety and Monitoring Board recommended study closure at 149 patients (before reaching the accrual goal of 160 patients) because an interim review of the data showed a low likelihood of detecting a difference between the two arms, even if the original accrual goal was met. Conclusions: Although well tolerated, fenretinide did not reduce the time-to-recurrence in patients with Ta, T1, or Tis TCC of the bladder.
59 citations
TL;DR: The purpose of the current analysis was to evaluate the cost‐effectiveness of chemoprevention utilizing a quality‐of‐life adjustment.
Abstract: BACKGROUND
The Prostate Cancer Prevention Trial (PCPT) demonstrated that finasteride reduces the prevalence of prostate cancer by 24.8% (risk reduction) but questions remain regarding the cost-effectiveness of widespread utilization. The purpose of the current analysis was to evaluate the cost-effectiveness of chemoprevention utilizing a quality-of-life adjustment.
METHODS
A Markov decision analysis model with probabilistic sensitivity analysis was designed to determine the lifetime prostate health-related costs, beginning at age 50 years, for men treated with finasteride compared with placebo. Model assumptions were based on data from the PCPT; Surveillance, Epidemiology, and End-Results program; literature review of costs, utilities, and transition rates among various prostate cancer health states; and local institutional cost data.
RESULTS
The quality-adjusted cost-effectiveness ratio for finasteride compared with men not receiving chemoprevention was $122,747 (in U.S.$) per quality-adjusted life-years saved (QALYs). If finasteride is assumed to not increase the incidence of high-grade tumors, the quality-adjusted cost-effectiveness ratio was $112,062 per QALYs. Sensitivity analysis found that chemoprevention of prostate cancer with an agent that has no effect on the prevalence of benign prostatic hyperplasia can render a cost-effectiveness ratio of <$50,000 per QALYs saved when applied to a high-risk population associated with a 25% risk reduction, and a cost of $30 per month.
CONCLUSIONS
Finasteride is unlikely to be cost-effective when considering the impact on survival differences among treated versus untreated groups. However, chemoprevention may be cost-effective in high-risk populations when taking into consideration adjustments for the impact on quality of life. Cancer 2008. © 2008 American Cancer Society.
57 citations
TL;DR: MA significantly reduced vasomotor symptoms with durable benefit over 6 months and MA 20 mg/d is the preferred dose.
Abstract: Purpose Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megesterol acetate (MA) at two doses versus placebo over 6 months. Patients and Methods Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a ≥ 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed. Results Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tam...
55 citations
TL;DR: This study provides the first epidemiological evidence supporting a connection between DSB gene variants and OPL development and suggests that the effects of high-order interactions should be taken into consideration when evaluating OPL predisposition.
30 citations
TL;DR: Finasteride significantly reduced prostate cancer risk regardless of the level of this risk, estimated either by multivariable risk or by PSA stratum; this suggests that finasteride exerts both treatment and preventive effects.
TL;DR: DNMT‐1 has a direct suppressive role in 15‐LOX‐1 transcriptional silencing that is independent of 15‐ LOX‐2 promoter DNA methylation, and was employed to study the effects of this methylation on 15‐loX‐ 1 expression in colon cancer cells.
Abstract: Methylation of promoter DNA contributes to transcriptional silencing of various tumor-suppressor genes in cancer. Transcriptional silencing of 15-lipoxygenase-1 (15-LOX-1) promotes tumorigenesis. Methylation of 15-LOX-1 promoter DNA occurs in some cancers, but its mechanistic role in 15-LOX-1 transcriptional silencing is unclear. We examined the mechanistic role of 15-LOX-1 promoter DNA methylation in 15-LOX-1 transcriptional regulation in human colorectal cancers. 15-LOX-1 promoter methylation occurred in colorectal cancer cells in vitro, in 36% of tumor tissue samples of colorectal cancer patients, and in virtually no normal colonic mucosa samples of 50 human subjects with no history of colorectal cancer or polyps. 15-LOX-1 promoter DNA methylation levels, however, did not correlate with 15-LOX-1 expression levels (Spearman’s r=0.21; P=0.38). We employed siRNA knockdown and genetic disruption models of DNA methyltransferases (DNMTs) to study the effects of this methylation on 15-LOX-1 expression in colo...
TL;DR: Cell‐cycle checkpoint controls regulate cell‐cycle progression and proliferation and are linked to tumorigenesis.
Abstract: BACKGROUND.
Cell-cycle checkpoint controls regulate cell-cycle progression and proliferation. Alterations in cell-cycle control mechanisms are linked to tumorigenesis.
METHODS.
This case-control study included 147 cases and 147 controls. The authors used a pathway-based approach to assess the association between 10 potential functional single-nucleotide polymorphisms from 7 cell-cycle control genes and the risk of oral premalignant lesions (OPLs). They also used classification and regression tree analysis to examine high-order gene-gene and gene-smoking interactions.
RESULTS.
Compared with the homozygous wild-type GG genotype of CCND1 P241P, individuals with the AG genotype exhibited an increased risk of OPL (odds ratio, 1.58; 95% confidence interval, 0.89-2.83), and carriers of the AA genotype had a significantly increased risk of OPL (odds ratio, 2.75; 95% confidence interval, 1.33-5.71), with risk increasing significantly with the increasing number of variant alleles (P = .006). The risk of OPL increased significantly as the number of unfavorable genotypes in the pathway increased (P = .002). The final decision tree in the classification and regression tree analysis contained 5 terminal nodes. Compared with the never smokers (the lowest risk group), the odds ratios for terminal nodes 2 through 5 ranged from 1.21 to 5.40.
CONCLUSIONS.
The results illustrated the advantage of using a pathway-based approach for analyzing gene-gene and gene-smoking interactions. Specifically, the authors showed that genetic polymorphisms in cell-cycle control pathway genes may contribute to the risk of OPL. Cancer 2008. © 2008 American Cancer Society.
TL;DR: An extensive meta-analysis supporting an inverse association between NSAID use and risk of breast cancer is reported, finding a statistically significant reduction in breast cancer risk associated with use of any NSAID.
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) clearly reduce the risk of human colorectal neoplasia in epidemiological and prospective randomized clinical studies of aspirin and nonaspirin NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, or coxibs ( 1 – 3 ). In contrast, the epidemiological and clinical data on NSAIDs in reducing breast cancer risk are not consistent. This inconsistency is likely attributable to contrasting expression patterns of COX-2, a key target of NSAIDs, in breast and colon neoplasia ( 4 , 5 ), and to differing activities of individual NSAIDs (which have varying selectivity for COX-2 vs COX-1), including a potentially selective impact of certain NSAIDs on hormone receptor – positive breast tumors. In this issue of the Journal, Takkouche et al. ( 6 ) report an extensive meta-analysis (involving 38 studies) supporting an inverse association between NSAID use and risk of breast cancer . They found a statistically signifi cant reduction in breast cancer risk associated with use of any NSAID (relative risk [RR] = 0.88, 95% confi dence interval [CI] = 0.84 to 0.93) and similar associations for aspirin (RR = 0.87, 95% CI = 0.82 to 0.92) and ibuprofen (RR = 0.79, 95% CI = 0.64 to 0.97). They found no evidence of a dose – response relationship, and some studies indicated that coxibs were also associated with a lower risk of breast cancer ( 7 , 8 ). This large-scale meta-analysis is consistent with several smaller meta-analyses ( 9 – 12 ). Furthermore, NSAIDs can prevent experimental breast cancer in numerous rodent models ( 4 , 5 ). Why then do individual observational and clinical studies vary substantially in
TL;DR: Highlights of the biology of preventive molecular targeting, cancer risk modeling, and trials of molecular-targeted agents, all moving toward the development of personalized preventive medicine are discussed.
TL;DR: The National Cancer Policy Board of the Institute of Medicine and National Research Council stated that a national strategy for cancer prevention and control should be developed.
Abstract: Prevention and control are key components of cancer research and the effort to reduce cancer incidence and mortality. The National Cancer Policy Board of the Institute of Medicine and National Research Council ([1][1]) stated that a national strategy for cancer prevention and control (CPC) should be
TL;DR: Thirty-six cytokines and angiogenic factors were measured in HN patients on a Phase II induction chemotherapy trial to investigate connections between biomarker signatures and clin...
Abstract: 6005 Background: 36 cytokines and angiogenic factors (C/AFs) were measured in HN patients on a Phase II induction chemotherapy trial to investigate connections between biomarker signatures and clin...
TL;DR: Working on the mission of CaPR—to address the current state of cancer prevention and how CaPR will advance and catalyze the field through this and future issues—has led me to reflect on my own journey as a cancer prevention researcher.
Abstract: D ear Colleagues,
Welcome to the inaugural issue of Cancer Prevention Research (CaPR). Working on the mission of CaPR—to address the current state of cancer prevention and how CaPR will advance and catalyze our field through this and future issues—has led me to reflect on my own journey as a
TL;DR: A retrospective analysis of ICH and cerebrovascular infarct (CVA) incidences in CNSM patients who received Bv-based treatment and the prevalence of CNSM, treatment with Bev, and ICD-9 codes for CVD, cerebralinfarcts and ICH are reported.
Abstract: 14507 Background: Bevacizumab (Bv) and other VEGF/VEGFR-targeting agents have become useful therapies for cancer and are active against primary and metastatic central nervous system malignancies (CNSM). Its use in patients with brain metastases, however, has been largely avoided over concerns for precipitating intracerebral hemorrhage (ICH) and also an increased risk of thromboembolic disease. We report here a retrospective analysis of ICH and cerebrovascular infarct (CVA) incidences in CNSM patients who received Bv-based treatment. Methods: Using institutional billing and pharmacy databases we reviewed the electronic records of 149,421 patients treated at the University of Texas M. D. Anderson Cancer Center between 9/1/02 and 8/31/06. CNSM were diagnosed in 6674 patients. The first 13,088 cancer patients without CNSM were analyzed as a control group. The prevalence of CNSM, treatment with Bev, and ICD-9 codes for CVD, cerebral infarcts, and ICH, and their temporal relationships were compared and analyzed...
TL;DR: The National Cancer Policy Board of the Institute of Medicine and National Research Council stated that a national strategy for cancer prevention and control should be developed.
Abstract: Prevention and control are key components of cancer research and the effort to reduce cancer incidence and mortality. The National Cancer Policy Board of the Institute of Medicine and National Research Council ([1][1]) stated that a national strategy for cancer prevention and control (CPC) should be