bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2755: Effect of food on pharmacokinetics of zibotentan (ZD4054) in healthy subjects aged &gt;65 years and ≤65 years
Authors: Tomkinson Helen , Kemp John , Wollseifen Thomas , Oliver Stuart , Morris Thomas 
Published: February 2011

Abstract
The pharmacokinetic (PK) profile of zibotentan (ZD4054), a small-molecule, specific endothelin A (ETA) receptor antagonist, was evaluated under fed and fasting conditions in two Phase I studies in healthy male subjects.
These two studies were open-label crossover studies in which half the subjects received a single zibotentan dose following a high fat meal and again after a 7-day washout in a fasted state. The other half received a single zibotentan dose in a fasted state initially and again 7 days later following a high fat meal. Study 1 (AstraZeneca study 4045IL/013) included nine subjects aged &gt;65 years who received single-dose zibotentan 25 mg and study 2 (AstraZeneca study D4320C00028) included 30 male subjects aged ≤65 years who received single-dose zibotentan 10 mg. AUC and Cmax were log-transformed prior to analysis using an analysis of variance model fitting for the effects of sequence, subject, period and treatment.
In subjects aged &gt;65 years who received zibotentan 25 mg, there was no difference in AUC values between the fed (GLS mean 15041 ng.h/ml) and fasted groups (GLS mean 14740 ng.h/ml; treatment ratio of fed/fasted [90% CI], 1.02 [0.8-1.30]). However Cmax was lower for fed (GLS mean 1005 ng/ml) than fasted subjects (GLS mean 1262 ng/ml; treatment ratio of fed/fasted [90% CI], 0.8 [0.58-1.08]). In subjects aged ≤65 years who received zibotentan 10 mg, there was a statistically significant decrease in AUC for fed subjects (GLS mean 4031 ng.h/ml) compared with fasted subjects (GLS mean 4711 ng.h/ml; treatment ratio of fed/fasted [90% CI], 0.86 [0.80-0.91]), and Cmax for fed subjects (GLS mean 357 ng/ml) compared with fasted subjects (GLS mean 470 ng/ml; treatment ratio of fed/fasted [90% CI], 0.76 [0.71-0.81]). In both studies, median tmax was 4 hours in the fed group versus 2 hours in the fasted group.
In study 2, a food effect on AUC was excluded because the corresponding 90% CIs were within the predefined limits of 0.8-1.25. However, a food effect could not be excluded for Cmax, because the lower limit of the 90% CI was below the predefined margin. The reduction in Cmax under fed conditions was consistent with a slower rate of absorption indicated by median tmax being delayed by 2 hours under fed conditions. The reduction in Cmax is not considered to be clinically relevant as efficacy is likely to be driven by AUC or time above a particular concentration, therefore future studies are being conducted without any food restrictions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2755.
Abstract 2757: NT5C2 single nucleotide polymorphisms affects survival and response in de novo AML patients with normal karyotype
Authors: Fyrberg Anna , Lofti Kourosh , Paul Esbjorn , Paul Christer , Nahi Hareth , Gréen Henrik 
Published: February 2011

Abstract
The nucleoside analog cytosine arabinoside (Cytosar®, AraC) is one of the corner stones in the treatment of acute myeloid leukemia (AML). Activated AraC is metabolized to inactive compounds by several intracellular enzymes. The levels of some of these enzymes have been correlated to effect of AraC and clinical outcome in patients with AML.
This study was designed to evaluate if single nucleotide polymorphisms (SNPs) in genes coding for enzymes involved in the inactivation of AraC affects the therapeutic response in AML-patients treated with AraC in combination with anthracyclines. Three SNPs were investigated in 96 de novo AML patients with normal karyotype and correlated to response and overall survival. Two SNPs were located in the cytidine deaminase gene (CDA, A79C, rs2072671 and C-451T, rs532545), deaminating and inactivating AraC to its corresponding uridine derivative, AraU. The third SNP (A7G, rs10883841) was in the NT5C2 gene coding for the cytosolic 5′-nucleotidase II (cN-II), responsible for dephosphorylation and hence inactivation of AraC monophosphate. All SNPs were in Hardy-Weinberg equilibrium and the allele frequencies were 34.4, 34.4 and 18.8% for CDA A79C and C-451T, and NT5C2 A7G, respectively. Patients that were wild type (A/A) for NT5C2 A7G were found to have a borderline significant higher response rate (51 complete responders of 60 patients with A/A vs 20 complete responders of 30 with A/G or G/G, p=0.06) and longer survival (median survival 1.66 years compared to 0.87 years, log-rank p=0.08) compared to the rest of the patients. The two CDA SNPs (A79C, C-451T) were found to be in linkage disequilibrium. Although statistically not significant, patients that were found to be homozygous for the alternate genetic variant of the CDA SNP had a shorter survival compared to patients carrying the wild type or heterozygous genetic variants.
In conclusion, our findings suggest that certain NT5C2 (cN-II) genotypes might affect the survival after chemotherapy and may provide useful information for treatment strategies, classification and individualized chemotherapy, and eventually used as prognostic marker.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2757.
Abstract 2760: Phase I study of MK-0646, the humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine + erlotinib (E) for advanced, previously untreated pancreatic cancer
Authors: Shroff Rachna T. , Varadhachary Gauri R. , Bhosale Priya , Ukegbu Lerma , Overman Michael J. , Wolff Robert A. , Abbruzzese James L. , Javle Milind M. 
Published: February 2011

Abstract
BACKGROUND: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/ Akt signaling pathways which are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. The combination of IGF-1R and EGFR antagonists has demonstrated synergy in preclinical pancreatic cancer models.
METHODS: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Blood was collected at study entry for IGF-1 and IGFBP-3 levels. Arm A: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4; Arm B: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4 + E 100 mg daily. Cycles were repeated q 4 weeks. Radiologic responses were measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival, response rate, toxicity and overall survival.
RESULTS: 22 pts enrolled, 15 males, 2 prior Whipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1-8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Dose limiting toxicity reached in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Radiologic responses: 5 PR (including 1 hepatic CR), 7 PD, 8 SD, 1 not evaluated, 1 not treated. TTP range (based on 12 pts) was 4 to &gt;36 weeks. Ranges for: IGF-1 levels, 28-280 ng/mL; IGFBP-3 levels, 900-4000 ng/mL. The range of IGF-1 to IGFBP-3 ratios for patients with PR and SD was .027-.036 versus a range of .034-.058 for patients with PD.
CONCLUSION: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2760.
Abstract 2779: Relationship of mammographic density with breast cancer subtypes
Authors: Gierach Gretchen L. , Lissowska Jolanta , Garcia-Closas Montserrat , Yang Xiaohong R. , Figueroa Jonine D. , Anzick Sarah , Wesolowska Ewa , Brinton Louise A. , Meltzer Paul S. , Boyd Norman F. , Sherman Mark E. 
Published: February 2011

Abstract
Background: Mammographic density (MD), a measure of the amount of radiologically dense breast tissue, is one of the strongest breast cancer risk factors. Studies have found that high MD increases risk for both estrogen receptor (ER)-negative and positive breast cancers, but data relating MD to breast cancer subtypes are limited.
Methods: We used data from the population-based Polish Breast Cancer Study to explore relationships between MD and breast cancer characteristics. This analysis includes 227 invasive breast cancers, which were available as frozen samples and used for mRNA and cytogenetic profiling, and fixed tissues, which were prepared as tissue microarrays for immunohistochemical analysis. Pre-treatment mammograms of the unaffected breast were retrieved for 184 (81%) cases ages 28-75 years. Craniocaudal views of digitized films were used to assess percent MD with Cumulus, a computer-assisted thresholding method. Analysis of variance (ANOVA) models were used to test the null hypothesis of no mean difference in MD between the breast cancer subtypes.
Results: Tumor subtypes were classified by key immunohistochemical markers as luminal A (ER+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor-2 (HER2)-; n=129), luminal B (ER+ and/or PR+, HER2+; n=6), HER2-expressing (ER-, PR-, HER2+; n=13), basal-like (ER-, PR-, HER2-, cytokeratin 5+, and/or HER1+; n=23), and unclassified (negative for all five markers; n=8). Five cases did not have interpretable staining for all five markers and were excluded. MD values were approximately normally distributed. Preliminary ANOVA models revealed no differences in mean percent MD by tumor subtypes (p=0.29) as follows: luminal A, 27.5% (95% confidence interval (CI): 24.9-30.2); luminal B, 27.0% (95% CI: 14.8-39.2); HER2-expressing, 27.2% (95% CI: 18.9-35.5); basal-like, 24.6% (95% CI: 18.4-30.8); and unclassified, 15.7% (95% CI: 5.2-26.3). In analysis of covariance models adjusted for age there was marginal evidence of elevated MD with the HER2-expressing subtype (p=0.04), but we cannot exclude the possibility that this is a chance finding.
Conclusions: Our results do not provide strong support for an association between percent MD and breast cancer subtypes. To identify additional clues as to the biology underlying the MD-breast cancer relationship, ongoing analyses will relate MD to mRNA and cytogenetic profiles and data for protein expression via immunohistochemistry available for additional markers as previously reported.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2779.
Abstract 278: Regulation of constitutive Met phosphorylation in breast cancer by EGFR
Authors: Mueller Kelly L. , Haddad Ramsi , Yang ZengQuan , Ethier Stephen P. , Boerner Julie L. 
Published: February 2011

Abstract
Breast cancer remains a major health problem, despite advances in detection, diagnosis, and treatment. Four genomic subtypes of breast cancer have been identified: luminal A and B, HER2 positive, and basal type breast cancers. Three of these subtypes help to define the proper targeted therapeutic as breast cancers of luminal subtypes tend to be estrogen receptor positive and treatable with tamoxifen while breast cancers of HER2 positive subtype are treatable with trastuzumab. The fourth subtype, the basal type breast cancers, has a poor prognosis and has yet to have a molecular target identified. One molecule highly expressed in basal type breast cancers is epidermal growth factor receptor (EGFR). However, targeting EGFR kinase activity with small molecule kinase inhibitors has yet to show efficacy in the treatment of breast cancers. Recently, a panel of EGFR expressing breast cancer cell lines was characterized as sensitive or resistant to EGFR kinase inhibitors. One mechanism of resistance to EGFR kinase inhibitors was found to be the constitutive activation of Met, another molecule associated with basal type breast cancers. Here, the mechanism of constitutive Met activation in EGFR tyrosine kinase inhibitor resistant breast cancer cells is explored. Previously, constitutive Met activation was found to associate with acquired EGFR inhibitor resistance in lung cancer via genetic amplification of Met. In the EGFR TKI resistant breast cancer cells with constitutive Met phosphorylation, Met was not amplified or significantly overexpressed. In addition, constitutive Met phosphorylation was found to occur independent of ligand (hepatocyte growth factor (HGF)) stimulation, as HGF was not expressed in the breast cancer cell lines and inhibiting HGF association with Met via an inhibitory antibody failed to reduce Met phosphorylation. These data suggest a ligand-independent mechanism for Met constitutive phosphorylation. Interestingly, ligand-independent Met activation can be mediated by Met association with other membrane molecules including integrins, tetraspanins and receptor tyrosine kinases, including EGFR. Co-immunoprecipitation studies demonstrated that EGFR and Met co-associate and that this association occurs independent of EGFR or Met kinase activities. In addition, Met phosphorylation was reduced with EGFR TKIs as well as with downregulation of EGFR expression. Taken together, these data suggest that one potential mechanism of EGFR TKI resistance in breast cancer cells is the association and transphosphorylation of Met by EGFR.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 278.
Abstract 2781: Expression patterns of the ERBB2 gene and its splice variant in mammary tissues and their associations with breast risk and survival
Authors: Ye Chuanzhong , Shu Xiao-Ou , Wen Wanqing , Qu Shimian , Courtney Regina , Gao Yu-Tang , Zheng Wei , Cai Qiuyin 
Published: February 2011

Abstract
Alternative splicing generates different transcripts from the same precursor mRNA. ERBB2 proto-oncogene is involved in the growth, invasion, and prognosis of breast cancer. The ERBB2-sp is a splice variant of ERBB2 that lacks the intracellular and transmembrane domains, which may alter the function of the ERBB2 gene. We hypothesize that the ERBB2-sp and the wild type ERBB2 gene may play a different role in the development and prognosis of breast cancer, and thus compared ERBB2 and ERBB2-sp mRNA expression in tumor tissue and adjacent non-tumor tissue in both breast cancer patients and benign breast disease (BBD) patients. Included in the study were 515 patients diagnosed with breast cancer and 206 patients diagnosed with BBD. These women were recruited as part of the Shanghai Breast Cancer Study and they provided samples of tumor tissue and adjacent non-tumor tissue to the study. Tumor tissues from patients with breast cancer had substantially higher levels of ERBB2 expression than those from patients with BBD (81vs 37, P &lt; 0.0001). On the other hand, adjacent non-tumor tissues from patients with breast cancer had substantially lower levels of ERBB2 expression than those from patients with BBD (20 vs 34, p=0.0254). In breast cancer cases, ERBB2 expression in tumor tissue was significantly higher than that in their paired adjacent non-tumor tissue (p=0.0028). No significant difference of ERBB-sp expression levels was found in any of the following comparisons, tumor tissues or adjacent normal tissues between breast cancer patients and BBD controls as well as between the tumor tissues and adjacent normal tissues in both breast cancer and BBD patients. In the comparison of tumor tissues between breast cancer patients and BBD controls, the ratio of ERBB2 to ERBB2-sp expression levels (ERBB2 /ERBB2-sp index) in tumor tissue was associated with a significantly increased breast cancer risk in a linear manner, with adjusted odds ratios (95% CI) increased from 1.00 (reference) to 1.33 (0.84-2.13), 1.82 (1.13-2.94), and 2.63(1.55-4.43) (P for trend &lt;0.001) from the lowest to the highest quintiles of expression groups. However, there were no apparent associations of expressions of ERBB2 and ERBB2-sp, or ERBB2/ERBB2-sp index in cancer tissue with either overall survival or disease-free survival. Our findings suggest that the expression of ERBB2 and its splice variant ERBB2-sp may play a different role in the development, but not prognosis, of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2781.
Abstract 2782: Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer
Authors: Tamimi Rulla M. , Wang Yihong , Collins Laura C. , Hu Rong , Schnitt Stuart J. , Colditz Graham A. , Connolly James L. 
Published: February 2011

Abstract
The growth hormone and insulin-like growth factor (IGF) axis plays an essential role in the growth and development of the mammary gland. More recently it has become evident that IGF1 and IGF1 receptor (IGF1R) may play a role in the early transformation of mammary cells. Using a nested case-control design, we examined the association between IGF1R expression in normal breast tissue from benign biopsies and subsequent risk of breast cancer within the Nurses' Health Study. We constructed tissue microarrays (TMAs) containing normal terminal ductal lobular units (TDLUs) from benign breast biopsies. Immunostains for IGF1R were performed on sections cut from the TMAs. A total of 312 women had both normal TDLUs included in the TMAs and evaluable IGF1R staining; 75 subsequently developed breast cancer (cases) and 237 did not (controls). The epithelial cells in the normal TDLUs were scored for both cytoplasmic and membranous staining for IGF1R. Membranous IGF1R expression in normal TDLU epithelial cells was inversely associated with subsequent breast cancer risk (OR= 0.49; 95%CI 0.26-0.93) independent of type of benign breast disease (BBD). In contrast, the presence of cytoplasmic IGF1R expression was positively associated with subsequent risk of breast cancer (OR=2.88, 95% CI 1.60-5.19). Women in which TDLU epithelial cells showed little or no membrane expression of IGF1R but high levels of cytoplasmic IGF1R were at the highest breast cancer risk and were 15 times more likely to develop subsequent breast cancer when compared with women who had little or no membranous or cytoplasmic IGF1R expression in their TDLU epithelium (OR=15.1, 95% CI 3.2-70.2). It has been demonstrated that stimulation of cells with IGF1 results in altered localization of IGF1R expression. Upon stimulation, IGF1R levels on the cell membrane decrease while internalized levels increase. Studies of other receptor tyrosine kinases indicate that chronic stimulation by the ligand results in increased internalization of the receptor. In this study, IGF1R expression patterns in the epithelial cells of normal TDLUs were associated with an increased risk of subsequent breast cancer. The results of this study support the hypothesis that the IGF1 pathway plays an important role in the early development of breast cancer and suggest that there may be opportunities for breast cancer chemoprevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2782.
Abstract 2788: Serum steroid hormone levels and risk of lung adenocarcinoma among postmenopausal women in Taiwan
Authors: Li Yao-Jen , Yang Shi-Yi , Chen Chuen-Fei , Liao Kuo-Meng , Chen Chien-Jen 
Published: February 2011

Abstract
Study goal: Lung cancer is the leading cause of death among women worldwide, ande adenocarcinoma is the most common histological subtype among non-smoking women. Among non-smoking population, the lung cancer incidence is higher than men. Previous studies have shown that hormone related factors, such us menstrual cycle, hormonal replacement therapy are associated with female lung cancer. Hormone related factors may play a role in lung cancer. Therefore, we hypothesized that hormone levels in serum among postmenopausal women may associated with lung adenocarcinoma.
Material and methods: This was a case-control study. The study participants came from a medical center which located on Taichung Taiwan, 9 serum steroid hormone markers were determined for 81 women with lung adenocarcinoma and 114 unrelated cancer-free women who were frequently matched by age and sample collecting time from age of menopause. All subjects were postmenopausal and without using hormone replacement therapies. Unconditional logistic regression analysis was used to calculate the odds ratio (OR) and its 95% confidence interval (95% CI) for each hormone markers. Potential confounding factors, such us BMI, age at menarche, parity, and age at enrollment were take into regression models.
Results: Compared to lowest tertile groups of hormone levels, the highest tertile groups of progesterone (OR, 0.34; 0.2-0.7), testosterone (OR, 0.37; 0.2-0.8), Free testosterone (OR, 0.40; 0.2-0.9), Androstenedione (OR, 0.29; 0.1-0.7), sex hormone-binding globulin (OR, 0.47; 0.2-1.0) were associated a decrease risk of lung adenocarcinoma among postmenopausal women after adjusted for age at enrollment, BMI. On the other side, serum estradiol (OR, 0.59; 0.3-1.3) and dehydroepiandrosterone sulfate (OR, 0.49; 0.2-1.0) levels showed non-significant decrease risk to female lung adenocarcinoma among postmenopausal subjects.
Conclusions: The serum sex steroid hormone levels among postmenopausal women may influence the risk to lung adenocarcinoma in Taiwan. Prospective designs will be necessary to clarify the association between serum hormone levels and risk of female lung adenocarcnoma.
Key word: serum, sex steroid hormone, post-menopause, lung adenocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2788.