bluuebunny/crossref_metadata_2025_split huggingface dataset:
3-Tesla MRI for the evaluation of spreading area of ductal carcinoma in situ: a comparative study with 1.5-Tesla MRI.
Authors: Kubo M , Shirahane K , Tanaka M 
Published: December 2010

Abstract
Abstract #4028
Background: High quality of space and temporal resolution is demanded from the diagnosis for intraductal spreading area of breast cancer. In our hospital, from April 2007, 3-Tesra (T) MRI was transduced and high resolution dynamic studies for bilateral mammary have been performed. However, superiority of 3-T MRI to 1.5-T MRI remains almost unproven in the evaluation of intraductal spreading area of breast cancer.&#x2028; Methods: We assessed 46 patients with primary ductal carcinoma in situ who underwent the 3-T or 1.5-T breast MRI as pre-operative examination between July, 2007 and March, 2008. Concerning the diagnosis of intraductal spreading area of breast cancer, we weighed 3T MRI against conventional 1.5T MRI. Using 1.5-T or 3-T MRI (Achieva, Philips), we injected contrast medium (Magnepist) with 0.2ml/kg body weight in 1ml/sec and photographed five aspects before injection and after injection for every 90 seconds. We obtained fat-sat T1-weighted magnetic resonance image (T1WI), multi-planar reconstruction (MPR) image and standard maximum intensity projection (MIP) image based on T1WI by coronal section, and furthermore slab MIP image with Aquerius net (Terarecon), and we evaluated the enhanced area.&#x2028; Results: 32 cases were examed with 1.5-T MRI, and 14 cases with 3-T MRI. In 1.5-T group, 10 cases (31%) were underestimated, additional resection were required intraoperativelly with cancer-cells positive surgical margin in 7 cases, and surgical margin was positive with carcinoma cells by final pathological findings in 4 cases. In one patient we were forced to changes from breast-conserving surgery to mastectomy, and two cases underwent reoperation (mastectomy) with the diagnosis of widely positive surgical margin.In comparison with 1.5 T MRI group, three (21%) were underestimated in 3-T MRI group, intraoperative addition resection in two cases, and surgical margin positive by the final pathological findings in two cases, respectively.&#x2028; Conclusions: The concern to enhance an artifact is known because 3-T MRI has high resolution, but it may be more useful in the evaluation of intraductal spreading area of breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4028.
Clinical significance of bone marrow micrometastasis detected by nested RT-PCR for cytokeratin-19 in breast cancer patients.
Authors: Hur L , Jung Y , Kim K 
Published: December 2010

Abstract
Abstract #4032
Purpose: Breast cancers frequently undergo distant metastasis during the early phase, on which the survival of patients is greatly dependent. It has been suggested that the occurrence of micrometastasis relates with other prognostic features of breast cancer, such as lymph node metastasis and the presence of vascular invasion. The aim of this study was to examine the presence of cytokeratin-19 mRNA in bone marrow aspirates obtained from breast cancer patients, and their possible correlation with distant disease free survival.&#x2028; Method: Between 1999 and 2003, bone marrow samples were obtained from 254 breast cancer patients during primary surgery. We separated the mononuclear fraction from the samples and carried out nested reverse transcriptase polymerase reaction (RT-PCR) for the detection of cytokeratin-19 mRNA using two different pairs of primers. The clinical and pathological data and the results of the bone marrow cytokeratin-19 nested RT- PCR were reviewed and analyzed together with clinical results on distant recurrence and survival. We also studied the possible correlations between CK-19 and the tumor size, nodal involvement, stage, and distant metastasis. The median follow up time was 57 months. The median age of patients was 46 years old.&#x2028; Results: 66(26%) of the 254 samples were cytokeratin-19 positive. And four stage VI patients and two patients lost during follow up period were excluded. 16 cases (24%) of in the cytokeratin-19 positive group showed a recurrent disease in distant organs. Whereas, 23(12.5%) out of 182 cytokeratin-19 negative patients had distant recurrences. Therefore CK-19 positive group have more distant recurrence than CK-19 negative group (p=0.024). And we found that CK-19 positive group have lower disease free survival rate than CK-19 negative group (p=0.017). However, there was no statistically significant difference in overall survival (p=0.083). The stage, nodal status, and estrogen receptor were independent of bone marrow micrometastasis.&#x2028; Conclusion: Bone marrow micrometastasis, detected by nested RT-PCR for cytokeratin-19, could be a useful predictive marker for the distant metastasis of breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4032.
Validation of breast cancer biomarkers between a field immunohistochemistry laboratory in Nigeria and its US-based counterpart.
Authors: Malaka DO , Khramtsov A , Oluwasola OA , Odetunde A , Falusi AG , Grushko T , Huo D , Olopade OI 
Published: December 2010

Abstract
Abstract #4039
Introduction: The importance of hormone receptor status in assigning treatment and the potential use of HER2 targeted therapy have made it imperative for laboratories to improve detection techniques. As inter-laboratory variability in immunohistochemical (IHC) tests may also affect epidemiologic studies of breast cancer subtypes in different countries, we conducted a validation study of breast cancer biomarkers between a well-established laboratory in the US and a field laboratory at the Institute for Medical Research and Training at the University College Hospital in Ibadan Nigeria.&#x2028; Method: 232 breast tumor blocks were evaluated for ER, PR, and HER2 at both laboratories using tissue micro arrays (TMA) technique. Web-based conferences were held periodically to discuss IHC staining protocols, standardize scoring systems and to resolve discrepant cases. Pathologists used whole slide imaging for joint review and kappa statistic (κ) was used to indicate concordance between the two laboratories. Fluorescence in situ hybridization was carried out to confirm HER2 status in all cases.&#x2028; Results: Initially, concordance analysis revealed an agreement of 91% (κ=0.52) for ER, 85% (κ=0.49) for PR, and 80% (κ=0.39) for HER2 between the two labs. Antigen retrieval techniques and scoring methods were identified as important reasons for discrepancy. After quality assurance and training, the agreement improved to 92% (κ=0.53) for ER, 88% (κ=0.64) for PR, and 94% (κ=0.75) for HER2. To date, florescence in situ hybridization (FISH) has been completed for 67 cases to confirm HER2 status, out of which 16 (24%) were shown to amplify the HER2 gene, 6 out of the 12 discordant HER2 results were resolved by FISH.&#x2028; Conclusion: We found web-based conference with TMA and digital microscopy a useful and cost-effective tool for quality assurance of IHC, consultation and collaboration between distant laboratories. Quality improvement exercises in testing of tumor biomarkers will reduce misclassification in epidemiologic study of breast cancer subtypes and provide much needed capacity building in resource poor field sites.&#x2028; Acknowledgement&#x2028; This study was carried out with the support of Breast SPORE NCI P50 CA125183, Breast Cancer Research Foundation and the Lee Jeans Entertainment Industry Fund.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4039.
Phase I-II study of the histone deacetylase inhibitor (HDACi) vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer (MBC): New York Cancer Consortium trial P7703.
Authors: Ramaswamy B , Bhalla K , Cohen B , Pellegrino C , Hershman D , Chuang E , Somlo G , Goetz M , Swaby R , Hopkins U , Christos P , Espinoza-Delgado I , Sparano JA 
Published: December 2010

Abstract
Abstract #404
Background: The oral HDACi vorinostat (V) sensitizes breast cancer cells to tubulin polymerizing agents and anti-VEGF directed therapies in vitro. We sought to determine the safety and efficacy of V plus paclitaxel (P) and bevacizumab (B) as first-line therapy for MBC.&#x2028; Methods: Eligible patients (pts) with measurable disease, ECOG PS 0 or 1, and no prior chemotherapy for MBC, received P (90mg/m2) on days 1, 8, 15 and B (10mg/kg) on days 1,15 every 28 days, plus V 200 mg (N=3) or 300 mg (N=28) BID orally for 3 days given the day before, day of, and day after each P dose. Response was assessed after every 3 cycles (RECIST). The trial was designed to distinguish between a response rate of &lt; 40% vs. &gt; 60% (alpha=0.10, beta=0.10) using Simon's optimal 2-stage design. At least 12 responses were required in the first 28 evaluable pts in the 1st stage and 21 of 41 in the 2nd stage.&#x2028; Results: There were no dose-limiting toxicities among the first 6 pts treated at the 1st (200 mg BID; N=3) and 2nd (300 mg BID; N=3) dose levels. Among the 26 evaluable pts treated at the recommended phase II dose of 300mg bid in the 1st stage, 14 patients had a partial response (PR-54%; 90% confidence interval [C.I.] 36%-71%), 6 had stable disease (SD) at 3 months and remain on treatment, 2 had SD as the best response with progressive disease (PD) at 11.8 and 15 months, and 4 had PD as their best response. Additionally, 2 of 3 pts treated at the first V dose level had a PR, indicating PR in 16 of 29 overall (55%, 90% C.I 38%-71%). Only 11 of 29 evaluable pts (38%) have progressed after a median followup of 10.5 months (R-2.3-14.9). Two pts had tumor biopsies and peripheral blood mononuclear cells (PBMC) collected before and 4 hours after the 3rd V dose (300 mg BID) which showed increased acetylation of K69 lysine residue of the chaperone protein Hsp 90, upregulation of Hsp70, and downregulation of AKT by Western Blot, providing evidence of Hsp90 inhibition in tumor and PBMC.&#x2028; &#x2028; Gr 3-4 toxicities included neutropenia (26%), neuropathy (23%), fatigue (16%), thrombosis (10%), vomiting (6%), hypertension (3%), and diarrhea (3%).&#x2028; Conclusions: Our preliminary findings indicate that the HDACi V inhibits Hsp90 and downregulates AKT in breast cancer in vivo, and enhances the effectiveness of P plus B in MBC. Accrual is nearly complete and the final efficacy analysis will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 404.
Combination of carboplatin and the mTor inhibitor RAD001 is a new therapeutic approach for p53-mutated breast cancer.
Authors: Liu H , Possinger K , Eucker J 
Published: December 2010

Abstract
Abstract #405
Platinum agents are very effective and commonly used chemotherapeutics for the treatment of many solid tumors. However, acquired and intrinsic resistance remains a major obstacle for platinum-based therapy. Recent evidence indicates that mTOR inhibition is a promising strategy to sensitize some p53-wild type solid tumors to conventional chemotherapies. Since p53-mutation is a common phenomenon in breast cancer, we investigated in this study the possibilities of the combined application of carboplatin and the mTOR inhibitor RAD001 in these human breast cancer cells in vitro.&#x2028; Combination of carboplatin and RAD001 resulted in synergistic inhibitions of cell proliferation both in p53-wild type (MCF-7, ZR-75), and in p53-mutated (SKBR-3, BT-474, BT-20), as well as drug resistant (tamoxifen-resistant MCF-7, adriamycin-resistant MCF-7) breast cancer cell lines as analyzed with Calcusyn software. Higher doses of the two drugs resulted in synergistically apoptosis after 24- or 48-hours treatment independent of p53-status of breast cancer cells. Investigation of several cell survival signaling pathways revealed an additively decreased phosphorylation of Erk, STAT3 and Akt after co-treatment suggesting that interference of cell survival signaling may be one of the mechanisms responsible for growth inhibition mediated by this combination.&#x2028; With low doses of the two drugs, we observed impaired cell cycle progression, additively reduced cyclins and CDKs, and enhanced p27 level by flow cytometry analysis and western blot. No rapid apoptosis and caspases-involved cell death were observed. Immunohistological analysis after prolonged treatment with low doses of the two drugs demonstrated that carboplatin alone resulted in the formation of endopolyploid cells in p53-mutated breast cancer cells. RAD001 alone had not such an effect, but strengthened this effect of carboplatin. In addition, decreased level of cyclin B1, the main driver of mitosis, was detected by the co-treatment of the two drugs. These data collectively suggest that the combination use of low doses of carboplatin and RAD001 may present a strategy to overcome the resistance of breast cancer to chemotherapy. It is a promising combination that warrants clinical evaluation.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 405.
BRCA1 methylation contributes to the triple-negative breast cancer phenotype.
Authors: Nwachukwu C , Grushko TA , Xu J , Khramtsov A , Olopade OI 
Published: December 2010

Abstract
Abstract #4050
Triple-negative breast cancers are tumors characterized by their lack of hormone receptors (ER and PR) and HER2. They are the most aggressive form and account for 10–17% of all breast carcinomas. A subgroup of triple negative tumors with a basal-like phenotype share morphological features and similar gene expression profiles with tumors from BRCA1 mutation carriers. It has recently been shown that inactivation of BRCA1 in breast epithelial stem cells restricts subsequent progenitor cells to a basal cell phenotype and promotes expansion of ER negative cells (Liu et al 2008, PNAS). While mechanisms of BRCA1 inactivation in sporadic tumors are not completely elucidated, methylation of the BRCA1 promoter is one important mechanism that contributes to loss of BRCA1 expression in sporadic breast cancer. We hypothesize that inactivation of BRCA1 by epigenetic mechanisms such as promoter methylation contributes to the triple negative phenotype.&#x2028; Materials and Methods: Using a combination of methylation specific PCR and Immunohistochemistry, 120 primary breast cancers were analyzed for methylation of the BRCA1 promoter and protein expression of ER, PR and HER2. All tumors with negative staining for ER, PR and HER2 were classified as triple negative and all others were classified as non triple-negative.&#x2028; Results: We were able to classify 111 of the 120 (%) tumors by IHC. We found that 30 out of 111 (27%) tumors were ER, PR, and HER2 negative (triple negative). BRCA1 methylation was detected in 14 out of 30 (47%) triple negative tumors, compared with 10 out of 81 (12%) other tumor phenotypes (p&lt;0.001).&#x2028; Conclusion: These data suggest that BRCA1 inactivation by mutation or methylation may in part drive breast tumor progression toward the triple negative phenotype. Ongoing work will evaluate epigenetic mechanisms regulating gene expression in triple negative breast cancers&#x2028; This abstract is supported by Breast Cancer Research Foundation and the Lee Jeans Entertainment Industry Fund.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4050.
MicroRNAs and epigenetics in human breast cancer.
Authors: Miyamoto K , Ushijima T 
Published: December 2010

Abstract
Abstract #4051
MicroRNAs (miRNAs), which regulate gene expression at the post-transcriptional level, are suggested to play important roles in carcinogenesis. To clarify the miRNAs dysregulation and the relation to epigenetic mechanisms in human breast cancer, we analyzed a breast cancer cell line, MDA-MB-468 that has previously been used for the genome-wide epigenetic analysis: methylation-sensitive-representational difference analysis (MS-RDA). Normal human mammary epithelial cells (HMEC) were compared with MDA-MB-468. The global expression profile (471 miRNAs) of these samples was examined using 3D-Gene Human miRNA oligo chip (Toray, Tokyo, Japan). We identified 4 miRNAs (0.8%), hsa-miR-200a, hsa-miR-429, hsa-miR-652 and hsa-miR-200b, which were expressed at ten-times higher levels in cancer cells and, conversely, 12 miRNAs (2.5%), hsa-miR-137, hsa-miR-138, hsa-miR-34b, hsa-miR-34c, hsa-miR-374, hsa-miR-376a, hsa-miR-422b, hsa-miR-452, hsa-miR-520e, hsa-miR-455, hsa-miR-554 and hsa-miR-574 that were silenced in the cancer cells. Expression analyses using other breast cancer cells (MCF-7, YMB-1-E, T-47D, MDA-MB-231) revealed a significant overexpression of 4 miRNAs, hsa-miR-200a, hsa-miR-429, hsa-miR-652 and hsa-miR-200b and frequent silencing of 5 miRNAs, hsa-miR-138, hsa-miR-34c, hsa-miR-376a, hsa-miR-452, and hsa-miR-455 in breast cancer cells. As for epigenetic mechanisms, overexpressed miRNAs were found to target silenced genes in the MDA-MB-468 cell line, and treatment of MDA-MB-468 with a demethylating agent, 5-aza-2'-deoxycytidine, restored the expression of 5 miRNAs, hsa-miR-137, hsa-miR-374, hsa-miR-520e, hsa-miR-554 and hsa-miR-574. Our results show the existence of a novel miRNA signature in breast cancer, suggesting that epigenetic mechanisms may be involved in the regulation of miRNA expression.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4051.
Role of the insulin receptor in IGF-system signaling and biology.
Authors: Oberg DH , Zhang H , Yee D 
Published: December 2010

Abstract
Abstract #4055
The role of the type I insulin-like growth factor (IGF) receptor (IGF1R) in breast cancer has been extensively studied, and has led to the development of several IGF1R inhibitors currently in clinical trials. The closely related insulin receptor (IR) has been shown to contribute to IGF signaling through the formation of IGF1R/IR-hybrid receptors and through a homodimer of an alternatively spliced form of the IR (IR-A). Understanding the role of the IR in cancer biology will help determine which receptor(s) in the IGF system should be targeted to efficiently inhibit IGF signaling. Our previous work has shown that selective downregulation of IGF1R by siRNA resulted in enhanced sensitivity to insulin through increasing the numbers of insulin receptor homodimers. To determine how downregulation of IR affected IGF1R signaling, we used T47D cells, a breast cancer cell line expressing both the IR and IGF1R, as our model system. We transiently downregulated IR levels using siRNA and evaluated signaling. 5 nM of insulin activated downstream signaling molecules, such as insulin receptor substrate 1(IRS-1) and Akt in control cells, but this response was diminished in the IR-downregulated cells. In contrast, 5 nM of IGF-I did not result in differences in signaling between IR-downregulated cells and control cells. Using IR shRNA, we created stable clones with IR levels reduced by more than 72%. IR shRNA clones demonstrated decreased insulin binding, as measured by 125I-insulin binding assay. Additionally, clones showed decreased response to insulin signaling. 5 nM of insulin activated IRS-1 and Akt in parental T47D cells, but this response was attenuated in the IR-downregulated clones. Proliferation was also decreased in response to 5 nM insulin in the clones compared to parental cells. In contrast, IGF-I mediated signaling was not altered in clones when compared to vector control cells. Further, no change in proliferation was observed in response to IGF-I between wild-type and IR shRNA clones. We also generated stable IR shRNA clones using LCC6 cells. Insulin signaling was reduced in LCC6 clones when compared to wild-type LCC6 cells. However, in contrast to the T47D clones, IGF-I signaling was increased in LCC6 IR shRNA clones. Thus, the role of the insulin receptor in cancer biology may be dependent upon the ratio of IR, IGF1R, and the hybrid receptor. If cells contain mostly homodimers of IGF1R and IR, then downregulation of IR may affect only insulin response. However, if there are high levels of hybrid receptor, then downregulation of IR could affect, and even augment, IGF1R signaling. Our data suggest that the ratio and confirmation states of both IR and IGF1R should be understood to predict the effect of receptor downregulation.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4055.
Recombinant human G-CSF increases invasiveness of breast cancer cells.
Authors: Webster DJ , Wilde ZJ , Orzol AR , Davis JL , Troxell ML , Bae D 
Published: December 2010

Abstract
Abstract #4057
Background: Recombinant human granulocyte-colony stimulating factor (rhG-CSF) is commonly given to breast cancer patients to prevent neutropenia during chemotherapy. It binds to the G-CSF receptor (G-CSFR) on neutrophil precursors, promoting their proliferation within the bone marrow. We observed breast cancer growth in patients with advanced breast cancer during rhG-CSF administration. The G-CSFR is present on some solid tumors, but has not been examined in breast cancer. We asked whether breast cancer cells express the G-CSFR, and whether rhG-CSF has any direct effects on breast cancer proliferation or invasion in vitro.&#x2028; Material and Methods: MDA MB231 is a highly aggressive ER–PR–Her2/neu– breast cancer cell line derived from a human pleural effusion. We analyzed this cell line for the presence of the G-CSFR by immunohistochemistry, reverse-transcriptase PCR (RT-PCR), Western Blot analysis and flow cytometry. We sequenced DNA products of RT-PCR to verify results. We examined the effects of physiologic doses of rhG-CSF on breast cancer cell proliferation and invasion using MTT proliferation and Matrigel transwell assays, respectively.&#x2028; Results: MDA MB231 breast cancer cells express G-CSFR protein and mRNA. Of seven known G-CSFR isoforms, we found evidence of isoforms 1 and 4. Treating MDA MB231 breast cancer cells with rhG-CSF at 50ng/ml did not increase cell proliferation, but did increase invasion across a Matrigel-coated transwell membrane. Cells treated with rhG-CSF appeared more stellate than untreated cells. Studies are ongoing to evaluate which signal transduction pathways and genes are involved in this increased invasion response. The effects of rhG-CSF on breast cancer growth in vivo are also being examined in murine models.&#x2028; Discussion: rhG-CSF is given routinely as part of many adjuvant chemotherapy regimens for breast cancer. Although dose-dense regimens using rhG-CSF have shown equivalent or improved survival when compared to standard dosing regimens, it is possible that rhG-CSF may increase the growth or invasive potential of some breast cancers. It is also possible that rhG-CSF could mobilize breast cancer cells from the bone marrow, making these cells more susceptible to chemotherapy. These possibilities should promote thoughful use of rhG-CSF in the clinical setting, and should factor into the design and implementation of clinical trials using rhG-CSF.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4057.