bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymph Node Transplantation in Breast Reconstruction Using Perforator Flaps.
Authors: LoTempio M. , Studinger R. , Vaisille J. , Chen C. , Levine J. , Allen R. 
Published: December 2010

Abstract
Introduction: For many women undergoing breast reconstruction, the negative impact of upper extremity lymphedema outweighs the benefits of breast reconstruction.Patients with lymphedema present a challenging problem, and typically is not addressed during the reconstruction process. Lymph node dissections have decreased secondary due to the advent of the sentinel node biopsy. However, 7% of patients undergoing sentinel lymph node biopsy develop lymphedema. Previous treatments options have not proved to be highly successful, and include lymphatic massage and lymphaovenous anastomosis. We introduce a combined treatment for breast reconstruction using deep inferior epigastric perforator flap (DIEP) along with lymph node transplantation for lymphedema.Methods: Beginning in 2007, 23 patients have undergone bilateral breast reconstruction using the DIEP along with simultaneous lymph node transplantation. Each patient had demonstrated upper extremity lymphedema by measurements and subjective findings. Of the 23 patients 18 had radiation therapy and five had sentinel node dissection. The lymph node flap was harvested surrounding the superficial circumflex vessels in conjunction with the DIEP. The combined DIEP and lymph nodes were anastomosed to the internal mammary artery. Preparation of the axilla included removal of scar tissue, and fixation of the lymph nodes into the axilla.Results: Each patient had an uncomplicated postoperative course. These patients started to experience resolutions of lymphedema as early as ten days after surgery and continued up to six months. Currently, 15 patients no longer need lymphatic massage nor wear compression garment. One patient had a recurrence of breast cancer. Each patient reported their arm circumference had improved and decreased morbidity associated with lymphedema.Conclusion: Lymph node transplantation is a relatively new and exciting option for the management of lymphedema. Women who undergo breast reconstruction using perforator flaps can have simultaneous lymph node transplantation with minimal morbidity. These patients experienced an overall 89% improvement of symptoms.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3112.
Does the Level of Axillary Node Clearance Influence Adjuvant Treatment in Patients with Breast Cancer?
Authors: Cannings E. , Nicol A. , Hansell D. 
Published: December 2010

Abstract
Background: The SIGN (Scottish Intercollegiate Guidelines Network) guidelines on axillary surgery do not advise as to whether level 1/2 or level 3 clearances should be performed when axillary clearance is required. Although there is a theoretical risk of increased morbidity, in experienced hands a level 3 clearance reduces the chance of residual tumour and allows for full staging.Materials and Methods: 124 consecutive axillary clearances (level 1, 2 and 3) were performed by a single operator. Level 1 and 2 nodes were removed as a single specimen, with level 3 nodes removed separately. Patient case notes, operation notes and pathology reports were used in the collection of data and all data were recorded in an Excel databaseResults: Of the 124 axillary clearances performed, 64 (52%) had level 1/2 lymph nodes positive for carcinoma. Of these 64 patients, 14 (11%) also had positive level 3 nodes. One patient (1%) had negative level 1/2 nodes but positive level 3 nodes. The Nottingham Prognostic Index (NPI) value increased in two patients when the level 3 nodes were included (6.6 to 7.6 and 4.3 to 5.3).Discussion: While it is generally accepted that axillary radiotherapy deals with residual level 3 nodal involvement, basic surgical oncologic principles would suggest that removal of as much tumour as possible should be performed. The patient with positive level 3 nodes but negative level 1/2 nodes would have been under-treated, with viable tumour remaining. Furthermore, the under-estimate of the NPI when level 3 nodes are not included could lead to sub-optimal adjuvant therapy being offered. The performance of a level 3 clearance can preclude the need for axillary radiotherapy, thereby reducing morbidity.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3114.
Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers May Reduce Breast Cancer Recurrence.
Authors: Chae Y. , Valsecchi M. , Lucca A. , Kim J. , Desai A. 
Published: December 2010

Abstract
There have been epidemiologic and biochemical findings alluding to the role of angiotensin converting enzyme inhibitors(ACEIs) and angiotensin receptor blockers(ARBs) in reducing the risk of developing cancer. To date, there exists no study that reported any relationship between their use and the risk of cancer recurrence. Thus, we investigated the associations between the use of ACEI/ARB and the risk of tumor recurrence among breast cancer patients without any evidence of disease.We reviewed the medical records of female patients diagnosed with stage II/III breast cancer in Albert Einstein Medical Center between 1999 and 2005 and later reached no evident disease (NED) stage after curative therapy. Follow up period was from 1999 to 2008 with mean and maximum being 4.4 years and 9.8 years, respectively. ACEI/ARB user was defined as patients taking the medication in NED stage for at least 6 months. Multivariate analyses were performed using logistic regression and Cox proportional hazard model.Of 707 cancer patients and of 335 cancer patients with hypertension, 164, representing 23.3% of total and 49.0% of those with hypertension were prescribed ACEI/ARB. ACEI/ARB use was associated with older age (P&lt;0.001), postmenopausal status (P&lt;0.001), and diabetes (P&lt;0.01). Fourteen percent (23/164) of ACEI/ARB users developed cancer recurrence, while 23.3% (125/541) of nonusers developed a recurrence (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.33-0.97; P=0.01). Kaplan-Meier survival analysis revealed that ACEI/ARB use was related to disease-free survival benefit (log-rank test P&lt;0.01). Five year disease-free survival for ACEI/ARB users was 0.85 compared with 0.76 for nonusers (P&lt;0.01). Adjusting for statistically significant variables above, ACEI/ARB use was associated with reduced risk of developing recurrence not only in all breast cancer patients but also when they were compared to a subset of the nonusers who had hypertension (AHR, 0.41; 0.23-0.80; P&lt;0.01). While ACEI/ARB use was not associated with reduced mortality in all breast cancer patients (AHR, 1.01; 95% CI: 0.61-1.65; P=0.36; log-rank test P=0.52), it was when compared to the subset of patients with hypertension (AHR, 0.43; 95% CI, 0.25-0.68; P&lt;0.01; log-rank test P&lt;0.01).The use of ACEI/ARB is related to reduced risk of developing recurrence in patients with breast cancer. This result provides clinical evidence, in accordance with existing biochemical and epidemiologic data, that antagonizing angiotensin system is inversely associated with tumor recurrence. However, prospective randomized trials are needed to validate this finding.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3121.
An Inhibitor of ADAMs (a Distintegrin and Metalloproteinase) Overcomes HER3-Mediated Resistance to Trastuzumab and Lapatinib.
Authors: Scherle P. , Marando C. , Covington M. , Yao W. , Newton R. , Friedman S. 
Published: December 2010

Abstract
Background: Inhibitors of HER-2/neu and EGF receptors such as trastuzumab, lapatinib, and erlotinib have demonstrated clinical efficacy but not all HER-2/neu or EGFR positive tumors respond and many that initially respond develop resistance. Ligand mediated HER-3 signaling results in tumor growth and survival and is a proposed mechanism of resistance to trastuzumab and lapatinib. Proteolytic cleavage of both ErbB ligands and receptors has been shown to be a critical event that results in ErbB pathway activation. Cleavage is necessary for the generation of soluble, functionally active forms of ErbB ligands and in the case of HER-2/neu, cleavage results in a shed extracellular domain (ECD) and a membrane bound fragment (p95) that contains a kinase domain with significant constitutive activity. In addition, it has been shown that the preferential association between HER3 and p95 can further activate the pathway. Both ErbB ligand and HER-2/neu cleavage are mediated by the ADAM family of proteases. Further, we have previously shown that the ADAM protease inhibitor, INCB7839, provides synergistic inhibition of HER2+ breast cancer cell line growth when combined with either trastuzumab or lapatinib. Materials and Methods: The HER-2 overexpressing BT-474 human breast cancer cell line was treated with either lapatinib or trastuzumab in the presence or absence of the HER-3 ligand, heregulin, and the effects on cell growth measured. The effects of the ADAM protease inhibitor INCB7839 in this system were also examined. Results: The addition of heregulin overcame the anti-proliferative effects of both lapatinib and trastuzumab on the growth of the BT-474 cell line in vitro. Addition of INCB7839 synergized with lapatinib or trastuzumab and importantly, restored the anti-proliferative effects of these agents in the presence of heregulin. Further, pretreatment of BT-474 cells with INCB7839 for 6 days, which we have previously shown completely eliminates the presence of the p95 form of HER2, amplified these effects, presumably by eliminating p95 before stimulating the cells with heregulin. Discussion: Together, these results confirm that heregulin can overcome the anti-proliferative effects of both trastuzumab and lapatinib as previously reported. Prevention of p95 formation by ADAM protease inhibitors appears to restore the anti-proliferative effects of both trastuzumab and lapatinib when heregulin/HER3 signaling occurs, negating a proposed mechanism of resistance to these agents in the clinic. These results suggest that combining an ADAM inhibitor with targeted inhibitors of the ErbB family can overcome HER-3-mediated resistance and enhance the clinical efficacy of approved HER2-targeted agents in the clinical setting. INCB7839 is currently under clinical investigation in combination with trastuzumab for women with metastatic breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3138.
Novel Cytotoxic Proteins of Bacillus thuringiensis Isolated from Peninsular India.
Authors: Devassy B. , Chubicka T. , Devaki G. , Nair H. , Padikala J. 
Published: December 2010

Abstract
Bacillus thuringiensis (Bt) is a versatile soil born bacterium with potential insecticidal activity over a wide range of species of agriculture pests. These unusual properties are due to the crystal (Cry) inclusion proteins largely produced during the sporulation. Recent findings indicate that some non-insecticidal crystal inclusions are selectively cytotoxic to cancer cells. The toxicity is due to the induction of membrane permeability and apoptosis in susceptible cells. Recently, we have reported the cytotoxic effect of proteins extracted from three native strains of Bacillus thuringiensis from the Western Ghats of Kerala (India). Studies have shown that these potent toxins exhibit selective cytotoxicity against some human breast cancer cells including MCF-7, MDA-MB-231, ZR-75 and SKBR3. Presently, we report the cytotoxic properties of more number of Bacillus thuringiensis isolates from Peninsular India, which are already assessed for their diversity. The cytotoxic properties of isolates were primarily analysed by the amplification of DNA using specific primers designed for cytotoxic parasporal genes. The strains showing positive result were subjected to in vitro cytotoxic analysis using cancer cell lines. The crystal proteins were harvested from 72h old cultures in sporulating medium, after confirming the lysis of the cells and release of the protein. The cytotoxic proteins were isolated by aqueous biphasic (sodium dextran sulfate/polyethylene glycol) separation method and purified by various chromatographic (sephadex/nickel coated columns) and electrophoretic procedures. The molecular weight of proteins isolated from different isolates was varying and ranged from 15 to 80 kDa. The pro-protein isolated was activated and subjected in vitro cytotoxicity assay on various normal as well as breast cancer cell lines. The protein was found to have strong cytocidal activities against tumour cells and the treated cells showed remarkable morphological alterations and apoptotic cell death. Thus, a new 14 isolates were found to be cytotoxic by the study. The study revealed that the diversity of cytotoxic Cry genes in Peninsular India is perplexingly high and specific to certain cancers. Considering these results, we suggest that the receptor-mediated action of crystal proteins against tumour cells may find a new place in the therapeutic as well as diagnostic field of cancer therapy and the bacteria and its genetic potential may be utilized as versatile tools against cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3143.
The Expression of Phosphorylated mTOR in Breast Cancer from BRCA1-Mutation Carriers.
Authors: Korski K. , Malicka A. , Wysocki P. 
Published: December 2010

Abstract
Background: The mammalian target of rapamycin (mTOR) is a serine-threonine kinase coupling growth stimuli and metabolic signals to cell cycle progression and protein synthesis. mTOR represents also a novel therapeutic target in various types of cancer. The role of mTOR in development and progression of breast cancer is not fully understood. There are studies suggesting that mTOR is responsible for the resistance of breast cancer to tamoxifen, trastuzumab and various chemotherapeutic agents. Since there are no studies evaluating the activation (phosphorylation) of mTOR in breast cancer cells carrying a germinal mutation of BRCA1, we have decided to assess activation of this kinase in tumor specimens in BRCA1-mutation carriers.Materials and methods: Formalin fixed paraffin-embedded tumor samples were obtained from 19 patients carrying BRCA1 germinal mutation and 24 patients with intact BRCA1 gene. All patients have been treated in the Great Poland Cancer Center between 2000-2008. The blocks were retrieved from the archives of the Department of Pathology and immunostained for phospho mTOR (Phospho-mTOR (Ser 2448), rabbit antibody, Cell Signaling).Results: Phosphorylation of mTOR was not detected in any of 19 patients carrying the mutated BRCA1 gene. Most of the BRCA1-mutated cancers were ER and HER2 negative (18 (95%) and 16 (94%), respectively). In the tumors with a wildtype BRCA1 gene, mTOR activation was detected in 12 samples (50%). Lack of mTOR phosphorylation was again observed mostly in ER and HER2 negative tissue samples (10 (83%) and 11 (92%), respectively).Discussion: Our findings have demonstrated differential activation of mTOR between tumors carrying a wild-type and mutated BRCA1 gene. We have also observed a negative correlation between ER and HER2 status and phosphorylation of mTOR. Although our study included a relatively low number of cases, the results indicate that activation of mTOR and probably also of its upstream targets do not play a crucial role in biology of tumors with a BRCA1 mutation or with the triple-negative phenotype.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3144.
Integrative Molecular Profiling of Triple Negative Breast Cancers Identifies Potential Therapeutic Targets Including Amplifications of FGFR2.
Authors: Turner N. , Turner N. , Lambros M. , Horlings H. , Horlings H. , Pearson A. , Sharpe R. , Mackay A. , Natrajan R. , Geyer F. , van Kouwenhove M. , Kreike B. , Ashworth A. , van de Vijver M. , van de Vijver M. , Reis-Filho J. 
Published: December 2010

Abstract
Triple negative breast cancers (TNBCs) have a relatively poor prognosis emphasising the need to identify new subtype specific target therapies. Based on the concept of oncogene addiction, we searched for potential therapeutic targets by identifying genes consistently over-expressed when amplified in TNBC. Fifty six TNBCs were subjected to high resolution tiling path microarray-based comparative genomic hybridisation (aCGH); out of these cases, 24 were also subjected to genome-wide microarray-based mRNA expression analysis. TNBCs showed a high level of genetic instability, with recurrent regions of amplification (&gt;4 copies) included multiple regions on 1q and 8q, 3q25, 10p14, 10q26, 13q34, 15q26 and 19q12-19q13. Integration of aCGH and expression data revealed 38 genes that were significantly overexpressed when amplified. This list includes known oncogenes and potential therapeutic targets, such as MCL1 (1q21.2), FGFR2 (10q26.3), BUB3 (10q26.3), RAB20 (13q34), PKN1 (19p13.12), and NOTCH3 (19p13.12). To validate FGFR2 as a therapeutic target, we screened a panel of cell lines, by western blotting and aCGH, and identified two TNBC cell lines with FGFR2 amplification. In these cell lines FGFR2 was constitutively active in a ligand independent manner, and RNA interference-mediated silencing of FGFR2 selectively decreased survival of cell lines harbouring FGFR2 amplification. Likewise FGFR2 amplified cell lines were highly sensitive to FGFR tyrosine kinase inhibitor PD173074 (IC50 &lt;20nM). Treatment with PD173074 induced apoptosis in amplified cell lines, as did treatment with PI3 kinase inhibitors LY294002 and BEZ-235 suggesting that apoptosis resulted from inhibition of AKT signalling. Examination of publically available CGH data sets confirmed FGFR2 amplification in 4% (5/124 95%CI 1.3-9.2%) of TNBC, with no cases of FGFR2 amplification in other subtypes (0/150, p=0.02). Our results suggest that FGFR2 amplification is a therapeutic target in a small subset of TNBCs.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3147.
Induction of Aggressive Breast Cancer in p53 Wild Type Cells by BRCA1-IRIS Overexpression.
Authors: ElShamy W. 
Published: December 2010

Abstract
Background: Agents that introduce genotoxic stresses in mammalian cells, such as paclitaxel (Taxol) or ionizing radiation activate a complex array of cellular responses, including p53 activation. As a component of the response to acute stress, p53 has a well-established role in protecting against cancer development. It is not surprising that half of all human tumors have mutated p53. We asked how then tumors are initiated in the cells that carry wild-type p53 allele?Material and Methods: Here we report the identification of a potential novel mechanism that induces tumor formation in p53 wild-type cells. Overexpression of the proto-oncogene, BRCA1-IRIS in human mammary epithelial (HME) cells not only upregulates the expression of the serine/threonine phosphatase; Wild-type p53-Induced Phosphatase (WIP1) through induction of p53 expression but also increases the WIP1 gene copy number in these cells. WIP1 is a negative regulator of p53 as well as p38MAPK. Both proteins are involved in arresting and/or killing cells with extensive genotoxic stresses. Failure to arrest or die in response to massive genotoxic stress leads to the propagation of damaged cells and the development of cancer. BRCA1-IRIS overexpressing cells failed to arrest or die when exposed to UV radiation or Taxol. In fact, treatment of normal HME cells with UV or Taxol upregulated the expression of BRCA1-IRIS and thus WIP-1, prevented p53 and p38MAPK activation and their death.Results: This data suggest that BRCA1-IRIS is perhaps involved in the acquisition of cellular resistance to these agents upon prolonged exposure. On the other hand, depletion of BRCA1-IRIS from tumor cell lines induced apoptosis even in cells with functional p53 and p38MAPK.Discussion: We propose that in p53 wild type cells, whether endogenous or UV- or chemotherapy-induced BRCA1-IRIS overexpression leads to the survival and proliferation of what most likely are severely damaged cells, leading to the transformation of mammary cells in vitro and the induction of breast tumors in vivo. We also propose that BRCA1-IRIS and WIP1 overexpression abrogates the homeostatic balance maintained by p38-p53-WIP1 pathway. Together with the ability of BRCA1-IRIS to upregulate Cyclin D1 expression increases the likelihood that BRCA1-IRIS is an oncogene that induces breast cancer progression when overexpressed, hence making it an attractive target for novel breast cancer therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3154.
GCIP Is a Tumor Suppressor in Breast Cancer.
Authors: Chang T. , Chang M. 
Published: December 2010

Abstract
Background: GCIP protein is a HLH-leucine zipper (HLH-LZ) proteins without basic DNA-binding region, which was identified to be a cyclin D1-binding protein and also was recognized as a human homologue of MAID protein (HHM). Recently, GCIP was found to function as a tumor suppressor in liver and colon tumorigenesis. In this study, we examined in vitro the functional role of GCIP in various breast cancer cell lines.Material and Methods: GCIP-directed siRNA construct was prepared and stable downregulation of GCIP in epithelial-like and nonaggressive/differentiated breast cancer cell line, MCF-7, were selected. In addition, two aggressive/ invasive breast cancer cells (MDA-MB231 and MDA-MB435s) that exhibit low levels of endogenous GCIP expression were transfected with p3x-GCIP-flag, respectively and stable GCIP-re-expressing transfectants were selected. The phalloidin staining cell morphology and functional assays with these stable GCIP downregulating or GCIP re-expressing were performed to characterize the biological effects of GCIP.Results: Stable MCF-7 cells with down-regulated GCIP expression acquired a mesenchymal-like shape and exhibited increased colony formation, migration and invasion capabilities. Furthermore, this was found to be associated with the loss of membrane E-cadherin and increased expression of the mescenchymal marker vimentin. In addition, both the stable MDA-MB231 and MDA-MB435s with GCIP-re-expression acquired an epithelial-like shape and exhibited decreased colony formation, migration and invasion capabilities.Conclusion: our previous study found that decreased expression of GCIP in breast carcinomas compared with normal ductal epithelium (P &lt; 0.001). In this study, we present evidence that GCIP inactivation contributes to the enhanced migratory and invasive capacity of MCF-7 and that GCIP re-expression inhibits a wild range of cellular functions related to the malignant properties of MDA-MB231 and MDA-MB435s, confirming that GCIP is a tumor suppressor in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3158.