bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of a Tire Friction and Performances of a Braking in a High Speed Driving
Authors: Oh Yumrak , Lee Hoguen
Published: August 2014

The goal of pavement is to deliver the fine roughness and the safe road surface to traffic. It requires a secured and comfortable surface using the controlled speed of road. Through adjusting driving speed, skid resistance can be altered in one of the performances of the pavement surface. In high speed driving, there might be a certain level of risk, not in the same level as the proposed roads. Hence, this study first analyzes the speed equation under a consideration of a braking distance and then suggests the friction coefficient in high speed driving with the principle of conservation of energy. If we accept simply that the coefficient of friction is independent of speed, the difference between analysis and test value for braking distance is greatly generated. Therefore we have to analyze the coefficient of friction as an exponential function of braking speed of a vehicle.
On the Bivariate Spectral Homotopy Analysis Method Approach for Solving Nonlinear Evolution Partial Differential Equations
Authors: Motsa S. S.
Published: August 2014

This paper presents a new application of the homotopy analysis method (HAM) for solving evolution equations described in terms of nonlinear partial differential equations (PDEs). The new approach, termed bivariate spectral homotopy analysis method (BISHAM), is based on the use of bivariate Lagrange interpolation in the so-called rule of solution expression of the HAM algorithm. The applicability of the new approach has been demonstrated by application on several examples of nonlinear evolution PDEs, namely, Fisher’s, Burgers-Fisher’s, Burger-Huxley’s, and Fitzhugh-Nagumo’s equations. Comparison with known exact results from literature has been used to confirm accuracy and effectiveness of the proposed method.
A Novel Memristive Multilayer Feedforward Small-World Neural Network with Its Applications in PID Control
Authors: Dong Zhekang , Duan Shukai , Hu Xiaofang , Wang Lidan , Li Hai
Published: August 2014

In this paper, we present an implementation scheme of memristor-based multilayer feedforward small-world neural network (MFSNN) inspirited by the lack of the hardware realization of the MFSNN on account of the need of a large number of electronic neurons and synapses. More specially, a mathematical closed-form charge-governed memristor model is presented with derivation procedures and the corresponding Simulink model is presented, which is an essential block for realizing the memristive synapse and the activation function in electronic neurons. Furthermore, we investigate a more intelligent memristive PID controller by incorporating the proposed MFSNN into intelligent PID control based on the advantages of the memristive MFSNN on computation speed and accuracy. Finally, numerical simulations have demonstrated the effectiveness of the proposed scheme.
The Interaction between Diabetes, Body Mass Index, Hepatic Steatosis, and Risk of Liver Resection: Insulin Dependent Diabetes Is the Greatest Risk for Major Complications
Authors: Wiggans M. G. , Lordan J. T. , Shahtahmassebi G. , Aroori S. , Bowles M. J. , Stell D. A.
Published: August 2014

Background. This study aimed to assess the relationship between diabetes, obesity, and hepatic steatosis in patients undergoing liver resection and to determine if these factors are independent predictors of major complications.Materials and Methods. Analysis of a prospectively maintained database of patients undergoing liver resection between 2005 and 2012 was undertaken. Background liver was assessed for steatosis and classified as <33% and ≥33%. Major complications were defined as Grade III–V complications using the Dindo-Clavien classification.Results. 504 patients underwent liver resection, of whom 56 had diabetes and 61 had steatosis ≥33%. Median BMI was 26 kg/m2(16–54 kg/m2). 94 patients developed a major complication (18.7%). BMI ≥ 25 kg/m2(P=0.001) and diabetes (P=0.018) were associated with steatosis ≥33%. Only insulin dependent diabetes was a risk factor for major complications (P=0.028). Age, male gender, hypoalbuminaemia, synchronous bowel procedures, extent of resection, and blood transfusion were also independent risk factors.Conclusions. Liver surgery in the presence of steatosis, elevated BMI, and non-insulin dependent diabetes is not associated with major complications. Although diabetes requiring insulin therapy was a significant risk factor, the major risk factors relate to technical aspects of surgery, particularly synchronous bowel procedures.
Smoking is Associated with Reduced Leptin and Neuropeptide Y Levels and Higher Pain Experience in Patients with Fibromyalgia
Authors: Bokarewa Maria I. , Erlandsson Malin C. , Bjersing Jan , Dehlin Mats , Mannerkorpi Kaisa
Published: August 2014

Smoking deregulates neuroendocrine responses to pain supporting production of neuropeptide Y (NpY) by direct stimulation of nicotinic receptors or by inhibiting adipokine leptin. Present study addressed the effect of cigarette smoking on adipokines and pain parameters, in 62 women with fibromyalgia (FM) pain syndrome with unknown etiology. Pain was characterized by a visual analogue scale, tender point (TP) counts, pressure pain threshold, and neuroendocrine markers NpY and substance P (sP). Levels of IGF-1, leptin, resistin, visfatin, and adiponectin were measured in blood and cerebrospinal fluid. Current smokers(n=18)had lower levels of leptin compared to ex-smokers (n=25,P=0.002), while the expected NpY increase was absent in FM patients. In smokers, this was transcribed in higher VAS-pain(P=0.04)and TP count(P=0.03), lower pain threshold(P=0.01), since NpY levels were directly related to the pain threshold (rho=0.414) and inversely related to TP counts (rho=-0.375). This study shows that patients with FM have no increase of NpY levels in response to smoking despite the low levels of leptin. Deregulation of the balance between leptin and neuropeptide Y may be one of the essential mechanisms of chronic pain in FM.
Corneal Collagen Cross-Linking with Hypoosmolar Riboflavin Solution in Keratoconic Corneas
Authors: Gu Shaofeng , Fan Zhaoshan , Wang Lihua , Tao Xiangchen , Zhang Yong , Mu Guoying
Published: August 2014

Purpose. To report the 12-month outcomes of corneal collagen cross-linking (CXL) with a hypoosmolar riboflavin and ultraviolet-A (UVA) irradiation in thin corneas.Methods. Eight eyes underwent CXL using a hypoosmolar riboflavin solution after epithelial removal. The corrected distance visual acuity (CDVA), manifest refraction, the mean thinnest corneal thickness (MTCT), and the endothelial cell density (ECD) were evaluated before and 6 and 12 months after CXL.Results. The MTCT was 413.9 ± 12.4 μm before treatment and reduced to 381.1 ± 7.3 μm after the removal of the epithelium. After CXL, the thickness decreased to 410.3 ± 14.5 μm at the last follow-up. Before treatment, the meanK-value of the apex of the keratoconus corneas was 58.7 ± 3.5 diopters and slightly decreased (57.7 ± 4.9 diopters) at 12 months. The mean CDVA was 0.54 ± 0.23 logarithm of the minimal angle of resolution before treatment and increased to 0.51 ± 0.21 logarithm at the last follow-up. The ECD was 2731.4 ± 191.8 cells/mm2before treatment and was 2733.4 ± 222.6 cells/mm2at 12 months after treatment.Conclusions. CXL with a hypoosmolar riboflavin in thin corneas seems to be a promising method for keratoconic eyes with the mean thinnest corneal thickness less than 400 μm without epithelium.
Proteomic Analysis of Gossypol Induces Necrosis in Multiple Myeloma Cells
Authors: Xu Renhua , Tian Enbing , Tang Haiping , Liu Chongdong , Wang Qingtao
Published: August 2014

Gossypol is a phenolic aldehyde extracted from plants and is known to be an antitumor agent to induce cancer cell apoptosis. In the present study, multiple myeloma cells were treated with gossypol, which resulted in an increase of cellular reactive oxygen species (ROS) and cell necrosis. Quantitative proteomic analysis was carried out to identify differentially expressed proteins between untreated and gossypol-treated cells. Proteomic analysis identified 4330 proteins, in which 202 proteins are upregulated and 383 proteins are downregulated in gossypol-treated cells as compared to the untreated cells. Importantly, proteomic and western blot analysis showed that apoptosis regulators BAK and Bax were upregulated in gossypol-treated cells, indicating that Bcl-2 associated death pathway was activated. Similarly, gossypol also induced upregulations of DNA mismatch repair proteins and DNA replication licensing factor, suggesting that gossypol caused significant DNA damage. Furthermore, upregulations of HLA class I and class II histocompatibility antigens and beta-2-microglobulin were observed in gossypol-treated cells, indicating that gossypol has a novel function to activate cellular immune responses. Our data demonstrate that the execution of necrosis is a complex process involving ROS, DNA damage, and Bcl-2 family proteins. Gossypol-activated immune responses are a potential new approach for multiple myeloma chemotherapy.
Hermite-Hadamard Type Inequalities for Superquadratic Functions via Fractional Integrals
Authors: Li Guangzhou , Chen Feixiang
Published: August 2014

We use basic properties of superquadratic functions to obtain some new Hermite-Hadamard type inequalities via Riemann-Liouville fractional integrals. For superquadratic functions which are also convex, we get refinements of existing results.
Interest of Boundary Kernel Density Techniques in Evaluating an Approximation Error of Queueing Systems Characteristics
Authors: Bareche Aïcha , Aïssani Djamil
Published: August 2014

We show the interest of nonparametric methods taking into account the boundary correction techniques for a numerical evaluation of an approximation error between the stationary distributions ofG/M/1andM/M/1queueing systems, when the density function of the general arrivals lawGin theG/M/1system is unknown and defined on a bounded support. To compute this error, we use two kinds of norms: theL1norm and the weight norm. Numerical examples based on simulation studies are presented for the two cases of considered norms. A comparative study of the results has been provided.
Targeting EphA3 Inhibits Cancer Growth by Disrupting the Tumor Stromal Microenvironment
Authors: Vail Mary E. , Murone Carmel , Tan April , Hii Linda , Abebe Degu , Janes Peter W. , Lee Fook-Thean , Baer Mark , Palath Varghese , Bebbington Christopher , Yarranton Geoffrey , Llerena Carmen , Garic Slavisa , Abramson David , Cartwright Glenn , Scott Andrew M. , Lackmann Martin
Published: August 2014

Eph receptor tyrosine kinases are critical for cell–cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow–derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3+/CD90+/Sca1+ mesenchymal/stromal cells with an EphA3 agonist leads to cell contraction, cell–cell segregation, and apoptosis. Treatment of mice with an agonistic α-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy. Cancer Res; 74(16); 4470–81. ©2014 AACR.
Abstract BS1-2: Reactive Stroma as Therapeutic Targets in Breast Cancer Bone Metastasis
Authors: Kang Y
Published: August 2014

Metastasis represents the most devastating stage of cancer progression. Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients. Discovering bone metastasis genes that are clinically relevant and functionally important are critical for the development of novel therapeutics for high-risk breast cancer patients. We apply a multidisciplinary approach to analyze the molecular basis of breast cancer bone metastasis, combining functional genomics tools with animal models and clinical analysis of cancer metastasis. Candidate bone metastasis genes were identified from gene expression profiling of highly bone metastatic cells derived after in vivo selection in animal models. Functional characterization of these genes revealed their novel role in mediating tumor-stromal interactions essential for the formation of osteolytic bone metastasis. We discovered a novel metalloprotease-initiated, EGFR-dependent paracrine signaling cascade among tumor cells, osteoblasts and osteoclasts that promotes the maturation of bone-degrading osteoclasts and formation of osteolytic lesions. Using in vivo imaging technology, we showed that TGFbis released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGFb target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. More recently, we identified osteoclast-derived miRNAs as biomarkers and therapeutic targets of osteolytic bone metastasis. Importantly, pharmaceutical inhibitors against EGFR, TGFb and Notch signaling pathways and miRNAs blocking osteoclast differentiation significantly reduce the development of bone metastasis, suggesting novel avenues for clinical management of skeletal complications of breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BS1-2.
Abstract ES3-2: Clinical Trial Designs for New Therapies: What Agents Should We Study?
Authors: DeMichele A
Published: August 2014

Biologically-targeted, novel agents hold great promise in breast cancer, but require adjustments to traditional study design, conduct and patient selection to be tested safely, effectively and economically. Key questions to be address in this talk include: Is the drug safe? Is it hitting the target? Can we identify the “right” patients to test? In what setting do we test it? Toxicities of these agents move well-beyond traditional myelosuppression and fatigue, encompassing almost every organ system and requiring changes in monitoring and management to assure safety. Dosing and assessment strategies must be aimed at optimally modulating target and assessing whether hitting the target has the desired effect on the natural history of the disease. The concurrent development of predictive biomarkers is necessary to select appropriate study subjects, which may be limited to a relatively small subset of patients with the disease. Finally, selecting the best therapeutic setting (treatment naïve, refractory, acquired resistance) can greatly impact the performance of the agent and requires knowledge of cancer biological evolution through the metastatic process.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-2.
Abstract ES4-1: Navigating the Obstacles and Risks of Survivorship: Breast Cancer Sexuality: Issues and Answers
Authors: Krychman M
Published: August 2014

The sexual consequences of breast cancer and its treatments are well known. Sexual difficulties include alteration in hormonal levels, changes in sexual organs and anatomy, vaginal and vulvar dryness, changes in libido, increased latency to orgasm and decreased intensity of orgasmic response. Changes in body image, sexual self-esteem and relationship dynamic tension may present as survivorship challenges for the breast cancer patient and her partner. Severe vulvo vaginal and clitoral atrophy as a result of chemotherapy and/or adjuvant hormone therapy, and loss of libido secondary to dyspareunia are widespread. Cytostatic medications that are prescribed for long-term use (aromatase inhibitors) can impact bone health, sexual functioning/satisfaction and overall quality of life. Many women on aromatase inhibitors have severe complaints of vulvar and vaginal atrophy.

Sexual dysfunction is common for breast cancer population and limited acceptable treatments are available. Minimally absorbed local vaginal estrogen use in this population remains controversial and a hotly debated controversial topic. More data should be forthcoming. There are multiple new innovative treatments in the research pipeline for female sexual dysfunction. DHEA intravaginal suppositories, Flibanserin and Bremelanotide (PT 141) remain promising although they have not been adequately studied in the breast cancer population. Ospemifene a novel estrogen agonist/ antagonist has demonstrated a strong estrogenic effect on the vaginal epithelium during a three month trial period and did not stimulate the endometrium; however, the medication did mildly aggravate hot flashes (this did not lead to drug discontinuation). Although not studied in breast cancer patients, pivotal Phase 3 data confirmed effectiveness of ospemifene as effective treatment for vulvovaginal atrophy. In a recent article in Menopause, Ospemifene and 4-hydroxyospemifene effectively prevented and treat breast cancer in Mtag. TG Transgenic Mouse.

Testosterone use remains off label and is not FDA approved, yet it is widely used in the non cancer population. New emerging safety data will be presented. Vaginal moisturizers, lubricants and dilators in association with genito pelvic floor therapy and intravaginal valium suppositories can be considered front line treatment for atrophy, dyspareunia and hypertonic vaginismus. New innovative data on non hormonal management of hot flashes is and important initial step in the overall management of the breast cancer patient who is suffering from sexual dysfunction.

A multi model treatment paradigm will be presented which will include pharmacologic, nonpharmacologic, and psychosocial interventions.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES4-1.
Abstract ES4-3: Risk of Developing Second Primary Breast Cancer among Survivors of Breast Cancer
Authors: Bernstein JL
Published: August 2014

Of the nearly 226,870 US women expected to develop breast cancer in 2012 and the over 3 million breast cancer survivors currently residing in the US, five to ten percent will develop a subsequent primary in the contralateral breast (CBC) (www.cancer.org). This risk of developing CBC is higher than the overall risk of breast cancer in the general population. The rising incidence of breast cancer, coupled with an improved survival potential after cancer diagnosis has placed an increased number of women at risk for CBC, yet the epidemiology is poorly understood. Despite common genetics and exposures shared by both breasts, only a fraction of women who survive their first primary will develop a second primary in the contralateral breast. Epidemiologic studies have identified factors associated with an increased risk of developing CBC, including family history of breast cancer, early age at diagnosis, hormonal factors, reproductive history, body-mass index, and tumor characteristics of the first primary e.g., lobular histology, stage and estrogen receptor (ER) status. The risk of developing CBC has also been associated with mutations of specific genes including BRCA1, BRCA2, and CHEK2. Importantly, the treatment a woman receives for her first primary breast cancer can also influence her risk of developing CBC; chemotherapy, hormonal therapies and tamoxifen significantly reduces the risk of developing CBC while the radiation received to the contralateral breast during radiotherapy increases the risk of CBC. Despite the number of established risk factors for increased CBC risk, their combined effect accounts for only a small portion of the CBCs that develop each year. It is unclear whether, and to what extent, genetic factors and radiation, individually or via interaction, contribute to the development of CBC. This talk will review the state of the field.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES4-3.
Abstract ES5-3: Investigating Breast Cancer with Single-Cell Sequencing
Authors: Navin NE
Published: August 2014

Tumors evolve from single cells. As they evolve, they acquire complex somatic mutations and diversify, forming distinct subpopulations of cells. This intratumor heterogeneity confounds basic research and clinical practice because tools do not exist to resolve it. Standard genomic methods are limited to reporting an average signal from a complex population of cells, because they require a large amount of input material. These bulk methods may mask population diversity and rare cells in the tumor - that may be the most malignant. To address this limitation my laboratory has developed single-cell sequencing tools to delineate intratumor heterogeneity and investigate mutational evolution in human cancers. We developed a method to profile genomic copy number in single cells and used this method to study genome evolution in triple-negative (ER−/PR−/Her2-) breast tumors (Navin et al., 2011 Nature) which revealed a punctuated model for copy number evolution. Recently, we have extended this method to obtain whole-genome, high-coverage sequencing data from single human tumor cells. From this data we can detect the full spectrum of genomic mutations, including point mutations, indels and microdeletions in single human cells. We applied this method to study clonal diversity in an estrogen-receptor-positive breast carcinoma and sequenced four single cells in addition to a population sample. In the population we detected only 36 coding mutations. However, our whole-genome single-cell sequencing data revealed hundreds of additional coding mutations, suggesting extensive clonal diversity in the tumor. Our data from this tumor support a mutator phenotype model for tumor progression, in which cancer is driven by elevating the rate of random mutations. Our studies show that a wealth of information can be obtained from studying single cancer cells, data that could not be obtained by analyzing the tumor en masse. We expect single-cell sequencing to have major clinical applications in early detection, analyzing scarce tissue samples and monitoring residual disease in patients with cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES5-3.
Abstract ES6-2: Evolving Trends in Implant Breast Reconstruction
Authors: Pusic A
Published: August 2014

For women undergoing mastectomy, implant breast reconstruction is increasingly common. Over the past 5 years, new trends in implant reconstruction have been evolving. The use of ‘next-generation’ silicone implants, acellular dermal matrices and fat grafting have expanded the range of options available to patients. In addition, for women undergoing both skin-sparing and nipple-sparing mastectomies, there is growing experience with single-stage implant reconstruction (i.e. implant placement directly at the time of mastectomy without use of a tissue expander). Finally, indications for post-mastectomy radiation continue to increase and this has important implications for long-term patient satisfaction with implant reconstruction.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES6-2.
Abstract ES8-2: Breast Cancer Stroma: A Predictor of Clinical Outcome and Tumour Heterogeneity
Authors: Bertos N , Finak G , Lesurf R , Saleh SM , Zhao H , Souleimanova M , Meterrisian S , Omeroglu A , Hallett M , Park M
Published: August 2014

Breast cancer heterogeneity is one of the principal obstacles both to predicting outcome and to determining an effective course of treatment for this disease. Individual cases demonstrate heterogeneity at multiple levels, including those parameters assessed by studies of gene expression, chromosomal aberrations, and classical and immuno-pathology. Although genomic technologies have been used to gain a better understanding of the impact of gene expression heterogeneity on breast cancer outcome by identifying gene expression signatures associated with clinical outcome, histopathological breast cancer subtypes, and a variety of cancer–related pathways and processes, relatively little is known about the effects of heterogeneity in the tumor microenvironment. We have addressed changes in stroma by analyzing changes in gene expression in stromal tissue associated with breast tumors when compared to normal breast tissue. We have integrated gene expression data from laser capture microdissected breast tumor stroma with matched normal stroma. Using this approach we have identified that the microenvironment of a breast tumor can be classified into one of six distinct molecular phenotypes exhibiting distinct biological functions and carrying prognostic information independent of existing therapeutic biomarkers and tumor subtypes. A trained predictor of 23 genes was developed and contains new information to stratify breast cancer subtypes. This is independent of clinical parameters and published predictors of outcome and identifies patients with poor outcome in multiple breast cancer expression data generated using using whole tissue. The stromal predictor selects poor outcome patients from multiple clinical subtypes of breast cancer and contains genes representing distinct biological features, including differential immune response, angiogenic response, as well as a hypoxic response. Elements of this signature are present in murine models of breast cancer. These results highlight the complex relationship between the tumor and its microenvironment, and underline the role that the stroma plays in tumor progression.

These results demonstrate an important role for the tumor microenvironment in defining breast cancer heterogeneity, with a consequent impact upon clinical outcome. Novel therapies could be targeted at the processes that define the stroma classes, suggesting new avenues for the development of individualized treatment regimens.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES8-2.
Abstract OT1-1-07: Human epidermal growth factor receptor 2 (HER2) suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (LTP112515)
Authors: Lin N , Danso MA , David AK , Muscato J , Rayson D , Houck WA , Ellis C , DeSilvio M , Garofalo A , Nagarwala Y , Winer E
Published: August 2014

Background: The combination of lapatinib (L) with trastuzumab (T) results in enhanced antitumor activity in preclinical models of HER2-positive breast cancer (BC), due to the complementary mechanisms of action of the two agents. In patients with prior T-treated HER2-positive metastatic BC (MBC), treatment with T plus L was associated with longer progression-free survival (PFS) and overall survival (OS) compared with L alone. The combination also had an acceptable safety and tolerability profile. In patients with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. Current common clinical practice for most patients experiencing clinical benefit from first-line treatment with T plus chemotherapy is to continue T as maintenance therapy after completion of the recommended number of chemotherapy cycles. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy.

Methods: In this open-label, Phase III study, 280 patients will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]), or T (6 mg/kg q3w) alone. Patients will receive study treatment until disease progression, death, discontinuation due to adverse events, or patient withdrawal. The primary endpoint is PFS; secondary endpoints are; OS, clinical benefit rate, and safety.

Key eligibility criteria include females, age ≥18 years with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Patients with stable brain metastases are eligible if entering the study on second-line treatment.

Efficacy endpoints will be analyzed in the intent-to-treat population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.667) from 18 weeks (T alone) to 27 weeks (L plus T). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. One interim analysis is planned for futility when approximately 97 PFS events (50% of the required events) have been observed. Safety endpoints will be analyzed in all randomized patients who receive ≥1 dose of study medication.

The trial is currently open for accrual in the United States and Canada.

ClinicalTrials.gov - NCT00968968

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-07.
Abstract OT1-2-01: NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx)
Authors: Cobleigh MA , Anderson SJ , Julian TB , Siziopikou KP , Arthur DW , Rabinovitch R , Zheng P , Mamounas EP , Wolmark N
Published: August 2014

Background: A significant amount of DCIS is ER negative and/or overexpresses HER2. This provides an opportunity to test molecular therapy in DCIS.

In xenograft models and cell lines, T boosts RT effectiveness. In T-treated HER2+ patients, apoptosis occurs within 1 wk of single agent T use, with T found in ductal aspirates. Ample safety evidence for T exists. T given during whole breast irradiation (WBI) may improve results for lumpectomy (Lx) resected HER2+ DCIS. A trial to examine this question will enhance the understanding of breast tumor biology and the prevention of such tumors and could possibly extend breast-conserving surgery benefits for women with DCIS.

Method: After Lx for pure DCIS, each patient's DCIS lesion is centrally tested for HER2 by IHC analysis. HER2 2+ tumors undergo FISH analysis. HER2 3+ or FISH+ patients can be randomly assigned to 2 doses of T, 3 weeks apart during WBI or to WBI alone.

Women ≥18 yrs. with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are clinically or pathologically node negative are eligible. Centrally tested DCIS must be HER2 +. ER and/or PR status must be known before randomization.

Primary aims are to determine if T decreases ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. B-43 will determine if DFS, recurrence-free interval, and OS can be improved with the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at163 ipsilateral breast cancer events (7.5–8 yrs. after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 5–31-12, 939 patients have been randomized.

NCT00769379Grant support: PHS NCI-U10-CA-69651, -12027, and NCI P30-CA-14599 from the US NCI and Genentech, Inc.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-2-01.
Abstract OT2-3-04: A PILOT PHASE II STUDY TO EVALUATE THE IMPACT OF DENOSUMAB ON DISSEMINATED TUMOR CELLS (DTC) IN PATIENTS WITH EARLY STAGE BREAST CANCER (ESBC)
Authors: Li J , Rugo HS
Published: August 2014

Background: Bone is the most common site of metastases in breast cancer (BC). The detection of keratin + cells (DTC) in bone marrow (BM) has been shown to correlate with an increased risk of disease recurrence. Receptor activator of nuclear factor kappa b (RANK) is critical to bone turnover. Pre-clinical studies have shown that the ligand to RANK (RANKL) can induce metastases of RANK-expressed tumor cells, and that treatment with a RANKL inhibitor can reduce BC metastases. Our previous study suggests that higher RANK expression in tumor at the time of diagnosis correlates with worse recurrent free survival (RFS). Denosumab, a humanized RANKL inhibitor, has been approved in patients (pts) with osteoporosis and metastatic BC to bone.

Trial design: We designed a nonrandomized, open label phase II pilot study evaluating the impact of denosumab on DTCs in pts with ESBC and DTCs following (neo) adjuvant chemotherapy. A total of 45 pts will be enrolled; treatment (Rx) consists of denosumab by subcutaneous injection monthly for 6 months, then every 12 weeks for 6 months for a total of one year. BMA will be repeated at 6 and 12 mo; samples will be evaluated for DTC and for specific gene expression.

Eligibility criteria: Eligible pts have completed adjuvant chemotherapy and at least 3 months (mo) of hormonal Rx as indicated, and have >10 DTC on screening bone marrow aspiration by immunomagnetic enrichment + flow cytometry (IE/FC).

Specific aims: The primary efficacy endpoint is the reduction of DTC/ml from >10DTC/ml to ≤ 10DTC/ml at 6 mo and one year, and the feasibility of denosumab use in this setting. Secondary and exploratory endpoints are to evaluate the correlation of DTC at each time point with BC recurrence, and to analyze gene expression of markers related to bone destruction and inflammation in sorted DTC.

Statistical methods: A total of 45 pts will be enrolled. Based on results from a previous trial testing zoledronic acid in a group of pts with similar eligibility, we expect to have evaluable BMA on 37 (82%) at 1 year. With standard Rx we expect 5% or fewer will have counts ≤10 DTC/ml at 1 year. Using STATA routine sample size (SAMPSI: sample size and power for means and proportions), as long as 20% of pts in treated group become DTC-negative, we will have 89% power to detect this degree of efficacy. These calculations are based on an “exact” test of the proportion of successes; those with reductions to ≤10DTC/ml in sample sizes of 37 based on one-sided testing at a 5% level of significance. We will compare the DTC/ml at 6 and 12 mo to baseline to evaluate reduction in counts.

Present accrual and target accrual: trial will be open in July, 2012 with target accrual of 45 pts.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-04.
Abstract OT3-3-07: Neoadjuvant bevacizumab with weekly nanoparticle albumin bound (nab)-paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide (AC) for triple negative breast cancer.
Authors: Snider JN , Allen JW , Young R , Schwartzberg L , Javed Y , Jahanzeb M , Sachdev JC
Published: August 2014

Background: Triple negative breast cancer (TNBC) predominantly clusters with “basal like” subtype on genomic profiling. Over-expression of Secreted Protein Acidic and Rich in Cysteine (SPARC) has been observed in basal like breast cancer (Charaffe-Jaufrett et al. Oncogene 2006; 2273–84). Endothelial transcytosis of nab- paclitaxel occurs via albumin- gp60 receptor-caveolin 1 interaction. SPARC entraps the albumin resulting in higher intratumoral accumulation, which may explain the increased efficacy of nab-paclitaxel (Desai et al. Translational Oncology 2009; 59–63). Exploiting this mechanism & the dysfunctional BRCA mediated DNA repair in basal tumors, we hypothesize that nab-paclitaxel + the DNA damaging drug carboplatin would produce high response rates in TNBC. Adding bevacizumab may enhance efficacy by blocking angiogenesis. In TNBC, pathologic complete remission (pCR) to neo-adjuvant therapy correlates with better disease-free survival (DFS). We hypothesize that high pCR rates can be achieved for patients with TNBC with this combination translating to an improved DFS than seen historically.

Methods: Patients with palpable & operable TNBC ≥ 2 cm are eligible for this single stage phase II trial. pCR (defined as the absence of invasive tumor cells) in the breast is the primary end point, while pCR in the breast + axillary nodes & pCR + near pCR (residual tumor < 5mm) in the breast are secondary end points. 57 evaluable patients are needed, assuming a pCR rate of 25% vs. 40% for the null & alternate hypotheses respectively. 35 patients have been accrued to date. Patients receive carboplatin AUC 6 day 1 & nab-paclitaxel 100mg/m2 days 1, 8 & 15 of a 28 day cycle for 4 cycles and then dose dense AC for 4 cycles. Bevacizumab is given at 10mg/kg Q 2 weeks with chemotherapy for the first 6 cycles. Surgery & radiation are per institutional standards. Bevacizumab is continued postoperatively to complete 1 year of treatment. A core biopsy for collection of fresh tumor tissue is required prior to the start of study treatment. Blood is collected at baseline, and after 4 & 8 cycles for biomarker analysis. Genomic and expression profiling will be undertaken for correlation with response.

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Celgene Corporation.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-07.
Abstract OT3-4-03: Prospective neo-adjuvant registry trial linking MammaPrint, subtyping and treatment response: Neo-adjuvant Breast Registry – Symphony Trial (NBRST)
Authors: Whitworth P , Gittleman M , Akbari S , Nguyen B , Baron P , Rotkiss M , Beatty J , Gibson J , Stork-Sloots L , de Snoo F , Beitsch P
Published: August 2014

Background: The FDA-approved MammaPrint 70 gene profile is performed on a diagnostic multi-gene array. This platform enables additional gene expression profiles to be analyzed simultaneously on one tumor specimen. One such gene expression profile is BluePrint, an 80 gene molecular subtyping profile that discriminates between three distinctive subtypes; Basal-type, Luminal-type, and HER2-type. By combining MammaPrint and BluePrint, patients can be stratified into the following subgroups: Luminal-type/MammaPrint Low Risk; Luminal-type/MammaPrint High Risk; HER2-type and Basal-type. Marked differences are observed in response to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint [Glück et al. ASCO 2012].

Trial design: NBRST is a prospective observational, case-only study linking MammaPrint and BluePrint to neo-adjuvant treatment response and Distant Metastases-Free Survival (DMFS) and Relapse-Free Survival (RFS). MammaPrint and BluePrint are assessed on fresh or formalin-fixed, paraffin-embedded core needle biopsy samples. Treatment is at the discretion of the physician, adhering to NCCN approved regimens or a recognized alternative.

Eligibility: The study will include women aged 18–90 with histologically proven breast cancer, who have started or are scheduled to start neo-adjuvant chemotherapy or neo-adjuvant hormonal therapy, after successful MammaPrint and BluePrint assessment, and who provide written informed consent. Additional inclusion criteria are that women must have had no excisional biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for the treatment of breast cancer.

Objectives: The main objectives of this registry study are to: 1. Measure chemosensitivity (as defined by pathological complete response [pCR]) or endocrine sensitivity (as defined by decrease in longest tumor diameter or RCB1) in the molecular subgroups as determined by combining MammaPrint and BluePrint results.2. Compare local IHC and FISH results with TargetPrint results and BluePrint results.3. Document impact of MammaPrint, TargetPrint and BluePrint results on treatment decisions.4. Assess the 2–3 and 5-year DMFS and RFS for the different molecular subgroups.

Statistical methods: Comparison of response rates between different molecular subgroups will be conducted using the Pearson Chi-square test.

Accrual: The trial started in August 2011 and there are currently 36 participating sites in the US. To date (June 06, 2012), 158 of the planned 400 patients have been enrolled.Clinical trial registry number: NCT01479101.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-03.
Abstract P1-01-13: Patterns of definitive axillary management in the era prior to reporting ACOSOG Z0011: comparison between NCCN Centers and hospitals in Michigan
Authors: Breslin T , Hwang S , Mamet R , Hughes M , Otteson R , Edge S , Moy B , Rugo H , Wong Y-N , Wilson J , Laronga C , Weeks J , Silver S , Marcom P
Published: August 2014

Background: The results of the ACOSOG- Z0011 trial have had potential practice changing implications for the management of patients with positive sentinel lymph node (SLN) undergoing lumpectomy and radiation for breast cancer. However, some evidence suggests a shift in axillary management even prior to the initial report of data supporting sentinel lymph node biopsy (SLNB) alone in mid-2010. We analyzed data in the National Comprehensive Cancer Network (NCCN) outcomes database from NCCN centers and the Michigan Breast Oncology Quality Initiative (MiBOQI) hospitals to examine institutional practice patterns with respect to use of completion axillary dissection (CALND) for SLN positive breast cancer in the years leading up to publication of these trial results. We hypothesized that CALND would be omitted more frequently in women treated at NCCN centers compared to those treated at MiBOQI programs.

Methods: We identified 2,172 women with clinical T1/T2 N0 breast cancer who underwent breast surgery and SLNB and had a positive SLN from 2007 through 2010 at one of 12 participating NCCN centers or 12 MiBOQI sites. Patient and tumor characteristics, definitive breast procedure, year of diagnosis, and institutional affiliation were analyzed as predictors of use of SLNB alone in univariate Chi-Square and multivariable logistic regression models.

Results: CALND was omitted in 314 (14.5%) of the 2,172 patients. Over time, there was a dramatic increase in the use of SLNB alone (12% in 2007 to 23% in 2010). In the univariate analyses, increased patient age, later year of diagnosis, lower T stage, and lower pathologic N stage were significant predictors of use of SLNB alone (all p < .0001). There was no association between definitive breast surgery type, hormone receptor status, Her-2 Neu status, or institutional affiliation and use of SLNB alone. In the multivariable model, older age at diagnosis, later year of diagnosis, and lower pathologic N stage remained significant independent predictors of SLNB alone. There were no significant differences in rates of omission of CALND between NCCN and MIBOQI sites.

Conclusions: Omission of CALND occurred frequently in women with SLN positive breast cancer cared for in both NCCN and MiBOQI institutions in advance of reporting results of ACOSOG-Z0011. This shift was seen in management of patients undergoing lumpectomy as well as mastectomy. Further study is warranted to determine the extent of durable practice changes as well as any impact on survival and local-regional control.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-13.
Abstract P1-01-21: Sentinel Lymph Node detection after previous breast tumour surgical resection: identification rate and false negative rate through a prospective multi institutional study.
Authors: Classe J-M , Andrieux N , de Lara Tunon C , Charitansky H , Lecuru F , Houpeau J-L , Faure C , De Blaye P , Houvenaeghel G , Kere D , Marchal F , Raro P , Lefebvre C , Dupré P-F , Rodier J-F
Published: August 2014

Background: Large multi institutional studies have pointed that previous surgical resection of breast tumours before axillary sentinel node detection (ASLND) was the main criteria of failure of this technique. Screening campaigns provide small tumours and despite efforts to obtain a diagnosis of early breast cancer, this is not always obtained, due to small tumours or false negative results of micro biopsies. The aim of our series was to assess identification rates and false negative rates of ASLND after previous surgical resection of breast tumours.

Material and Methods: In a prospective multi institutional setting (14 multidisciplinary teams), we have included patients with a previous breast tumour surgical resection for the diagnosis of infiltrative breast adenocarcinoma. Patients with only a core biopsy and no surgical removal of the tumor before axillary surgery were not included. Each patient underwent a secondary surgical procedure for ASLND and axillary lymphadenectomy, and sometimes a breast secondary surgical procedure for margins. ASLND was performed with the combined method, with blue dye and technetium. Pathology was performed with serial sectioning, eosin safron and immune histo chemistry (IHC).

Results: From July 2006 to November 2011, 138 patients where included. The median tumor size was 9mm. Identification rate was 86% (118/138). A macrometastasis was found in 11 cases, in a sentinel node (9), or in a non sentinel node(2). False negative rate was 9% (1 false negative sentinel node with macrometastasis in non sentinel node from lymphadenectomy/11 cases with a macrometastasis in either a sentinel node or a non sentinel node). In 1 case a micrometastasis was found in a sentinel node through IHC, with a macrometastasis in a non sentinel node from lymphadenectomy. Without IHC or without the decision of performing a complementary lymphadenectomy in the case of micrometastasis, the false negative rate would have been 18%.

Conclusions: After previous surgical resection of early breast cancer, ASLND remains feasible with a low identification rate of 86%, despite the use of the combined method. The False negative rate is acceptable with the use of IHC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-21.