bluuebunny/crossref_metadata_2025 huggingface dataset:
A Modern Cohort of Duodenal Obstruction Patients: Predictors of Delayed Transition to Full Enteral Nutrition
Authors: Bairdain Sigrid , Yu David C. , Lien Chueh , Khan Faraz Ali , Pathak Bhavana , Grabowski Matthew J. , Zurakowski David , Linden Bradley C.
Published: August 2014

Background. A common site for neonatal intestinal obstruction is the duodenum. Delayed establishment of enteral nutritional autonomy continues to challenge surgeons and, since early institution of nutritional support is critical in postoperative newborns, identification of patients likely to require alternative nutritional support may improve their outcomes. Therefore, we aimed to investigate risk factors leading to delayed establishment of full enteral nutrition in these patients.Methods. 87 patients who were surgically treated for intrinsic duodenal obstructions from 1998 to 2012 were reviewed. Variables were tested as potential risk factors. Median time to full enteral nutrition was estimated using the Kaplan-Meier method. Independent risk factors of delayed transition were identified using the multivariate Cox proportional hazards regression model.Results. Median time to transition to full enteral nutrition was 12 days (interquartile range: 9–17 days). Multivariate Cox analysis identified three significant risk factors for delayed enteral nutrition: gestational age (GA) ≤ 35 weeks (P < .001), congenital heart disease (CHD) (P=.02), and malrotation (P = .03).Conclusions. CHD and Prematurity are most commonly associated with delayed transition to full enteral nutrition. Thus, in these patients, supportive nutrition should strongly be considered pending enteral nutritional autonomy.
Jaccoud’s Arthropathy in Gout: An Unusual Association
Authors: Donato Alves Tayana , Oliveira Isabela S. , Fadul Luiza C. , Santiago Mittermayer B.
Published: August 2014

Jaccoud’s arthropathy (JA) is a deforming arthropathy observed mainly in patients with systemic lupus erythematosus. We report the case of a 41-year-old Brazilian man with a 10-year history of intermittent monoarthritis followed by bouts of polyarthritis affecting large and small joints. He presented deformities typical of JA and subcutaneous nodules. Histopathological findings of a nodule biopsy were consistent with gouty tophi. To our knowledge, this is the first report of JA secondary to chronic gout.
Systematic Analysis of the Association between Gut Flora and Obesity through High-Throughput Sequencing and Bioinformatics Approaches
Authors: Chiu Chih-Min , Huang Wei-Chih , Weng Shun-Long , Tseng Han-Chi , Liang Chao , Wang Wei-Chi , Yang Ting , Yang Tzu-Ling , Weng Chen-Tsung , Chang Tzu-Hao , Huang Hsien-Da
Published: August 2014

Eighty-one stool samples from Taiwanese were collected for analysis of the association between the gut flora and obesity. The supervised analysis showed that the most, abundant genera of bacteria in normal samples (from people with a body mass index (BMI)≤24) wereBacteroides(27.7%),Prevotella(19.4%),Escherichia(12%),Phascolarctobacterium(3.9%), andEubacterium(3.5%). The most abundant genera of bacteria in case samples (with a BMI≥27) wereBacteroides(29%),Prevotella(21%),Escherichia(7.4%),Megamonas(5.1%), andPhascolarctobacterium(3.8%). A principal coordinate analysis (PCoA) demonstrated that normal samples were clustered more compactly than case samples. An unsupervised analysis demonstrated that bacterial communities in the gut were clustered into two main groups: N-like and OB-like groups. Remarkably, most normal samples (78%) were clustered in the N-like group, and most case samples (81%) were clustered in the OB-like group (Fisher’sP  value=1.61E-07). The results showed that bacterial communities in the gut were highly associated with obesity. This is the first study in Taiwan to investigate the association between human gut flora and obesity, and the results provide new insights into the correlation of bacteria with the rising trend in obesity.
Natural Circulation Characteristics of a Symmetric Loop under Inclined Conditions
Authors: Yang Xingtuan , Sun Yanfei , Liu Zhiyong , Jiang Shengyao
Published: August 2014

Natural circulation is an important process for primary loops of some marine integrated reactors. The reactor works under inclined conditions when severe accidents happen to the ship. In this paper, to investigate the characteristics of natural circulation, experiments were conducted in a symmetric loop under the inclined angle of 0~45°. A CFD model was also set up to predict the behaviors of the loop beyond the experimental scope. Total circulation flow rate decreases with the increase of inclined angle. Meanwhile one circulation is depressed while the other is enhanced, and accordingly the disparity between the branch circulations arises and increases with the increase of inclined angle. Circulation only takes place in one branch circuit at large inclined angle. Also based on the CFD model, the influences of flow resistance distribution and loop configuration on natural circulation are predicted. The numerical results show that to design the loop with the configuration of big altitude difference and small width, it is favorable to reduce the influence of inclination; however too small loop width will cause severe reduction of circulation ability at large angle inclination.
A Few Integrable Couplings of Some Integrable Systems and (2+1)-Dimensional Integrable Hierarchies
Authors: Feng Binlu , Zhang Yufeng , Dong Huanhe
Published: August 2014

Two high-dimensional Lie algebras are presented for which four (1+1)-dimensional expanding integrable couplings of the D-AKNS hierarchy are obtained by using the Tu scheme; one of them is a united integrable coupling model of the D-AKNS hierarchy and the AKNS hierarchy. Then (2+1)-dimensional DS hierarchy is derived by using the TAH scheme; in particular, the integrable couplings of the DS hierarchy are obtained.
Bifurcation Analysis of a Lotka-Volterra Mutualistic System with Multiple Delays
Authors: Meng Xin-You , Huo Hai-Feng
Published: August 2014

A class of Lotka-Volterra mutualistic system with time delays of benefit and feedback delays is introduced. By analyzing the associated characteristic equation, the local stability of the positive equilibrium and existence of Hopf bifurcation are obtained under all possible combinations of two or three delays selecting from multiple delays. Not only explicit formulas to determine the properties of the Hopf bifurcation are shown by using the normal form method and center manifold theorem, but also the global continuation of Hopf bifurcation is investigated by applying a global Hopf bifurcation result due to Wu (1998). Numerical simulations are given to support the theoretical results.
Definite Ocular Sarcoidosis Using Endobronchial Ultrasonography with Transbronchial Needle Aspiration
Authors: Warrasak Sukhuma , Saenghirunvattana Sawang , Euswas Ataya , Methasiri Santa , Worapongpaiboon Surapon , Nirapathpongporn Supranee
Published: August 2014

Purpose. To introduce a minimally invasive procedure, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), to obtain a pathologic evidence of a definite ocular sarcoidosis in a patient who initially presented with presumed ocular sarcoidosis with pulmonary involvement.Methods. An EBUS-TBNA procedure was performed at perihilar lymph nodes, subcarina, and right paratrachea of the patient and specimen obtained was sent for histocytopathological studies.Result. Histocytopathological findings revealed aggregates of epithelioid histiocytes forming a noncaseous granuloma, a hallmark of sarcoidosis.Conclusion. EBUS-TBNA should be considered an alternative procedure to provide cytohistopathology proven diagnosis of definite ocular sarcoidosis.
The Efficacy of Sucralfate and Chlorhexidine as an Oral Rinse in Patients with Recurrent Aphthous Stomatitis
Authors: Soylu Özler Gül , Okuyucu Şemsettin , Akoğlu Ertap
Published: August 2014

Aim. In this study, we compared the efficacy of sucralfate suspension with chlorhexidine as an oral rinse in patients with recurrent aphthous stomatitis (RAS) in terms of pain relief and healing time.Materials and Methods. The subjects with a complaint of recurrent oral aphthous ulcers less than 1 cm in diameter on the first day of the occurrence of the ulcer and between 20 and 40 years were included in the study. Seventy patients completed the study. The patients were randomized into two groups as SCH group and CHX group. Changes in pain scores, healing time, and side effects of the treatments were evaluated.Results. The mean value of pain scores on the days after the treatment from the first day to the seventh day was significantly higher in CHX group than SCH group (P≤0.05). On the seventh day after the treatment, the ulcers were completely reepithelialized in 23 patients in SCH group and in 19 patients in CHX group. The difference was statistically significant (P≤0.05). In SCH group, the mean healing time of ulcers was1.97±1.56days whereas it was2.80±3.00days in CHX group. The difference was statistically significant (P≤0.05). No side effects were recorded in either of the groups.Conclusion. Topical sucralfate suspension is an easy, safe, inexpensive, and effective treatment option for RAS to obtain pain relief and shorten the healing time of oral ulcers.
Reduction of Cogging Torque in Dual Rotor Permanent Magnet Generator for Direct Coupled Wind Energy Systems
Authors: Paulsamy Sivachandran
Published: August 2014

In wind energy systems employing permanent magnet generator, there is an imperative need to reduce the cogging torque for smooth and reliable cut in operation. In a permanent magnet generator, cogging torque is produced due to interaction of the rotor magnets with slots and teeth of the stator. This paper is a result of an ongoing research work that deals with various methods to reduce cogging torque in dual rotor radial flux permanent magnet generator (DRFPMG) for direct coupled stand alone wind energy systems (SAWES). Three methods were applied to reduce the cogging torque in DRFPMG. The methods were changing slot opening width, changing magnet pole arc width and shifting of slot openings. A combination of these three methods was applied to reduce the cogging torque to a level suitable for direct coupled SAWES. Both determination and reduction of cogging torque were carried out by finite element analysis (FEA) using MagNet Software. The cogging torque of DRFPMG has been reduced without major change in induced emf. A prototype of 1 kW, 120 rpm DRFPMG was fabricated and tested to validate the simulation results. The test results have good agreement with the simulation predictions.
Abstract ES2-2: Triple Negative Breast Cancer: Subtypes, Molecular Targets, and Therapeutic Approaches
Authors: Pietenpol JA
Published: August 2014

The term “triple negative breast cancer” (TNBC) is used to classify 10%–20% of all breast cancers that lack estrogen receptor (ER) and progesterone receptor expression as well as amplification of the human epidermal growth factor receptor 2 (HER2)1. Disease heterogeneity and the absence of well-defined molecular targets have made treatment of TNBC challenging. To make significant clinical advances for TNBC patients, integrative and comprehensive genomic and molecular analyses of TNBC are required to understand the complexity of the disease as well as to allow identification of homogeneous subsets and ‘driver pathways’ that can then be therapeutically targeted. In response to this need, we compiled an extensive number of TNBC gene expression (GE) profiles and initiated molecular subtyping of the disease2. We identified two basal-like TNBC subtypes with cell cycle and DDR GE signatures (BL1 and BL2); two mesenchymal subtypes with high expression of genes involved in differentiation and growth factor pathways (M and MSL); an immunomodulatory (IM) type; and a luminal subtype driven by androgen signaling (LAR). Differential GE was used to designate 25 TNBC cell line models representative of these subtypes. Predicted ‘driver’ signaling pathways were pharmacologically targeted in these preclinical models as proof of concept that analysis of distinct GE signatures can inform therapy selection. Representative BL1 and BL2 subtype cell lines preferentially respond to cisplatin. Mesenchymal, basal, and luminal subtype lines with aberrations in PI3K signaling have the greatest sensitivity, in general, to phosphatidylinositol 3-kinase (PI3K) inhibitors. The LAR subtype cell lines express AR and are uniquely sensitive to bicalutamide (AR antagonist). We have also developed “TNBCtype,” a web-based subtyping tool for candidate TNBC tumor samples using our GE metadata and classification methods3. The approaches used and data generated have value for biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

1. Dent, R., Trudeau, M., Pritchard, K.I., Hanna, W.M., Kahn, H.K., Sawka, C.A., Lickley, L.A., Rawlinson, E., Sun, P., and Narod, S.A. (2007). Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13, 4429–4434. 2. Lehmann, B.D., Bauer, J.A., Chen, X., Sanders, M.E., Chakravarthy, A.B., Shyr, Y., and Pietenpol, J.A. (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121: 2750–67. 3. Chen, X., Li, J., Gray, W.H., Lehmann, B.D., Bauer, J.A., Shyr, Y., and Pietenpol, J.A. (2012). TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer. Cancer informatics 11, 147–156.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES2-2.
Abstract ES2-3: The Clonal and Mutational Composition of Triple Negative Breast Cancers
Authors: Aparicio S
Published: August 2014

The notion that cancers are mosaics, composed of clones of cells has been fundamental to cancer biology for several decades. Clonal evolution may underpin clinical features of cancer, such as emergence of treatment resistance, the heterogeneous responses of metastatic disease within individual patients and divergence between primary and metastatic disease. Spatial and temporal variation in clonal composition poses significant challenges for diagnostic sampling and disease monitoring. We have recently developed next generation sequencing approaches to these questions and applied them to the understanding of mutational and clonal composition of primary triple negative breast cancers (TNBC). The notion that triple negative breast cancers form a distinct disease entity is already strongly challenged by expression analysis and small scale mutational analysis. Our results show that both the mutational composition and clonal structure of primary triple negative breast cancers is in fact a complete spectrum, exploding the notion of TNBC (currently defined), as a distinct disease. Clonal analysis suggests a means by which the genetic complexity might be reduced by following patient evolution over time and space. I will discuss the specific implications of the mutational and transcriptome landscapes of TNBC in relation to possible disease biologies.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES2-3.
Abstract ES3-3: Clinical Trial Designs for New Therapies: What Endpoints Should We Use?
Authors: Hudis CA
Published: August 2014

The selection of endpoints is critical to the interpretation of clinical trials results. In early phase clinical trials investigators seek evidence of activity, then predictors of clinical benefit, and in most randomized trials, accepted surrogates of meaningful benefit. At one extreme we may seek improvements in overall survival while in another we may be satisfied simply with evidence of tumor stabilization or changes in circulating biomarkers. In between these extremes are intermediate and composite endpoints including “partial responses”, “clinical benefit rate”, and those that are time-dependent endpoints such as disease-free or progression free survival. Many of the discussions and disagreements we hear in the context of drug development, benefit, and approval can be linked to a fundamental lack of agreement on the value and meaning of many of these endpoints. Activity of a given novel agent may, or may not, persuade some investigators, clinicians, and patients, that it is a worthwhile addition to our treatment options. On the other hand, a small but statistically significant improvement in overall survival in advanced cancer may, or may not, convince this same audience that the tested treatment is worthy of approval and use. Again, the intermediate endpoints may be unreliable or only weak predictors of more profound benefits. We will review and explore these issues considering not only the endpoints themselves but also their meaning in specific clinical settings and the impact of endpoint selection on further drug development.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-3.
Abstract ES7-2: Tumor Dormancy from an Experimental Biologist's Perspective
Authors: Chambers AF
Published: August 2014

Survival from breast cancer has improved steadily over the past decades. However, most breast cancer deaths are due to metastasis, and considerably less progress has been made against metastatic disease. We still know remarkably little about preventing or delaying metastatic recurrence or effectively treating the cancer if it does recur. Making breast cancer treatment even more challenging is the fact that breast cancer patients may appear to be cured of their disease, only to have it return later. These recurrences can happen even decades after apparently successful primary treatment. This creates years of uncertainty for breast cancer patients, who do not know if they have been cured or if the cancer will return, and makes clinical management difficult.

We have used experimental models, both in vitro and in vivo, to try to understand the process of breast cancer metastasis. We have found that a population of cancer cells can remain as dormant cells, and have shown that these cells can resist being killed by cytotoxic chemotherapy that successfully kills actively diving cells. Experimental studies raise questions that must be addressed clinically. For example, what is the prevalence of dormant cells in breast cancer patients – are they common or rare? Are there factors inherent to the cancer cells that influence the likelihood of dormant cells persisting and subsequently re-awakening? Conversely, are there host microenvironmental factors, such as diet, exercise or stress, that can influence whether dormant cells persist and re-awaken? This information will be important in learning better how to prevent, delay and treat metastatic breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES7-2.
Abstract MS1-1: Targeting PI3K
Authors: Cantley L , Lewis C. Cantley
Published: August 2014

Phosphoinositide 3-Kinase (PI3K) is a central enzyme in a signaling pathway that mediates cellular responses to growth factors. The signaling pathway downstream of PI3K is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism and cell growth. Mutational events that lead to hyperactivation of the PI3K pathway result in hamartoma syndromes and cancers. Activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI3K (PIK3CA) or inactivating mutations in PTEN, a phosphoinositide 3-phosphatases that reverses the effects of PI3K, are among the most common events in solid tumors, especially breast cancers. Drugs that target PI3K are in clinical trials for a variety of cancers. It is likely that PI3K pathway inhibitors will need to be combined with other drugs to be broadly effective. We have employed genetically engineered mouse models that develop cancers due to mutations in genes in the PI3K pathway and are using these models to explore the efficacy of PI3K pathway inhibitors as single agents or in combination with other drugs. We are also interrogating the role of PI3K in the growth and survival of Brca1/p53 mutant breast cancers. The role of PI3K inhibitors for treating cancers in these mouse models and in human trials will be discussed.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS1-1.
Abstract P1-01-05: The Efficacy of Arm Node Preserving Surgery Using Axillary Reverse Mapping for Preventing Lymphedema in Patients with Breast Cancer: The results from a 2-year follow-up
Authors: Lee J-H , Son G-T , Choi J-E , Kang S-H , Lee S-J , Bae Y-K
Published: August 2014

Purpose: The axillary reverse mapping (ARM) technique to identify and preserve arm nodes during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) was developed to prevent lymphedema. In our previous study, we evaluated the incidence of lymphedema after ARM and the difference in arm circumference between arm node preserved group and unpreserved group, after short term follow up. The purpose of this study was to investigate the location and metastatic rate of the arm node, and to evaluate the further follow-up results of the differences in arm circumference after arm node preserving surgery.

Methods: From January 2009 to December 2011, 116 breast cancer patients who underwent ARM were included. Blue-dye (2.5ml) was injected into the ipsilateral upper-inner arm. At least 20 minutes after injection, SLNB or ALND was performed and blue-stained arm nodes and/or lymphatics were identified. Patients were divided into two groups, an arm node preserved group (87 patients had ALND, 10 patients had SLNB) and an unpreserved group (15 patients had ALND, 4 patients had SLNB). The difference in arm circumference between preoperative and postoperative time points was checked in both groups.

Results: The mean number of identified blue stained arm nodes was 1.41±0.66. The mean follow up period was 16.24(3∼24)months. In the majority of patients (86.2%), arm nodes were located between the lower level of the axillary vein and just below the second intercostobrachial nerve. The location of the arm node was the inferolateral side of axillary and thoracodorsal vessels in 62 patients (53.4%), the inferomedial side in 46 patients (39.7%), the superolateral side in 5 patients (4.3%), and the superomedial side in 3 patients (2.6%) In the arm node unpreserved group, 5 patients (4.3%) had metastasis in their arm node. When comparing between arm circumferences in ipsilateral upper-extremity of the arm node preserved group and unpreserved group, in the SLNB group, there was no significant difference. But in the ALND group, the arm circumference changes of the arm node unpreserved group were bigger than that of the preserved group (0.50±1.15 vs 0.16±0.76, p = 0.066).

There were no lymphedema cases among the arm node preserved group, but one lymphedema developed in the unpreserved group(5.2%). There was no locoregional recurrence in both group in follow up periods.

Conclusion: After further follow-up, this study showed some differences in arm circumference between two groups. Arm node preserving was possible in all breast cancer patients with identifiable arm nodes, during ALND or SLNB, except for those with high surgical N stage, and lymphedema and locoregional recurrences did not develop in patients with arm node preserving surgery.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-05.
Abstract P1-01-08: A Nomogram for predicting two or less axillary lymph node involvement for breast cancer
Authors: Ahn SK , Kim JS , Kim Mk , Lee JW , Kim T , Kim JY , Moon HG , Han W , Noh D-Y
Published: August 2014

BACKGROUND: Completion axillary lymph node dissection (ALND) is currently the standard of care in the event of a positive sentinel lymph node biopsy (SLNB). However, result from Z0011 indicate that women with a one or two involved axillary nodes and clinical T1-T2 tumors undergoing lumpectomy with radiation therapy followed by systemic therapy do not benefit from completion of ALND in terms of survival. As a result, the use of intraoperative frozen section during SLNB will be declined.

OBJECTIVE: To define possible predictors of having two or less involved axillary node using preoperative image study to provide information for surgeons making decision about sparing intraoperative frozen section analysis of sentinel lymph node.

METHODS: We reviewed the records of 1214 patients with clinical T1-T2 and clinical node negative invasive breast cancer. None of these patients were in situ cancer on initial gun biopsy nor received neoadjuvant chemotherapy. Factors associated with having three or more involved axillary nodes were evaluated by univariate and multivariate logistic regression analysis.

RESULTS: Among 1214 patients, 203 patients (16.7%) had three or more positive nodes. On a multivariate analysis, having three or more positive nodes was associated with primary tumor size by breast US, axillary LN grade according to cortical thickness by US and presence of axillary LN enlargement on chest CT. The area under ROC curve corresponding to the multivariate logistic regression model applied to dataset of 1214 patients was 0.827 (95% CI: 0.793–0.860). When applied to a validation dataset of 378 patients, it was 0.899 (95% CI: 0.841–0.957). A nomogram to predict the probability of having two or less axillary nodes involvement based on patients' age and preoperative image findings was developed from the multivariate logistic regression model.

CONCLUSION: Patients with a low probability of having three or more positive nodes can be identified from preoperative image finding. The nomogram developed will be helpful to surgeons making decision about sparing intraoperative frozen section analysis of sentinel lymph.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-08.
Abstract P1-01-11: Is OSNA mRNA copy number in sentinel lymph node biopsy predictive of further disease in the axilla?
Authors: Rusby JE , Agabiti E , Waheed S , Barry P , Roche N , Allum W , Gui G , MacNeill F , Christaki G , Osin P , Nerurkar A
Published: August 2014

Introduction: Intra-operative assessment of sentinel nodes (SLNs) allows immediate completion axillary dissection (cALND) in breast cancer patients. Molecular assessment such as one-step nucleic acid amplication (OSNA) promises greater sensitivity and provides a more accurate quantitative assessment than traditional methods.

Our unit policy is to proceed to cALND in patients with macrometastases but not for micrometastases. However, evidence of upstaging has led us to seek to raise the threshold for proceeding to cALND. The CK19 mRNA copy number is an expression of the metastatic burden in the SLN and may be related to the presence of additional disease in the cALND. Since the original copy number threshold between micro (250–5000 copies/microliter) and macrometastasis (>5000 copies/microliter) was based on few patients and serial pathological sections, we investigated the mRNA copy number in patients with and without additional disease in the cALND.

Methods: All patients in our unit undergo pre-operative axillary ultrasound with fine needle aspiration cytology of any suspicious nodes. Those with malignant cytology proceed directly to ALND. Radiologically and cytologically node negative patients undergo sentinel lymph node biopsy (SLNB) and OSNA. Electronic records of consecutive patients with invasive breast cancer undergoing SLNB with OSNA from August 2011 to March 2012 were retrospectively reviewed. Two parameters of mRNA copy number were examined: Copy number of the highest copy number SLN and the summed copy numbers of all positive SLNs. Their relationship to the presence of further disease in the axilla was examined using Student's t test.

Results: Of 201 SLNBs, 45 (22%) had macrometastasis-positive OSNA and therefore underwent cALND (1 patient declined). Twenty patients (45%) had no further positive nodes (a negative cALND) with a total axillary metastatic burden of 1–2 in 11–27 nodes. Twenty four (55%) showed further disease (a positive cALND) with a burden of 2–20 in 9–30 nodes, including the SLNs.

There was no significant difference in tumour size or grade between patients with additional positive nodes in the cALND compared with those with no further disease.

There was no significant difference in the copy number of the highest copy number positive SLN (p = 0.44) or in the summed copy number of all positive SLNs (p = 0.36) between the cALND positive and negative groups.

Conclusion: OSNA CK19 mRNA copy number does not correlate with the cALND metastatic burden. Therefore, raising the copy number threshold may be too simplistic as a method to better select patients with high probability of a positive cALND. A predictive model will be derived based on multivariate analysis of the larger patient population (>400 patients) that will have undergone SLNB with OSNA by the time of SABCS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-11.
Abstract P1-01-15: Accuracy of sentinel lymph node in determining the requirement for second axillary surgeries in early breast cancer with retrospective application of the Z0011 criteria.
Authors: Waters PS , Fennessy PJ , Alazawi D , Sweeney KJ , Kerin MJ
Published: August 2014

Background: Lymph node status is the most important prognostic marker in breast cancer management. The ACOSOG Z0011 trial reported no difference in survival in patients undergoing sentinel lymph node biopsy(SLNB) alone versus axillary lymph node dissection(ALND) in T1-T2 tumours with 1–2 positive lymph nodes.

Aims: Whether sentinel lymph node biopsy was a true representative of axillary burden. We also addressed whether application of criteria from Z0011 trial would have prevented patients undergoing second axillary surgery.

Methods: All patients with T1-T2 tumours undergoing sentinel node biopsy were included in our study (n = 1019). Analysis of our prospectively updated breast cancer database was performed. Minitab version 16.0 was used for statistical analysis.

Results: 1019 SLNB procedures for T1 & T2 tumours were performed over a 7 year period. 730 patients were reported as histologically negative and 289 were positive(<1 node = 194, >1 node = 95). Of the lymph node positive group, 223 patients progressed to axillary clearance. Staging of 149 patients remained unchanged with 74 patients being upstaged with having >2 lymph nodes reported as positive. 72 patients from the SLNB negative group also had an axillary clearance. 5 of these patients had further axillary disease with 1 patient being upstaged having >2 positive lymph nodes. With application of Z0011 criteria 220 patients would have avoided second axillary surgery.

Conclusions: The accuracy of sentinel lymph node biopsy in determining tumour burden has been demonstrated. Furthermore application of Z0011 will have major cost savings for the health service with decreased patient stay and morbidity.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-15.
Abstract P1-01-17: The impact of triple negativity on lymph node positivity in breast cancer.
Authors: Weber JJ , Bellin LS , Milbourn DE , Wong J
Published: August 2014

Introduction: Triple negative breast cancer (TNBC), defined as estrogen, progesterone, and HER2/Neu receptor-negative is biologically more aggressive than non-TNBC. Whether TNBC presents at a more advanced local/regional stage is controversial. We sought to determine whether TNBC had more frequent lymph node positivity.

Methods: ER and PR status was determined by routine immunohistochemical analysis. HER2/Neu status was determined by immunohistochemistry; if 2+ equivocal status was noted, fluorescence in situ hybridization was performed for confirmation. Patients with a clinically negative axilla underwent sentinel lymph node biopsy, and if the sentinel node was positive, underwent immediate completion axillary node dissection. Lymph node positivity was determined by hematoxlyn-eosin staining. The main outcome measures were lymph node status and pathologic tumor size. Statistical differences were compared by means of paired t-test and chi-squared test where appropriate.

Results: Between January 1, 2004 and December 31, 2010, 501 women with invasive breast cancer were treated at our institution. These patients ranged in age from 25 to 93 years (mean 57.6 yr), with 53.1% of patients self-reported as non-Hispanic white and 43.7% non-Hispanic black. TNBC patients were younger (mean 55.0 yr vs. 58.3 yr, p = 0.005), and were more often non-Hispanic black (52.7% vs. 41.1%, p = 0.03). The mean pathological tumor size of the entire population was 1.86 cm (range 0 to 18 cm). One hundred twelve patients (22.4%) were TNBC. The mean pathological tumor size for TNBC compared to non-TNBC patients was 2.07 cm (range 0 to 8.7 cm) and 1.80 cm (range 0 to 18 cm) (p = 0.068). There was a statistically significant difference in the T-stage at presentation between TNBC and non-TNBC tumors (T1, 58.9% TNBC vs. 72.0% non-TNBC; T2, 34.8% TNBC vs. 22.4% non-TNBC; T3/T4, 6.3% TNBC vs. 5.6% non-TNBC, p = 0.02). One hundred sixty patients (31.9%) were node positive. The number of positive lymph nodes in the TNBC patients ranged from 1–18, and the non-TNBC ranged from 1–35 (TNBC mean 2.94 vs. non-TNBC mean 3.94, p = 0.09). TNBC patients were more often node positive than non-TNBC (39.3% vs. 29.3%, p < 0.05). However, when stratified by T-stage, the differences did not achieve statistical significance (T1, 31.8% TNBC vs. 21.8% non-TNBC, p = 0.11; T2, 51.3% vs. 46.0%, p = 0.70; T3/T4, 57.1% vs. 59.1%, p = 1.0), despite a trend toward greater node positivity in earlier T-stage TNBC tumors.

Conclusions: TNBC is more frequently lymph node positive than non-TNBC. This is largely attributable to more node positivity in early T-stage tumors. These data provide further evidence for the poor prognosis of TNBC and the increased likelihood of nodal metastases in early T-stage tumors.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-17.
Abstract P1-01-18: The results of 55 consecutive cases of intra-operative sentinel node analysis using real time polymerase chain reaction detection of cytokeratin 19 and mammoglobin expression (Metasin) to direct immediate axillary clearance.
Authors: Nadi K , Sharaiha Y , Sai-Girdhar P , Huws A , Khawaja S , Holt S
Published: August 2014

The standard management of early beast cancer is complete excision of the primary from the breast by either wide local excision or mastectomy and sentinel node biopsy to stage the axilla. The standard of care in the UK remains clearance of the axilla in node positive patients. Unless immediate multiple frozen section histology is available, positive patients require a second operation between 3 and 6 weeks later, with the associated increased cost, inconvenience and risk.

By using the real time polymerase chain reaction (PCR) to detect mammary derived cells in the sentinel lymph nodes (SLN), we aim to provide the surgeon with a reliable indicator of the presence or absence of nodal macro-metastases within a timeframe that will allow axillary clearance to be performed under the same anaesthetic as the initial surgery. We detect cytokeratin 19 (CK19) or mammoglobin within the lymph node using reagents developed by the UK National Health Service under the name Metasin.

Method: 55 consecutive patients undergoing SLN biopsy as part of their initial treatment for early breast cancer were tested using the Metasin. The nodes were divided into 2mm slices and alternate sections submitted to PCR and the remainder to conventional histology. The results were compared and an assessment of the costs made. The time taken report the Metasin result to the surgeon was recorded.

Results: Five patients had positive results by Metasin and proceeded to immediate axillary clearance. When compared to histology there were no false positive results (0%). Two patients were negative on Metasin testing with the threshold set at 2 mm but positive on histology (3.6%). The average time for the test was 43.2 minutes and the mean number of lymph nodes was 2.3. The average cost is £40 to test 2 nodes.

Discussion: The test is accurate. The two false negative cases were found to be due to the sampling, the metastases being only present by chance in the histologically examined specimens and not due to assay failure. The total cost to run the test for 55 patients was £2,520. The cost for completion axillary clearance as a separate procedure is estimated at £2,227. The total saving for 5 cases is about £11,000, making the test cost saving as well as safer, more acceptable to the patients and limiting delay in starting adjuvant therapies. The additional time of surgery caused by using Metasin was minimal.

Conclusion: Metasin has become our standard of care in patients requiring SLN biopsy and generally avoids second surgeries to clear the axilla in positive cases. We are considering analyzing the complete node using this technique and this would eliminate false negatives caused by sampling and offer further cost savings in the histology department.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-18.
Abstract P1-01-25: Sentinel lymph node biopsy in breast cancer: The approach in day surgery under local anaesthesia for quality-of-life and significant cost reduction
Authors: Ricci F , Capuano LG , Saralli E , Di Legge P , Violante A , Polistena A , Scala T , Pacchiarotti A , Cannas P , Cianni R , Fanelli G , Bellardini P , De Masi C
Published: August 2014

Background: Sentinel lymph node biospy (SLNB) is widely used in the management of breast cancer patients without axillary metastases or inflammatory breast cancer (IBC).

Methods: From Jan. 1st 2006 through Dic. 31st 2011 we performed 302 SLNB at St. M. Goretti Hospital. Mammary carcinoma was diagnosed as malignant by aspiration citology and/or biospy. In all cases with positive citology or biospy, we performed quadrantectomy and SLNB at the same time. All patients underwent pre-operative lymphoscintigraphy with intradermal pericicatritial and/or periareola injection of 12–15 MBq 99Tc colloidal albumin particles 50–80 nm size range, in 0,2 ml saline solution. We never used vital blue dye. All patients underwent surgical treatment 3–12 h. later. We performed SLNB and quadrantectomy in day surgery (DS) and local anaesthesia (LA) with 2% of Carbocaine. Axillary incision was 3–4 cm. This study was approved by an ethics committee, was discussed with all patients and informed consent was obtained.

Purpose of the study is to investigate the approach in DS under LA for quality of life and significant cost reduction.

Results: Six patients underwent pre-operative lymphoscintigraphy the radiotracer did not show any sentinel lymph node (SLN), in five cases we performed axillary dissection (AD). In one case of young patient who had previously been treated with chemotherapy for non-Hodgkin's lymphoma, negative positron emission tomography (PET), we performed quadrantectomy without AD. In three cases the axilla was positive. In four cases of multifocal (MF) and two of multicentric (MC) invasive breast cancer, the SLN was identified in axilla and SLNB was perfomed. SLNB in MF and MC tumors was similar to unifocal cancers. Only one case of MC cancer the SLN was positive. Six patients classified T4b according to AJCC, were treated with neoadjuvant chemotherapy (NC). The axilla was negative to ultrasound (US), PET and citology. After completion of NC, lymphatic mapping was able to identify SLN and we performed SLNB. In these patients SLN was negative. In two cases of male cancer the axilla was negative to clinical examination, in both cases SLN was positive for macrometastases. Six cases showed axillary isolated tumor cells (ITC). Eighteen micrometastases. Thirty-two macrometastases. In two case of negative SLN there was a positive second palpable lymph node. One case showed a double SLN in the axilla and internal mammary chain, only the internal mammary lymph node was positive.

The SLN identification rate was 99%. After surgery we distributed a questionnaire to the patients about the acceptability of this approach.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-25.
Abstract P1-01-26: Procoagulant biomarkers may direct axillary nodal surgery
Authors: Shaker H , Bundred NJ , Glassey E , Kirwan CC
Published: August 2014

Background: Preoperative accurate staging of the axilla (through identifying invasive breast cancers with subclinical nodal metastases) will reduce the need for repeat axillary surgery.

Tissue factor (TF) is overexpressed in cancer and is shed into the circulation leading to activation of the thrombin (extrinsic clotting) pathway. D-dimer is a fibrin degradation product and reliable systemic marker of thrombin pathway activation. TF and d-dimer are raised in breast cancer and may act as biomarkers to identify invasive cancer patients with undiagnosed lymph node (LN) metastases requiring axillary nodal clearance.

Methods: Plasma d-dimer and TF were measured pre-operatively using ELISA in patients undergoing curative surgery and sentinel node biopsy (SNB) for invasive breast cancer (n = 125). D-dimer was considered to be raised if it was above the clinically used upper limit of normal of 500ng/ml and if TF was above 200pg/ml. D-dimer and TF were correlated with the presence or absence of axillary metastases at sentinel node biopsy.

Results: Median age was 61 years (range 24–84). Mean invasive tumour size was 16.7 mm (range 1.6–70). One hundred and eleven (79%) invasive cancers were oestrogen receptor positive, 93 (67%) were progesterone receptor positive and 17(12%) were HER2 receptor positive.

Pre-operative d-dimer was higher in LN positive (mean 599 ng/ml, 95% CI 415–864, n=32) versus LN negative (454ng/ml, 95% CI 400–514, n=93, p = 0.068) invasive cancer. TF was not significantly higher in LN positive cancer (vs LN negative), although TF did show weak correlation with d-dimer (r = 0.2, p = 0.03).

Sixty eight patients (54%) had raised TF and 59 (47%) had raised d-dimer. On multivariate analysis (age, tumour size, invasive grade, ER status and presence of lymphovascular invasion as covariates) a raised pre-operative d-dimer combined with a raised pre-operative TF was a significant independent predictor of node positivity (odds ratio 6.43, CI 1.70–24.27, p = 0.006). Markers of systemic thrombin pathway activity (i.e. a combination of plasma d-dimer and TF) had a sensitivity of 91%, specificity of 32%, positive predictive value of 32% and negative predictive value of 92%.

Conclusion: High levels of clotting activation are seen in breast cancer patients.

Over 90% of patients with no axillary lymph node metastases had normal pre-operative levels of plasma TF and d-dimer. Combination of systemic markers of thrombin pathway activation may help predict axillary nodal involvement.

The role of thrombin pathway activation in breast cancer metastasis is under ongoing investigation.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-26.
Abstract P1-04-01: Loss of Notch4 reduces mammary tumorigenesis by MYC and activated KRAS
Authors: Rodriguez EM , Bishop JM
Published: August 2014

Over-expression of Notch receptors and aberrant Notch signaling have been reported in both preinvasive ductal carcinoma in situ and invasive breast cancer. The Notch 4 receptor, in particular, is preferentially activated in human breast cancer stem cell-enriched populations, and inhibition of Notch 4 reduces tumor formation of human breast cancer cells in xenograft models (Harrison, 2010). Myc gene amplification has also been found in about 15% of breast tumors, and 22%–35% of tumors exhibit overexpression of Myc at the transcriptional level. Transgenic mice over-expressing MYC develop invasive adenocarcinomas and preferentially harbor secondary activating mutations in KRas. We examined whether Notch receptors were activated in mouse mammary tumors over-expressing MYC and activated KRAS (KRASV12) and found Notch 4 to be significantly activated in these tumors compared to normal mammary tissue. Furthermore, Notch 4 was localized to the nucleus in the tumors over-expressing MYC and KRASV12, but not in mammary glands over-expressing MYC or activated KRASV12 alone. To examine the requirement of Notch4 in mammary tumorigenesis by MYC and KRASV12, we transplanted mammary epithelial cells isolated from Notch4 knockout mice and wild-type mice that have been transduced with MYC and KRASV12 into the mammary glands of syngeneic mice. There was a significant reduction in the onset of tumorigenesis in mammary glands that had been transplanted with mammary epithelial cells lacking Notch4. These findings suggest that Notch4 is important in mammary tumorigenesis induced by cooperation of MYC and activated RAS. We are currently examining the relevance of Nocth4 activation in human breast cancers that over-express MYC and the mechanism by which Notch4 promotes tumorigenesis by Myc and activated RAS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-01.
Abstract P1-04-08: Evidence for anti-apoptosis function of GNB1 in human breast cancer
Authors: Wazir U , Kasem A , Sharma AK , Jiang W , Mokbel K
Published: August 2014

INTRODUCTION: Guanine nucleotide binding protein beta polypeptide 1 (GNB1) integrates signals between receptors and effector proteins and regulates certain signal transduction receptors and effectors. We have hypothesised that GNB1 is involved in the anti-apoptosis pathway mediated by mTor. Therefore, this protein may play role in human carcinogenesis, however, there has been no investigations of this potential role published in the literature. The aim of the study was to investigate the mRNA expression of GNB1 in human breast cancer and examine the relationship between its expression and the tumour characteristics and disease outcome. Furthermore, the correlation between GNB1 and mTORC1 was also investigated.

METHODS: Specimens of breast cancer (BC) tissues (N = 136) and normal tissues (N = 30) underwent RNA extraction and reverse transcription. GNB1 transcript levels were determined using real-time quantitative PCR. Expression levels were analysed against clinicopathological data accrued over a 10 year follow-up period.

RESULTS: Significantly higher mRNA transcript levels were found in the breast cancer specimens compared to normal glandular tissue in paired samples (p = 0.0029). The expression of GNB1 mRNA was demonstrated to increase with increasing TNM stage (from 0.01 to 15.9) and this reached statistical significance when comparing TNM1 vs. TNM2/3/4 (p = 0.036). Furthermore, the expression levels increased with increasing tumour grade and this reached statistical significance when comparing grade 2 vs. grade 3 (p = 0.006). GNB1 expression was found to be higher in ductal tumours compared with non-ductal tumours (p = 0.0081). The patients who developed recurrent disease or died from breast cancer had higher expression levels than those who had been disease-free after a median follow-up period of 10 years (p = 0.017). Those who died from breast cancer had significantly higher levels than those who have remained disease-free (33.9 vs. 0.01, p = 0.0009). GNB1 showed a significantly positive correlation with mTORC1 mRNA levels (r = 0.57, p < 0.000001).

CONCLUSION: GNB1 expression was found to be significantly higher in BC specimens compared to normal breast tissue. Higher transcript levels were significantly associated with unfavourable pathological parameters and adverse clinical outcomes. These observations in addition to the positive correlation with mTORC1 levels support the hypothesis that GNB1 is an important upstream component of the anti-apoptosis pathway and, therefore, can be a potential target for therapeutic intervention in human breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-08.