bluuebunny/crossref_metadata_2025 huggingface dataset:
SAVING THE CRITICALLY INJURED TRAUMA PATIENT: A RETROSPECTIVE ANALYSIS OF 1000 USES OF INTRAOSSEOUS ACCESS
Authors: Lewis Pip , Wright Chris
Published: August 2014

Objectives & Background

Intraosseous (IO) access is becoming increasingly accepted in adult populations as an alternative to peripheral vascular access, however there is still insufficient evidence in large patient groups supporting its use.

Methods

Retrospective review. This paper reports on the use of intraosseous devices over a 7 year period from August 2006 to August 2013 during combat operations in Afghanistan. A search of the Joint Theatre Trauma Registry (JTTR-UK), a database of all trauma patients treated by Defence Medical Services in Iraq and Afghanistan, was carried out looking for all the incidences of intraosseous access use during this time. Adults were defined as patients aged 17 or above. Patient demographics, injuries, treatments and complications were retrieved. The results were collated and analysed using Excel TM (Microsoft).

Results

1014 intraosseous devices were used in 830 adult patients with no major complications. The rate of minor complications, the majority of which were device failure, was 1.38%. 5124 separate infusions of blood products or fluids occurred via intraosseous access, with 36% being of packed red cells. On average each casualty received 6.95 different infusions of blood products and fluids, and 3.28 separate infusions of drugs through intraosseous access. 32 different drugs were infused to 367 patients via IO, the most frequent being anaesthetic agents. Intraosseous access was used in the pre-hospital environment, during tactical helicopter evacuation and within hospitals.

Conclusion

Intraosseous access can be used for the infusion of a wide variety life saving medications, quickly, easily with low complication rates. This highlights its valuable role as an alternative method of obtaining vascular access, vital when resuscitating the critically injured trauma patient.
PAIN SOLUTION IN THE EMERGENCY SETTING (PASTIES); AN OPEN-LABEL RANDOMISED TRIAL OF PATIENT-CONTROLLED ANALGESIA (PCA) VERSUS ROUTINE CARE IN PATIENTS ATTENDING THE EMERGENCY DEPARTMENT WITH TRAUMATIC INJURIES
Authors: Smith Jason E , Rockett Mark , Squire Rosalyn , Hayward Chris , Creanor Siobhan , Ewings Paul , Barton Andy , Pritchard Colin , Benger Jonathan
Published: August 2014

Objectives & Background

Pain is the commonest reason that patients present to an Emergency Department (ED), but is often not treated effectively. Patient controlled analgesia (PCA) is used in other hospital settings but there is little evidence to support its use in emergency patients. This study (one of two parallel trials) aimed to assess the effectiveness and cost-effectiveness of PCA in emergency patients with traumatic injuries.

Methods

Prospective multi-centre randomised trial of PCA versus routine care (nurse-titrated analgesia) in emergency department patients presenting with traumatic injuries, who required IV opioid analgesia and admission to hospital. Participants were randomised to receive either routine care or PCA, and followed for the first 12 hours of their hospital stay. The primary outcome measure was hourly participant-recorded pain, scored using a visual analogue scale (VAS), with primary statistical analyses based on the standardised (scaled from 0–100) area-under–the-curve (AUC) of each participant's pain scores, with adjustment for time of admission, centre and baseline pain score.

Results

200 participants (71% male) were recruited from 4 centres, mean (SD) age of 43 (15.0) years. Preliminary analysis showed mean (SD) standardised pain AUCs were 47.2 (21.9) for the routine care group and 44.0 (24.0) for the PCA group. Provisional adjusted analyses indicated a slightly lower (but not statistically significant) standardised pain AUC in the PCA group than for the routine care group (mean difference (routine care -PCA): 2.7; 95% confidence interval; –2.4 to 7.8).

Conclusion

Provisional results indicate that there is no statistically significant reduction in pain using PCA compared to routine care for emergency department patients with traumatic injuries. Further analyses are in progress, in particular, of total morphine consumption and cost-effectiveness.
DETERMINING THE EFFECTIVENESS OF EDUCATIONAL INTERVENTIONS IN PAEDIATRIC EMERGENCY CARE
Authors: Roland Damian , Charadva Creana , Coats Tim , Matheson David
Published: August 2014

Objectives & Background

Demonstrating educational interventions improve patient care can been difficult. This study aimed to perform an extensive assessment of a bespoke e-learning package on the NICE Feverish illness in Children Guideline to aid the development of an evaluation model.

Methods

An e-learning package was designed featuring an interactive traffic light table page. For each of the 5 domains and the three risk categories there was a video describing the features within that domain. The e-learning package also contained a pre- and post- learning section consisting of a demographic questionnaire, an attitudinal survey and knowledge testing. The weblink to the e-learning package was distributed to 12 Emergency Departments throughout England in August 2012.

Results

A total of 202 junior doctors expressed an interest in undertaking the intervention, 115 (56.9%) commenced the package, 91 (45.3%) completed the pre-learning and 58 (28.7%) completed the post-learning.

There was an average 1 point improvement (scale 1–10) in perceived safety, confidence and competence in relation to management of febrile children after the package had been completed (p<0.0001). The Knowledge Test scores improved significantly in MCQs (Z −3.942, p<0.001). ROLMA matrices, a previously published methodology of describing adherence to evidence based practice, were used to examine case-notes of children with undifferentiated febrile illness at the lead site (n=48 patient pre-intervention and n=20 patients post-learning). There was a trend to improved evidence based management in the post learning group but this was not significant (Chi-Square 2.776, p=0.096). Overall data in the lead department demonstrated a rise in admissions of children with undifferentiated fever compared to 2011 but less than the 5 previous years despite a rise in presentations over that time.

In respect of satisfaction and success with the e-learning system 83.6% (56/67) participants agreed or strongly agreed.

Conclusion

It is important any educational intervention is thoroughly examined as positive findings in respect of satisfaction or knowledge gain may not equate to behaviour change. The continued poor assessment of educational interventions results in potentially continued poor practice or educational technique. A new framework for evaluation (the 7Is) will be presented as a solution.
INTRANASAL KETAMINE FOR PROCEDURAL SEDATION
Authors: Hall Dani , Robinson Alison
Published: August 2014

Objectives & Background

The safety of intravenous ketamine in procedural sedation is well described.1 2Guidelines produced by NICE3and the College of Emergency Medicine4are used by Emergency Departments (ED) nationwide. To avoid cannulation, opioids are frequently administered to children intranasally5, avoiding first-pass metabolism.6Intranasal ketamine (INK) is an effective analgesic in children7and has been successfully utilised in prehospital and military settings.8 9However, a recent survey revealed that INK is not currently in use in UK paediatric EDs.10

To determine the current level of evidence of the use of INK in procedural sedation in children we developed a clinical scenario and three part question.

A 4 year old child presents with a lip laceration. Options for closure are under procedural sedation in the ED or general anaesthetic in theatre. You feel he would be suitable for procedural sedation. Your department's policy is intravenous ketamine. However the child is very upset and you feel the trauma of cannulation will adversely affect quality of sedation. Would INK be an alternative?

Methods

In [children undergoing procedural sedation] does [intranasal ketamine] result in [rapid onset, safe, effective sedation without prolonged recovery]?

Using the search strategy outlined in table 1, seven relevant papers were identified.11–18

Results

Efficacy

INK can be successfully used to sedate children for dental procedures at 3–6 mg/kg.11–135 mg/kg facilitates cannulation prior to induction of anaesthesia.14–16An ED based double-blinded RCT compared sedation with 3,6 and 9mg/kg INK17. The study was small and was terminated early due to high sedation failures.

Safety

All studies demonstrated 3–9 mg/kg INK is safe, with no serious adverse events.

Efficiency

At 3–9mg/kg, time to onset ranged from 3.6–9.4 minutes with recovery time between 30–69 minutes.11–17

Conclusion

An ideal agent for procedural sedation in the Paediatric ED is safe, easily delivered with rapid onset and recovery. The limited but growing evidence supports the use of INK to achieve this, although ideal dose is still unclear. All published studies to date have varying flaws with strict protocols defining adequate sedation and a lack of validated dissociative sedation scale potentially limiting reported success. More studies are emerging with a recent proposal presented to the PERUKI group. INK may still make its way into Paediatric EDs in the not too distant future.
Haemorrhage after liver biopsy in a dog with portosystemic shunt
Authors: Katić Nikola , Katić Christina , Reifinger Martin , Dupré Gilles
Published: August 2014

A 5‐year‐old intact female Chihuahua was transferred to our hospital for attenuation of a portosystemic shunt. The attenuation was done by means of cellophane banding and a routine liver biopsy was taken. Postoperatively, the dog developed haemoabdomen and the haematocrit dropped to 11 per cent. Relaparotomy revealed an acute haemorrhage from the biopsy site and partial liver lobectomy was performed to control bleeding. Despite all attempts at treatment, the dog developed serious metabolic and respiratory derangements and eventually died after an episode of respiratory arrest. With this report, the authors want to raise awareness of this potentially fatal complication and motivate the readers to weigh the benefit of additional information against the risk a ‘simple’ liver biopsy could entail in animals undergoing portosystemic shunt attenuation.
Conditions for primitivity of unital amalgamated full free products of finite-dimensional C*-algebras
Authors: Torres-Ayala Francisco
Published: August 2014

We consider amalgamated unital full free products of the form A1*D A2, where A1, A2 and D are finite-dimensional C*-algebras and there are faithful traces on A1 and A2 whose restrictions to D agree. We provide several conditions on the matrices of partial multiplicities of the inclusions D ↪ A1 and D ↪ A2 that guarantee that the C*-algebra A1*D A2 is primitive. If the ranks of the matrices of partial multiplicities are one or all entries are 0 or ≥ 2, we prove that the algebra A1*D A2 is primitive if and only if it has a trivial center.
ADAPTIVE SEGMENTATION APPROACH FOR HUMAN ACTION DATA
Authors: GAO CHUNMING , LI CHANGHUI , TAN GUANGHUA , GUO SONGRUI , XIAO KE
Published: August 2014

Temporal segmentation of human motion data is an essential preparation process for action recognition. Due to the variability in the temporal scale of human action and the complexity of representing articulated motion, the research of it encounters many difficulties. Especially, when the number of behaviors contained in the motion sequences is unknown in advance, traditional algorithms cannot segment sequences successfully. In this paper, we extend previous works on change-points detection by probabilistic principle component analysis (PPCA). Based on it, an algorithm which is an extension of PCA and Maximum Mean Discrepancy between samples is proposed for estimating the cluster number. Finally, we optimize our approach and detect cyclic units of each action by aligned cluster analysis. We evaluate and compare the approach with the state-of-the-art methods on Synthetic data, Motion Capture Dataset and Kinect data. Experimental results demonstrate the effectiveness of our approach.
WRIST RHYTHM DURING WRIST JOINT MOTION EVALUATED BY DYNAMIC RADIOGRAPHY
Authors: Kawashima Hiroki , Tada Kaoru , Suganuma Seigo , Tsuchiya Hiroyuki , Sanada Shigeru
Published: August 2014

We hypothesized that wrist joint motion involves a "wrist rhythm" similar to the scapulohumeral rhythm. Therefore, we used a flat-panel detector to evaluate the ratio of radiolunate and capitolunate joint motions during wrist joint motion by dynamic radiography. The subjects were 20 healthy men. Dynamic imaging of the wrist joint was performed during active exercise for a total of ten seconds. In this study, we defined the radiocarpal (RL angle) and midcarpal joint angle (CL angle) as the wrist joint angle in the obtained images and measured the variation of these angles. The average curve was plotted and regression lines calculated from the average curve. The ratio was calculated from the slopes of the regression lines of the RL CL angles. These findings indicated that the ratio of the RL and CL angle motions was approximately 1:4 during palmar flexion and approximately 2:1 during dorsiflexion.
LOCKING FINGER DUE TO A PARTIAL LACERATION OF THE FLEXOR DIGITORUM SUPERFICIALIS TENDON: A CASE REPORT
Authors: Seki Yasuhiro , Kuroda Hiroshi
Published: August 2014

A 39-year-old woman sustained a small wound on the palm of her right hand, which quickly healed naturally; however, a month later pain and limited range of motion were noted in her right finger. Surgery revealed the radial half of the flexor digitorum superficialis (FDS) tendon was ruptured and formed a flap, which hooked at the entrance of the A1 pulley. The proximal stump was sutured to the remaining ulnar (normal) side of the FDS tendon. Locking occurs between the tendon flap and the tendon sheath; therefore, when there is no fibrous tendon sheath near the partially ruptured tendon, locking will not occur.
Application of Hybrid Functions for Solving Duffing-Harmonic Oscillator
Authors: Heydari Mohammad , Loghmani Ghasem Brid , Hosseini Seyed Mohammad. , Karbassi Seyed Mehdi
Published: August 2014

A numerical method for finding the solution of Duffing-harmonic oscillator is proposed. The approach is based on hybrid functions approximation. The properties of hybrid functions that consist of block-pulse and Chebyshev cardinal functions are discussed. The associated operational matrices of integration and product are then utilized to reduce the solution of a strongly nonlinear oscillator to the solution of a system of algebraic equations. The method is easy to implement and computationally very attractive. The results are compared with the exact solution and results from several recently published methods, and the comparisons showed proper accuracy of this method.
A New Algorithm for System of Integral Equations
Authors: Rasulov Abdujabar , Kilicman Adem , Eshkuvatov Zainidin , Raimova Gulnora
Published: August 2014

We develop a new algorithm to solve the system of integral equations. In this new method no need to use matrix weights. Beacause of it, we reduce computational complexity considerable. Using the new algorithm it is also possible to solve an initial boundary value problem for system of parabolic equations. To verify the efficiency, the results of computational experiments are given.
A Fuzzy Identity‐Based Signature Scheme from Lattices in the Standard Model
Authors: Yang Chunli , Zheng Shihui , Wang Licheng , Tian Miaomiao , Gu Lize , Yang Yixian
Published: August 2014

A fuzzy identity‐based signature (FIBS) scheme allows a user with identity ID to issue a signature that could be verified with identity ID′ if and only if ID and ID′ lie within a certain distance. To obtain an FIBS scheme that can resist known quantum attacks, we use the double‐trapdoor technique from ABB10a for secret key extracting and the vanishing trapdoor technique from Boyen10 for message signing. In addition, in order to reflect the functionality of fuzziness, Shamir secret sharing scheme is also used in our construction. In this paper, we propose an FIBS scheme from lattices and prove that this new scheme achieves strong unforgeability under selective chosen‐identity and adaptive chosen‐message attacks (SU‐sID‐CMA) in the standard model. To the best of our knowledge, our scheme is not only the first FIBS scheme from lattices without random oracles but also the first FIBS scheme that achieves strong unforgeability.
An Improved Sequential Initiation Method for Multitarget Track in Clutter with Large Noise Measurement
Authors: Ji Daxiong , Li Dongdong
Published: August 2014

This paper proposes an improved sequential method for underwater multiple objects tracks initiation in clutter, estimating the initial position for the trajectory. The underwater environment is complex and changeable, and the sonar data are not very ideal. When the detection distance is far, the error of measured data is also great. Besides that, the clutter has a grave effect on the tracks initiation. So it is hard to initialize a track and estimate the initial position. The new tracks initiation is that when at least six of ten points meet the requirements, then we determine that there is a new track and the initial states of the parameters are estimated by the linear least square method. Compared to the conventional tracks initiation methods, our method not only considers the kinematics information of targets, but also regards the error of the sonar sensors as an important element. Computer simulations confirm that the performance of our method is very nice.
Improved NN‐GM(1,1) for Postgraduates’ Employment Confidence Index Forecasting
Authors: Wang Lu
Published: August 2014

Postgraduates’ employment confidence index (ECI) forecasting can help the university to predict the future trend of postgraduates’ employment. However, the common forecast method based on the grey model (GM) has unsatisfactory performance to a certain extent. In order to forecast postgraduates’ ECI efficiently, this paper discusses a novel hybrid forecast model using limited raw samples. Different from previous work, the residual modified GM(1,1) model is combined with the improved neural network (NN) in this work. In particullar, the hybrid model reduces the residue of the standard GM(1,1) model as well as accelerating the convergence rate of the standard NN. After numerical studies, the illustrative results are provided to demonstrate the forecast performance of the proposed model. In addition, some strategies for improving the postgraduates’ employment confidence have been discussed.
An Estimator of Heavy Tail Index through the Generalized Jackknife Methodology
Authors: Liu Weiqi , Xing Hongwei
Published: August 2014

In practice, sometimes the data can be divided into several blocks but only a few of the largest observations within each block are available to estimate the heavy tail index. To address this problem, we propose a new class of estimators through the Generalized Jackknife methodology based on Qi’s estimator (2010). These estimators are proved to be asymptotically normal under suitable conditions. Compared to Hill’s estimator and Qi’s estimator, our new estimator has better asymptotic efficiency in terms of the minimum mean squared error, for a wide range of the second order shape parameters. For the finite samples, our new estimator still compares favorably to Hill’s estimator and Qi’s estimator, providing stable sample paths as a function of the number of dividing the sample into blocks, smaller estimation bias, and MSE.
On New Conservation Laws of Fin Equation
Authors: Gün Polat Gülden , Orhan Özlem , Özer Teoman
Published: August 2014

We study the new conservation forms of the nonlinear fin equation in mathematical physics. In this study, first, Lie point symmetries of the fin equation are identified and classified. Then by using the relationship of Lie symmetry andλ-symmetry, newλ-functions are investigated. In addition, the Jacobi Last Multiplier method and the approach, which is based on the factλ-functions are assumed to be of linear form, are considered as different procedures for lambda symmetry analysis. Finally, the corresponding new conservation laws and invariant solutions of the equation are presented.
Control of Nonlinear Distributed Parameter Systems Based on Global Approximation
Authors: Du Chunyan , Xing Guansheng
Published: August 2014

We extend an iterative approximation method to nonlinear, distributed parameter systems given by partial differential and functional equations. The nonlinear system is approached by a sequence of linear time-varying systems, which globally converges in the limit to the original nonlinear systems considered. This allows many linear control techniques to be applied to nonlinear systems. Here we design a sliding mode controller for a nonlinear wave equation to demonstrate the effectiveness of this method.
Robust Stabilization of Linear Switching Systems with Both Input and Communication Delays
Authors: Jia Lili , Sheng Zunbing
Published: August 2014

This work is concerned with stabilization control of a class of linear switching systems with time-delays in both the input and the communication channels. It is observed that the time-delay in communication channel leads to the mismatch between the plant and the controller. Such a phenomenon can be accounted for by reconstructing switching signal for the overall closed-loop system. Therefore, we derive some sufficient stability conditions by using multiple Lyapunov functions approach and, moreover, present a robust controller design methodology. A numerical example is presented to demonstrate the effectiveness of the proposed method.
Abstract P1-07-06: Effect of biospecimen variables on proteomic biomarker assessment in breast cancer
Authors: Meric-Bernstam F , Akcakanat A , Chen H , Sahin A , Tarco E , Carkaci S , Adrada B , Singh G , Anh-Do K , Garces Z , Mittendorf EA , Babiera G , Wagner J , Bedrosian I , Krishnamurthy S , Symmans WF , Gonzalez-Angulo AM , Mills G
Published: August 2014

Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target. We sought to determine how tumor heterogeneity and biospecimen variables affect assessment of PI3K/Akt/mTOR pathway activation.

Methods: Intraoperative image-guided core-needle biopsies (CNB) of primary breast tumors were prospectively collected in 53 patients with invasive breast cancer. After surgery, specimens were collected from the center and periphery of the excised tumor. CNB, central and peripheral surgical specimens were assessed with reverse phase proteomic arrays (RPPA), H&E and immunohistochemistry (IHC).

Results: The expression of standard of care markers ER, PR, and HER2 by RPPA correlated well between biospecimen types. Overall, there was a significant correlation between the expression of 132 (86%) of 154 different markers in the center and periphery; the correlation was significantly higher for smaller tumors, and with shorter cold ischemia time. Expression of many investigational prognostic markers and druggable targets on CNB correlated with expression in the surgical specimen (average of center and periphery), while others, such as EGFR and c-MET, had a weak correlation. Of 154 RPPA markers, 132 (86%) were not statistically different between the center and periphery, and 97 (67%) were not different between the CNB and the surgical specimen. On analysis of the PI3K/AKT/mTOR pathway, pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimens. However, pAkt S473, pS6 S235/236 and pS6 240/244 levels were higher in CNB than the central specimens both by RPPA and by IHC. When patients were classified by RPPA PI3K pathway activation score, there was a moderate agreement between classification on the CNB and central specimens (Cohen's Kappa 0.539). However 9 of 20 tumors classified as having PI3K activation on CNB were classified as not having pathway activation on central specimens.

Conclusions: There is remarkable homogeneity in expression of biomarkers within a tumor. However, proteomic markers are differentially expressed by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared to surgical samples.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-06.
Abstract P1-14-18: Overall survival results of a multicenter randomized phase II study in locally advanced breast cancer patients treated with or without celecoxib for HER2 negative tumor (Remagus 02 trial)
Authors: Giacchetti S , Pierga J-Y , Delaloge S , Asselain B , Brain E , Guinebretière JM , Che-Lehman J , Mathieu M-C , Sigal B , Marty M
Published: August 2014

Background: Cox 2 is frequently over expressed in breast cancers. Celecoxib is a COX-2 inhibitor with anti angiogenic and pro-apoptotic activities. There are few data of anti-COX2 treatment in breast cancers. and no data on the impact of neoadjuvant anti COX 2 agent on survival.

Patients and methods/: From May 2004 to October 2007, 340 stage II-III breast cancer patients were included in a phase II randomized trial and received 4 cycles (c) of epirubicin (75 mg/m2)–cyclophosphamide (750 mg/m2) q 3 w followed by 4 (c) of docetaxel (100 mg/m2) q 3 w. Pts with HER2 negative tumors (220 pts) were randomized to receive or not neoadjuvant celecoxib (200 mg bid) combined with docetaxel. All pts with hormone receptors positive tumor received hormonal treatment according to menopausal status (Pierga et al BCRT 2010). We report here overall survival (OS) and disease free survival (DFS) data and prognostic factors analyses at 5 years.

Results/: At a median follow up of 49 months, the median DFS and OS are not reached for the whole population and none of them is significantly different between pts who received celecoxib or who did not (p = respectively 0.62 and 0.36). Celecoxib had no impact either on clinical and pathological complete response rate (pCR). DFS is significantly higher in patients who achieved pCR as compared to those who did not (p = 0.017; RR = 0.21 [0.051–0.88], whereas OS is borderline significant [p = 0.07; RR = 0.19 (0.026–1.4)]. Patients with triple negative (TN) tumors (78 pts) achieved worst DFS (p = 0.02) and OS (p <0.001) than non triple negative ones despite their higher pCR rate, 29.5 % [95 % CI 19;7-40;9 %] vs 11.4 % in all the other subgroups. At multivariate analysis including 7 factors [tumor size, clinical lymph node, grade (1 vs. 2and 3), pCR, ER, PR, TN], factors which influenced OS and DFS were pCR (p = 0.034 & 0.013 and PgR expression (p = 0.046 & 0.01).

Conclusion/: Celecoxib had no influence on pCR, DFS or OS. Despite higher pCR rate triple negative breast cancer patients' subgroup remains with the poorest outcome.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-18.
Abstract P1-14-19: Breast-Conserving Surgery after Neoadjuvant Chemotherapy is Oncologically Safe for Stage III Breast Cancer Patients
Authors: Shin H-C , Han W , Moon H-G , Im S-A , Park S-J , Noh D-Y
Published: August 2014

Background The use of breast-conserving surgery (BCS) in patients with large breast tumors downstaged by neoadjuvant chemotherapy (NCT) remains controversial in clinical stage III breast cancer patients because of the possibility of residual tumor and resistance to NCT. The aims of this study were 1) to evaluate the local recurrence (LR) rate depending on the use of NCT and 2) to determine the oncologic safety of BCS after NCT by comparing LR between patients treated with preplanned/downstaged BCS and patients treated with NCT and mastectomy in clinical stage III breast cancer patients.

Patients and Methods Between 2000 and 2007, 166 patients with clinical stage III breast cancer received BCS or mastectomy after NCT (NCT group) and 193 patients with clinical stage III breast cancer who underwent surgery first (Surgery group). Among 166 patients of the NCT group, 94 patients (56.6%) received mastectomy after NCT (mastectomy after NCT group), 39 patients (23.5%) received preplanned BCS (preplanned BCS group) and 33 patients (19.9%) received downstaged BCS (downstaged BCS group). The LR rates between the groups were compared.

Results At a median follow-up period of 66.9 months (range, 6.5 to 104.1 months), 11 patients in the NCT group and 7 patients in the Surgery group had developed LR. The 5-year LR-free survival rates were 93.6% in the NCT group and 95.9% in the Surgery group and the LR rates were not significantly different between the groups (p = 0.196). In the NCT group, LRs were observed in 6 patients in the mastectomy after NCT group, 3 patients in the preplanned BCS group and 2 patients in the downstaged BCS group. The 5-year LR-free survival rates were 94.4% in the mastectomy after NCT group, 92.0% in the preplanned BCS group and 93.9% in the downstaged BCS group, respectively (p = 0.953).

Conclusions Our study demonstrated that the LR was not different depending on the use of NCT in the clinical stage III breast cancer patients. Also, clinical stage III breast cancer patients who received preplanned or downstaged BCS after NCT showed similar LR-free survival rates compared to patients who received mastectomy after NCT. This result supports that BCS after NCT in clinical stage III patients is oncologically safe in terms of LR if primary breast tumor size has became 5cm or less after NCT.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-19.
Abstract P1-15-05: GSTP1 polymorphism is associated with chemotherapy induced neuropathy
Authors: Miltenburg NC , Opdam M , Winter M , van Geer M , Oosterkamp HM , Boogerd W , Linn SC
Published: August 2014

Background: Peripheral neuropathy is a common and potentially debilitating side-effect of microtubule-stabilizing agents like docetaxel and is characterized by sensory symptoms like numbness, tingling and burning pain. Docetaxel induced neuropathy may occur in up to 37% of patients and can be dose limiting, thus potentially reducing its chemotherapeutic efficacy. Doxorubicine has occasionally been described to be associated with neuropathy.

With this background we investigated the role of various single nucleotide polymorphisms (SNPs) to predict chemotherapy-induced neuropathy. The exploration of SNPs and an association with incidence or severity of neuropathy is important, because it can result in identifying individuals being at higher risk of neurotoxicity.

Methods: The MATADOR study is a prospective, non-blinded randomized phase II/III trial for patients with invasive breast cancer, comparing TAC (docetaxel 75 mg/m2 as 1 hour i.v. infusion q 3 weeks, in combination with doxorubicin and cyclophosphamide for 6 cycles) with AC dose dense (doxorubicin and cyclophosphamide q 2 weeks)(ISRCTN61893718).

In total 180 interesting SNPs were selected that are involved in metabolism, distribution and excretion of drugs and tested on DNA that was isolated from tumor or from tumor surrounding tissue. We selected 20 SNPs for further analyses because of reported associations with chemotherapy-induced neuropathy (see table).

In the first analysis DNA of 45 patients was analyzed as a pilot, comparing DNA of 23 neuropathy patients with that of 22 controls. The primary hypothesis was to identify SNPs associated with NCI-CTC grade ≥2 neuropathy.

Results: Interim toxicity data from the MATADOR study demonstrated that 30 of 580 patients had grade ≥2 neuropathy. GSTP1 114Ala/114Val genotype was associated with grade ≥2 neuropathy. Twelve out of 14 (86%) patients with this genotype had chemotherapy-induced neuropathy compared to 11 out of 31 (35%) without this genotype (chi-square test p = 0.002).

Conclusion: We found a correlation between GSTP1 114Ala/114Val genotype, involved in detoxification, and development of grade ≥2 neuropathy during treatment with chemotherapy. Updated results will be presented at the meeting.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-05.
Abstract P2-01-01: Establishment and validation of circulating tumor cell-based prognostic nomograms in 497 first-line metastatic breast cancer patients
Authors: Giordano A , Reuben JM , Egleston BL , Hajage D , Hortobagyi GN , Cristofanilli M , Pierga J-Y , Bidard F-C
Published: August 2014

Background: Several prognostic clinical and pathological characteristics have been reported to be independently associated with survival in metastatic breast cancer (MBC). Circulating tumor cells (CTCs) isolated by CellSearch® from peripheral blood of MBC patients was shown to be an additional strong independent prognostic factor for survival and progression of disease. The aim of this study was to combine CTC and other predictors in a nomogram that would allow clinicians to assess, on an individual basis, the prognosis of patients starting first-line chemotherapy for MBC.

Patients and Methods: CTCs were counted before the start of treatment using the US Food and Drug Administration–cleared CellSearch® technology. We used a training set of 237 MBC patients starting a first line chemotherapy from the MD Anderson Cancer Center (MDACC, Houston, TX, USA), and nomograms were established to calculate the predicted probability of overall survivals (OS) at 1, 2 and 3 years. These nomograms were externally validated using an independent data set of 260 patients starting a first line chemotherapy from the prospective Institut Curie 2006–04 study (Paris, France). Discriminatory ability of the models was assessed using Harrell's c-statistic examining the model in the training sample (U.S. data) and the validation sample (French data). Accuracy of the nomograms was assessed both within the training sample and the validation sample via calibration plots at 1, 2 and 3 years. Covariates computed in the model were: age, subtype of disease, presence of visceral metastasis, bone metastasis, performance status, and CTCs.

Results: Table1 describes patient characteristics. Median follow-up was of 24.5 and 29 months, respectively in the MDACC and Institut Curie. The C-statistics for OS was 0.7338 in the training set and 0.7229 in the validation set. For the calibration plots, we averaged Cox predictions at two years within the quintiles of the ordered predictions. Within each quintile, we also estimated the unadjusted probability of death using Kaplan-Meier survival estimators. We then plotted unadjusted versus model average predictions at 1, 2 and 3 years. The nomograms discriminated OS prediction at 1, 2 and 3 years very well.

Conclusions: Patients with first-line MBC present a wide range of survival duration, and our ability to assess prognosis and predict risks of progression and death on the basis of clinic-pathologic findings is limited. The validated nomograms represent an important tool for estimating prognosis, support treatment-decisions and clinical trial stratification in MBC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-01.
Abstract P2-01-02: Circulating Tumor Cells (CTC) may Express HER2/neu in Patients With Early HER2/neu Negative Breast Cancer – Results of the German SUCCESS C Trial
Authors: Jaeger BAS , Rack BK , Andergassen U , Neugebauer JK , Melcher CA , Scholz C , Hagenbeck C , Schueller K , Lorenz R , Decker T , Heinrich G , Fehm T , Schneeweiss A , Lichtenegger W , Beckmann MW , Pantel K , Sommer HL , Friese K , Janni W
Published: August 2014

Background: There is growing evidence that the HER2/neu-status of distant metastases or minimal residual disease in blood and bone marrow may differ from the primary tumor in patients with breast cancer. The HER2/neu-status of CTCs was prospectively evaluated in patients with HER2/neu negative primary breast cancer randomized into the German multicenter SUCCESS C study.

Methods: The SUCCESS C trial is a randomized Phase III study comparing FEC-Docetaxel (FEC-Doc) vs. Docetaxel-Cyclophosphamid (DC) as well as 2 years of a lifestyle-intervention in patients with early, HER2/neu negative, node positive or high-risk node negative primary breast cancer.

As part of the translational research program, 23ml peripheral blood were drawn after adjuvant chemotherapy. In 505 samples, the prevalence of CTCs and their HER2/neu-status were assessed using the CellSearch System (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with anti-CK8/18/19 and anti-CD45 antibodies. A fluorescein conjugate antibody with anti-CK-Fluorescein Isothiocyanate (FITC) was used for HER2/neu phenotyping. The cut-off for CTC-positivity was ≥ 1 CTC and for HER2/neu ≥ 1 CTC with strong HER2/neu-staining (+++).

Results: 26,9% of pts (n = 136) were positive for CTCs (mean 1.78; range 1–7; median = 1). The number of detected CTC was distributed as follows: 1 CTC (n = 76; 55.9%), 2 CTCs (n = 35; 25.7%), 3 CTCs (n = 13; 9.6%), 4 CTCs (n = 7; 5.2%) and ≥ 5 CTCs (n = 5; 3.7%). HER2/neu staning of CTCs was not detectable or weak in 26.5% (n = 36) and 4.4% (n = 6) of CTC positive patients respectively and therefore categorized as HER2/neu negative. In 32.4% of the CTC-positive patients (n = 44), we detected moderate and in 36.8% (n = 50) strong HER2/neu-staining of ≥ 1 CTC per sample. No association was found between CTCs or the HER2/neu-status of CTCs with tumor size, histopathological grading, hormone receptor status or axillary lymph node involvement.

Conclusions: The data of this trial confirm previous findings that patients with HER2/neu negative primary breast cancer can show HER2/neu positive minimal residual disease. These results underline the importance of frequent HER2/neu determination during follow up and disease progression. Survival data within the Success C trial will give further insight into the tumor biology of HER2/neu negative disease.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-02.
Abstract P2-01-10: Immunocytochemistry staining for estrogen and progesterone receptor in circulating tumor cells: Concordance between primary and metastatic tumors.
Authors: Bischoff FZ , Pham T , Wong KL , Villarin E , Xu X , Kalinsky K , Mayer JA
Published: August 2014

Introduction: Estrogen (ER) and progesterone receptor (PR)) status is recommended by immunohistochemistry (IHC) and is considered standard practice for selection of treatment options in all breast cancer patients. Because biopsy is not often feasible in every patient presenting with recurrent and/or metastatic disease, circulating tumor cells (CTCs) offer an attractive alternative source of tumor tissue for determining ER/PR status. In addition, CTCs enable monitoring for more effective course of treatment.

Experimental Design: Twenty ml of peripheral blood was collected prospectively from 34 patients diagnosed with late stage metastatic/recurrent breast cancer. CTCs were isolated using the microfluidic OncoCEE platform. A cocktail of antibodies was utilized for CTC capture, and detection was accomplished with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on CK+/CD45- CTCs captured directly within the microchannel and then compared to IHC performed on the primary and/or metastatic tumor.

Results: CK+/CD45−/DAPI+ cells were detected in 22 of 34 (65%) patients with late stage breast cancer and assessed for ER/PR immunocytochemistry. Among the 22 cases with one or more CTCs, a concordance of 75% (15/20) and 90% (9/10) in ER/PR status between primary and metastatic tumor was observed, respectively. An overall concordance of 86% (19/22) was achieved. Five cases were discordant based on primary tissue alone; however, two of these cases are concordant when compared to the metastatic biopsy. Thus, only three cases were found to be discordant: all three were positive by IHC on the primary and/or metastatic tumor but negative by CTCs and all three had relatively low numbers of CTCs detected.

Conclusions: There is significant heterogeneity of ER/PR protein expression in CTCs and primary/metastatic tumor biopsy. In addition, hormonal status may change over time due to therapy. ER/PR ICC on CTCs using the OncoCEE platform is shown to be feasible, with high concordance (86%) as compared to primary and/or metastatic biopsy (by IHC). The significance of heterogeneity at the ER/PR protein level in CTCs related to the prognosis and predictive response to anti-estrogen therapy needs further evaluation in larger prospective clinical trials.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-10.
Abstract P2-01-13: Prognostic value of Circulating Tumor Cells count at progressive disease after first line chemotherapy metastatic breast patients in a large prospective multicenter trial including serum tumor markers (IC 2006–04 study)
Authors: Pierga J-Y , Hajage D , Bachelot T , Delaloge S , Brain E , Campone M , Asselain B , Cottu PH , Dieras V , Bidard F-C
Published: August 2014

Background: The IC 2006–04 study included prospectively 267 metastatic breast cancer patients before the start of first line chemotherapy. We previously reported and confirmed the prognostic and predictive of CTC counts before the start of treatment and after 3–4 & 6–9 weeks of treatment (Pierga, JY SABCS 2010, Ann Oncol 2012). We report here the results of the last CTC count performed at tumor progression (i.e. end of first line chemotherapy).

Methods: Patients were included in the study from 06/07 to 9/09. CTC were counted by the CellSearch® system at tumor progression (clinical and/or radiological progression).

Results: 211 patients experienced a tumor progression at time of final data analysis and the planned CTC count has been performed in 61 patients. High CTC count (≥5 CTC/7.5ml) at progression was observed in 22 patients (36%) and was associated with elevated Cyfra 21–1 and ALP and was not associated with elevated CEA, CA 15–3, LDH, the elapsed progression-free survival, the onset of new metastasis. No CTC was detected at tumor progression in the 5 patients with HER2+ disease, in line with our previous results. The prognostic markers for overall survival at tumor progression were high CTC count (median overall survival 8 vs 19 months, p = .0006) and elevated Cyfra 21–1 (p = .001). Other serum markers (CEA, CA15-3, ALP, LDH) and tumor subtypes had no prognostic value at univariate analysis. At multivariate analysis, the two prognostic factors for overall survival were high CTC count (RR = 2.3 p = 0.03) and elevated Cyfra 21–1 (RR = 3.6 p = 0.02).

Conclusion: In the prospective IC 2006–04 study, among the different markers tested at tumor progression during the first line chemotherapy for metastatic breast cancer, high CTC count and elevated Cyfra 21–1 levels were the only two independent prognostic markers for overall survival.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-13.
Abstract P2-04-08: Targeted Expression of the Human Chaperone BAG3 to the Murine Mammary Gland Dysregulates Mammary Gland Development and Differentiation By Unrestricted Expansion of Luminal Cells
Authors: Virador VM , Casagrange G , Raafat A , Callahan R , Kohn E
Published: August 2014

BAG3 is a pro-survival pro-invasion chaperone. We hypothesized that human BAG3 overexpression in murine breast would contribute to mammary tumorigenesis. We generated transgenic mice ectopically expressing hBAG3 in the mammary gland under the control of the Mouse Mammary Tumor Viral promoter (MMTV-hBAG3). hBAG3 was expressed in luminal cells throughout the ductal tree in multiple transgenic lines. Targeted expression of hBAG3 dysregulated mammary gland development by both increasing proliferation and differentiation. hBAG3 mammary glands had increased epithelial elongation at 5 weeks of age, premature glandular differentiation at 10 weeks, and features of ductal hyperplasia at week 13 with increased Ki67 and p-Histone H3 in the luminal compartment. At week 13 hBAG3 induced acinar differentiation. BAG3 pro-survival gain of function was recapitulated post-partum with delayed involution. Mammary glands of MMTV-hBAG3 had alveolar persistence three days after forced involution where non-transgenic controls demonstrated typical involution-driven apoptosis and remodeling. We crossed heterozygous MMTV-hBAG3 to WAP-Int3 mice with absent alveolar development in pregnancy. hBAG3 caused alveolar budding in the WAP-Int3 background. We hypothesized hBAG3 gain of function in the mammary gland would promote tumorigenesis. On aging, mammary glands of heterozygous MMTV-hBAG3 displayed densely crowded acinar structures with atypia, consistent with hyperplastic alveolar nodule (HAN). We subjected MMTV-hBAG3 mice to either multiparity or chemical carcinogenesis. After two pregnancies, most MMTV-hBAG3 animals had hyperplastic mammary ductal lesions (MMTV-hBAG3 6/7, 86%; FVB/N 1/7, 14%). Eighteen weeks post 7,12-dimethylbenz(a)antracene (DMBA) treatment, virgin females from five different transgenic lines had more hyperplastic lesions (MMTV-hBAG3 mean 6.3 lesions/gland, N=13, FVB/N mean 3.6 lesions/gland, N=9; p = 0.04), some with atypical hyperplasia. Transgenic MMTV-hBAG3 females developed ER and PR (+) malignant tumors (5/19), 26% while non-transgenic controls had none (0/12). WAP-Int3 mice developed tumors as early as two pregnancies. Heterozygous WAP-Int3xMMTV-BAG3 had the same tumor frequency but preliminary data suggest increased aggressiveness and metastasis. Collectively, our results indicate that MMTV-hBAG3 promotes proliferation, dysregulates mammary gland development and promotes hyperplasia and tumorigenesis and may provide a novel mouse model to represent the human ER+ luminal breast cancer subtype.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-08.
Abstract P2-05-15: Assessment of Notch Signaling Pathway Components as Biomarkers for Triple Negative Breast Cancer: Comparison of Triple Negative Breast Cancer Cell Lines and Human Breast Cancer Samples.
Authors: Zlobin A , Olsauskas-Kuprys R , Hodge S , O'Toole M , Ersahin C , Osipo C
Published: August 2014

Background: Treatment options for patients presenting with TNBC are limited, primarily because there is no approved targeted therapy available. Canonical breast cancer targets such as estrogen receptor and HER2/neu proteins are absent in TNBC. Furthermore, there is an urgent need to uncover biomarkers in this disease in light of its costly treatment as compared to non-TNBC treatment and, more importantly, its poor prognosis as evidenced by aggressive tumor metastasis and high patient mortality. While Notch-1 target gene expression has been reported to be linked to various types of malignancies, we propose that since Notch signaling pathway is involved in cancer cell proliferation and survival it could be a likely oncogenic driver and possible target in certain TNBC patients.

Methods: Human TNBC cell lines BT-549, MDA-MB-231, and MDA-MB-468 were used to measure endogenous relative mRNA transcript levels of Notch genes and gene targets by means of real time PCR. In addition, the RNA from formalin-fixed, paraffin-embedded specimen from women-diagnosed with TNBC who had undergone breast surgery was also analyzed for comparable gene expression for similar targets following Laser capture micro-dissection.

Results: The in vitro results show that mRNA transcripts of Notch-4, Deltex-1, Hes-1 and -Hes5, as well as upstream Notch regulator PEA3 targets IL-8 and MMP-9 were increased in MDA-MB-468 and BT-549 cells as compared to MDA-MB-231 cells (n = 3–5). In the clinical sample specimens, Notch-1, Jagged-1, and Hes-5 genes were up-regulated, while the Notch-4 gene was down-regulated in TNBC patients as compared to normal control specimens from reduction mammoplasty (n = 4).

Conclusions: Our data present the heterogeneity of TNBC disease. They also indicate that the Notch signaling pathway is up-regulated in certain TNBC cell lines and human TNBC breast cancer tissue. Lastly, these results suggest that some components of Notch signaling may be viable biomarkers to better predict Notch activity for future therapeutic interventions using Notch inhibitors.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-15.