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1076Background: TNBC lacks expression of steroid hormone receptors and HER2. This phenotype shows high metastatic potential, with particular predilection to lungs and brain. Determination of geneti...

Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Trial design: This is an open-label, national multicenter phase 2 study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic triple negative breast cancer (TNBC). A prospective, molecular correlative study is being carried out on germinal DNA of study population. Eligibility criteria: Patients must have locally advanced or metastatic breast cancer with estrogen receptor-negative (ER < 1%), progesterone receptor-negative (PR < 1%), and human epidermal growth factor receptor 2-negative (Her2-) (0, 1+) or, e.g. in HER2 2+ cases, fluorescent in situ hybridization (FISH) < ratio of 1.8, status. Previous chemotherapy including an anthracycline and a taxane (unless one or both were clinically contraindicated) is mandatory. Up to one prior chemotherapy regimen for metastatic disease is permitted, with the exception of treatment with eribulin and gemcitabine. Patients must have: Measurable disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; adequate bone marrow reserve, liver and renal function. Specific aims: The main objective of this trial is to evaluate the activity of eribulin plus gemcitabine in terms of overall response rate (ORR; RECIST 1.1). Secondary end-points are: Feasibiliy, safety (CTC-AE V4.0), progression-free and overall survival. The molecular correlative study aim is to assess the role of germinal DNA polymorphisms and BRCA mutations in predicting efficacy and toxicity with the combination regimen. Statistical methods: The primary endpoint is the ORR. The study is being carried out according to Optimal Simon's two stage design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A total of 83 (37 in the first stage, 46 in the second one) assessable patients will be needed to guarantee 90% power under a α-level of 5%. Genotypic correlations with clinical responses and toxicities will be performed using a two-tailed Fisher's exact test. A logistic regression analysis including patients' genotypes will be used to identify independent prognostic variables influencing both clinical responses and toxicities. Present accrual and target accrual: A total of 83 eligible patients will be enrolled from multiple institutions. To date (June 09, 2015), the first stage has been closed with 37 patients enrolled. The second stage is now recruiting 46 additional patients. Citation Format: Musolino A, Caldara A, Montemurro F, Frassoldati A, Cavazzini G, Cavanna L, Todeschini R, Camisa R, Tognetto M, Pinto C. Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer. ERIGE Trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-05.

The problem of the evaluation of eddy currents induced in a conductive cylinder is here reconsidered under the light of possible application in the electromagnetic launch context. In particular we derive an analytical solution when the system is excited by a sinusoidal current flowing on a saddle coil moving in the axial direction. Subsequently we consider an arrangement of such coils distributed in the axial and azimuth direction. When properly fed they produce a travelling wave of flux distribution which is able to exert a thrust force on the conductive cylinder. Since the governing vector field equation is not separable in the cylindrical coordinate, an approach based on the second order vector potential (SOVP) formulation has been here adopted. Scalar field equations are obtained whose solutions are expressed in terms of Bessels function.

In this paper a double stator tubular linear induction machine is presented and its performance are discussed for a possible use as a catapult in the electromagnetic acceleration of aircrafts. Based on the use of the Fourier transform in the direction of the motion, a semi analytical model that is able to take into account the end effects due to the finite length of the stators is derived. The effectiveness of the model has been proved by comparison with a numerical analysis based on the Finite Elements Method. The reported results obtained by the two methods shows an excellent agreement that makes the proposed model as a valuable tool for a preliminary design of the device.

Purpose To determine whether human epidermal growth factor receptor 2 (HER2) –positive status is associated with risk of breast cancer diagnosis in the interval between mammographic screening, we estimated the distribution of features of aggressive tumor behavior in a general population with newly diagnosed breast cancer and known screening status. Patients and Methods We evaluated all invasive breast cancers (N = 641) that were systematically collected by the Parma Province Cancer Registry and diagnosed in women age 50 to 69 years from 2004 to 2007. From this population, 292 screen-detected cancers and 48 interval cases with negative screening mammograms on expert rereading (true interval cancers) were selected for study purposes. Unconditional logistic regression adjusted for age and tumor size was used to determine whether interval cancers were associated with selected clinicobiologic characteristics. Results Tumors with a high histologic grade (odds ratio [OR], 1.8; 95% CI, 1.2 to 3.8), high proliferative rate (OR, 2.4; 95% CI, 1.2 to 4.5), negative estrogen receptor status (OR, 1.6; 95% CI, 1.1 to 3.1), or HER2-positive status (OR, 3.4; 95% CI, 1.7 to 7.1) were more likely to be diagnosed in the interval between screening. Women age less than 60 years with HER2-positive breast cancer were four times more likely to be diagnosed in the interval between screening compared with only a two-fold increased risk for older women. Conclusion This population-based cancer registry study demonstrated that HER2-positive tumors account for a substantial proportion of mammographic screening failure. The distribution of biologic characteristics in screen-detected cancers differs from that observed in interval cancers and may account in part for the more aggressive behavior of interval-detected cases.

Purpose This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) –positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). Patients and Methods In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m2) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. Results A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). Conclusion The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

This study addresses the sensitivity analysis of non-linear circuits in their transient and periodic behaviour. The circuits here considered are built of connections of N-ports with frequency-dependent parameters whose input and output quantities are expanded in the wavelet domain. The use of wavelet instead of the Fourier analysis allows a significant increase in the sparsity of the matrices with a comparable accuracy and convergence rate. In addition, by using the proper wavelet basis, it is possible to analyse both the steady state and the transient behaviour. The adjoint system method is used to obtain the sensitivities of the response of the circuit with respect to the design parameters. The multiport connection is described in terms of scattering parameters and the hierarchical approach is extended to the adjoint system. Computational aspects are discussed and examples of application of the proposed technique are reported. The results are compared with those obtained by the use of other techniques.

The solution of large and complex coupled electromechanical problems requires high performance computing resources. In the last years the use of Graphic Processing Units (GPUs) has gained increasing popularity in scientific computing because of their low cost and parallel architecture. In this paper the authors report the main results of the GPU approach to the parallelization of a research code for the electromagnetic launcher analysis. Programming a GPU - based environment poses a number of critical issues that have to be carefully addressed in order to fully exploit the potentiality of the system. Data have to be properly organized in order to fit the Single Instruction Multiple Data scheme; the data transfer between the host and the device, as well as the memory management of the GPU deserve accurate programming. Two examples of application of the parallelized code have been reported to show the performance improvements that can be obtained in the numerical analysis of both rail and induction launchers.

The goal of this study is to determine and localize the generators of different components of middle latency auditory evoked potentials (MLAEPs) through intracerebral recording in auditory cortex in man (Heschl's gyrus and planum temporale). The present results show that the generators of components at 30, 50, 60 and 75 msec latency are distributed medio-laterally along Heschl's gyrus. The 30 msec component is generated in the dorso-postero-medial part of Heschl's gyrus (primary area) and the 50 msec component is generated laterally in the primary area. The generators of the later components (60–75 msec) are localized in the lateral part of Heschl's gyrus that forms the secondary areas. The localization of N100 generators is discussed.

Helical launchers have become attractive for launching large masses to intermediate velocities because of their high inductance gradient. At these velocities the commutation of the brushes assumes great importance and it is supposed to be the main limiting factor of their performance. The possible presence of destructive arcs and the dissipation of the commutation energy in the brush material are serious problems that affect these launchers. A numerical model based on an equivalent circuit approach is adopted here to investigate the commutation process and to address the dissipation of the commutation energy in the brush material owing to the presence of arcs. A comparison with the performance predicted by neglecting the arcs has been carried out. This comparative analysis has clearly evidenced the need to consider the presence of the arcs also in the preliminary design of the device. Both the integrity of the brushes and the final velocity of the armature may be heavily affected.

507 Background: This is a randomized phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage pathological complete response (pCR), defined as complete disappearance of invasive tumor in breast and axillary nodes. Methods: chemotherapy (CT) consists of weekly paclitaxel x 12 followed by FE75C x 4. Pts randomized to arm A receive CT plus weekly trastuzumab; in arm B pts receive CT plus lapatinib 1250 mg po daily; in arm C pts receive CT plus weekly trastuzumab and lapatinib 750 mg po daily. The study sample size has been calculated according to the two-step Simon’s design. The overall planned accrual was 120 pts. P95HER2 expression will be measured by bioTheranostics, Inc (San Diego) to explore if there is a clinically relevant difference in the pCR rate according to p-95 status. Gene expression profile analysis to identify a predict...

We report two cases of pineal gland cysts, both in young girls, causing aqueductal stenosis and symptomatic hydrocephalus, which were diagnosed and treated by Talairach's stereotactic method. This procedure permitted aspiration of the cyst content, normalization of aqueductal stenosis, and a differential histological diagnosis. Postoperative computed tomographic scan examination showed a stable reduction of the cystic volume and a complete clearance of the hydrocephalus. At present, the two patients are clinically normal and are leading a productive life (follow-up, 42 and 40 mo). It is important that this kind of nonneoplastic lesion be identified, in order to avoid confusion with pineal tumors and possible inappropriate treatment. Pineal cysts rarely become symptomatic. Up to the present, only 27 symptomatic cases have been described in the literature. Of those, signs of intracystic bleeding were found in 17 of the 21 cases in which the cyst contents were known. Moreover, in our own two cases, numerous hemosiderin-laden macrophages were present in the cystic fluid. We think, therefore, that intracystic bleeding has been the determining factor for the occurrence of symptoms in most of these cases. The authors underline the advantages of this type of stereotactic management, which can provide both diagnosis and treatment and thus avoid the possible risks of surgical excision and/or of radiotherapy.

Due to its high inductance gradient the helical launcher has become attractive for launching large masses at intermediate and high velocities. At these velocities the brushes commutation assumes a great importance and is supposed to be the main limiting factor in the performance of helical launchers. A numerical model based on an equivalent circuit approach is adopted here to investigate the commutation mechanism and to address the dissipation of the commutation energy in the brush material.

This paper presents a new passive magnetic bearing system that is capable to rotate without contact at a short distance from a dedicated stator. The magnetic suspension is assured by the repulsion between two arrangements of permanent magnets located both on toroidal shaped stator and rotor. The stator magnets are surrounded by a conductive sheet. The presence of eddy currents due to the relative motion between the rotor magnets and the conductive sheet allows overcoming the intrinsic instability of the system. The dependence of the stabilizing force on the angular velocity will be determined as well as the levitation force, the magnetic drag force and the power dissipated in the conductor sheet by the stabilizing eddy currents.

The present article proposes an approach to evaluate the “quality” of equivalent circuits of complex devices obtained by a novel technique based on constitutive subcircuits and particle swarm optimization and to “improve” their performances. In particular, the robustness of the obtained circuits is evaluated by a sensitivity analysis, which leads to the identification of the bounds of its frequency response, since different runs of the global extraction procedure lead to slightly different equivalent circuits (yet topologically coincident). The analysis of the numerical results gives insight on the robustness of a single case and, at the same time, attests to the efficiency of the proposed method.

In this paper we compare the effectiveness of the time, wavelet and Hilbert-Huang domain analysis of waveforms from a Non Destructive Test (NDT) equipment. The analysis of the signals from NDT systems is one of the most important activities in the recognition of the presence of possible defects that are usually associated with the presence of echoes from the defects themselves. Very often the echoes traveling back to the sensors are superimposed with the signal from the transducer. We analyze the waveforms obtained by couples of sensors in order to extract the echoes and to recognize the points were they originate. Data are obtained by a measurement campaign on a concrete wall and on masonry specimens of different texture and thickness.

This paper addresses the sensitivity analysis of nonlinear circuits in their transient and periodic behavior. The circuits here considered are built of connections of N-ports described in the wavelet domain. The wavelet harmonic balance allows obtaining an effective tool for the analysis of these circuits when they are nonlinearly terminated. A significant increase in the sparsity of the matrices and a comparable accuracy and convergence with respect to the Fourier analysis is obtained. Furthermore by using the proper wavelet basis (periodized or not) is it possible to analyze steady state and transient behavior. The adjoint system method is used to obtain the sensitivity of the response of the circuit with respect to the design parameters.

The present paper is the first approach to the design of a PLC system onboard trains. The problems existing in this environment are described, and a selection of the channel, based on security and functional issues is presented. The channel is characterized in the time and frequency domain, and considerations on the implementation of an OFDM communication protocol are given.

This paper presents a nonlinear decision feedback channel estimation technique for Discrete Multi Tone (DMT) transmission in broadband indoor powerline communications (PLC). The estimation is carried out in a decision directed mode and the decisions are made using a modified self organizing map (SOM) classifier. The performance of the proposed method is evaluated through simulations over measured power line channels. It is shown that when nonlinearities at the transmitted signal are significant, a nonlinear decision feedback at the receiver improve the symbol error rate (SER).

The case here reported reflects the difficulty in diagnosing meningeal extramedullary hematopoiesis (EMH), which clinically appeared concomitantly with primary cerebral lymphoma and occurred in a patient with HIV infection and severe pancytopenia. Pancytopenia secondary to HIV infection could be hypothesized as a predisposing factor for the ectopic development of hematopoietic tissue outside the bone marrow. Although rare, intracranial EMH should always be considered in the differential diagnosis of headache and other endocranial hypertension symptoms in patients with chronic bone marrow dysfunction.

In this paper a new technique is proposed for blind channel identification and equalization in orthogonal frequency-division multiplexing (OFDM) communication over power-lines. The proposed scheme is based on a competitive neural network which utilizes the frequency domain data in the receiver performing a nonlinear decision-directed equalization. This method allows for blind tracking of the time variant channel response and is robust to impulsive noise and non-linearities. Numerical simulations for a realistic indoor power-line show the potentiality of the proposed estimation procedure.

This paper is dedicated to the development of a fast and accurate method for the transient analysis of microwave circuits with frequency dependent parameters and nonlinear loads. A convolution operator has been developed expanding the report input and output quantities by wavelets on the interval to overcome the intrinsic difficulty of this kind of problems in which nonlinear elements are better described in the time domain while circuit components are mostly characterized in the frequency domain. Because of their generality and easiness of use, the scattering parameters are used. A wavelet balance approach is discussed to solve the nonlinear equations arising from the presence of nonlinear terminations. Computational aspects are discussed and the results of application of this technique are compared with those obtained by other methods showing the accuracy and the efficiency of the proposed technique. (6 pages)

Early age at onset is generally considered an indicator of genetic susceptibility to breast cancer. To address both the proportion of early-onset breast cancer associated with BRCA-1 or BRCA-2 germline mutation and the contribution of germline mutations to the clinical features and outcome of these tumors, we analyzed molecular status and clinical variables of a population-based sample of 66 Italian women diagnosed with breast cancer before the age of 40 who were unselected for family history. BRCA mutations were screened by automated sequencing of the entire BRCA-1 and BRCA-2 coding regions and splice junctions. Twenty-eight late-onset (over 45 years), sporadic, breast cancers were designated as "control group" for comparisons with early-onset cases. BRCA mutations (10 BRCA-1 and 6 BRCA-2) were detected in 15 (22.7%) out of 66 tested patients. The combination of ER, PR, HER-2/neu negativity and p53 positivity was significantly more frequent in BRCA-1 positive tumors than in BRCA-2 positive and non-BRCA tumors (P = 0.03). Taken collectively, BRCA-positive tumors correlated with high histologic grade and ER negativity compared with non-BRCA and sporadic tumors (P = 0.05 and 0.003, respectively). There were no significant differences between BRCA-associated breast cancers (BABC) and non-BABC in relapse-free, event-free, and overall survival. Our data confirm that the combination of age at onset and tumor phenotype can provide an efficient model for identifying individuals with a high probability of carrying BRCA mutations and support the hypothesis that breast cancer in BRCA carriers is qualitatively distinct from other early-onset breast cancers and from late-onset, sporadic, breast carcinomas. Further studies on incident cases are necessary to define the independent prognostic significance of germline BRCA mutations. (c) 2007 Elsevier Ltd. All rights reserved.

In this paper, we analyze the effects of power lines parameters' uncertainties on the efficiency of a powerline communication (PLC) system. An estimate of the upper and lower bounds' system response due to the uncertainties is given. The analyzed system is schematized as a connection of multiport devices described by their scattering parameter matrices and an adjoint method for sensitivity calculations, based on the use of a wavelet expansion, is used to determine the bounds. The wavelet based sensitivity analysis allows a direct determination of the time domain sensitivity avoiding computationally expensive convolution integral calculations; in addition a fast and accurate bounds calculation is obtained avoiding statistical Monte Carlo simulations. The bounds determination allows the estimate of noteworthy quantities for the tuning of currently used modulation schemes for PLC such as orthogonal frequency-division modulation.

This paper describes the design and testing of a novel permanent magnet clutch based on a magnetorheological fluid. It was inspired by a prototype previously developed by the authors and contains a novel gap shape conceived to reduce torque loss in the disengaged operating mode. Several geometries and material arrangements were investigated and the performance in terms of transmissible torque in different operating conditions was assessed using finite element numerical models. The prototype was manufactured and some experimental tests were performed. The new prototype was rated on the basis of performance indices and the design effectiveness was proven by a higher value of efficiency in the disengaged operating mode.

594 Background: Outcomes for women with pT1aN0M0 breast cancers (BC) may vary by biologic subtype. A higher proportion of HER2-positive BCs diagnosed in the interval between scheduled screening rou...

e15236 Background: Although germline BRCA2 mutations, and to a lesser extent BRCA1 mutations, are associated with an increased risk of pancreatic cancer (PC), the influence of BRCA mutations on family history (FH) and clinical characteristics of PC patients is less elucidated. Methods: A clinical database review from two Genetic Oncology Services of the Emilia Romagna Region (nothern Italy) identified 25, non-Ashkenazi, Italian families in which at least one patient with PC had at least one first-degree relative with BRCA-associated breast and/or ovarian cancer. Results: A total of 31 PC patients (male/female ratio: 1.21) were evaluated. Median age at diagnosis was 66 years (range 33-91); 19 (61%) patients were diagnosed with metastatic disease. Ten (32%) patients having at least one first-degree relative with PC were considered familial pancreatic cancers (FPC), while 21 (68%) with no FPC clustering were considered sporadic (SPC). Seventeen (45%) patients had one first-degree relative with BRCA mutation....

Introduction: The combination of a mammalian target of rapamycin (mTOR) inhibitor and an aromatase inhibitor has been shown to significantly increase progression-free survival (PFS) in patients with estrogen receptor-positive (ER+) advanced or metastatic breast cancer. Ridaforolimus is an alternative mTOR inhibitor with high potency and specificity. We hypothesized that triplet therapy with ridaforolimus, dalotuzumab (a humanized monoclonal antibody targeting the IGF-1 receptor [IGFR]), and exemestane (R/D/E) would be more effective than doublet therapy with ridaforolimus and exemestane (R/E). Methods: This phase 2, randomized, open-label trial enrolled 80 postmenopausal patients who had high-proliferation (KI67 staining) ER+ breast cancer that had progressed following treatment with a nonsteroidal aromatase inhibitor. Patients received either triplet therapy, at the previously determined maximum tolerated dose of oral ridaforolimus 10 mg QD×5, dalotuzumab 10 mg/kg/week IV, and oral exemestane 25 mg/day (R/D/E, n=40), or doublet therapy with R 30 mg QD×5 and E 25 mg/day (R/E, n=40). Dose increases of R to 20 or 40 mg QD×5 were permitted in the R/D/E or R/E arms, respectively, in the absence of grade ≥2 stomatitis after cycle 1. The R dose could be reduced in either arm for toxicity. The primary endpoint was PFS in the ITT population by central review. Adverse events (AE) of clinical interest (Tier 1) included stomatitis, pneumonitis, hearing loss, and hyperglycemia. Results: Baseline characteristics were balanced between treatment groups. The median PFS was 23.3 (95% CI, 8.71, 38.43) weeks for R/D/E versus 31.9 (95% CI, 16.00, 39.29) weeks in the R/E arm (hazard ratio, 1.18; 80% CI, 0.81-1.72; P=0.565). All patients experienced at least one AE. 5 (12.8%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively, discontinued the study because of AE. Serious drug-related AE occurred in 2.6% of the R/D/E arm and 15% of the R/E arm. Dose modifications due to AE occurred in 10.3% and 50% in the R/D/E and R/E arms, respectively (difference -39.7%; 95% CI, -56.7, -20.4). Tier 1 AE were primarily grade 1-2 in severity. Stomatitis occurred in 76.9% (30/39 patients) in the R/D/E arm vs 95.0% (38/40 patients) in the R/E arm (P=0.021), and grade 3-4 stomatitis was similar between arms (23.1% vs 25%). Pneumonitis occurred in 5.1% vs 22.5% (P=0.027) and hearing loss occurred in 1 patient in each treatment arm (2.6% vs 2.5%), all grade 1-2. Hyperglycemia occurred at a similar rate in both treatment arms (28.2% vs 27.5%), with grade 3-4 events in 4 (10.3%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively. Conclusions: The combination of R 10 mg QD×5, D, and E did not improve PFS when compared to R 30 mg QD×5 plus E. The incidence rates of AE were lower in the R/D/E arm than the R/E arm for most categories of adverse events, likely because of the higher dose of R in the R/E arm. The efficacy reported for R/E in this study is similar to that reported in previous studies evaluating mTOR inhibitors in combination with exemestane in ABC. Overlapping toxicities and lower doses likely contributed to the lack of improved PFS with the addition of the IGFR inhibitor to this combination. Citation Format: Hope S Rugo, Olivier Tredan, Jungsil Ro, Serafin Morales, Antonino Musolino, Noemia Afonso, Marta Ferreira, Kyong Hwa Park, Javier Cortes, Antoinette R Tan, Joanne L Blum, Lamar Eaton, Christine K Gause, Adelle (Zhen) Wang, Ellie Im, David J Mauro, José Baselga. Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-1.

In the present work we study the treatment of parameters' uncertainties in complex circuits, i.e. composed by lumped and distributed elements. These problems are usually treated by the use of Monte Carlo techniques, which are extremely time consuming. A simple procedure for the calculation of the upper and lower limit of the response is defined by using the wavelet expansion in time domain. When only a part of the circuit is affected by uncertainties we use the Thevenin's equivalent in the wavelet domain (straightforwardly evaluated) to further reduce the analysis' complexity

OBJECTIVES The value of HER-2/neu status as a predictor of response to anthracycline-based chemotherapy is still a matter of debate. We evaluated the contribution of HER-2/neu gene amplification and other biologic markers in predicting response to different doses of neoadjuvant anthracycline-based chemotherapy. METHODS Clinical and pathologic records of 115 primary breast cancer patients were reviewed. Forty-eight and 67 patients received high (doxorubicin > or =20 mg/m2/wk; epirubicin > or =30 mg/m2/wk) and moderate-low anthracycline dose intensity regimens, respectively. Pathologic diagnosis, hormonal receptor status (HR), Ki67, and HER-2/neu status were assessed on tumor samples before neoadjuvant chemotherapy. HER-2/neu was determined by fluorescence in situ hybridization (FISH). RESULTS HER-2/neu amplification was observed in 29/115 (25%) tumors, 18 from moderate-low-dose and 11 from high-dose group. In the univariate analysis, a high Ki67 index (> or =20%) and positive clinical axillary nodes were predictive of an objective tumor response (P = 0.033 and 0.001, respectively). In the multivariate analysis, Ki67 was the only factor predictive of response (OR = 3.08, 95% CI = 1.1-8.5, P = 0.03). HER-2/neu status was not a factor in predicting objective response to different anthracycline dose intensities. The same finding was observed with regards to HR and Ki67. CONCLUSIONS In our series, no significant dose-response relationship was found according to HER-2/neu status.

In this paper the bounds of the frequency response of an indoor power line channel are derived taking into account also the effects of the nonlinear behavior of the electrical devices plugged to the sockets. From the high frequency signal point of view the communication channel is a linear system formed by an interconnection of transmission lines terminated on time varying loads that depend on the values of the mains voltage. In order to obtain an estimate of the bounds of the frequency response of the channel the load impedances are written as the sum of a nominal behaviour and a number of elementary pulse shaped terms with uncertain weights. The sensitivity functions of the frequency response with respect to these weights are evaluated and upper and lower bounds are consequently estimated. Comparison has been performed with the simulations obtained by using Monte Carlo methods.

This work is focused on the study of multiconductor transmission lines (MTL) with uncertain parameters; i.e. the values of r, l, c and g can vary in an interval. The wavelet expansion in time domain is used in order to obtain an accurate and low cost representation of the line in terms of an algebraic system. The wavelet representation applied to the study of MTL with variation of the electrical parameters, allow us to easily calculate a set of equivalent distributed generators which represent the effects of the disturbance produced by the parameter variation. This analysis allows us to directly evaluate the response bounds related to the parameters uncertainties without performing repeated simulations (Morite Carlo Method).

We report the first case in Italy of a non-Ashkenazi double heterozygote for BRCA1 and BRCA2 genes. This finding is predictably rare, with a maximum frequency of 1/250,000. The proband and her mother were diagnosed with early-onset breast cancer. No other relatives with breast and/or ovarian cancer were observed. The implications of this case in regard to genetic testing and counseling are substantial.

This paper presents a numerical formulation for the analysis of sliding contacts between moving conductors based on a hybrid FEM (finite element method) MOM (method of moments) technique. The use of the equivalence theorem allows splitting the complete problem in a number of interior problems and in an exterior one. The coupling of these problems is performed via the imposition of the continuity conditions of fields on the fictitious surfaces that enclose the moving conductors. Suitable additional boundary conditions are imposed on the sliding surfaces in order to ensure the proper current flux through the contacts. The proposed formulation is applied to the analysis of the performance of a rail-launcher. The results of the simulations show the capability of the formulation to take into account the characteristic phenomena of these devices and in particular the presence of the velocity skin effect. Comparisons between the results obtained by the proposed formulation and by other methods are reported.

BACKGROUND The current study was designed to assess the activity and safety of a novel combination therapy for patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS Forty-three consecutive patients with recurrent or refractory aggressive NHL were treated with lomustine (chloroethylnitrosourea [CCNU]; 60 mg/m2 on Day 1), ifosfamide (1.5 g/m2 on Days 1, 2 and 21, 22), bleomycin (5 mg/m2 on Days 1, 5 and 21, 25), vincristine (1.4 mg/m2 on Days 1, 8 and 21, 28), and cisplatin (25 mg/m2 on Days 3, 4, 5 and 23, 24, 25), every 42 days (CIBO-P regimen). RESULTS Thirty-nine patients (91%) were evaluable for response. The median patient age was 63 years. Thirty-five percent of the patients had received ≥ 2 lines of previous chemotherapy and 40% had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall objective response rate was 77% (95% confidence interval [95% CI], 63–90%), including 19 (49%) complete (CR) and 11 (28%) partial responses. CIBO-P induced responses in primary refractory disease and in patients treated for second or subsequent disease recurrences. A CR with previous therapy was the most important factor associated with a significantly higher CR rate. The median duration of response was 6 months (95% CI, 4.4–7.7 months) and the median survival duration was 10.7 months (95% CI, 5.9–18.1 months). Five patients (11.6%) remained disease free for ≥ 24 months. By multivariate analysis, a CR with previous therapy and average dose intensity of CIBO-P drugs were independent prognostic factors for time-to-treatment failure, whereas a CR with previous therapy and serum lactate dehydrogenase were independent predictors for survival. Myelosuppression was the most frequent serious complication of this regimen. However, none of the patients had hemorrhage with thrombocytopenia, and only 2 patients (5%) had febrile neutropenia. CONCLUSIONS In the current study, CIBO-P was a novel, highly active, and safe combination therapy for patients with refractory disease with a poor prognosis or for patients with multiply recurrent aggressive NHL. Cancer 2005. © 2005 American Cancer Society.

In this paper, the numerical analysis of a complete launch package, composed by a homopolar generator feeding a rail launcher, is described. Because of the nonlinear and time varying characteristics of both generators and launchers, a separate analysis of the two devices is not always able to provide highly accurate previsions about the performance of the overall system. The analysis has been performed here by using an integral formulation that transforms the Maxwell's equations into an equivalent electric network, whose parameters vary together with the evolution of the system. The presence of sliding contacts and the consequent velocity skin effect in both the generator and the launcher have been taken into account. The most important electromechanical quantities have been reported; the results of the simulations shows the effectiveness of the software used for this coupled analysis.

The paper deals with the problem of the analysis of transmission lines characterized by random parameters. The scope of the work is to determine lower and upper bounds to the direct and crosstalk response of a transmission line when the per unit length or the geometrical parameters are characterized by random variations. A sensitivity analysis is performed first, and then a very simple estimate of the lower and upper bounds of the voltage response is given. The accuracy of the determined bounds is shown by performing a Monte Carlo procedure over two different transmission lines.

Considerable data are available to support the resection of hepatic metastases in patients with colorectal cancer, but there are relatively few studies on the role of pulmonary metastectomy. The small number of such studies is mainly noncontemporaneous and predates the use of preoperative neoadjuvant chemotherapy. A retrospective analysis of 31 patients with pulmonary metastases from colorectal cancer treated with surgery and perioperative chemotherapy between 1995 and 2003 was performed. Twenty patients (65%) proceeded directly to surgery and 5 of these received postoperative chemotherapy. Eleven patients (35%) received preoperative chemotherapy, which consisted of a fluoropyrimidine in combination with oxaliplatin or mitomycin-C, except for 1 patient who received single agent irinotecan. Nine of 11 patients (82%) had a partial response and 2 patients (18%) had stable disease. A total of 39 thoracic surgeries (6 bilateral and 1 incomplete) were performed. There were no postoperative deaths. Four of 20 patients (20%) who had initial surgery had postoperative complications, compared with 18% of the preoperative chemotherapy group. Overall 3- and 5-year survival rates after the first thoracic surgery were 65.2% (95% CI, 35.1%-83.9%) and 26.1% (95% CI, 4.3%-56.2%), respectively. Based on the limited data from this study, disease-free interval, number of pulmonary metastases, previous resection of hepatic metastases, prethoracotomy carcinoembryonic antigen levels, and preoperative chemotherapy were not found to be significant prognostic factors for survival. Therefore, surgical resection of lung metastases is associated with low morbidity and mortality and results in long-term survival for 20%-30% of patients. Moreover, preoperative chemotherapy produced a high response rate, with no patients experiencing disease progression before surgery.

Introduction Incidence of primary bilateral breast cancer (BBC) is rare and does not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life time risk of developing contralateral breast cancer. Objectives To address both the proportion of BBC associated with BRCA1/2 germline mutations and the contribution of germline mutations to the clinical features and outcome of these tumors. Materials and methods We identified 263 BBC patients (pts) from a cohort of 9585 women with a first primary breast cancer systematically collected by the Cancer Registry of Parma Province from 1978 to 2006. Among these, 55 women, unselected for family history, were subjected to BRCA1/2 testing. In addition, 55 unilateral breast cancer pts, which tested negative for BRCA1/2 mutations, were evaluated as control group. Results BRCA mutations were detected in 13 (24%) of 55 BBC pts. Family history of breast cancer was identified in 8% of these pts compared with 7% of non-carriers (P = 0.64). Synchronous BBC was significantly rarer in BRCA carriers than in non-carriers. In addition, BRCA-positive pts were younger at diagnosis than BRCA-negative ones. The combination of high histologic grade, ER, PR, and HER2 negativity in both bilateral tumors was more frequent among BRCA-1 positive tumors than BRCA-2 positive and non-BRCA tumors (P Conclusions Our data show that the combination of BBC occurrence and breast tumor phenotype can provide an efficient model for identifying individuals with high risk for BRCA mutations and support the hypothesis that BBC in BRCA carriers is qualitatively distinct from non-BRCA BBC and from sporadic, unilateral breast cancer. Further studies of incident cases are needed to better define the prognostic value of BRCA mutations. Disclosure All authors have declared no conflicts of interest.

A method for the evaluation of forces and torque in static and quasistatic problems solved by adopting hybrid formulations is presented. The examined formulations are based on the use of the equivalence theorem that allows the definition of interior and exterior problems that are coupled by the continuity interface conditions. On the surfaces where the continuity conditions are imposed equivalent sources are present. These equivalent sources produce the same fields and potentials outside the fictitious surfaces as the enclosed body does. Resultant forces and torque acting on the bodies enclosed by each surface are evaluated by using these fictitious sources. Results obtained by the proposed method applied to magnetostatic and eddy current problems are compared in terms of accuracy and CPU time with results obtained by other methods and, where available, by experimental set up.

In this paper a new railgun configuration in order to reduce the effects of ablation is proposed. The railgun is segmented into several stages that are separated by an insulating material. Each stage has its own feeding circuit and an auxiliary rail launcher to create and accelerate at the proper velocity a plasma arc. The first stage is fired initially; firing of further stages is operated synchronously with the position and the velocity of the pellet. The rail portion consisting of insulating material between two adjacent stages is used to extinguish the plasma arc from the previous one. If the next stage is properly fired, the pellet is driven by a new plasma arc whose thermodynamic quantities have better characteristics than those of the extinguished one. The analysis of the performance of the multistage railgun has been carried out considering different number of stages and of pellet masses. The characteristic quantities of the plasma arc are schematised by means of a one-dimensional model.

In this paper the transition between the sections of a generator driven induction launcher is investigated. During the transition a possible mismatch of the currents in the sleeve with the driving coils currents can give rise to strong braking force. If the sleeve is not in coaxial position with the barrels, forces in the transverse direction of motion can produce contacts with the flyway tube. Transverse motion of the sleeve has to be considered. The equations of motion are derived assuming a rigid projectile and a flyway restoring force that is proportional to the local deformation. A full 3-D analysis, required because of the departure from the coaxial configuration, has been performed by means of a computer code based on an integral formulation of the Maxwell equations; the resulting equations are those of an electrical time-varying network. Simulations of the behaviour of the system have been performed to search for the optimal initial position of the sleeve in the second section. The results show that smooth transition between the sections is obtained if the energization of the coils of the second section is done in correspondence with the proper positions of the sleeve. Under these conditions the motion is characterized by the greater muzzle velocity.

A hybrid method for nonlinear electromagnetic analysis that combines the Method of Moments (MOM) and the Finite Element Method (FEM) is presented. By using the equivalence principle, an interior and an exterior problem are used to study the actual problem. The MOM is used for the solution of the exterior problem where equivalent surface currents replace the solid bodies and generate the fields in the free space. The FEM is used to solve the interior problem defined into the solid bodies with given conditions at their boundaries. Considering that the actual fields are given by the sum of the fields in the two problems, a nonlinear matrix equation for the problem solution is obtained by forcing the continuity of the actual tangential electric and magnetic fields on the boundary of the nonlinear solid bodies. Two-dimensional numerical results are used to show the characteristics of the method by the analysis of test cases and by comparison with other numerical methods.

In this paper the electromagnetic interferences radiated from a railgun operating with plasma armatures are studied. The level of emission during the initial explosion of the fuse barrel that forms successively the metallic arc is computed by integrating numerically Maxwell's equations in complete form via a suitable numerical code, written in C++ programming language, and based on a three-dimensional finite difference algorithm in the space and in the time domain. The electric and magnetic field during the acceleration of the plasma armature, successive to its formation, are evaluated by means of a quasi-stationary model based on the assumed transient current distribution in the rails and the armature and on a given relation between the current and the position of the armature. The results indicate that both methods can be considered useful tools in the analysis of the electromagnetic environment around rail launchers.

TPS651 Background: Overcoming endocrine resistance (ER) is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer (BC). Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with ER. Up to 8% pts with HR+/ human epidermal growth factor receptor 2 negative (HER2–) BC have amplification of the FGFR1 gene. Dovitinib (DOV), a potent inhibitor of FGFR, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor demonstrated antitumor activity in heavily pretreated BC pts with FGF-pathway amplification (FGFR1, FGFR2, or FGF3). The objective of this study is to determine if DOV plus fulvestrant (FUL) can improve outcomes in postmenopausal pts with endocrine resistant HER2-/HR+ BC. Methods: This multicenter, randomized, double-blind, placebo-controlled, ph II trial (NCT01528345) will enroll postmenopausal pts with HER2–/HR+ locally advanced or metastatic BC (N=150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting. Pts will be randomized 1:1 (stratified by FGF amplification and presence of visceral disease) to receive intramuscular FUL (500 mg q4w [with an additional dose 2 weeks after the initial dose]) plus oral DOV (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Primary endpoint is progression free survival (investigator’s assessment; RECIST v1.1). Secondary endpoints include overall response rate (investigator’s assessment; RECIST v1.1), duration of response, overall survival, time to deterioration of ECOG performance status, pt-reported outcome scores over time, safety, and assessment of plasma pharmacokinetic concentrations of FUL and DOV. Additionally, the pharmacodynamic effect of DOV on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to DOV will be explored. As of 21 Jan 2013, 128 pts had molecular screening; 73 pts are enrolled (of these 9 pts are FGF amplified). Clinical trial information: NCT01528345.

Background: In order to investigate mechanisms of resistance to angiogenesis inhibitors, Notch and Delta-like 4 ligand (DLL4) expression was correlated with response and survival in a series of bevacizumab treated advanced colon cancer patients. DLL4-mediated Notch signalling has recently emerged as an attractive target for angiogenesis-based cancer therapies, given that DLL4 is an important component of Notch-mediated stem cell self-renewal and vascular development. DLL4-induced Notch signalling mediates tumour-resistance to anti-VEGF therapy by inducing the formation of large vessels and activating multiple pathways in preclinical models. Method: Notch and DLL4 expression was evaluated by immunohistochemistry (IHC) on 65 primary colon cancer patients enrolled within randomized clinical trials assessing first-line bevacizumab plus chemotherapy. Results: Notch positivity was localized to the cytoplasm of malignant epithelial cells. In all, 10/60 (17%) evaluable primary tumours had a high Notch expression. Five of the 10 cases (50%) with high Notch expression experienced progressive disease compared with 5/49 (10%) Notch negative cases (p=0.008). Median progression-free survival (PFS) was 2.8 months for Notch positive cases compared with 13.07 months for Notch negative cases (p=0.045). Membranous and/or cytoplasmic DLL4 immunoreactivity of tumour vessels was observed in 30/56 (54%) evaluable colon cancers. No correlation was found between DLL4 expression and clinical outcome. Conclusion: Clinical trials investigating the therapeutic efficacy of bevacizumab in colon cancer did not explore the impact of DLL4-Notch pathway on response and clinical outcome. Our results seem to suggest that high Notch expression might be involved in tumour resistance in colon cancer patients treated with bevacizumab. Citation Format: Francesca Negri, Cecilia Bozzetti, Pellegrino Crafa, Costanza Lagrasta, Stefano Cavalli, Giuseppe Pedrazzi, Giorgio Gardini, Ione Tamagnini, Rosa Porzio, Luigi Cavanna, Carlo Paties, Ida Romano, Antonino Musolino, Gianluca Tomasello, Pier Giorgio Petronini, Andrea Ardizzoni. Notch and DLL4 expression in bevacizumab-treated colon cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4646. doi:10.1158/1538-7445.AM2013-4646 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

3,4-Dihydroxyphenylacetic acid (DOPAC) is commonly considered to be the main dopamine (DA) metabolite produced by monoamine oxidase (MAO); however, the initial product of DA oxidation is 3,4-dihydroxyphenylacetaldehyde (DOPALD). Owing to technical difficulties in detecting DOPALD from a biological matrix, no studies have so far been performed to measure brain levels of this aldehyde in vivo. In this work, using transstriatal microdialysis in freely moving rats, we identified DOPALD by HPLC coupled to a coulometric detector. In chromatograms obtained from microdialysis samples, DOPALD appeared as a peak with a retention time coincident with that of the standards obtained via enzymatic and chemical synthesis. On the other hand, DOPALD was undetectable ex vivo from rat striatal homogenates. This discrepancy is probably due to the preferential extraneuronal localization together with the high reactivity of the aldehyde, which is rapidly removed by the dialysis probe, whereas the ex vivo procedure allows its condensation and enzymatic conversion. Measurement of DOPALD levels as a routine procedure might represent a reliable tool to evaluate DA oxidative metabolism directly, in vivo. Moreover, parallel detection of DOPALD and DOPAC levels in brain dialysate may make it possible to distinguish between the activity of MAO and aldehyde dehydrogenase. DOPALD, like many endogenous aldehydes, has been shown to be toxic to the cell in which it is formed. Therefore, in vivo measurement of DOPALD levels could highlight new aspects in the molecular mechanisms underlying both acute neurological insults and neurodegenerative diseases.

In this paper, an equivalent network model for transformer analysis including hysteretic effects is presented. The nonlinear electromagnetic problem is reduced to the analysis of an equivalent network by integrating Ohm's law inside every elementary volume into which the solid bodies of the examined system are subdivided. The model allows the analysis of the electromagnetic field distribution for the evaluation of local saturation effects by using fine discretizations. Furthermore it gives a simple and efficient equivalent circuit of the transformer for external effects determination by using coarse discretizations. Hysteresis effects in the steady state case can be taken into account by an equivalent hysteretic loop obtained from standard measurements. The method has been tested by comparison with experimental data.