Modelling and quantifying Mode I interlaminar fracture in particle-toughened CFRPs

Four-dimensional time-resolved Synchrotron Radiation Computed Tomography (SRCT) has been used to capture Mode I delamination propagation in particle-toughened Carbon Fibre Reinforced Polymers (CFRPs). Digital Volume Correlation (DVC) was used in order to measure ply opening displacements at the crack tip, permitting the interlayer strain ahead of the crack tip to be quantified. Estimates at which toughening particles de-bonded and/or fractured were made, giving insight into the effects of particle type and particle size on the fracture mico-mechanisms. The experiments are complemented by a 2D plane-strain finite element (FE) model, which investigated the effects of particle strength and toughness on the ply opening displacement and crack path by modelling the particles as 1D cohesive segments. Previous work has shown that Mode I crack propagation in particle-toughened interlayers involves a process zone rather than a distinct crack tip. Therefore, Augmented Finite Element Method (A-FEM) elements were used in the simulation, since the elements can account for both bifurcating and merging cracks within a single element. The nodal displacements in the simulation were compared to the DVC results, illustrating a potential path through which more complex FE simulations may be validated against experimental results in the future

Deformation mechanisms of idealised cermets under multi-axial loading

The response of idealised cermets comprising approximately 60% by volume steel spheres in a Sn/Pb solder matrix is investigated under a range of axisymmetric compressive stress states. Digital volume correlation (DVC) analysis of X-ray micro-computed tomography scans (μ-CT), and the measured macroscopic stress-strain curves of the specimens revealed two deformation mechanisms. At low triaxialities the deformation is granular in nature, with dilation occurring within shear bands. Under higher imposed hydrostatic pressures, the deformation mechanism transitions to a more homogeneous incompressible mode. However, DVC analyses revealed that under all triaxialities there are regions with local dilatory and compaction responses, with the magnitude of dilation and the number of zones wherein dilation occurs decreasing with increasing triaxiality. Two numerical models are presented in order to clarify these mechanisms: (i) a periodic unit cell model comprising nearly rigid spherical particles in a porous metal matrix and (ii) a discrete element model comprising a large random aggregate of spheres connected by non-linear normal and tangential “springs”. The periodic unit cell model captured the measured stress-strain response with reasonable accuracy but under-predicted the observed dilation at the lower triaxialities, because the kinematic constraints imposed by the skeleton of rigid particles were not accurately accounted for in this model. By contrast, the discrete element model captured the kinematics and predicted both the overall levels of dilation and the simultaneous presence of both local compaction and dilatory regions with the specimens. However, the levels of dilation in this model are dependent on the assumed contact law between the spheres. Moreover, since the matrix is not explicitly included in the analysis, this model cannot be used to predict the stress-strain responses. These analyses have revealed that the complete constitutive response of cermets depends both on the kinematic constraints imposed by the particle aggregate skeleton, and the constraints imposed by the metal matrix filling the interstitial spaces in that skeleton.The authors are grateful to the Office of Naval Research (ONR) for their financial support through grant number N00014121063

Trastuzumab Emtansine Plus Non-Pegylated Liposomal Doxorubicin in HER2-Positive Metastatic Breast Cancer (Thelma): A Single-Arm, Multicenter, Phase Ib Trial

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m2) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m2 of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m2 administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients

Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients

BACKGROUND: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). METHODS: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. RESULTS: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). CONCLUSIONS: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies

Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategie

Who are the women who enrolled in the POSITIVE trial: a global study to support young hormone receptor positive breast cancer survivors desiring pregnancy

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, <42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). Interpretation: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)