RIB plus an NSAI is indicated for premenopausal pts with hormone-receptor–positive (HR+), HER2− ABC based on data from the ML-7 trial (NCT02278120), including progression-free survival (PFS), which ...was longer with RIB vs PBO (median 23.8 vs 13.0 months; HR 0.55; P<0.0001). It is important to understand how PFS data translate to pt benefit in terms of OS and QoL. Maintenance of functioning, work productivity and activity, and pain reduction have been reported for the overall population. We present updated OS and QoL data (cutoff: 30 November 2018) for pts who received an NSAI.
Pre/perimenopausal pts with HR+/HER2− ABC, ≤ 1line of prior chemotherapy, and no prior endocrine therapy for ABC were randomized 1:1 to receive RIB or PBO plus goserelin with either an NSAI (letrozole or anastrozole) or tamoxifen. The primary endpoint was PFS. OS, the key secondary endpoint, was evaluated by stratified log-rank test in the overall population and summarized using Kaplan-Meier methods. Time to 10% deterioration (TTD) was estimated using the EORTC QLQ-C30 patient questionnaire and a stratified log-rank test.
The NSAI cohort included 248 pts in the RIB arm and 247 in the PBO arm. As of the data cutoff, 37.1% of patients in the RIB arm and 18.6% of pts in the PBO arm remained on treatment. Of the pts who discontinued study treatment, 69.2% in the RIB arm and 73.1% in the PBO arm started subsequent therapy. Median OS was not reached in the RIB arm vs 40.7 months in the PBO arm (hazard ratio, 0.699 95% CI, 0.501-0.976), and the benefit of adding RIB was generally consistent across pt subgroups within this cohort. Median TTD in global QoL was 34.2 months in the RIB arm vs 23.3 months in the PBO arm (hazard ratio, 0.69 95% CI, 0.52-0.91). Analyses of key QoL domains will be presented at the meeting. Updated analyses of adverse events revealed no unexpected safety signals.
RIB plus an NSAI prolonged OS and improved QoL vs PBO plus an NSAI in premenopausal pts with HR+, HER2– ABC. Additional follow-up did not reveal any new safety signals in this subgroup.
NCT02278120.
John McGuire, PhD, of MediTech Media, LLC funded by Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Y. Lu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Clinical trial study fee, grant, advisory board, speaker: Novartis; Advisory / Consultancy, Consultation fee: Pfizer; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (self): Roche; Research grant / Funding (self): Merck Sharp & Dohme; Research grant / Funding (self): Pfizer; Research grant / Funding (self): GlaxoSmithKline. A. Bardia: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Radius Health; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Immunomedics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Innocrin; Advisory / Consultancy: Biothernostics Inc.; Advisory / Consultancy, Travel / Accommodation / Expenses: Spectrum Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Taiho; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Daiichi Pharma. R.V. Vázquez: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche. M.A. Colleoni: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Honoraria (self): Novartis; Advisory / Consultancy: OBI Pharma; Advisory / Consultancy: Puma Biotechnology; Advisory / Consultancy: Celldex. D. Tripathy: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer. B.R. Lanoue: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. D. Chandiwana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. A. Ridolfi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. G. Hughes: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. J.P. Zarate: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. I. Gounaris: Non-remunerated activity/ies: PharmaMar; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. N. Harbeck: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer. All other authors have declared no conflicts of interest.
An iterative numerical method is described by which the non-linear material damping of a structural member can be evaluated in a simple way. It is shown that the results of a conventional finite ...element approach can be combined with the damping-stress function, which is assumed to be known from experimental data, to obtain the loss factor of a particular structure. For this reason the dynamic stiffness concept is utilized in which the imaginary part of the modulus of elasticity is a function of stress range. Since stress amplitude depends also on the amount of damping present in structure, a numerically iterative scheme is developed for the computation of the non-linear structural damping. Independently of the type of intercoupling between stress distribution function and damping-stress function, suitable solutions may be obtained to yield the loss factor of a particular member. This fast converging approach is accurate, stable and may be generalized to evaluate the loss factor for any structure.
From the available literature, it is unclear what proportion of pancreatic adenocarcinomas express estrogen receptors (ERα, ERβ), progesterone receptors (PR), and androgen receptors (AR), and if any ...of these markers have prognostic significance. We aimed to assess (1) the expression and (2) the correlation of the aforementioned markers with clinicopathological parameters and prognosis in patients with pancreatic adenocarcinoma. During a five-year period, 60 patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution. Immunohistochemical stains of the studied markers were quantified by Image analysis system. ERα expression was positively associated with PR expression. Moreover, ERβ was inversely associated with the presence of metastases, whereas no significant associations implicated AR. As far as the prognostic significance of the studied receptors is concerned, higher ERα expression correlated with poorer survival at the univariate analysis, but the finding dissipated at the multivariate approach. No significant associations with overall survival were noted regarding the other receptors. The role of sex hormone receptors in the survival from pancreatic adenocarcinoma seems rather limited. Further prospective studies assessing those receptors should ideally be designed in order to confirm our results and possibly outline additional correlations between other steroid receptors and features of pancreatic adenocarcinoma.
To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apcmin/+ genetic background. Here, we ...show that Apcmin/+/Tpl2–/– mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2–/– mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2. The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and inflammation increased progressively with time. The rate of increase of both, however, was more rapid in Apcmin/+/Tpl2–/– mice, suggesting that the positive feedback initiated by inflammatory signals originating in developing polyps is more robust in these mice. This may be because these mice have a higher intestinal polyp burden as a result of the enhancement of tumor initiation.
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