Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

HER2 negative; Ipatasertib; PI3K/AKTHER2 negativo; Ipatasertib; PI3K/AKTHER2 negatiu; Ipatasertib; PI3K/AKTPurpose PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects.This work was supported by Genentech/Roche. Medical writing assistance was provided by Jennifer Kelly, MA (Medi-Kelsey Ltd), funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Marketing (as) Rhetoric: paradigms, provocations, and perspectives

In this collection of short, invited essays on the topic of marketing (as) rhetoric we deal with a variety of issues that demonstrate the centrality of rhetoric and rhetorical considerations to the pursuit of marketing scholarship, research and practice. Stephen Brown examines the enduring rhetorical power of the 4Ps; Chris Hackley argues for the critical power of rhetorical orientations in marketing scholarship but cautions us on the need to work harder in conceptually connecting rhetorical theory and modern marketing frameworks; Shelby Hunt explains how rhetorical processes are incorporated in his inductive realist model of theory generation, using one of his most successful publications as an illustration; Charles Marsh demonstrates what Isocrates’ broad rhetorical project has to teach us about the importance of reputation cultivation in modern marketing; Nicholas O’Shaughnessy uses an analysis of Trump’s discourse to argue that political marketing as it is currently conceived is ill-equipped to engage effectively with the rhetorical force of Trump’s ‘unmarketing’; Barbara Phillips uses Vygotsky’s work on imagination to investigate the important of pleasure and play in advertising rhetoric; and finally, David Tonks, who in many ways started it all, reiterates the need for marketers to recognise the strength of the relationship between marketing and persuasion

Astrophysics with the Laser Interferometer Space Antenna

Laser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy as it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and other space-based instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA's first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed: ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or intermediate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help make progress in the different areas. New research avenues that LISA itself, or its joint exploitation with studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe

The dynamic interplay of hope vs fear appeals in a referendum context

The file attached to this record is the author's final peer reviewed version.This article makes a contribution by articulating, for the first time, how hope and fear appeals were constructed as a rhetorical media device in a political advertising campaign context, specifically the 2014 Scottish independence referendum. Based on a qualitative content analysis of both sides’ campaigning materials, an understanding of the fluid, responsive and symbiotic nature of these emotional appeals and how they are utilized against the other is outlined. The research reveals core dimensions for constructing persuasive media appeals. While, fear appeals should strive to create a threat perceived to be relevant, and significant, the deployed hope appeals should focus on generating alternative positive visions and be goal congruent. By understanding contested (political) campaigns, new types of hybrid hope and fears appeal emerge (i.e. hope and fear reduction appeals). Taking these findings together, allows the authors to provide prescriptions on how certain message appeal types might be used to induce particular emotional effects in the audience