First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PURPOSE: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). PATIENTS AND METHODS: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. RESULTS: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. CONCLUSION: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.This study was supported by Genentech Inc. The Drug Development Unit, The Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research (London) is supported in part by programme grants from Cancer Research UK. Support was also provided by Experimental Cancer Medicine Center grants (to The Institute of Cancer Research and the Cancer Research UK Center), the National Institute for Health Research Biomedical Research Center (jointly to The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research) and the Wellcome Trust (grant 090952/Z/09/Z to Dr. Ang). Paul Workman is a Cancer Research UK Life Fellow.Originally published by the American Association for Cancer Research in Clinical Cancer Research January 1, 2015 21; 77 http://dx.doi.org/10.1158/1078-0432.CCR-14-094

Expression of Emotion: When It Causes Trauma and When It Helps

The idea that clients should be encouraged to express strong emotion regarding the traumas they have suffered is widely assumed. This paper asks whether the empirical literature supports the underlying assumption that emotional expression leads to positive outcomes (better health and dissipation of distress). Studies in which individuals who have been given an opportunity to express emotions about past traumas are compared with subjects placed in appropriate control conditions are reviewed. The empirical literature suggests that eliciting emotion is harmful when it is not associated with reappraisal of past trauma, but helpful when the reappraisal occurs. The following guideline emerges: if trauma is to be revisited, it should be accompanied by reappraisal. Since this is sometimes difficult to engineer, alternative approaches for working with victims of trauma, not involving revisiting the trauma, are offered. Additionally, it is suggested that it can be helpful to identify the nature of the problem arising from the traumatic experience, and then provide therapeutic intervention that addresses the problem

Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor–Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer

Purpose: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797).Patients and Methods: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) +/- palbociclib 125 mg +/- luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy.Results: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent +/- LHRH agonist and giredestrant + palbociclib +/- LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib +/- LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors.Conclusions: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer

Drawing the Figure Using References for an Online Comic

An accurate enactment of a comic story requires accurate drawing of the human figure\u27s poses, emotions, and perspective. A two-year drawing research investigation, during which I created the comic The Planet Closest To Heaven, has allowed me to reflect on the most effective use of references. Real people were used as models, along with other styles of drawing and other references that included mirrors, photos, and books. I have discovered that using a variety of references conveys the many different situational moods of comic book story telling. The complete project is made up of pencil drawing, inking, charcoal, computer media and printing, resulting in a printed graphic novel