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B: The dashed line represents 5 CTCs/7.5 mL. C: White circles indicate the location of the lymph node lesion with documented PR, demonstrating a 46% reduction in size from baseline. CT, computerized tomography; CTC, circulating tumor cells; PR, partial response; PSA, prostate-specific antigen.

Purpose:In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.Patients and Methods:In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate.Results:Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug–drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2–71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%.Conclusions:Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

LLQ=15.6 mg/mL. LLQ shown by horizontal reference line. N=1 for 400 mg GSK2636771 plus 160 mg enzalutamide 160 mg escalation cohort. LLQ, lower limit of quantification.

Supplementary Table 1. PCWG2 criteria for progression.

Dashed lines represent 95% confidence intervals. PCWG2, Prostate Cancer Working Group 2; PSA, prostate-specific antigen.

Supplementary methods: PTEN screening

Supplementary Table 2. Summary of serious adverse events.

Purpose: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance. Patients and Methods: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate. Results: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug–drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2–71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%. Conclusions: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

The interpretation of jazz style is crucial to the element of swing in any jazz ensemble performance. Today, many charts for both large and small instrumental and vocal jazz ensembles are well marked with articulations and expression markings. However, in some cases, there is nothing to guide the musician. This article addresses some common jazz articulations and style situations and provides a set of guidelines to help instructors and students decide how to treat notes and rhythms in swing style. Use of these concepts can help an ensemble sound more authentic and can help students better understand jazz articulations and styles.

Jazz music and jazz musicians have often been linked for better or worse to the world of addictive substances. Many talented jazz musicians either had their careers sidetracked or prematurely ended due to their addiction to drugs and/or alcohol. The rigors of nightly performances, travel, and for many musicians a disapproving society exacted a toll that impacted the creativity of many artists of the genre. The fact that drug and alcohol use had a significant impact on the performance levels of numerous jazz musicians in the 1940's and 1950's has been much discussed, but more study of that impact is warranted. While recent research has provided new information regarding this challenging topic, there is still much to learn. Indeed, a number of questions for inquiry may be posed. Among those questions are the following: Was the work of these jazz artists truly inspired? Would their creative output have been enhanced had they not been addicted to substances? What was the impact of the addictive substances on their ability to function as creative artists and is there evidence to refute or verify that impact? Are there identifiable traits in certain artists that allowed them to be creative in spite of their addictions? This examination presents an evaluation of the evidence of the link between creativity and substance abuse especially as it relates to selected jazz artists during this time period and how they remained creative and actually prospered in their careers in spite of addictions to controlled substances.

Cohort studies indicate that starting highly active antiretroviral therapy (HAART) when the CD4+ T-cell count is less than 200 cells/muL is associated with poor outcomes. These studies have been unable to address how early HAART should be initiated, however. This report uses a modeling approach to compare starting HAART at a mean CD4+ T-cell count greater than 350 cells/microL (early) versus less than 350 cells/microL but greater than 200 cells/microL (later).A Markov model tracks people with HIV infection through 6 disease stages defined by CD4+ T-cell count ranges over a 25-year period. Transition probabilities between the disease stages for 6-month periods vary according to initial viral load. Sequences of different first-line, second-line, and "salvage" antiretroviral regimens are defined, and their impact on transition probabilities is estimated. HAART effectiveness is based on data from an urban hospital-based HIV clinic, supplemented by clinical trial data. The model computes the incremental cost-effectiveness of alternative treatment patterns and includes sensitivity analyses for a range of plausible alternative input values.Starting HAART earlier rather than later increases total lifetime costs by $19,074, increases years of life by 1.21 years, increases discounted quality-adjusted life-years by 0.61, and has an incremental cost-effectiveness ratio of $31,266 per quality-adjusted life-year. Early therapy is more cost-effective when the impact of HAART on well-being is smaller.Initiation of HAART at a CD4+ T-cell count greater than 350 cells/microL may be cost-effective (less than $50,000 per quality-adjusted life-year) compared with initiating HAART at a CD4+ T-cell count less than 350 cells/microL but greater than 200 cells/muL and may result in longer quality-adjusted survival.

Background Adherence to highly active antiretroviral therapy (HAART) of 95% or greater seems to be required for successful treatment of HIV/AIDS. Efforts to simplify regimens to improve adherence are ongoing, including the advent of once-daily (QD) dosing regimens, which are presumed to be beneficial, although data regarding their overall impact on adherence are not yet available. Objective To assess patient perceptions of the impact on adherence of 10 attributes of HAART, including QD dosing, and to compare 7 actual regimens based on patients' perceptions of their likelihood to promote adherence. Methods Two hundred ninety-nine highly treatment-experienced patients with HIV/AIDS completed a questionnaire that evaluated perceptions of the impact on adherence of 10 HAART regimen attributes using a modified adaptive conjoint analysis. Patients' perceptions of the likelihood that they would adhere to 7 actual HAART regimens were scored on Likert scales. Results : Pill count, dosing frequency, and adverse events had the greatest impact on patients' perceived ability to adhere to antiretroviral medication regimens. QD was the preferred dosing frequency, but QD dosing regimens did not score better than other regimens. Among actual regimens, predicted adherence was highest for a twice-daily (BID) regimen with 2 pills daily, no dietary restrictions, and 1 prescription and copayment and lowest for a BID regimen with 13 pills daily, food requirements, and 3 prescriptions and copayments. Conclusions All HAART regimen attributes studied were perceived to have an impact on adherence, but pill count, dosing frequency, and adverse events had the greatest perceived impact. These data are of potential importance to clinicians as they seek to structure HAART regimens to which their patients are most likely to adhere.

The author sits down with five renowned jazz educators--Jamey Aebersold, David Baker, Dan Haerle, Rufus Reid, and Jerry Coker--for an enlightening conversation about the state of jazz education.