IntroductionFucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human ...immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. MethodsCA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. ResultsPatients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 90%). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval CI) was higher with BMS-986012 plus nivolumab (38% 20.7%-57.7%) than with monotherapy (4% 0.8%-11.0%). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively. ConclusionsBMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).
Abstract Background Sample size calculations for treatment trials that aim to assess health-related quality-of-life (HRQOL) outcomes are often difficult to perform. Researchers must select a target ...minimal clinically important difference (MCID) in HRQOL for the trial, estimate the effect size of the intervention, and then consider the responsiveness of different HRQOL measures for detecting improvements. Generic preference-based HRQOL measures are usually less sensitive to gains in HRQOL than are disease-specific measures, but are nonetheless recommended to quantify an impact on HRQOL that can be translated into quality-adjusted life-years during cost-effectiveness analyses. Mapping disease-specific measures onto generic measures is a proposed method for yielding more efficient sample size requirements while retaining the ability to generate utility weights for cost-effectiveness analyses. Objectives This study sought to test this mapping strategy to calculate and compare the effect on sample size of three different methods. Methods Three different methods were used for determining an MCID in HRQOL in patients with incontinence: 1) a global rating of improvement, 2) an incontinence-specific HRQOL instrument, and 3) a generic preference-based HRQOL instrument using mapping coefficients. Results The sample size required to detect a 20% difference in the MCID for the global rating of improvement was 52 per trial arm, 172 per arm for the incontinence-specific HRQOL outcome, and 500 per arm for the generic preference-based HRQOL outcome. Conclusions We caution that treatment trials of conditions for which improvements are not easy to measure on generic HRQOL instruments will still require significantly greater sample size even when mapping functions are used to try to gain efficiency.
Historically, posterior shoulder instability has been a challenging problem for contact athletes and orthopedic surgeons alike. A complete understanding of the normal shoulder anatomy and ...biomechanics and the pathoanatomy responsible for the instability is necessary for a successful clinical outcome. In addition, the surgeon must be familiar with the diagnostic imaging and physical examination maneuvers required for the correct diagnosis without missing any other concurrent abnormalities. This understanding will allow orthopedists to plan and execute the appropriate management, whether this may involve conservative or surgical intervention. The goal should always be to correct the abnormality and have the patient return to play with full strength and no recurrent instability.
Abstract This cadaveric study aimed to determine if acetabular retroversion demonstrates predictable changes with age that could inform understanding of factors that may contribute to the ...pathophysiology of femoroacetabular impingement. Two-hundred forty pelves were divided into young and old groups. Version was measured at the cranial (5 mm below superior rim), central (transverse of acetabulum), and caudal (5 mm above inferior rim) locations. The data showed a significant difference between young (10 ± 10°) and old (13 ± 9°) cranial version ( P = .02). Cranial retroversion increases with age and may reflect a developmental component in the etiology of the focal rim impingement lesion or ossification of the damaged labrum. Global acetabular retroversion does not appear to change with age and may reflect a congenital etiology.
Primary percutaneous coronary intervention (PCI) is the preferred reperfusion method in patients with ST-elevation myocardial infarction (STEMI) if it can be performed in a timely manner in ...high-volume centers. Regional STEMI networks improve timely access to PCI but are frequently criticized for being single center. To determine if results of regional STEMI systems could be replicated and achieve similar outcomes in 2 separate geographic regions, we examined the prospective databases of 2 large regional STEMI networks that use identical standardized protocols and integrated transfer systems. The Minneapolis Heart Institute (MHI) database included 2,266 patients with STEMI from 31 hospitals (498 at the PCI hospital, 1,033 transferred from 11 hospitals <60 miles away, and 735 transferred from 19 hospitals 60 to 210 miles away). The Iowa Heart Center (IHC) database included 1,206 patients with STEMI from 24 hospitals (710 at the PCI hospital, 266 transferred from 10 hospitals <60 miles away, and 230 transferred from 13 hospitals 60 to 120 miles away). Median total door-to-balloon times for the PCI hospital, zone 1, and zone 2 patients were 64, 95, and 123 minutes for the MHI and 59, 102, and 136 for the IHC (p <0.05 for each comparison between MHI and IHC). Overall in-hospital, 30-day, and 1-year mortalities was 4.8%, 5.4%, and 8.0% respectively (p = NS for each comparison between MHI and IHC). In conclusion, the use of identical protocols in 2 large regional STEMI systems in geographically separate locations produced nearly identical outcomes, adding to evidence that regional STEMI centers expand timely access to PCI.
Polypharmacy increases the risk of cytochrome P450-based drug-drug interactions (CYP450-DDIs), leading to decreased therapeutic efficacy or increased drug toxicity.
The aims of this study were to ...investigate the utility of a new CYP450-DDI software, InterMED-Rx, in aiding pharmacists in detecting CYP450-DDIs in hospitalized elderly patients and to ascertain pharmacists' agreement on how to intervene for each CYP450-DDI.
A consensus panel of geriatric pharmacists first established guidelines for managing clinically relevant pharmacokinetic CYP450-DDIs. A prospective study was then conducted of patients newly admitted to a geriatric hospital whose pharmaceutical profile underwent analysis with InterMED-Rx. Rates and types of interventions were recorded.
Pharmacists' interrater agreement on how to manage CYP450-DDIs was initially only moderate (Cohen's κ, 0.51; 95% CI, 0.39-0.62), but improved subsequent to deliberation (Cohen's κ, 0.79; 95% CI, 0.70-0.88). Persistent disagreement involved interactions between 2 drugs with similar affinities for the same cytochrome. One hundred patients with polypharmacy (≥5 medications) aged 82.3 years (range, 65-96), with a mean (SD) of 12.2 (4.1) drugs (range, 5-27) were recruited for the prospective study. Eighty percent of patients had at least 1 CYP450 DDI detected with InterMED-Rx. A total of 238 CYP450-DDIs were identified involving CYP3A4 (70.2%), CYP2D6 (22.7%), and CYP2C9 (3.4%) substrates or inhibitors. Nineteen percent of patients received immediate medication adjustment, and 39% required follow-up of clinical signs, symptoms, and laboratory tests to determine whether future modification was needed. More than one half (56%) of all patients who required clinical follow-up had further medication adjustment prior to discharge.
Use of the InterMED-Rx software identified elderly patients at risk for pharmacokinetic interactions and facilitated interventions aimed at reducing adverse drug events. Although consensus can be reached among pharmacists on how to intervene for many CYP450-DDI scenarios, certain situations allow for multiple intervention strategies.
Common abnormalities of the optic fundus are illustrated in this article. The authors provide brief clinical descriptions and discuss a test used to screen for a shallow anterior chamber of the eye ...before dilating the pupil.
PDF
