GlaxoSmithKline (United States)

Understanding the origin, distribution, and biology of different cell populations in chimeric mice is critical for interpreting the pathological changes developed in these models. To this aim, the methodological work presented here illustrates the validation and application of a collection of labeling techniques to differentiate between specific mouse and human tissue/cell components in formalin-fixed paraffin-embedded samples from chimeric mice, especially those bearing human tumor and immune cells. First, broad approaches to identify cells of human origin using ubiquitous immunohistochemical targets such as HLA-A, Ku80, and human mitochondrial 60 kDa protein (hMito) were established using specimens from humanized mice and a human tissue microarray including both normal and neoplastic samples. Due to its crisp membranous immunoreactivity, HLA-A was the most useful marker for visual human cell identification; however, Ku80 and hMito may be suitable options when HLA-A is not expressed in the cells of interest. Importantly, using one or more of these markers provides a broad range of coverage for the vast majority of human-derived cells in chimeric mice. Second, tailored immunohistochemical or in situ hybridization methodologies to distinguish specific human or mouse cell subsets are presented, focusing on immune/inflammatory cells and human chimeric antigen receptor (CAR) T-cells. These diverse approaches are accompanied by descriptions of case examples highlighting practical diagnostic and experimental applications in the context of various humanized mouse models. While not comprehensive, this work represents a valuable starting reference for pathologists and investigators working with humanized mouse models and seeking to add spatial resolution to the complex landscape of chimeric tissues.

Anemia, highly prevalent among patients receiving maintenance dialysis, may be associated with adverse outcomes. This study describes the patient characteristics, anemia treatment patterns, clinical event rates, and health care resource utilization of patients receiving hemodialysis (HD) in the United States and in a subpopulation of patients hyporesponsive to erythropoietin-stimulating agents (ESAs). Using data from the US Renal Data System, a retrospective, population-based descriptive cohort study of adults with Medicare Parts A and B coverage receiving maintenance HD was conducted. ESA hyporesponsiveness was defined as ESA Resistance Index ≥2 (ESA units/kg/wk/g hemoglobin/L) or ESA dose ≥450 U/kg/wk (within 8 weeks of index (January 1, 2018). Anemia treatments and clinical events were assessed using medical claims during follow-up, until death, loss of Medicare, kidney transplantation, or December 31, 2019. Outcome rates were calculated as number of events divided by follow-up time with 95% confidence intervals based on Poisson distribution. Of the overall prevalent HD population (N = 209,408), 20,223 were ESA hyporesponders. Relative to the overall prevalent HD population, the ESA hyporesponder subpopulation had a higher rate of red blood cell transfusion events (91.1 [95% CI, 90.1-92.2] vs 32.4 [95% CI, 32.2-32.6] per 100 person-years [PY]), thromboembolic events (80.7 [95% CI, 79.3-82.2] vs 71.0 [95% CI, 70.6-71.4] per 100 PY), major adverse cardiovascular events (30.2 [95% CI, 29.6-30.9] vs 20.3 [95% CI, 20.2-20.5] per 100 PY), gastrointestinal erosions (61.8 [95% CI, 60.6-63.0] vs 40.2 [95% CI, 40.0-40.5] per 100 PY), and all-cause mortality (26.2 [95% CI, 25.6-26.8] vs 16.9 [95% CI, 16.8-17.1] per 100 PY). Hospitalizations occurred more frequently in the ESA hyporesponder subpopulation (2.45 vs 1.56 per PY) than in the overall prevalent HD population. This study was not designed to determine causality. The ESA hyporesponder subpopulation had a high burden of red blood cell transfusion use, clinical events, and health care resource utilization.

Patients immunosuppressed because of disease and/or therapy are at increased risk of developing herpes zoster (HZ) and related complications. However, HZ risk due to immunosuppressive medication remains underexplored across a broad spectrum of medication classes and conditions. To estimate HZ risk among US adults initiating immunosuppressive therapy, across underlying conditions. This retrospective study used administrative claims from the Optum Research Database (October 1, 2015, to December 31, 2022) to identify incident HZ diagnoses and the proportion of HZ with complications. Included patients were aged 18years or older and had at least a 12-month baseline period of continuous enrollment with medical and pharmacy benefits. Analyses produced incidence rates (IRs) of HZ during periods of immunosuppression and nonimmunosuppression and compared patients initiating immunosuppressive therapy (immunosuppressed subcohort) vs matched controls who did not (nonimmunosuppressed subcohort). Cox regression analyses compared HZ hazards and a logistic regression model compared the difference in the occurrence of postherpetic neuralgia (PHN) following HZ diagnosis. In patients initiating immunosuppressive medications (N = 528,283), the overall HZ IR was 18.2 (95% CI = 17.9-18.4) per 1,000 person-years. Patients with the highest IRs were those treated with Janus kinase inhibitors (30.5 [95% CI = 25.0-36.9] per 1,000 person-years), rituximab (27.8 [95% CI = 25.2-30.6] per 1,000 person-years), or cyclophosphamide (27.5 [95% CI = 19.3-38.1] per 1,000 person-years). Patients had a higher HZ risk when using immunosuppressive medications (adjusted hazard ratio 2.86 [95% CI = 2.76-2.95]) and with increasing numbers of immunosuppressive medication classes (one vs none: 2.45 [95% CI = 2.37-2.54]; at least 2 vs none: 4.04 [95% CI = 3.87-4.21]). The immunosuppressed subcohort had a higher HZ hazard (adjusted hazard ratio: 1.39 [95% CI = 1.35-1.43]), higher frequency of HZ complications (21.4% vs 18.8% of HZ cases developed PHN, P < 0.001), and increased odds of PHN (adjusted odds ratio: 1.22 [95% CI = 1.14-1.31]) compared with the nonimmunosuppressed subcohort. Immunosuppressive medication use was associated with a higher risk of HZ and HZ-related complications. Measures to prevent HZ before immunosuppressive treatment initiation should be considered according to Advisory Committee on Immunization Practices recommendations and other professional organizations.

The authors declare no conflicts of interest. The views presented herein are the consensus views of the authors and not those of their respective employers.

Abstract Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous, non-invasive condition characterized by the proliferation of malignant epithelial cells within the duct, with variable risk of progression to invasive disease. Current standard treatment involves surgical resection followed by possible adjuvant endocrine therapy and/or adjuvant radiation. However, a substantial proportion of DCIS may never progress to invasive disease and thus may be overtreated with the current standard of care. Consequently, active surveillance (AS) is emerging as a treatment option for patients with DCIS. DCIS is definitely a risk factor for breast cancer, and should be reframed as an opportunity for preventive intervention. RECAST (Re-evaluating Conditions for Active Surveillance Suitability as Treatment) is a Phase II adaptive platform trial studying the efficacy of up front endocrine therapy to identify appropriate candidates for long-term active surveillance versus those who would benefit from standard surgical treatment. Patients with hormone receptor positive DCIS of any grade undergo baseline breast MRI and are randomized to one of four hormonal therapy regimens, including standard endocrine therapy, z-endoxifen, elacestrant or HAV-008 with the potential to offer equivalent or improved benefit with less adverse effects. Serial MRI at 3 and 6 months is then used to evaluate change in background parenchymal enhancement (BPE) and DCIS lesion. Patients deemed low risk based on imaging response have the option to continue AS and avoid surgery and radiation and continue their endocrine therapy for 3 years. The primary endpoint of the trial is to determine whether novel endocrine therapy increases the fraction of patients who will be suitable for long-term AS as measured by the fraction of patients who remain on active surveillance at 7 months compared to control. To date, over 50 patients are enrolled in the trial. Our target accrual of 400 patients. A total of 17 (34%) patients have reported an AE, all grade 1 or 2, with no serious adverse events reported and no safety signals identified. Of the 50 patients currently on treatment, 25 have reached or gone beyond the 6-month mark and 22 (88%) of those patients remain on active surveillance with a median follow up of 351 days. At the 3 month point, one patient progressed on imaging and two chose to come off surveillance due to other reasons. At 6 months, 8% (2/25) progressed on imaging and one additional patient has proceeded to surgery at the 1 year point. One patient who went on to have surgery was found to have invasive disease (pT1bN0). Robust accrual continues at sixteen currently active sites with five more sites anticipated to open in the next few months. The shift to using hormonal therapy in the neoadjuvant setting allows investigators to assess response to endocrine therapy, characterize risk of progression to invasive cancer and helps to better inform treatment-making decisions before continuing AS or proceeding with surgery, and appropriately assesses the value of endocrine risk reduction prior to surgery to avoid it. The trial uses a patient-centered approach and gives all patients a window of opportunity to assess their response as well as medication tolerability to make an informed decision about treatment approach. Citation Format: K. C. Hewitt, C. Yau, R. Mukhtar, C. Thompson, J. Hui, K. Westbrook, J. Jackson, C. Carruthers, C. Farley, S. Bommakanti, K. Brownson, B. Fan, I. Meszoely, T. Balija, M. H. Mcnatt, P. Gilman, J. Marti, T. Li, S. Horton, A. Borowsky, J. Rosenbluth, L. Esserman. Initial results from RECAST DCIS: Multicenter platform trial testing active surveillance and novel endocrine therapy agents for DCIS management [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-08.

IntroductionAsthma imposes a high disease burden, with approximately half of patients experiencing uncontrolled disease despite inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy. A previous randomised controlled trial demonstrated clinical benefits of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) single-inhaler triple therapy (SITT) versus FF/VI dual therapy in patients with moderate-severe asthma without a requirement for exacerbation history. Here, we present the protocol for the PERFORM pragmatic trial, comparing the effectiveness of initiating FF/UMEC/VI SITT via the ELLIPTA® inhaler (GSK) versus continuing or initiating non-ELLIPTA ICS/LABA usual care for a broad patient population with uncontrolled asthma.MethodsPERFORM is a 52-week, stratified, randomised, open-label, active-controlled, parallel-group, global pragmatic trial enrolling adult patients with uncontrolled asthma, currently untreated or treated with ICS or ICS/LABA therapy. Patients will be randomised 1:1 to either initiate once-daily FF/UMEC/VI (intervention) or continue or initiate non-ELLIPTA ICS/LABA (control), receiving treatment in a usual care setting. The primary endpoint is the change from baseline in trough forced expiratory volume in 1 s at week 24. The key secondary endpoint is whether patients achieve improvement (≥ 0.5-point decrease from baseline) in the Asthma Control Questionnaire-7 score at week 24. Other secondary endpoints include clinical remission, health-related quality of life, and work and activity impairment. The trial aims to randomise 1136 patients (568 per arm).Planned OutcomesPERFORM is a pragmatic randomised controlled trial generating data relevant to a broad population of patients with uncontrolled asthma representative of routine clinical practice. This trial will also include the first prospective data on clinical remission for patients treated with inhaled therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-026-00346-1.

BackgroundGepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial that selectively inhibits bacterial replication through a distinct binding site, unique mechanism of action and, for most target pathogens, well-balanced inhibition of two Type II topoisomerase enzymes (DNA gyrase and topoisomerase IV). Gepotidacin was recently approved by the FDA for the treatment of uncomplicated urinary tract infections (uUTI). This study evaluated the effects of several antimicrobial susceptibility testing (AST) variables on standardized (i.e., CLSI, EUCAST) testing methods for key uUTI uropathogens.Variables shown to significantly impact gepotidacin BMD MICs and/or DD zone for EnterobacteralesMethodsThe in vitro activity of gepotidacin and levofloxacin was evaluated using 4 CLSI AST methods: broth microdilution (BMD), broth macrodilution (MD), agar dilution (AD) and disk diffusion (DD). 85 clinical isolates were included for MIC testing and 90 isolates for DD, including E. faecalis (EF), S. saprophyticus (SS), and several Enterobacterales species known to be implicated in uUTI. Variables (BMD and DD only) including but not limited to inoculum concentration, temperature, atmospheric conditions, pH, and urine were tested.ResultsGepotidacin mean reference BMD MICs varied no more than 1 dilution over multiple days, for all species tested. MICs were comparable between the 3 MIC testing methods with MICs for 84 of 85 isolates within ± 1 dilution. Reference gepotidacin mean disk results varied by approximately 1-2 mm over multiple testing days. Mueller Hinton agar data was similar for DD with the exception of SS and Remel in which the majority of results were > 3mm larger. Variables shown to significantly impact gepotidacin BMD MICs and/or DD zone for Enterobacterales are shown in the table below.Results were similar for SS and EF with the exception of EF and SS DD zones being more impacted by inoculum variation and no impact of temperature on EF and SS MICs and DD zones.ConclusionWhen performing susceptibility testing with gepotidacin it is important to control the following variables, which were shown in this study to have the most impact on results: high inoculum concentration, high temperature (for Enterobacterales only), pH, incubation in 5% CO2 (for DD only) and testing of BMD MICs in urine.DisclosuresNicole E. Scangarella-Oman, MS, GSK: Employee|GSK: Stocks/Bonds (Public Company) Josh West, BS, GSK: Employee|GSK: Stocks/Bonds (Public Company)