Prostate-specific Antigen Density as a Selection Tool Before Magnetic Resonance Imaging in Prostate Cancer Screening: An Analysis from the STHLM3MRI Randomized Clinical Trial.

Background And Objective: Prostate cancer screening is challenged by overdetection, overtreatment, and high resource use. Prostate-specific antigen (PSA) density (PSAD) correlates more strongly with clinically significant cancer than PSA alone. We compare outcomes using various PSAD cutoffs to select men for magnetic resonance imaging (MRI).

Prostate Cancer Testing Between Screening Rounds: Evidence from the STHLM3-MRI Trial.

Background And Objective: The STHLM3-MRI screening-by-invitation trial found that magnetic resonance imaging (MRI)-based screening for prostate cancer (PCa) improved early detection in comparison to systematic biopsy. The aim of the present study was to describe testing and PCa incidence between screening rounds of the STHLM3-MRI trial.

Methods: The study population comprised men aged 50-74 yr in the MRI (experimental) arm of the STHLM3-MRI trial without a PCa diagnosis in the first round.

Estimating and presenting non-linear associations with restricted cubic splines.

Most of the regression models commonly used in epidemiology-including logistic regression and methods for time-to-event outcomes such as Cox regression-define the relationship between a set of covariates and the outcome of interest using linear functions, thus making implicit assumptions of linearity for continuous covariates. Categorizing continuous covariates, which represents a common option to address non-linearities, introduces additional assumptions and has recognized limitations in terms of results interpretation. Restricted cubic splines (RCS) offer a flexible alternative tool that can improve the model fit in the presence of non-linear associations, overcoming many of the limitations of categorical approaches and providing information on the shape of the exposure-outcome relationship.

Anti-CD14 treatment in patients with severe COVID-19: Clinical and biological effects in a Phase 2 randomized open-label adaptive platform clinical trial.

Background And Research Question: CD14-dependent innate immunity contributes to poor outcomes in COVID-19 pneumonia. We tested the clinical and biological efficacy of a blocking monoclonal antibody to CD14 (IC14) for treatment of severe COVID-19 pneumonia and the utility of a biomarker of CD14 pathway activation in predicting outcome.

Study Design And Methods: We report a preplanned secondary analysis of the I-SPY COVID Trial, which enrolled hospitalized patients with severe COVID-19 pneumonia at 19 medical centers in the U.

Prognostic Value of the Circulating Tumor DNA Fraction in Metastatic Castration-resistant Prostate Cancer: Results from the ProBio Platform Trial.

Background And Objective: The aim of this study was to evaluate the prognostic value of undetectable circulating tumor DNA (ctDNA) and the dose-response relationship between ctDNA levels and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC).

Methods: We analyzed data for patients enrolled in the ProBio trial up to November 2022 who received an androgen receptor pathway inhibitor or taxane. We compared survival outcomes between patients with undetectable ctDNA and those with detectable ctDNA randomized to physician's choice or investigational arms.

Evaluating the performance of existing tools to predict clinically significant prostate cancer in men with indeterminate lesions on biparametric MRI and development of a novel multiplex model: a prospective cohort study.

Background: Indeterminate lesions on prostate MRI, such as PI-RADS 3, present a clinical challenge due to their equivocal nature, complicating biopsy decisions in men undergoing testing for prostate cancer. Understanding the predictive capacity of biomarkers and risk calculators is critical to improve clinical decision-making and reduce unnecessary biopsies.

Methods: In this prospective cohort study, men with PI-RADS 3 findings on biparametric MRI (bp-MRI) who underwent combined biopsy (fusion targeted and systematic) in the STHLM3-MRI randomised clinical trial (first- and second-rounds) and at Capio St Göran's Hospital (Capio PCC), Sweden were included, representing screening-by-invitation, repeat screening, and clinical practice cohorts, respectively.

A Comparison of Stockholm3, Serum Biomarkers, and Risk Calculators to Predict Prostate Cancer in a Racially and Ethnically Diverse Cohort: Evaluation of the Stockholm3 Multiethnic SEPTA Trial.

Purpose: The purpose of this study was to compare performance of Stockholm3 in an external validation with commonly used prostate cancer biomarkers and risk calculators.

Materials And Methods: SEPTA was a multicenter trial validating Stockholm3 in a racially/ethnically diverse population of men meeting local care guidelines for prostate biopsy (2019-2023). In total, 2115 (98%) men with complete data for risk calculators and biomarkers were included.

Repeat Prostate Cancer Screening using Blood-based Risk Prediction or Prostate-specific Antigen in the Era of Magnetic Resonance Imaging-guided Biopsies : A Secondary Analysis of the STHLM3-MRI Randomized Clinical Trial.

Background And Objective: The use of blood-based risk prediction tools has been proposed to improve prostate cancer screening, but data on repeated screening are lacking. Our aim was to compare outcomes using the blood tests prostate-specific antigen (PSA) and Stockholm3 for repeat prostate cancer screening.

Methods: In the population-based screening-by-invitation STHLM3-MRI trial, men aged 50-74 yr were invited to participate in screening.

Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB).

Estimating and presenting hazard ratios and absolute risks from a Cox model with complex nonlinear interactions.

Interaction analysis is a critical component of clinical and public health research and represents a key topic in precision health and medicine. In applied settings, however, interaction assessment is usually limited to the test of a product term in a regression model and to the presentation of results stratified by levels of additional covariates. Stratification of results often relies on categorizing or making linearity assumptions for continuous covariates, with substantial loss of precision and of relevant information.

Prostate cancer incidence and mortality in men exposed to α1-adrenergic receptor antagonists.

Background: α1-Adrenergic receptor antagonists are commonly used to treat benign prostatic hyperplasia. Preclinical studies suggest that they induce cell death and inhibit tumor growth. This study evaluated the risk of prostate cancer death in men using α1-adrenergic receptor antagonists.

Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening: The STHLM3-MRI Randomized Clinical Trial.

Importance: Prostate cancer guidelines often recommend obtaining magnetic resonance imaging (MRI) before a biopsy, yet MRI access is limited. To date, no randomized clinical trial has compared the use of novel biomarkers for risk estimation vs MRI-based diagnostic approaches for prostate cancer screening.

Objective: To evaluate biomarker-based risk estimation (Stockholm3 risk scores or prostate-specific antigen [PSA] levels) with systematic biopsies vs an MRI-enhanced strategy (PSA levels and MRI with systematic and targeted biopsy) for the detection of clinically significant prostate cancer in a screening setting.

Repeated Prostate Cancer Screening Using Prostate-Specific Antigen Testing and Magnetic Resonance Imaging: A Secondary Analysis of the STHLM3-MRI Randomized Clinical Trial.

Importance: Magnetic resonance imaging (MRI) has been proposed to enhance the benefit-to-harm ratio of prostate cancer screening, but data on repeated screening outcomes are lacking.

Objective: To describe outcomes of prostate-specific antigen (PSA)-based screening with MRI and prostate biopsies at repeat screening.

Design, Setting, And Participants: This secondary analysis examined the population-based, screen-by-invitation STHLM3-MRI randomized clinical trial, which recruited Swedish men aged 50 to 74 years.

Side effects of low-dose tamoxifen: results from a six-armed randomised controlled trial in healthy women.

Background: Adherence to adjuvant tamoxifen therapy is suboptimal, and acceptance of tamoxifen for primary prevention is poor. Published results indicate effect of low-dose tamoxifen therapy. Using questionnaire data from a randomised controlled trial, we describe side effects of standard and low-dose tamoxifen in healthy women.

Cost-effectiveness of Prostate Cancer Screening Using Magnetic Resonance Imaging or Standard Biopsy Based on the STHLM3-MRI Study.

Importance: The combination of prostate-specific antigen (PSA) testing with magnetic resonance imaging (MRI) for prostate cancer detection has rarely been evaluated in a screening context. The STHLM3-MRI screening-by-invitation study (NCT03377881) has reported the benefits of using MRI with subsequent combined targeted and standard biopsies compared with using standard biopsies alone.

Objective: To investigate the cost-effectiveness of prostate cancer screening using MRI with combined targeted and standard biopsies compared with standard biopsies alone among men aged 55 to 69 years in Sweden, based on evidence from the STHLM3-MRI study.

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations.

Introduction: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.

Association of 5α-Reductase Inhibitors With Prostate Cancer Mortality.

Importance: There is evidence that 5α-reductase inhibitors (5-ARIs), a standard treatment of benign prostate hyperplasia, are associated with a decrease in the incidence of prostate cancer (PCa). However, studies to date have had conflicting results regarding the association with prostate cancer mortality (PCM).

Objective: To evaluate the association of treatment with 5-ARIs with PCM in men without a prior diagnosis of PCa.

Clinical Trial Protocol for ProBio: An Outcome-adaptive and Randomised Multiarm Biomarker-driven Study in Patients with Metastatic Prostate Cancer.

ProBio is an outcome-adaptive, multiarm, multiple-assignment randomised, biomarker-driven platform trial in men with metastatic castration-resistant prostate cancer. Here we describe the amended clinical protocol, focusing on expansion of the trial to include patients with de novo metastatic hormone-sensitive prostate cancer.