POP-REFINE: A Comprehensive Framework for Evaluating and Optimizing Representativeness in Clinical Trials.

Clinical research has historically failed to include representative levels of historically underrepresented populations and these inequities continue to persist. Ensuring representativeness in clinical trials is crucial for patients to receive clinically appropriate treatment and have equitable access to novel therapies; enhancing the generalizability of study results; and reducing the need for post-marketing commitments focused on underrepresented groups. As demonstrated by recent legislation and guidance documents, regulatory agencies have shown an increased interest in understanding how novel therapies will impact the patient population that will receive them.

Mediators of racial and ethnic inequities in clinical trial participation among patients with cancer, 2011-2023.

Background: Although racially and ethnically minoritized populations are less likely to participate in cancer trials, it is unknown whether social determinants of health (SDOH) explain these inequities. Here we identify SDOH factors that contribute to racial and ethnic inequities in clinical trial participation among patients with 22 common cancers.

Methods: This retrospective cohort study used electronic health record data (2011-2023) linked to neighborhood (US Census tract) data from multiple sources.

Augmenting control arms with real-world data for cancer trials: Hybrid control arm methods and considerations.

Background: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information.

Methods: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies.

Considerations for the Use of Machine Learning Extracted Real-World Data to Support Evidence Generation: A Research-Centric Evaluation Framework.

A vast amount of real-world data, such as pathology reports and clinical notes, are captured as unstructured text in electronic health records (EHRs). However, this information is both difficult and costly to extract through human abstraction, especially when scaling to large datasets is needed. Fortunately, Natural Language Processing (NLP) and Machine Learning (ML) techniques provide promising solutions for a variety of information extraction tasks such as identifying a group of patients who have a specific diagnosis, share common characteristics, or show progression of a disease.

A Zn(II)-functionalized COF as a recyclable catalyst for the sustainable synthesis of cyclic carbonates and cyclic carbamates from atmospheric CO.

A simple covalent organic framework (COF) bearing β-ketoenamine units as a potential heterogeneous ligand for Zn-catalyzed fixation and transformation of CO into value-added chemicals is reported. Catalytic investigations convincingly demonstrated that the Zn-functionalized covalent organic framework (Zn@TpTta) exhibits perfect catalytic activity in the fixation of CO for diverse epoxides with various substituents under sustainable conditions. A variety of terminal epoxides and slightly more complicated disubstituted epoxides were transformed into the corresponding cyclic carbonates with satisfactory to excellent yields (, 69 to 99% yield) upon exposure to CO (1 atm) under solvent-free conditions (sustainable approach).

Accounting for Delayed Entry in Analyses of Overall Survival in Clinico-Genomic Databases.

Background: Clinico-genomic databases favor inclusion of long-term survivors, leading to potentially biased overall survival (OS) analyses. Risk set adjustments relying on the independent delayed entry assumption may mitigate this bias. We aimed to determine whether this assumption is satisfied in a dataset of patients with advanced non-small cell lung cancer (aNSCLC), and to give guidance for clinico-genomic OS analyses when the assumption is not satisfied.

Differential frequency in imaging-based outcome measurement: Bias in real-world oncology comparative-effectiveness studies.

Background: Comparative-effectiveness studies using real-world data (RWD) can be susceptible to surveillance bias. In solid tumor oncology studies, analyses of endpoints such as progression-free survival (PFS) are based on progression events detected by imaging assessments. This study aimed to evaluate the potential bias introduced by differential imaging assessment frequency when using electronic health record (EHR)-derived data to investigate the comparative effectiveness of cancer therapies.

Rolling continual reassessment method with overdose control: An efficient and safe dose escalation design.

In phase 1 dose escalation studies, dose limiting toxicities (DLTs) are defined as adverse events of concern occurring during a predefined time window after first dosing of patients. Standard dose escalation designs, such as the continual reassessment method (CRM), only utilize this binary DLT information. Thus, late-onset DLTs are usually not accounted for when CRM guiding the dose escalation and finally defining the maximum tolerated dose (MTD) of the drug, which brings safety concerns for patients.

Cu/CuO NPs architectured COF: a recyclable catalyst for the synthesis of oxazolidinedione atmospheric cyclizative CO utilization.

The present study describes the favourable construction of a crystalline covalent organic framework (COF) with exceptional surface area, tunable pore size and huge CO2 capture efficiency to facilitate a novel multicomponent cyclization by introducing CO2 into extremely reactive organic skeletons. In the presence of a catalytic Cu/CuxOy NP-loaded COF, several 2-bromo-3-alkylacrylic acids combined with several amine derivatives and CO2 (0.1 MPa) are converted to the desired oxazolidinediones in excellent yields (up to 96%) under alkali-free conditions and ambient temperature.

An efficient Bayesian platform trial design for borrowing adaptively from historical control data in lymphoma.

To reduce a clinical trial's cost and ethical risk to its enrollees, some oncology trial designers have suggested borrowing information from similar but already completed trials to reduce the number of patients needed for the current study. Motivated by competing drug therapies for lymphoma, we propose a Bayesian adaptive "platform" trial design that uses commensurate prior methods at interim analyses to borrow adaptively from the control group of an earlier-starting trial. The design adjusts the trial's randomization ratio in favor of the novel treatment when the interim posterior indicates commensurability of the two control groups.

Borrowing from Historical Control Data in Cancer Drug Development: A Cautionary Tale and Practical Guidelines.

Some clinical trialists, especially those working in rare or pediatric disease, have suggested borrowing information from similar but already-completed clinical trials. This paper begins with a case study in which relying solely on historical control information would have erroneously resulted in concluding a significant treatment effect. We then attempt to catalog situations where borrowing historical information may or may not be advisable using a series of carefully designed simulation studies.

Dermatofibroma: Atypical Presentations.

Dermatofibroma is a common benign fibrohistiocytic tumor and its diagnosis is easy when it presents classical clinicopathological features. However, a dermatofibroma may show a wide variety of clinicopathological variants and, therefore, the diagnosis may be difficult. The typical dermatofibroma generally occurs as a single or multiple firm reddish-brown nodules.

Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials.

Purpose: Colorectal cancer (CRC) occurs predominantly in older persons. To provide more statistical power to assess risk/benefit in older patients, we examined the clinical benefit of bevacizumab (BV) plus fluorouracil-based chemotherapy in first-line metastatic CRC (mCRC) treatment in patients aged > or = 65 years, using data pooled from two placebo-controlled studies.

Patients And Methods: Pooled efficacy data for 439 patients > or = 65 years old randomized to BV plus chemotherapy (n = 218) or placebo plus chemotherapy (n = 221) in study 1 and study 2 were retrospectively analyzed on an intent-to-treat basis for overall survival (OS), progression-free survival (PFS), and objective response.

Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107.

Purpose: In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response.

Quantifying the treatment effect explained by markers in the presence of measurement error.

Surrogate markers or intermediate markers are important in identifying subjects with high risk of a serious disease or for monitoring disease progression of a subject on treatment. Quantifying the proportion of treatment effect (PTE) explained by markers has been studied extensively. Due to reasons such as biological variation, limited machine precision, etc.

Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab.

Background: Bevacizumab (Avastin; rhuMab VEGF), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), significantly prolongs survival when added to intravenous 5-fluorouracil-based chemotherapy in first-line metastatic colorectal cancer (CRC) treatment. Because antiangiogenic agents might inhibit wound healing, we assessed postoperative wound healing complications in two randomized trials of 5 mg/kg bevacizumab in CRC treatment.

Methods: We assessed the wound healing complications in patients who: (1) underwent cancer surgery 28-60 days before study treatment and (2) underwent major surgery during study treatment.

Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer.

Purpose: Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluorouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV.

Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial.

Objective: This investigation examined whether raloxifene, a selective estrogen receptor modulator, affects the risk for Alzheimer's disease.

Method: The Multiple Outcomes of Raloxifene Evaluation was a randomized, placebo-controlled trial among postmenopausal women with osteoporosis. The effect of raloxifene (60 or 120 mg/day) on vertebral fractures was the primary outcome.

Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.

Objective: To examine the effect of raloxifene on major adverse events that occur with postmenopausal estrogen therapy or tamoxifen.

Methods: The Multiple Outcomes of Raloxifene Evaluation, a multicenter, randomized, double-blind trial, enrolled 7,705 postmenopausal women with osteoporosis. Women were randomly assigned to raloxifene 60 mg/d or 120 mg/d or placebo.

Effect of raloxifene on the incidence of elevated low density lipoprotein (LDL) and achievement of LDL target goals in postmenopausal women.

Objective: To determine the extent to which raloxifene can maintain low density lipoprotein cholesterol (LDL-C) levels below 160 mg/dL or reduce elevated LDL-C levels to below lipid-lowering goals in postmenopausal women.

Patients And Methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial randomized 7705 postmenopausal women to placebo or raloxifene (60 mg or 120 mg) daily for a core treatment phase of 3 years. Changes in LDL-C and other serum lipids in a subset of women was a predefined secondary objective.

Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study.

Unlabelled: Different risk factors may influence the effectiveness of osteoporosis therapies. The interaction of 30 baseline risk factors and the effectiveness of raloxifene in the MORE study were assessed. The efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures.

Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk.

Unlabelled: The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD.