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BACKGROUND: While 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/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 (Census tract) data from multiple sources. Patients were followed from diagnosis to clinical study drug receipt (proxy for trial participation), death, or last recorded activity. Associations were assessed using Cox proportional hazards models adjusted for clinical factors (diagnosis year, age, sex, performance status, stage, cancer type). To elucidate which area-level SDOH underlie racial/ethnic inequities, mediation analysis was performed using nonlinear multiple additive regression tree models. RESULTS: This study included 250105 patients (64.7% non-Latinx White, 8.9% non-Latinx Black, 5.2% Latinx). Black and Latinx patients were more likely to live in economically/socially marginalized areas (eg, disproportionately minoritized [measure of segregation], limited English proficiency [LEP], low vehicle ownership) than White patients. Black (3.7%; HR = 0.55 [CI = 0.52-0.60]) and Latinx patients (4.4%; HR = 0.63 [CI = 0.58-0.69]) were less likely to participate in trials than White patients (6.3%). Fewer patients in economically/socially marginalized neighborhoods participated in trials. Mediators explained 62.2% (CI = 49.5%-74.8%) of participation inequities between Black and White patients; area-level SDOH-including segregation (29.9% [CI = 21.2%-38.6%]) and vehicle ownership (11.6% [CI = 7.0%-16.1%])-were the most important mediators. Similarly, Latinx-White participation inequities were mediated (65.1%, [CI = 49.8%-80.3%]) by area-level SDOH such as segregation (39.8% [CI = 28.3%-51.3%]), LEP (11.6%, [CI = 2.8%-20.4%]), and vehicle ownership (9.6% [CI = 5.8%-13.5%]). CONCLUSIONS: To improve racial/ethnic diversity in cancer trials, efforts to address barriers related to adverse neighborhood SDOH factors are necessary.

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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. Results: Simulated data were generated under varying residual-bias assumptions (no bias: HRRWD = 1) and experimental treatment effects (target trial scenario: HRExp = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HRRWD away from 1), and with weaker experimental treatment effects (i.e. HRExp closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies. Conclusion: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development.

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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. However, using these ML-extracted data for research still introduces unique challenges in assessing validity and generalizability to different cohorts of interest. In order to enable effective and accurate use of ML-extracted real-world data (RWD) to support research and real-world evidence generation, we propose a research-centric evaluation framework for model developers, ML-extracted data users and other RWD stakeholders. This framework covers the fundamentals of evaluating RWD produced using ML methods to maximize the use of EHR data for research purposes.

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A simple covalent organic framework (COF) bearing ß-ketoenamine units as a potential heterogeneous ligand for ZnII-catalyzed fixation and transformation of CO2 into value-added chemicals is reported. Catalytic investigations convincingly demonstrated that the ZnII-functionalized covalent organic framework (Zn@TpTta) exhibits perfect catalytic activity in the fixation of CO2 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 (i.e., 69 to 99% yield) upon exposure to CO2 (1 atm) under solvent-free conditions (sustainable approach). On the other hand, this ZnII-loaded covalent organic framework also displayed excellent performance in facilitating atmospheric cyclizative CO2 capture, which led to the formation of diverse cyclic carbamates (i.e., 61 to 94% yield) from unsaturated amine systems using N-iodosuccinimide (NIS) as an iodinating agent and PEG-400 as a biodegradable and green polymeric solvent under base-free conditions (sustainable approach). The newly synthesized COF-based catalyst, namely, Zn@TpTta, has been completely characterized by SEM (scanning electron microscopy), EDX (energy dispersive X-ray analysis), HRTEM (high-resolution transmission electron microscopy), BET (Brunauer-Emmett-Teller), PXRD (powder X-ray diffraction), XPS (X-ray photoelectron spectroscopy), ICP (inductively coupled plasma), etc. More intriguingly, the catalytic system could be recycled over five times without a noticeable loss of catalytic performance for both reactions. This study opens an avenue for the Zn(II) embedded COF as a promising platform for regulating regioselectivity.

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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. METHODS: We analyzed the association of timing of next-generation sequencing (NGS) testing with real-world OS (rwOS) in patient data from a United States-based nationwide longitudinal deidentified electronic health records-derived database. Estimates of rwOS using risk set adjustment were compared with estimates computed with respect to all patients, regardless of NGS testing. RESULTS: The independent delayed entry assumption was not satisfied in this database, and later sequencing had a negative association with the hazard of death after sequencing. In a model adjusted for relevant characteristics, each month delay in sequencing was associated with a 2% increase in the hazard of death. However, until the median survival time, estimates of OS using risk set adjustment are similar to estimates computed for all patients, regardless of NGS testing. CONCLUSIONS: rwOS analyses in clinico-genomic databases should assess the independent delayed entry assumption. Comparisons versus broader population may be useful to evaluate the rwOS differences between calculations using risk set adjustment and patient cohorts where the bias relates to overrepresentation of long survivors. IMPACT: This study illustrates practices that can increase the interpretability of findings from OS analyses in clinico-genomic databases.

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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. METHODS: Using a nationwide de-identified EHR-derived database, we first analyzed imaging assessment frequency patterns in patients diagnosed with advanced non-small cell lung cancer (aNSCLC). We used those RWD inputs to develop a discrete event simulation model of two treatments where disease progression was the outcome and PFS was the endpoint. Using this model, we induced bias with differential imaging assessment timing and quantified its effect on observed versus true treatment effectiveness. We assessed percent bias in the estimated hazard ratio (HR). RESULTS: The frequency of assessments differed by cancer treatment types. In simulated comparative-effectiveness studies, PFS HRs estimated using real-world imaging assessment frequencies differed from the true HR by less than 10% in all scenarios (range: 0.4% to -9.6%). The greatest risk of biased effect estimates was found comparing treatments with widely different imaging frequencies, most exaggerated in disease settings where time to progression is very short. CONCLUSIONS: This study provided evidence that the frequency of imaging assessments to detect disease progression can differ by treatment type in real-world patients with cancer and may induce some bias in comparative-effectiveness studies in some situations.

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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. Previously, several extensions of CRMs, such as the time-to-event CRM (TITE-CRM), fractional CRM (fCRM) and the data augmented CRM (DA-CRM), have been proposed to handle this issue without prolonging trial duration. However, among the model-based designs, none of the designs have explicitly controlled the risk of overdosing as in the escalation with overdose control (EWOC) design. Here we propose a novel dose escalation with overdose control design using a two-parameter logistic regression model for the probability of DLT depending on the dose and a piecewise exponential model for the time to DLT distribution, which we call rolling-CRM design. A comprehensive simulation study has been conducted to compare the performance of the rolling-CRM design with other dose escalation designs. Of note, the trial duration is significantly shorter compared to traditional CRM designs. The proposed design also retains overdose control characteristics, but might require a larger sample size compared to traditional CRM designs.

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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.

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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. In this setting, our design can supplement a control arm with historical data, and randomize more new patients to the novel treatments. This design is both ethical and economical, since it shortens the process of introducing new treatments into the market, and any additional costs introduced by this design will be compensated by the savings in control arm sizes. Our approach performs well via simulation across settings with varying degrees of commensurability and true treatment effects, and compares favorably to an adaptive "all-or-nothing" approach in which the decision to pool or discard historical controls is based on a simple ad-hoc frequentist test at interim analysis. We also consider a three drug extension where a new imaginary intervention joins the platform, and show again that our procedure performs well via simulation.

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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. We use an MCMC-driven Bayesian hierarchical parametric survival modeling approach to analyze data from a sponsor's colorectal cancer study. We also apply these same models to simulated data comparing the effective historical sample size, bias, 95% credible interval widths, and empirical coverage probabilities across the simulated cases. We find that even after accounting for variations in study design, baseline characteristics, and standard-of-care improvement, our approach consistently identifies Bayesianly significant differences between the historical and concurrent controls under a range of priors on the degree of historical data borrowing. Our simulation studies are far from exhaustive, but inform the design of future trials. When the historical and current controls are not dissimilar, Bayesian methods can still moderate borrowing to a more appropriate level by adjusting for important covariates and adopting sensible priors.

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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. We report here two atypical presentations of dermatofibroma - Atrophic dermatofibroma and keloidal presentation of dermatofibroma. Clinical dermal atrophy is a common phenomenon in dermatofibromas as demonstrated by the dimpling on lateral pressure. However, this feature is exaggerated in the atrophic variant of dermatofibroma. Atrophic dermatofibroma is defined by dermal atrophy of more than 50% of the lesion apart from the usual features of common dermatofibroma. The keloidal variant of dermatofibroma should not be overlooked as a simple keloid. The findings of keloidal change in dermatofibromas may support that trauma is a possible cause of dermatofibroma.

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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. Safety analysis was based on reports of targeted adverse events in treated patients. RESULTS: Median OS with BV plus chemotherapy was 19.3 v 14.3 months with placebo plus chemotherapy (hazard ratio [HR] = 0.70; 95% CI, 0.55 to 0.90; P = .006). Patients treated with BV plus chemotherapy had a median PFS of 9.2 v 6.2 months for placebo plus chemotherapy patients (HR = 0.52; 95% CI, 0.40 to 0.67; P < .0001). The objective response rate was 34.4% with BV plus chemotherapy versus 29.0% with placebo plus chemotherapy (difference not statistically significant). Rates of BV-associated adverse events in the pooled BV plus chemotherapy group were consistent with those reported in the overall populations for the two studies. CONCLUSION: Analysis of pooled patient cohorts age >/= 65 years from two similar trials in mCRC indicates that adding bevacizumab to fluorouracil-based chemotherapy improved OS and PFS, similar to the benefits in younger patients. Also, the risks of treatment do not seem to exceed those in younger patients with mCRC.

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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. PATIENTS AND METHODS: For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. RESULTS: Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. CONCLUSION: In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

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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. markers are generally measured with error. The estimated PTE ignoring the measurement error could be biased, which may lead to incorrect conclusions. In this article, we adjust for the measurement error using regression calibration to construct a less biased estimator of excess relative odds, a quantity to measure the treatment effect explained by markers. The method is applied to data from a clinical study in osteoporosis.

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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. Cases were reviewed for wound healing complications occurring < or = 60 days after surgery. RESULTS: With cancer surgery 28-60 days before study treatment, wound healing complications occurred in 3/230 (1.3%) bevacizumab-treated patients and 1/194 (0.5%) control patients. With major surgery during study treatment, 10/75 bevacizumab-treated patients (13%) and 1/29 control patients (3.4%) had wound healing complications. Bevacizumab-treated patients experienced complications with surgery < or = 30 and 31-60 days after the last dose. CONCLUSIONS: Bevacizumab administered in combination with 5-fluorouracil/leucovorin-based chemotherapy 28-60 days after primary cancer surgery caused no increased risk of wound healing complications compared with chemotherapy alone. While wound healing complications were increased in patients who had major surgery during bevacizumab therapy, the majority of bevacizumab-treated patients experienced no complications.

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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. PATIENTS AND METHODS: The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival. RESULTS: The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P < or = .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019). CONCLUSION: The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer.

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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. Development of mild cognitive impairment and dementia was a secondary outcome. Women were given clinical and cognitive evaluations at baseline and annually. After 3 years, among the 5,386 women enrolled at participating sites, those who had clinical symptoms of dementia or scored in the lowest 10th percentile on cognitive screening were evaluated by a blinded dementia specialist and had brain scans and laboratory tests to evaluate dementia etiology. Dementia was diagnosed by a blinded adjudication committee. RESULTS: Of the 5,386 women, 5,153 (95.7%) were classified as cognitively normal, 181 (3.4%) had mild cognitive impairment, and 52 (1.0%) had dementia, 36 with Alzheimer's disease. Compared to those taking placebo, women receiving 120 mg/day of raloxifene had a 33% lower risk of mild cognitive impairment (relative risk, 0.67; 95% confidence interval [CI], 0.46-0.98) and somewhat lower risks of Alzheimer's disease (relative risk=0.52, 95% CI=0.22-1.21) and any cognitive impairment (relative risk=0.73, 95% CI=0.53-1.01). Risks of mild cognitive impairment, Alzheimer's disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene. CONCLUSIONS: Raloxifene at a dose of 120 mg/day, but not 60 mg/day, resulted in reduced risk of cognitive impairment in postmenopausal women.

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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. Outcomes included venous thromboembolism, cataracts, gallbladder disease, and endometrial hyperplasia or cancer. RESULTS: During a mean follow-up of 3.3 years, raloxifene was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1; 95% confidence interval [CI] 1.2-3.8). The excess event rate was 1.8 per 1,000 woman-years (95% CI -0.5-4.1), and the number needed to treat to cause 1 event was 170 (95% CI 100-582) over 3.3 years. Risk in the raloxifene group was higher than in the placebo group for the first 2 years, but decreased to about the same rate as in the placebo group thereafter. Raloxifene did not increase risk for cataracts (RR 0.9; 95% CI 0.8-1.1), gallbladder disease (RR 1.0; 95% CI 0.7-1.3), endometrial hyperplasia (RR 1.3; 95% CI 0.4-5.1), or endometrial cancer (RR 0.9; 95% CI 0.3-2.7). CONCLUSION: Raloxifene was associated with an increased risk for venous thromboembolism, but there was no increased risk for cataracts, gallbladder disease, endometrial hyperplasia, or endometrial cancer. LEVEL OF EVIDENCE: I

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