Comparing duration of response and duration of clinical benefit between fulvestrant treatment groups in the CONFIRM trial: application of new methodology.
Ontology highlight
ABSTRACT:
SUBMITTER: Garnett SA
PROVIDER: S-EPMC3586113 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The conventional battery for genotoxicity testing is not well suited to assessing the large number of chemicals needing evaluation. Traditional in vitro tests lack throughput, provide little mechanistic information, and have poor specificity in predicting in vivo genotoxicity. New Approach Methodologies (NAMs) aim to accelerate the pace of hazard assessment and reduce reliance on in vivo tests that are time-consuming and resource-intensive. As such, high-throughput transcriptomic and flow cytometry-based assays have been developed for modernized in vitro genotoxicity assessment. This includes: the TGx-DDI transcriptomic biomarker (i.e., 64-gene expression signature to identify DNA damage-inducing (DDI) substances), the MicroFlow® assay (i.e., a flow cytometry-based micronucleus (MN) test), and the MultiFlow® assay (i.e., a multiplexed flow cytometry-based reporter assay that yields mode-of-action (MoA) information). The objective of this study was to investigate the utility of the TGx-DDI transcriptomic biomarker, multiplexed with the MicroFlow® and MultiFlow® assays, as an integrated NAM-based testing strategy for screening data-poor compounds prioritized by Health Canada’s New Substances Assessment and Control Bureau. Human lymphoblastoid TK6 cells were exposed to 3 control and 10 data-poor substances, using a 6-point concentration range. Gene expression profiling was conducted using the targeted TempO-SeqTM assay, and the TGx-DDI classifier was applied to the dataset. Classifications were compared with those based on the MicroFlow® and MultiFlow® assays. Benchmark Concentration (BMC) modeling was used for potency ranking. The results of the integrated hazard calls indicate that five of the data-poor compounds were genotoxic in vitro, causing DNA damage via a clastogenic MoA, and one via a pan-genotoxic MoA. Two compounds were likely irrelevant positives in the MN test; two are considered possibly genotoxic causing DNA damage via an ambiguous MoA. BMC modeling revealed nearly identical potency rankings for each assay. This ranking was maintained when all endpoint BMCs were converted into a single score using the Toxicological Prioritization (ToxPi) approach. Overall, this study contributes to the establishment of a modernized approach for effective genotoxicity assessment and chemical prioritization for further regulatory scrutiny. We conclude that the integration of TGx-DDI, MicroFlow®, and MultiFlow® endpoints is an effective NAM-based strategy for genotoxicity assessment of data-poor compounds.
2022-11-15 | GSE213454 | GEO
Project description:BackgroundAt the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died. A final analysis of OS was subsequently planned for when 75% of patients had died.MethodsPatients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (±3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (±3) days thereafter. OS was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy were also reported. All statistical tests were two-sided.ResultsIn total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500 mg (n = 362) or 250 mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg (hazard ratio = 0.81; 95% confidence interval = 0.69-0.96; nominal P = .02). There were no clinically important differences in SAE profiles between the treatment groups; no clustering of SAEs could be detected in either treatment group. Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups.ConclusionsIn patients with locally advanced or metastatic estrogen receptor-positive breast cancer, fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified.
| S-EPMC3906991 | biostudies-literature
Project description:Comparing diagnostic tests on accuracy alone can be inconclusive. For example, a test may have better sensitivity than another test yet worse specificity. Comparing tests on benefit risk may be more conclusive because clinical consequences of diagnostic error are considered. For benefit-risk evaluation, we propose diagnostic yield, the expected distribution of subjects with true positive, false positive, true negative, and false negative test results in a hypothetical population. We construct a table of diagnostic yield that includes the number of false positive subjects experiencing adverse consequences from unnecessary work-up. We then develop a decision theory for evaluating tests. The theory provides additional interpretation to quantities in the diagnostic yield table. It also indicates that the expected utility of a test relative to a perfect test is a weighted accuracy measure, the average of sensitivity and specificity weighted for prevalence and relative importance of false positive and false negative testing errors, also interpretable as the cost-benefit ratio of treating non-diseased and diseased subjects. We propose plots of diagnostic yield, weighted accuracy, and relative net benefit of tests as functions of prevalence or cost-benefit ratio. Concepts are illustrated with hypothetical screening tests for colorectal cancer with test positive subjects being referred to colonoscopy.
| S-EPMC5471848 | biostudies-other
Project description:We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32-92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a, miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition, miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.
| S-EPMC9329443 | biostudies-literature
Project description:Development of a new low density stress response microarray to evaluate biological effects of contaminants in Mytilus sp: laboratory validation. In this work, we investigated the health status of mussels caged in three sites of the Sardinian coastlines characterized by different levels of contamination (Fornelli “F” considered as reference site, Cala-Real “CR” and PortoTores “PT”). A new low density oligonucleotide microarray platform was used to investigate the gene expression regulation in the studied sites. The new platform consists of 465 probes covering the same number of genes. Target genes were selected to cover most of the well-known biological processes in the stress response documented over the last decade in bivalve species at the cellular and tissue levels. Moreover, a battery of well-established biomarkers (comprising biomarkers of stress, genotoxicity and exposure) was employed. Chemical analysis revealed relatively higher loads of heavy metals (Pb and Cu) as well as total polyaromatic hydrocarbons in “PT”. In animals caged in site “CR”, functional genomics analysis of the microarray data rendered 78 DEGs involved in 11 biological processes. Animals exposed in PT showed 105 DEGs that were characterized by the regulation of 14 biological process among them Mitochondrial activity, adhesion to substrate, DNA metabolism, Translation, metal resistance and Cytoskeleton. Biomarker data termed as lysosomal membrane stability, Lysosomal/cytoplasm ratio, lipofuscine accumulation and metallothionein protein content were in trend with transcriptomic output. Moreover immunhistochemical analysis on digestive gland sections revealed higher tubulin accumulation in mussels from PT confirming the gene expression pattern of the gene. Our data should be carefully considered in view of the use of the new platform in monitoring programs .
2019-04-04 | GSE97099 | GEO
Project description:Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials. Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO. Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy. We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness. GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.
| S-EPMC8754433 | biostudies-literature
Project description:BackgroundThe production of biopolymers from waste resources is a growing trend, especially in high-population countries like Egypt. Beta-glucan (β-glucan) belongs to natural polysaccharides that are derived from plant and microbial origins. In this study, following increasing demands for β-glucan owing to its bioactive properties, a statistical model to enhance microbial β-glucan production was evaluated for its usefulness to the food and pharmaceutical industries. In addition, a trial to convert β-glucan polymer to nanostructure form was done to increase its bioactivity.ResultsIngredients of low-cost media based on agro-industrial wastes were described using Plackett-Burman and central composite design of response surface methodology for optimizing yeast β-glucan. Minerals and vitamin concentrations significantly influenced β-glucan yield for Kluyveromyces lactis and nitrogen and phosphate sources for Meyerozyma guilliermondii. The maximum predicted yields of β-glucan recovered from K. lactis and M. guilliermondii after optimizing the medium ingredients were 407 and 1188 mg/100 ml; respectively. For the first time, yeast β-glucan nanoparticles (βGN) were synthesized from the β-glucan polymer using N-dimethylformamide as a stabilizer and characterized using UV-vis spectroscopy, transmission electron microscope (TEM), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FT-IR). The average size of βGN was about 300 nm as determined by DLS. The quantitative variation of functional groups between β-glucan polymer and βGN was evaluated by FT-IR for explaining the difference in their biological activity against Normal Homo sapiens-Hela contaminant and Hepatic cancer cell lines.ConclusionsEnriching the low-cost media based on agro-industrial wastes with nutritional ingredients improves the yield of yeast β-glucan. The present study succeeds to form β-glucan nanoparticles by a simple method.
| S-EPMC10116484 | biostudies-literature
Project description:Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here, we describe a systematic method called Genomic Identification of Significant Targets in Cancer (GISTIC) designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving ~35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. About half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have different properties than those with overlapping focal EGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome. Keywords: SNP analysis, gliomas, chromosomal aberrations
2007-12-11 | GSE9635 | GEO
Project description:BackgroundThe objective of postgraduate year (PGY) training programs is to inculcate in medical graduates the expected levels of skills in patient care. This study compared the core clinical competencies of trainees who received PGY training at Chang Gung Memorial Hospital by attending the pilot training program in different groups.MethodsWe used six 10-min test stations for clinical performance evaluation, which comprised four and two test stations designed for objective structured clinical examination and procedural skill, respectively, to evaluate the learning outcomes of the trainees. The trainees were divided into three groups according to the training programs that they had attended.ResultsThe aspects of clinical performance included history taking, physical examination, medical communication, logical thinking, and problem-solving abilities. The trainees who selected the surgery-based training program exhibited a higher performance at the station for aseptic surgical preparation than the other two groups (p = 0.0261). The trainees who selected the internal medical training program (p = 0.0020) exhibited a higher performance at the station for abdominal pain in children.ConclusionsA well-designed postgraduate training program should develop trainees' competencies, particularly clinical operational skills. The results of this study may provide useful insight into methods for improving the design of training programs. Additional investigation is necessary for understanding the effects of different programs on the clinical performance of trainees.
| S-EPMC7580520 | biostudies-literature
Project description:Statistical methodologies have a wider range of practical applications in every applied sector including education, reliability, management, hydrology, and healthcare sciences. Among the mentioned sectors, the implementation of statistical models in health sectors is very crucial. In the recent era, researchers have shown a deep interest in using the trigonometric function to develop new statistical methodologies. In this article, we propose a new statistical methodology using the trigonometric function, namely, a new trigonometric sine-G family of distribution. A subcase (special member) of the new trigonometric sine-G method called a new trigonometric sine-Weibull distribution is studied. The estimators of the new trigonometric sine-Weibull distribution are derived. A simulation study of the new trigonometric sine-Weibull distribution is also provided. The applicability of the new trigonometric sine-Weibull distribution is shown by considering a data set taken from the biomedical sector. Furthermore, we introduce an attribute control chart for the lifetime of an entity that follows the new trigonometric sine-Weibull distribution in terms of the number of failure items before a fixed time period is investigated. The performance of the suggested chart is investigated using the average run length. A comparative study and real example are given for the proposed control chart. Based on our study of the existing literature, we did not find any published work on the development of a control chart using new probability distributions that are developed based on the trigonometric function. This surprising gap is a key and interesting motivation of this research.
| S-EPMC10434955 | biostudies-literature