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A method is proposed for standardizing life table cumulative failure rates for various cohorts so that they are adjusted to the distribution of exposure by age group for a particular cohort. An approximate standard error for the standardized cumulative failure rate is presented. Application of the methodology is illustrated by a numerical example. [ABSTRACT FROM AUTHOR]

This is a review of 418 patients with cancer of the pyriform sinus who had complete treatment at University of Texas M. D. Anderson Hospital, treated over a 28-year time span. Treatment modalities used included radiation therapy, surgery, and planned combined treatment, primarily in the form of surgery and postoperative radiation therapy. Superficial lesions, with no impairment of laryngeal motility, are suitable for irradiation therapy planned for cure. (The policies of treatment have changed throughout the years). Analysis is made comparing the results of the larger groups of patients treated by surgery only, or surgery followed by postoperative radiation therapy. There is a significant lower incidence of failure above the clavicle in the combined treatment group, and a better 5-year survival. Rate of recurrences and the specific sites of failure above the clavicles are discussed, as well as the means of preventing such. The causes of death between 2 and 5 years are presented. [ABSTRACT FROM AUTHOR]

Aim: To examine the associations between visceral adipose tissue (VAT) and brain structural measures at midlife and explore how these associations may be affected by age, sex and cardiometabolic factors., Methods: We used abdominal and brain magnetic resonance imaging data from a population-based cohort of people at midlife in the UK Biobank. Regression modelling was applied to study associations of VAT volume with total brain volume (TBV), grey matter volume (GMV), white matter volume, white matter hyperintensity volume (WMHV) and total hippocampal volume (THV), and whether these associations were altered by age, sex or cardiometabolic factors., Results: Complete data were available for 17 377 participants (mean age 63 years, standard deviation = 12, 53% female). Greater VAT was associated with lower TBV, GMV and THV (P < .001). We found an interaction between VAT and sex on TBV (P < .001), such that the negative association of VAT with TBV was greater in men (β = -2.89, 95% confidence interval [CI] -2.32 to -10.15) than in women (β = -1.32, 95% CI -0.49 to -3.14), with similar findings for GMV. We also found an interaction between VAT and age (but not sex) on WMHV (P < .001). The addition of other cardiometabolic factors or measures of physical activity resulted in little change to the models., Conclusions: VAT volume is associated with poorer brain health in midlife and this relationship is greatest in men and those at younger ages., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Are two adjacent genes in the same operon? What are the order and spacing between several transcription factor binding sites? Genome browsers are software data visualization and exploration tools that enable biologists to answer questions such as these. In this paper, we report on a major update to our browser, Genome Explorer, that provides nearly instantaneous scaling and traversing of a genome, enabling users to quickly and easily zoom into an area of interest. The user can rapidly move between scales that depict the entire genome, individual genes, and the sequence; Genome Explorer presents the most relevant detail and context for each scale. By downloading the data for the entire genome to the user's web browser and dynamically generating visualizations locally, we enable fine control of zoom and pan functions and real-time redrawing of the visualization, resulting in smoother and more intuitive exploration of a genome than is possible with other browsers. Further, genome features are presented together, in-line, using familiar graphical depictions. In contrast, many other browsers depict genome features using data tracks, which have low information density and can visually obscure the relative positions of features. Genome Explorer diagrams have a high information density that provides larger amounts of genome context and sequence information to be presented in a given-sized monitor than for tracks-based browsers. Genome Explorer provides optional data tracks for the analysis of large-scale data sets and a unique comparative mode that aligns genomes at orthologous genes with synchronized zooming., Importance: Genome browsers provide graphical depictions of genome information to speed the uptake of complex genome data by scientists. They provide search operations to help scientists find information and zoom operations to enable scientists to view genome features at different resolutions. We introduce the Genome Explorer browser, which provides extremely fast zooming and panning of genome visualizations and displays with high information density., Competing Interests: The authors declare no conflict of interest.

The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy. Ball et al. (Ball et al. in Ther Innov Regul Sci 55:705-716, 2021) have reported on how the Final Rule has been implemented by large pharmaceutical companies. This paper explores the experiences of small sponsor companies regarding the Final Rule, to understand the current challenges that they have been facing to meet aggregate IND safety reporting requirements., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Computer-assisted synthetic planning has seen major advancements that stem from the availability of large reaction databases and artificial intelligence methodologies. SynRoute is a new retrosynthetic planning software tool that uses a relatively small number of general reaction templates, currently 263, along with a literature-based reaction database to find short, practical synthetic routes for target compounds. For each reaction template, a machine learning classifier is trained using data from the Pistachio reaction database to predict whether new computer-generated reactions based on the template are likely to work experimentally in the laboratory. This reaction generation methodology is used together with a vectorized Dijkstra-like search of top-scoring routes organized by synthetic strategies for easy browsing by a synthetic chemist. SynRoute was able to find routes for an average of 83% of compounds based on selection of random subsets of drug-like compounds from the ChEMBL database. Laboratory evaluation of 12 routes produced by SynRoute, to synthesize compounds not from the previous random subsets, demonstrated the ability to produce feasible overall synthetic strategies for all compounds evaluated.

Concerns regarding cardiac adverse events during and after cancer care include contractile dysfunction, dysrhythmia, and inflammation. Clinical trials and practice guidelines may require or recommend sequential ejection fraction determinations for early recognition of contractile dysfunction, bio-marker screening where inflammation or contractile dysfunction could be anticipated, and multiple electrocardiograms with timings of cardiac intervals. In some instances, surveillance schedules used in clinical trial protocols have been incorporated in recommendations without revision or critical scrutiny. When adverse events are rare and interpretative parameters imperfect, false positive results may lead to delay or interruption of vital cancer treatment, may suggest that further cardiac testing be undertaken, and may add to patient anxiety. The risks of excessive monitoring also include inconvenience and increased cost. This paper looks at areas where surveillance recommendations may be problematic, specifically, ejection fractions, cardiac biomarkers, and electrocardiographic monitoring are considered. Changes reported following surveillance monitoring of cancer patients using these parameters may reflect true adverse events or clinically relevant future risk, but interpretative uncertainty or true physiologic change that is unrelated to the drug in question should be considered. Clinicians may not be sufficiently aware of the degree to which reported changes may reflect surveillance artifacts. A balance that incorporates both the likelihood of an event that could be prevented along with clinical implications is suggested. The authors recognize that differentiating among these variables is not always possible yet advocate for modifying surveillance schedules to balance the frequency and severity of events that can be mitigated, based on reliable data. SIGNIFICANCE STATEMENT: The authors' concerns regarding the predictive value of surveillance initiatives are explored. Confounding factors and false-positive results may add to the expense of cancer care and/or compromise optimal therapeutic initiatives., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Reports of cardiac adverse events from oncology clinical trials often are at variance with reports derived from clinical observations or data-base reviews. These differences may lead to confusion, as different levels of risks abound in the literature, and the true cardiac risk of using some agents is uncertain. Additionally, such discrepancies may lead to the creation of over-cautious surveillance algorithms. Reasons for these reported differences are complex and often reflect subtleties in the criteria for individual patient evaluation. Both clinical trial data and real-world data have potential flaws that make reconciliation problematic. Importantly, however, both provide crucial information regarding the risk of adverse events. Major factors contribute to these differences including different tools used to diagnose events, and how those tools are interpreted. Additionally, differences in the populations of clinical trial participants and real-world populations play a crucial role. This paper looks at these differences and provides a perspective intended to help clinicians interpret reported variations in event rates derived from highly scrutinized clinical trials and broader real-world data., (© 2022. The Author(s).)

Background: Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity., Methods: HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy., Results: Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (r b  = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks., Conclusion: The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy., Competing Interests: Declaration of competing interest HS Rugo has received travel, accommodations, and expenses from Amgen, Merck, Viatris Inc, Pfizer, and Puma Biotechnology and research funding (provided to the Regents of the University of California) from Eisai, Genentech/Roche, Lilly, Macrogenics, Merck, Novartis, OBI Pharma, Daiichi, Immunomedics, and Pfizer. EJ Pennella was a paid employee of Mylan Inc (now Viatris Inc) during the time of the study and may hold stock with the company. U Gopalakrishnan, HF Koch, and A Barve are paid employees of Viatris Inc and may hold stock with the company. M Hernandez-Bronchud has served as a consultant/advisory board member for Viatris Inc. S Loganathan, S Deodhar, and A Marwah are paid employees of Biocon Research Ltd and may hold stock with the company. C Akewanlop has received travel, accommodations, and expenses from Amgen, AstraZeneca, Roche, and Bristol-Myers Squibb. CF Waller is a consultant/advisory board member for Viatris Inc. J Herson, A Manikhas, JD Parra, MLT Abesamis-Tiambeng, I Vynnychenko, I Bondarenko, V Sriuranpong, S Roy, and EP Yanez Ruiz have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE., Methods: HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient., Results: At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan-Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up., Conclusion: This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015.

This paper describes the need to prepare for the development of antiviral therapeutics for the next pandemic. Preparation would consist of a stockpiling of best practices for clinical trial design, analysis and operations during the current SARS-CoV-2 pandemic as well as continuous development of treatments and methodology between pandemics. This development would be facilitated by a global clinical trial pandemic reserve similar to the military reserves consisting of medical and quantitative methods professionals who would remain engaged between pandemics. Continuous identification of potential antiviral drugs and diagnostic methods would also be needed. Specific methodology addressed includes the importance of large simple trials, follow up time, efficacy endpoint, appropriate estimands, non-inferiority trials, more sophisticated patient accrual models and procedures for data sharing between clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Metabolomics, synthetic biology, and microbiome research demand information about organism-scale metabolic networks. The convergence of genome sequencing and computational inference of metabolic networks has enabled great progress toward satisfying that demand by generating metabolic reconstructions from the genomes of thousands of sequenced organisms. Visualization of whole metabolic networks is critical for aiding researchers in understanding, analyzing, and exploiting those reconstructions. We have developed bioinformatics software tools that automatically generate a full metabolic-network diagram for an organism, and that enable searching and analyses of the network. The software generates metabolic-network diagrams for unicellular organisms, for multi-cellular organisms, and for pan-genomes and organism communities. Search tools enable users to find genes, metabolites, enzymes, reactions, and pathways within a diagram. The diagrams are zoomable to enable researchers to study local neighborhoods in detail and to see the big picture. The diagrams also serve as tools for comparison of metabolic networks and for interpreting high-throughput datasets, including transcriptomics, metabolomics, and reaction fluxes computed by metabolic models. These data can be overlaid on the metabolic charts to produce animated zoomable displays of metabolic flux and metabolite abundance. The BioCyc.org website contains whole-network diagrams for more than 18,000 sequenced organisms. The ready availability of organism-specific metabolic network diagrams and associated tools for almost any sequenced organism are useful for researchers working to better understand the metabolism of their organism and to interpret high-throughput datasets in a metabolic context.

Purpose: Cardiac ultrasound provides important structural and functional information that makes identification of cardiac abnormalities possible. Left ventricular ejection fraction (LVEF) provides the most commonly used parameter for recognition of treatment-related cardiac dysfunction. Random reading variance and physiologic factors influence LVEF and make the reported value imperfect. We attempt to quantitate the likelihood of false positive events by computer simulation., Methods: We simulated four visits on hypothetical trials. We assumed a baseline LVEF of 55% and normal distribution with regard to reading error and physiologic variation. 1,000 trials of sample size 1,500 were simulated. In a separate simulation, 1,000 patients entered with LVEFs of 45, 43, and 41% to estimate true positive incidence., Results: At each examination, less than 1.0% of false positives were noted. The cumulative false positive rate over four visits was 3.60%. True cardiotoxicity identification is satisfactory only when LVEF declines substantially., Conclusion: A 3.60% false positive rate in trials where the expected level of toxicity is low suggests that false positives are troubling and may exceed true positive results. Strategies to reduce the number of false positive results include making confirmatory studies mandatory. Evaluating increases along with decreases obtains some estimation of variance., (© 2019 S. Karger AG, Basel.)

Importance: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy., Objective: To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer., Design, Setting, and Participants: Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred., Interventions: Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane., Main Outcomes and Measures: The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events., Results: Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%)., Conclusions and Relevance: Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome., Trial Registration: clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42.