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DTSTART;TZID=America/New_York:20200915T130000
DTEND;TZID=America/New_York:20200915T140000
DTSTAMP:20260423T105441
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SUMMARY:A New Hybrid Phase I-II-III Clinical Trial Paradigm
DESCRIPTION:Frontiers in Biostatistics Seminar \nTuesday September 15\, 2020 at 1:00PM Eastern Time \nPeter F. Thall\, PhD\nDepartment of Biostatistics\nUniversity of Texas M.D. Anderson Cancer Center \nAbstract: Conventional evaluation of a new drug\, 𝐴\, is done in three phases. Phase I relies on toxicity to determine a “maximum tolerable dose” (MTD) of 𝐴\, in phase II it is decided whether 𝐴 at the MTD is “promising” in terms of response probability\, and if so a large randomized phase III trial is conducted to compare 𝐴 to a control treatment\, 𝐶\, based on survival time or progression free survival time. This paradigm has many flaws. The first two phases may be combined by conducting a phase I-II trial\, which chooses an optimal dose based on both efficacy and toxicity\, with evaluation of 𝐴 at the optimal phase I-II dose then done in phase III. In this talk\, I will describe a new paradigm\, motivated by the possibility that the optimal phase I-II dose may not maximize mean survival time with 𝐴. A hybrid phase I-II-III design is presented that allows the optimal phase I-II dose of 𝐴 to be re-optimized based on survival time data after the first stage of phase III. The hybrid design relies on a mixture model for the survival time distribution as a function of efficacy\, toxicity\, and dose. A simulation study is presented to evaluate the design’s properties\, including comparison to the more conventional approach that does not re-optimize the dose of 𝐴 in phase III. \nA recording of this seminar is available on your YouTube Channel.
URL:https://ds.dfci.harvard.edu/event/a-new-hybrid-phase-i-ii-iii-clinical-trial-paradigm/
CATEGORIES:Seminar
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DTSTART;TZID=America/New_York:20200922T140000
DTEND;TZID=America/New_York:20200922T150000
DTSTAMP:20260423T105441
CREATED:20200915T212158Z
LAST-MODIFIED:20200917T142852Z
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SUMMARY:Cancer Development\, Heterogeneity and Dynamics from Premalignancy to Drug Refractory Disease
DESCRIPTION:Data Science Seminar \nSeptember 22\, 2020\n2:00PM ET \nIgnaty Leshchiner\, PhD\nPostdoctoral Fellow\, Harvard Medical School/Brigham and Women’s Hospital \nZoom link: http://bit.ly/DSSept22 \nAbstract: \nReal-time study of tumor emergence and progression in patients will help predict and ultimately change the course of the patient’s disease. This could be achieved by inferring genotypes of heterogeneous cell populations within the tumor\, their fitness\, growth rates\, corresponding expression patterns and drug tolerance states. We have developed a set of computational methods to infer the order of tumor-initiating events and to follow the dynamics and competition of cancer cell populations during disease progression and treatment. The package\, PhylogicNDT\, uses tumor genomic data to reconstruct the process of tumor formation\, natural growth kinetics\, competition and spread of resistance clones. We applied this package to 2\,658 primary cancers to reconstruct developmental trajectories and history of common tumor types in premalignancy and early malignancy state; reconstruct cancer cell populations and growth rates\, fitness and kinetics of individual clones during natural progression of leukemia in vivo; analyze spatial progression of resistance clones and find new resistance mechanisms in a large cohort of rapid autopsy cases. By integrating blood biopsy (ctDNA)\, solid tissue biopsy and autopsy data we show that resistance often emerges in multiple distant metastatic sites simultaneously\, with evidence of multiple resistance mutations present in the blood’s ctDNA at the same time. Finally\, we combine bulk and single cell sequencing data to help identify genetically distinct clones and explain their phenotypic differences. We envision that treatment decisions will improve with better understanding of tumor development\, clonal structure and microenvironment\, and the path tumor takes to become malignant and progress after treatment.
URL:https://ds.dfci.harvard.edu/event/cancer-development-heterogeneity-and-dynamics-from-premalignancy-to-drug-refractory-disease/
CATEGORIES:Seminar
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DTSTART;TZID=America/New_York:20200929T130000
DTEND;TZID=America/New_York:20200929T140000
DTSTAMP:20260423T105441
CREATED:20200922T173720Z
LAST-MODIFIED:20200923T183848Z
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SUMMARY:3D Spatial Organization Within Tumors
DESCRIPTION:Data Science Seminar \nSeptember 29\, 2020\n1:00PM ET \nMartin Aryee\, PhD\nAssistant Professor of Pathology\, Harvard Medical School\nAssistant Molecular Pathologist\, Massachusetts General Hospital \nZoom link: https://dfci.zoom.us/j/95524743149?pwd=SzN4cjJZUnhsNVl3dXNmZjZ1N3F4QT09 \nAbstract: The spatial organization of biological systems can impart additional functionality beyond that of the individual components. This is true at a range of scales – from cells in a tissue to individual genes and regulatory elements in a single genome. High-throughput assays that permit spatial measurements have advanced greatly in the past decade and revealed oncogenic architectural alterations in tumors at the tissue\, cellular and chromosome levels. Here I will discuss tumor spatial organization in gastrointestinal malignancies at two different scales. First\, I will describe how we used single-cell RNA-Seq and RNA in situ hybridization in pancreatic cancer to identify cell state and tissue architecture changes induced by contact with stromal cancer-associated fibroblasts (CAFs). We analyzed the spatial architecture of cell states in 195 pancreatic tumors\, mapping over 300\,000 individual cancer cells. We were able to classify different types of tumor glands based on their cell-type composition\, and show that these functional units can be used to characterize tumors in ways not evident from analyses of dissociated single cells. Second\, I will discuss findings from a recent study of 3D genome organization within colon cancer cell nuclei. We found oncogenic changes at the level of regulatory chromatin loops and topologically associated domains (TADs)\, but the most surprising and striking change involves a large-scale repackaging of heterochromatin that appears to restrain tumor progression\, representing a failed anti-tumor epigenetic brake.
URL:https://ds.dfci.harvard.edu/event/3d-spatial-organization-within-tumors/
CATEGORIES:Seminar
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