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Table of microinjected drugs

Microinjection of olaratumab does not inhibit PDGFRα, ERK, or S6 phosphorylation.

All adverse events reported on the study

Supplementary Legend

Distinct drug induced phenotypes and apoptotic responses specific to drug mechanism of action are seen at sites of CIVO microinjection.

Purpose:A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS).Patients and Methods:We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.Results:The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.Conclusions:These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.See related commentary by Sleijfer and Lolkema, p. 3897

Representative images of tumors from patients who received radiation treatment.

Device performance

Clinical Trial Design

Increased phosphorylation of PDGFR� and downstream effectors in an undifferentiated pleomorphic sarcoma displaying a lack of apoptotic response to microdosed doxorubicin.

A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed ComparativeWe conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.

“Motions and Spaces: What Collides in Ben Jonson's Epigrams,” reads Jonson's epigrams in terms of the distinct ways they manage fluid social forms. Drawing on the new formalist theory of Caroline Levine, the essay defines Jonson's epigrams as short poems that transform collisions, turning the rhythms and motions of social forms into whole and still literary forms. Jonson's epigrams are – despite his demurrals – narratives, telling stories of how figures of shame or praise were instituted out of conflict. Movements of social forms are transformed into poetic and whole forms. The critical heritage on the epigrams can be mapped in terms of an emphasis upon movement or stillness, and the essay proceeds through a range of poems in order to see how movement produces stillness; process and structure, or motion and space, become co-constitutive of the poems. Reading several satiric epigrams and several epigrams of praise, the essay attempts to shift understanding of the epigrams from thinking about people and social relations as they are toward thinking about people and social relations as they become. Jonson's translation of Horace's The Art of Poetry stakes out poetry's purpose: “Things sacred from profane to separate; / The public from the private,” and this essay explores how that process works in Jonson's epigrams.

Objectives: To characterize adventitial vasa vasorum (VV) in unilaterally symptomatic patients and evaluate its association with intraplaque hemorrhage (IPH) and symptom status. Background: Adventitial VV is thought to be a primary source of IPH and a potential marker for plaque instability. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been shown capable of quantifying adventitial VV in the carotid artery. Methods: Patients with ischemic cerebrovascular symptoms within the past 6 months and ipsilateral carotid plaques underwent MR imaging examination, which included a multi-contrast protocol for detecting IPH and a DCE-MRI protocol for measuring adventitial VV. Both the symptomatic and contralateral asymptomatic arteries were studied. Adventitial VV was measured at consecutive slices as adventitial Ktrans from kinetic modeling. Maximum adventitial Ktrans across all slices were calculated for each artery. Results: From the 27 patients (22 men; 69±10 years) recruited, 50 arteries had adventitial Ktrans measurements. IPH arteries (0.142±0.042 vs. 0.112±0.029 min-1, p Conclusions: Adventitial VV demonstrated significant associations with IPH and symptom status. In vivo assessment of adventitial VV by DCE-MRI may be useful in studying plaque pathogenesis or risk stratification, but further examination through prospective studies is needed.

A new horizon in imaging of atherosclerotic plaque is the use of contrast enhancing agents to investigate molecular and cellular markers. This chapter reviews the state of the art in contrast-enhanced imaging of atherosclerotic plaque. Topics include enhancement characteristics of different plaque tissues, modeling of dynamic contrast-enhanced MRI, and targeted contrast agents. For each topic, specific techniques for image acquisition and post-processing are presented. Quantitative results are summarized for experiments conducted with histological validation. Finally, potential applications of these techniques in detecting vulnerable lesions and in drug development are discussed.