Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Rapid T 1 -weighted 3D spoiled gradient-echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast-enhanced MRI (DCE-MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. T 1 -weighted dynamic contrast-enhanced (DCE)-MRI is an established method for assessing microvascular changes associated with disease in tissues. It is most commonly used in cancer imaging (1-15), but has also been applied in a range of inflammatory conditions (16,17,41) and in cerebral (18) and cardiac (19) ischemia. Quantitative DCE-MRI has the potential to provide physiological information related to the functional status of tissue microvasculature. This information is available via the application of a tracer kinetic model-usually a compartmental model that describes the rate of transfer of contrast agent between the blood pool and the extracellular extravascular space (EES) (20).All models of contrast agent kinetics require the concentration of contrast agent in the blood pool (the arterial input function (AIF)) to be determined. Simple models assume a simplified functional form for the AIF, and additionally assume that the same functional form is valid for all individuals (16,21). However, it has been shown that using a simplified standard AIF leads to large systematic errors in model output parameters such as the volume transfer constant K trans and blood volume v b (22,42). Additionally, it is generally assumed that interpatient variability in factors such as heart rate and kidney function will lead to differences in the true form of AIF between individuals. An AIF that is accurately measured in each patient studied is therefore the accepted aim for kinetic modeling using contrast agents, even if it one that is met in only a minority of studies (6,13,23).In many settings it is not possible to perform an AIF measurement reliably, due either to data acquisition constraints or the lack of a suitable artery within the imaging field of view (FOV) from which to obtain an AIF. In such cases it would be desirable to utilize an assumed form of AIF that provides sufficient information to allow an accurate estimation of model parameters. Here we present a functional form of AIF that meets this requirement. We obtained this AIF from a population of 67 individually measured AIFs from the abdomens of 23 patients. We also show that the variability associated with the population of AIFs is low. Finally, we show that the use of the new functional form of the population AIF improves the reproducibility of tracer kinetic model parameters, and conclude that it is valid to use an assumed form of AIF if it is not possible to acquire AIFs from individual patients. MATERIALS AND METHODS PatientsTwenty-three patients (...

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Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674-82)