21 research outputs found

    A Dynamic Programming Approach to Adaptive Fractionation

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    We conduct a theoretical study of various solution methods for the adaptive fractionation problem. The two messages of this paper are: (i) dynamic programming (DP) is a useful framework for adaptive radiation therapy, particularly adaptive fractionation, because it allows us to assess how close to optimal different methods are, and (ii) heuristic methods proposed in this paper are near-optimal, and therefore, can be used to evaluate the best possible benefit of using an adaptive fraction size. The essence of adaptive fractionation is to increase the fraction size when the tumor and organ-at-risk (OAR) are far apart (a "favorable" anatomy) and to decrease the fraction size when they are close together. Given that a fixed prescribed dose must be delivered to the tumor over the course of the treatment, such an approach results in a lower cumulative dose to the OAR when compared to that resulting from standard fractionation. We first establish a benchmark by using the DP algorithm to solve the problem exactly. In this case, we characterize the structure of an optimal policy, which provides guidance for our choice of heuristics. We develop two intuitive, numerically near-optimal heuristic policies, which could be used for more complex, high-dimensional problems. Furthermore, one of the heuristics requires only a statistic of the motion probability distribution, making it a reasonable method for use in a realistic setting. Numerically, we find that the amount of decrease in dose to the OAR can vary significantly (5 - 85%) depending on the amount of motion in the anatomy, the number of fractions, and the range of fraction sizes allowed. In general, the decrease in dose to the OAR is more pronounced when: (i) we have a high probability of large tumor-OAR distances, (ii) we use many fractions (as in a hyper-fractionated setting), and (iii) we allow large daily fraction size deviations.Comment: 17 pages, 4 figures, 1 tabl

    Tocilizumab in patients hospitalised with COVID-19 pneumonia: efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

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    Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C

    Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

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    This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation

    Aortic valve-sparing repair with autologous pericardial leaflet extension has low long-term mortality and reoperation rates in children and adults

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    We sought to establish whether there was a difference in outcome after aortic valve repair with autologous pericardial leaflet extension in pediatric and adult populations. In our study, 128 patients (pediatric and adult) underwent valvular pericardial extension repair at our institution from 1997 through 2006. The patients were divided into either the pediatric group (< or =18 years of age; n = 54/128, 42%), with a mean age of 8.4 +/- 5.4 (range, 0-17 years), or the adult group (n = 74/128, 58%), with a mean age of 48.9 +/- 19.7 (range, 19-85 years). The endpoints of the study were mortality and reoperation rates. Thirty-day mortality for the adult group was 0, and for the pediatric group it was 1/54 (1.8%), with no statistical difference (P = .1) between the groups. Late mortality for the pediatric group was 2/54 (3.7%) and in the adult group was 2/74 (2.7%). There was no statistical difference (P = .12) between the groups. In the pediatric group, there were 6 total reoperations (6/54) in 5 patients, with one patient undergoing reoperation twice. From these 6 cases, 3 were re-repair and 3 had aortic valve replacement; the mean interval between original repair and reoperation was 4.3 +/- 2.5 years (range, 0.1-7.7 years). In the adult group, there were 5 total reoperations (5/74). From these 5 cases, 3 had aortic valve replacement and 2 re-repair; the mean interval between original repair and reoperation was 3.5 +/- 3 years (range, 0.1-7 years). There was no statistical difference in the reoperation rate between the 2 groups (P= .38). At late follow-up, 82% of all patients in the adult group had no aortic regurgitation or only a trace (grades 0 and 1) and 78% of all patients in the pediatric group had no aortic regurgitation or only a trace (grades 0 and 1). There was no statistical difference in either aortic regurgitation (P = .06) or aortic stenosis (P = .28) between the 2 groups. Aortic valve repair with autologous pericardial leaflet extension has low mortality and morbidity rates, as well as good mid-term durability in both the pediatric and the adult groups

    Tricuspid valve repair using autologous pericardium annuloplasty in adults

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    Uncorrected functional tricuspid regurgitation can lead to long-term morbidity and mortality. To evaluate our results using autologous pericardium annuloplasty to treat tricuspid regurgitation, we retrospectively reviewed 59 consecutive adult patients aged 19 years to 83 years (58.7 +/- 15.5 years) who underwent tricuspid valve annuloplasty between 2000 and 2003. Concomitant procedures consisted of mitral valve surgery in 83% of patients, aortic valve surgery in 28%, coronary bypass in 31%, and atrial-septal defect correction in 28%. Annuloplasty was performed using a strip of pericardium treated in glutaraldehyde 0.6% for 10 min. Two rows of continuous horizontal mattress Gore-Tex sutures were used to secure the pericardium to the tricuspid annulus. Follow-up was performed in 100% of the patients, and the mean follow-up was 4.4 +/- 1.2 years (range, 2.4 to 7 years). Postoperative death within 30 days occurred in 1 of 59 patients (1.6%). None of the patients required reoperation related to tricuspid regurgitation or stenosis. The actuarial survival rate was 98.4% at 7 years after operation. Echocardiography was performed in 58 of 58 surviving patients (100%). Up to 7 years postoperatively, tricuspid regurgitation was trace in 67.2% of patients, mild in 31%, and moderate in 1.8%; there was no occurrence of severe regurgitation on follow-up. Our results indicate that autologous pericardium tricuspid annuloplasty is a useful procedure in patients with moderate or severe tricuspid regurgitation. This procedure provides a durable, reproducible annuloplasty of the tricuspid valve
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