A Dynamic Programming Approach to Adaptive Fractionation

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)

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

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 a greater early re-operation rate in congenital versus acquired valve disease

Objective: We sought to establish whether there was a difference in outcome after aortic valve repair with autologous pericardial leaflet extension in acquired versus congenital valvular disease. Methods: One hundred and twenty-eight patients underwent reparative aortic valve surgery at our institution from 1997 through 2005 for acquired or congenital aortic valve disease. The acquired group (43/128) (34%) had a mean age of 56.4 ± 20.3 years (range, 7.8–84.6 years) and the congenital group (85/128) (66%) had a mean age of 16.9 ± 19.2 years (range, 0.3–82 years). The endpoints of the study were mortality and reoperation rates. Results: Thirty-day mortality was 0/43 (0%) in the congenital group and 1/85 (1.1%) in the acquired group. Late mortality in the acquired group was 3/43 (7%) and 3/84 (3.5%) in the congenital group (neither early nor late proportion of mortality is significantly different between the two groups, according to the nonparametric Binomial test for proportions). There were 13 total reoperations among 11 patients: 1/43 (2.3%) in the acquired group and 10/85 (11.7%) in the congenital group (p = 0.07). Two patients from the congenital group were reoperated on twice. The mean interval between original repair and reoperation was 3.6 ± 5 years (range, 0–7 years) for acquired and 3.5 ± 2.5 years (range, 0–7 years) for the congenital group (Wilcoxon 2-sample test, p = 0.7). Total early reoperation rate (≪30 days after first surgery) was 11/128 (8.5%); for the congenital group 9/85 (10.5%) and for the acquired group 2/43 (4.6%). Early reoperation rate was significantly higher among the congenital group (p = 0.013). The remaining patients are well at mean follow-up of 2.8 ± 2.4 years (range 0–7.9). In the acquired group, the mean postoperative aortic regurgitation and stenosis grade by echocardiography was 0.5 ± 0.3 (scale, 0–4) and 0.3 ± 0.1, respectively. In the congenital group, the follow-up, mean aortic regurgitation and stenosis were 0.9 ± 0.8 and 0.5 ± 0.3, respectively. Conclusions: There was no significant difference in early or late mortality and late reoperation rate between the two groups. Early reoperation rate was higher in the congenital versus the acquired aortic valvular disease group. This study supports the fact that the valve-sparing technique is safe and reproducible and repeatable in patients with acquired valve disease

Aortic Valve Sparing and Restoration With Autologous Pericardial Leaflet Extension is an Effective Alternative in Pediatric Patients

We sought to evaluate the durability and efficacy of aortic valve repair with autologous pericardial leaflet extension in children. From 1997 through 2006, 54 patients underwent aortic valve repair with autologous pericardial leaflet extension at a mean age 8.4 ± 5.3 years (range, 0 to 17 years). Primary endpoints were early and late mortality, freedom of reoperation, and late valve function. Thirty-day and late mortality were one in 54 (1.8%) and two in 53 (3.7%), respectively. There were seven re-operations in six patients, and one patient was re-operated twice. Re-operations were re-repairs in four cases and replacements in three cases. The mean interval between original repair and re-operation was 4.3 ± 2.5 years. Mean severity grade of post-repair intraoperative aortic regurgitation (AR) was 0.3 (range, grade 0 to 4). At late follow-up, 87.7% of all patients had no AR or only a trace (grade 0-1). Seven patients (12.9%) had mild AR (grade 2-3) and none severe (grade 4); 94.4% had no aortic stenosis or only a trace (grade 0-1), 5.5% had mild (grade 2-3), and none severe. This technique delays potential complications from other approaches to valve pathology and allows a normal growth of the aortic annulus. Although, our data show that this technique has a low mortality and morbidity, more studies are needed to elucidate durability and late outcome

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

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

Long-term results of mitral valve repair using autologous pericardium annuloplasty

The use of autologous pericardium for annuloplasty during mitral valve repair is a subject of controversy; hence, the study aim was to evaluate the authors' long-term results using this technique. A retrospective review was conducted of 173 consecutive patients (mean age 59.6 +/- 16.3 years; range: 19-92 years) who underwent mitral valve repair complemented by annuloplasty between January 1998 and December 2003. The major causes of mitral regurgitation (MR) were annular dilatation and prolapse of the posterior leaflet. Annuloplasty was performed in all patients using a strip of pericardium treated with 0.6% glutaraldehyde for 10 min. Two rows of continuous horizontal mattress Gore-Tex sutures were used to secure the pericardium to the mitral annulus. Follow up continued for a mean period of 5.25 +/- 1.62 years (range: 1.97 to 9.43 years), and was complete. Three patients (1.7%) died within 30 days of surgery. Subsequently, five patients (2.9%) with MR (with or without mitral stenosis) underwent reoperation at a mean of 3.0 +/- 2.7 years after the initial surgery. At seven years after surgery the actuarial survival rate was 92.5%, and freedom from reoperation 97.1%. Follow up echocardiography was performed in 160 patients. Among these patients, no MR was detected in 34 (21.2%), while 88 (55%) had grade 1 MR, 35 (21.8%) grade 2, and three (1.8%) had grade 3. None of the patients had grade 4 MR. The study results indicated that autologous pericardium mitral annuloplasty of the mitral valve provides effective, durable and reproducible repair, and avoids the use of foreign materials

Tricuspid valve repair using autologous pericardium annuloplasty in adults

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

Pathologic findings in pericardium and native valve tissues after aortic valve-sparing with autologous pericardial leaflet extension

Aortic valve repair with autologous pericardial leaflet extension is a valuable treatment option for aortic valve disease. The study aim was to examine and describe the histopathologic changes in native and pericardial extension leaflet tissues after this procedure. The pathologic findings of nine patients (mean age 26.7 +/- 2.9 years; range: 0-77 years) who underwent aortic valve repair with autologous leaflet extension were analyzed. The initial diagnosis included: bicuspid aortic valve (n = 4), truncus arteriosus (n = 3), ventricular septal defect (n = 1) and subaortic stenosis (n = 1). The pathologic endpoints of the study were fibrosis, calcification and myxomatous changes, based on a scale from 0 to 3. Fibrosis and calcification demonstrated similar grade results in the pericardial and native tissues; no statistical difference was observed (p = 0.261 and p = 0.999, respectively. Myxomatous degeneration was greater in the native tissue (p = 0.012). Among the native tissue group, five patients were graded 1 and three graded 3 for myxomatous degeneration. Among the pericardial tissue patients, six were graded 0, and one each were graded 1, 2, or 3. Following aortic valve repair with pericardial leaflet extension, both the pericardial and native valve tissue are susceptible to myxomatous degeneration, fibrosis, and calcification. Among the present patients, myxomatous degeneration was more often present in the native tissue, but there was no difference in calcification or fibrosis between the native and pericardial tissue groups

Alcohol use in donors is a protective factor on recipients' outcome after heart transplantation

The outcome of heart transplantation is highly influenced by good donor selection. Because a history of alcoholism is prevalent among potential heart donors, we sought to explore the effect of alcohol use in donors on the outcome of heart transplantation in the recipient. A total of 437 consecutive patients underwent heart transplantation from January 2002 through September 2005. Patients' files were retrospectively studied. Mean follow-up period was 3.14+/-1.9 years (range, 3 days to 6.5 yrs). The cohort was divided into two subgroups. The alcoholic donor group (ADG) included 98 of 421 patients and the nonalcoholic donor group (NADG) included 323 of 421 patients. Mean age was 35.3+/-11.4 yrs (range, 18-66) for the ADG and 33+/-12.2 yrs (range, 18-62) for the NADG. Mortality among the ADG was 7 of 98 (7.1%) and for NADG was 55 of 323 (17.1%) (P=0.015). The mean interval time between transplant and mortality was, for ADG, 27.7+/-20.6 months (range, 0.07-51) and for NADG, 16.4+/-19.6 months (range, 0.14-73) (P=0.031). Survival rate was significantly higher among the ADG at 72.8+/-1.9 months compared with NADG at 66.2+/-1.5 months (P=0.019). Overall rejection rate was 22 of 421 (5.2%); rejection rate was 17 of 323 (5.2%) in NADG and 5 of 98 (5.1%) in ADG. Rejection free survival was 74.6+/-0.85 with no significant difference between the two groups (P=0.85). The chronic alcoholism of donors was found to be a protective factor regarding the outcome after heart transplantation. Significant differences were found in mortality rate and survival after heart transplantation between the ADG and NADG. These data support the fact that it is safe to use donors' hearts regardless of a history of alcoholism