Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall ...survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion n = 7, myocardial infarction n = 5, unstable angina n = 3, pericarditis n = 2, arrhythmia n = 12, and heart failure n = 1). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.
Summary
Background
Knowledge of anticoagulation status during dabigatran therapy may be desirable in certain clinical situations.
Objective
To determine the coagulation tests that are most useful for ...assessing dabigatran's anticoagulant effect.
Methods
Peak and trough blood samples from 35 patients taking dabigatran 150 mg twice daily, and one sample each from 30 non‐anticoagulated individuals, were collected. Mass spectrometry and various coagulation assays were performed. ‘Therapeutic range’ was defined as the range of plasma dabigatran concentrations determined by mass spectrometry between the 2.5th and 97.5th percentiles of all values.
Results
The therapeutic range was 27–411 ng mL−1. The prothrombin time (PT) and activated partial thromboplastin time (APTT), determined with multiple reagents, and activated clotting time (ACT) were insensitive to therapeutic dabigatran: 29%, 18% and 40% of samples had a normal PT, APTT, and ACT, respectively. However, normal PT, ACT and APTT ruled out dabigatran levels above the 75th percentile. The thrombin clotting time (TCT) correlated well and linearly with dabigatran levels below the 50th percentile, but was unmeasurable above it. The dilute thrombin time, ecarin clotting time and ecarin chromogenic assay showed linear correlations with dabigatran levels over a broad range, and identified therapeutic and supratherapeutic levels.
Conclusions
The prothrombin time, APTT and ACT are often normal in spite of therapeutic dabigatran plasma levels. The TCT is useful for detecting minimal dabigatran levels. The dilute thrombin time and chromogenic and clotting ecarin assays accurately identify therapeutic and supratherapeutic dabigatran levels. This trial is registered at www.clinicaltrials.gov (#NCT01588327).
Poor body composition metrics (BCM) are associated with inferior cancer outcomes; however, in early breast cancer (EBC), there is a paucity of evidence regarding the impact of BCM on toxicities. This ...study investigates associations between BCM and treatment-related toxicity in patients with EBC receiving anthracyclines and taxane-based chemotherapy.
Pretreatment computerized tomographic (CT) images were evaluated for skeletal muscle area (SMA), skeletal muscle density (SMD), and fat tissue at the third lumbar vertebrae. Skeletal muscle index (SMI = SMA/height
) and skeletal muscle gauge (SMG = SMI × SMD) were also calculated. Relative risks (RR) are reported for associations between body composition measures and toxicity outcomes, after adjustment for age and body surface area (BSA).
BCM were calculated for 151 patients with EBC (median age, 49 years; range, 23-75 years). Fifty patients (33%) developed grade 3/4 toxicity, which was significantly higher in those with low SMI (RR, 1.29;
= 0.002), low SMG (RR, 1.09;
= 0.01), and low lean body mass (RR, 1.48;
= 0.002). Receiver operating characteristic analysis showed the SMG measure to be the best predictor of grade 3/4 toxicity. Dividing SMG into tertiles showed toxicity rates of 46% and 22% for lowest versus highest tertile, respectively (
= 0.005). After adjusting for age and BSA, low SMG (<1,475 units) was significantly associated with hematologic (RR, 2.12;
= 0.02), gastrointestinal grade 3/4 toxicities (RR, 6.49;
= 0.02), and hospitalizations (RR, 1.91;
= 0.05).
Poor BCMs are significantly associated with increased treatment-related toxicities. Further studies are needed to investigate how these metrics can be used to more precisely dose chemotherapy to reduce treatment-related toxicity while maintaining efficacy.
.
ANTi-History Deal, Nicholous M; Hartt, Christopher M; Mills, Albert J
2023
eBook
Odprti dostop
There has been a surge of ANTi-History research over the last 15 years. ANTi-Historybrings together the most impactful efforts to develop, apply and critique ANTi-History in one comprehensive book.
Context.
The formation and evolution of light elements in the Universe act as important cosmological constraints. It has long been assumed that the oldest stars of the Galaxy display the primordial ...lithium abundance in their outer layers, although studies of stellar physics have proven that this abundance must have decreased with time. The primordial Li abundance deduced from the observations of the cosmic background is, indeed, larger than the maximum observed in these stars. Recent observations have given evidence of a large Li abundance dispersion in very metal-poor stars. Many of these stars are carbon-rich, that is, the so-called carbon-enhanced metal-poor (CEMP) stars. A large number of them also present overabundances of s process elements (CEMP-s).
Aims.
We address the general question of the observed abundances in metal-poor stars and we focus our study on the case of CEMP-s stars. We study how the accretion of the wind of stellar companions, especially asymptotic giant branch stars, modifies the element abundances of metal-poor stars and, in particular, lithium, taking into account the stellar structure and the hydrodynamic processes that take place after accretion. We compare the results with the observations of lithium and heavier elements in these old stars on the main sequence.
Methods.
We use the Montréal/Montpellier stellar evolution code, which includes atomic diffusion and thermohaline convection, to compute the internal structure of the proto-CEMP-s stars and their evolution, from Fe/H = −2.31 down to Fe/H = −5.45. We study a number of cases that vary according to the masses of the stars, their ages, metallicities, and the distances to their respective companions.
Results.
We show that the observations of lithium dispersion that is associated (or not) with carbon enrichment are well accounted for in terms of accretion on to the metal-poor stars of the winds of stellar companions, with accreted masses smaller than those considered in previous studies. The derived primordial value is in accordance with the cosmological results.
Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared ...pharmacokinetics (PK) and efficacy of PEGylated liposomal doxorubicin (PLD) with non-liposomal doxorubicin (NonL-doxo) in an intracranial model of BC.
Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6 mg/kg IV × 1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg) or in combination (4.5 mg/kg) with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence.
Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, CI 31-38), which was significantly longer than controls (26d CI 25-28; p = 0.0012) or NonL-doxo treatment (23.5d CI 18-28, p = 0.0002). Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d CI 31-38 versus 29.5d CI 25-34; p = 0.006).
PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose Patients undergoing radical cystectomy face substantial but highly variable risks of major complications. Risk stratification may be enhanced by objective measures such as sarcopenia. ...Sarcopenia (loss of skeletal muscle mass) has emerged as a novel biomarker associated with adverse outcomes in many clinical contexts relevant to cystectomy. Based on these data we hypothesized that sarcopenia would be associated with increased 30-day major complications and mortality after radical cystectomy for bladder cancer. Materials and Methods We performed a retrospective study of patients treated with radical cystectomy at our institution from 2008 to 2011. Sarcopenia was assessed by measuring cross-sectional area of the psoas muscle (total psoas area) on preoperative computerized tomography. Cutoff points were developed and evaluated using ROC curves to determine predictive ability in men and women for outcomes of major complications and survival. Results Of 224 patients with bladder cancer 200 underwent preoperative computerized tomography within 1 month of surgery. Total psoas area was calculated with a mean score of 712 and 571 cm2 /m2 in men and women, respectively. A clear association was noted between major complications and lower total psoas area in women using a cutoff of 523 cm2 /m2 to define sarcopenia (AUC 0.70). Sarcopenia was not significantly associated with complications in men. There was a nonsignificant trend of sarcopenia with worse 2-year survival. Conclusions Sarcopenia in women was a predictor of major complications after radical cystectomy. Further research confirming sarcopenia as a useful predictor of complications would support the development of targeted interventions to mitigate the untoward effects of sarcopenia before cancer surgery.
Context. Chemical element transport processes are among the crucial physical processes needed for precise stellar modelling. Atomic diffusion by gravitational settling is usually taken into account, ...and is essential for helioseismic studies. On the other hand, radiative accelerations are rarely accounted for, act differently on the various chemical elements, and can strongly counteract gravity in some stellar mass domains. The resulting variations in the abundance profiles may significantly affect the structure of the star. Aims. The aim of this study is to determine whether radiative accelerations impact the structure of solar-like oscillating main-sequence stars observed by asteroseismic space missions. Methods. We implemented the calculation of radiative accelerations operating on C, N, O, Ne, Na, Mg, Al, Si, S, Ca, and Fe in the CESTAM code using the single-valued parameter method. We built and compared several grids of stellar models including gravitational settling, some with and others without radiative accelerations. We considered masses in the range 0.9, 1.5 M⊙ and three values of the metallicity around the solar value. For each metallicity we determined the mass range where differences between models due to radiative accelerations exceed the uncertainties of global seismic parameters of the Kepler Legacy sample or expected for PLATO observations. Results. We found that radiative accelerations may not be neglected for stellar masses higher than 1.1 M⊙ at solar metallicity. The difference in age due to their inclusion in models can reach 9% for the more massive stars of our grids. We estimated that the percentage of the PLATO core program stars whose modelling would require radiative accelerations ranges between 33% and 58% depending on the precision of the seismic data. Conclusions. We conclude that in the context of Kepler, TESS, and PLATO missions which provide (or will provide) high-quality seismic data, radiative accelerations can have a significant effect when properly inferring the properties of solar-like oscillators. This is particularly important for age inferences. However, the net effect for each individual star results from the competition between atomic diffusion including radiative accelerations and other internal transport processes. Rotationally induced transport processes for instance are believed to reduce the effects of atomic diffusion. This will be investigated in a forthcoming companion paper.
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