Low-dose hypersensitivity in Chinese hamster V79 cells targeted with counted protons using a charged-particle microbeam

The Gray Laboratory charged-particle microbeam has been used to assess the clonogenic ability of Chinese hamster V79 cells after irradiation of their nuclei with a precisely defined number of protons with energies of 1.0 and 3.2 MeV. The microbeam uses a 1-mum. silica capillary collimator to deliver protons to subcellular targets with high accuracy. The detection system is based on a miniature photomultiplier tube positioned above the cell dish, which detects the photons generated by the passage of the charged particles through an 18-mum-thick scintillator placed below the cells. With this system, a detection efficiency of greater than 99% is achieved. The cells are plated on specially designed dishes (3-mum-thick Mylar base), and the nuclei are identified by fluorescence microscopy. After an incubation period of 3 days, the cells are revisited individually to assess the formation of colonies from the surviving cells. For each energy investigated, the survival curve obtained for the microbeam shows a significant deviation below I Gy from a response extrapolated using the LQ model for the survival data above 1 Gy. The data are well fitted by a model that supports the hypothesis that radioresistance is induced by low-dose hypersensitivity. These studies demonstrate the potential of the microbeam for performing studies of the effects of single charged particles on cells in vitro. The hypersensitive responses observed are comparable with those reported by others using different radiations and techniques. (C) 2001 by Radiation Research Society.

The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC + ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with > 10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML. Leukemia (2011) 25, 1122-1127; doi:10.1038/leu.2011.59; published online 8 April 2011

Biological effectiveness on live cells of laser driven protons at dose rates exceeding 109 Gy/s

The ultrashort duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 109 Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source.

Biological Cell Irradiation At Ultrahigh Dose Rate Employing Laser Driven Protons

The ultrashort duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 10⁹Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source. 

Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.

Renal and cardiovascular effects of caffeine:a dose-response study

The effects of increasing oral doses of caffeine (45, 90, 180 and 360 mg) on effective renal plasma flow (ERPF), plasma renin activity (PRA), serum electrolytes, plasma noradrenaline, blood pressure and heart rate were studied in eight healthy male volunteers. Urine volume was increased by 360 mg of caffeine only. At caffeine doses greater than 90 mg urinary sodium excretion was significantly increased. There were no changes in ERPF. Serum potassium was significantly reduced by 360 mg of caffeine. Caffeine increased systolic pressure in a dose related manner. Diastolic pressure was also increased, but not in relation to dose. A 360 mg dose of caffeine produced a late increase in heart rate. These changes were not associated with any alterations in PRA or in plasma noradrenaline.

A Randomized, Double-Blind, Dose-Finding, Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

BACKGROUND: Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. OBJECTIVE: To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of =50% in baseline prostate-specific antigen (PSA) levels. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. RESULTS AND LIMITATIONS: The study met its primary end point with a statistically significant dose-response relationship in confirmed =50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A =50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p

Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate

Background: Fluticasone propionate was introduced in 1993 in the UK as a potentially safer inhaled corticosteroid than those already in use. The efficacy and safety of fluticasone has been established at recommended doses of 200 µg/day, but not at the higher doses that are often used.

Methods: Growth retardation was observed in six severely asthmatic children after introduction of high-dose fluticasone propionate treatment (dry powder). Assessment of cortisol response was by insulin-induced hypoglycaemia in three cases, by short tetracosactrin test in two, and by low-dose tetracosactrin and 24-hour urinary cortisol/creatinine ratio in one.

Findings: Six children with growth retardation noted after treatment with high-dose fluticasone propionate were found to have adrenal suppression. In one case the growth rate and cortisol response returned to normal 9 months after the fluticasone dose was reduced to 500 µg/day.

Interpretation: When high doses of fluticasone propionate are used, growth may be retarded and adrenal suppression may occur.

Optimization of image quality and dose for Varian aS500 electronic portal imaging devices (EPIDs)

This study was carried out to investigate whether the electronic portal imaging (EPI) acquisition process could be optimized, and as a result tolerance and action levels be set for the PIPSPro QC-3V phantom image quality assessment. The aim of the optimization process was to reduce the dose delivered to the patient while maintaining a clinically acceptable image quality. This is of interest when images are acquired in addition to the planned patient treatment, rather than images being acquired using the treatment field during a patient's treatment. A series of phantoms were used to assess image quality for different acquisition settings relative to the baseline values obtained following acceptance testing. Eight Varian aS500 EPID systems on four matched Varian 600C/D linacs and four matched Varian 2100C/D linacs were compared for consistency of performance and images were acquired at the four main orthogonal gantry angles. Images were acquired using a 6 MV beam operating at 100 MU min(-1) and the low-dose acquisition mode. Doses used in the comparison were measured using a Farmer ionization chamber placed at d(max) in solid water. The results demonstrated that the number of reset frames did not have any influence on the image contrast, but the number of frame averages did. The expected increase in noise with corresponding decrease in contrast was also observed when reducing the number of frame averages. The optimal settings for the low-dose acquisition mode with respect to image quality and dose were found to be one reset frame and three frame averages. All patients at the Northern Ireland Cancer Centre are now imaged using one reset frame and three frame averages in the 6 MV 100 MU min(-1) low-dose acquisition mode. Routine EPID QC contrast tolerance (+/-10) and action (+/-20) levels using the PIPSPro phantom based around expected values of 190 (Varian 600C/D) and 225 (Varian 2100C/D) have been introduced. The dose at dmax from electronic portal imaging has been reduced by approximately 28%, and while the image quality has been reduced, the images produced are still clinically acceptable.

Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin:a randomized, double-blind, placebo-controlled trial

To evaluate the dose-response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes.

Radiobiology at ultra-high dose rates employing laser-driven ions

The potential that laser based particle accelerators offer to solve sizing and cost issues arising with conventional proton therapy has generated great interest in the understanding and development of laser ion acceleration, and in investigating the radiobiological effects induced by laser accelerated ions. Laser-driven ions are produced in bursts of ultra-short duration resulting in ultra-high dose rates, and an investigation at Queen's University Belfast was carried out to investigate this virtually unexplored regime of cell rdaiobiology. This employed the TARANIS terawatt laser producing protons in the MeV range for proton irradiation, with dose rates exceeding 10 Gys on a single exposure. A clonogenic assay was implemented to analyse the biological effect of proton irradiation on V79 cells, which, when compared to data obtained with the same cell line irradiated with conventionally accelerated protons, was found to show no significant difference. A Relative Biological effectiveness of 1.4±0.2 at 10 % Survival Fraction was estimated from a comparison with a 225 kVp X-ray source. © 2013 SPIE.

Investigations of DNA damage induction and repair resulting from cellular exposure to high dose-rate pulsed proton beams

Studies regarding the radiobiological effects of low dose radiation, microbeam irradiation services have been developed in the world and today laser acceleration of protons and heavy ions may be used in radiation therapy. The application of different facilities is essential for studying bystander effects and relating signalling phenomena in different cells or tissues. In particular the use of ion beams results advantageous in cancer radiotherapy compared to more commonly used X-rays, since the ability of ions in delivering lethal amount of doses into the target tumour avoiding or limiting damage to the contiguous healthy tissues. At the INFN-LNS in Catania, a multidisciplinary radiobiology group is strategically structured aimed to develop radiobiological research, finalised to therapeutic applications, compatible with the use of high dose laser-driven ion beams. The characteristic non-continuous dose rates with several orders of magnitude of laser-driven ion beams makes this facility very interesting in the cellular systems' response to ultra-high dose rates with non-conventional pulse time intervals cellular studies. Our group have projected to examine the effect of high dose laser-driven ion beams on two cellular types: foetal fibroblasts (normal control cells) and DU145 (prostate cancer cells), studying the modulation of some different bio-molecular parameters, in particular cell proliferation and viability, DNA damage, redox cellular status, morphological alterations of both the cytoskeleton components and some cell organelles and the possible presence of apoptotic or necrotic cell death. Our group performed preliminary experiments with high energy (60 MeV), dose rate of 10 Gy/min, doses of 1, 2, 3 Gy and LET 1 keV/µm on human foetal fibroblasts (control cells). We observed that cell viability was not influenced by the characteristics of the beam, the irradiation conditions or the analysis time. Conversely, DNA damage was present at time 0, immediately following irradiation in a dose-dependent manner. The analysis of repair capability showed that the cells irradiated with 1 and 2 Gy almost completely recovered from the damage, but not, however, 3 Gy treated cells in which DNA damage was not recovered. In addition, the results indicate the importance of the use of an appropriate control in radiobiological in vitro analysis.