Out-of-field cell survival following exposure to intensity-modulated radiation fields

PURPOSE:
To determine the in-field and out-of-field cell survival of cells irradiated with either primary field or scattered radiation in the presence and absence of intercellular communication.
METHODS AND MATERIALS:
Cell survival was determined by clonogenic assay in human prostate cancer (DU145) and primary fibroblast (AGO1552) cells following exposure to different field configurations delivered using a 6-MV photon beam produced with a Varian linear accelerator.
RESULTS:
Nonuniform dose distributions were delivered using a multileaf collimator (MLC) in which half of the cell population was shielded. Clonogenic survival in the shielded region was significantly lower than that predicted from the linear quadratic model. In both cell lines, the out-of-field responses appeared to saturate at 40%-50% survival at a scattered dose of 0.70 Gy in DU-145 cells and 0.24 Gy in AGO1522 cells. There was an approximately eightfold difference in the initial slopes of the out-of-field response compared with the a-component of the uniform field response. In contrast, cells in the exposed part of the field showed increased survival. These observations were abrogated by direct physical inhibition of cellular communication and by the addition of the inducible nitric oxide synthase inhibitor aminoguanidine known to inhibit intercellular bystander effects. Additional studies showed the proportion of cells irradiated and dose delivered to the shielded and exposed regions of the field to impact on response.
CONCLUSIONS:
These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields with cellular communication between differentially irradiated cell populations playing an important role. Validation of these observations in additional cell models may facilitate the refinement of existing radiobiological models and the observations considered important determinants of cell survival.

Temporal characterization and in vitro comparison of cell survival following the delivery of 3D-conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT)

A phantom was designed and implemented for the delivery of treatment plans to cells in vitro. Single beam, 3D-conformal radiotherapy (3D-CRT) plans, inverse planned five-field intensity-modulated radiation therapy (IMRT), nine-field IMRT, single-arc volumetric modulated arc therapy (VMAT) and dual-arc VMAT plans were created on a CT scan of the phantom to deliver 3 Gy to the cell layer and verified using a Farmer chamber, 2D ionization chamber array and gafchromic film. Each plan was delivered to a 2D ionization chamber array to assess the temporal characteristics of the plan including delivery time and 'cell's eye view' for the central ionization chamber. The effective fraction time, defined as the percentage of the fraction time where any dose is delivered to each point examined, was also assessed across 120 ionization chambers. Each plan was delivered to human prostate cancer DU-145 cells and normal primary AGO-1522b fibroblast cells. Uniform beams were delivered to each cell line with the delivery time varying from 0.5 to 20.54 min. Effective fraction time was found to increase with a decreasing number of beams or arcs. For a uniform beam delivery, AGO-1552b cells exhibited a statistically significant trend towards increased survival with increased delivery time. This trend was not repeated when the different modulated clinical delivery methods were used. Less sensitive DU-145 cells did not exhibit a significant trend towards increased survival with increased delivery time for either the uniform or clinical deliveries. These results confirm that dose rate effects are most prevalent in more radiosensitive cells. Cell survival data generated from uniform beam deliveries over a range of dose rates and delivery times may not always be accurate in predicting response to more complex delivery techniques, such as IMRT and VMAT.

Interactions of 12-lipoxygenase with phospholipase A(2) isoforms following platelet activation through the glycoprotein VI collagen receptor

Recent studies implicate the collagen receptor, glycoprotein VI (GPVI) in activation of platelet 12-lipoxygenase (p12-LOX). Herein, we show that GPVI-stimulated 12-hydro(peroxy)eicosatetraenoic acid (H(P)ETE) synthesis is inhibited by palmityl trifluromethyl ketone or oleyloxyethyl phosphocholine, but not bromoenol lactone, implicating secretory and cytosolic, but not calcium-independent phospholipase A(2) (PLA(2)) isoforms. Also, following GPVI activation, 12-LOX co-immunoprecipitates with both cytosolic and secretory PLA(2), (sPLA(2)). Finally, venoms containing sPLA(2) acutely activate p12-LOX in a dose-dependent manner. This study shows that platelet 12-H(P)ETE generation utilizes arachidonate substrate from both c- and sPLA(2) and that 12-LOX functionally associates with both PLA(2) isoforms. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Patterns of hospitalisation before and following initiation of haemodialysis: a 5 year single centre study

Background: The utilisation of healthcare resources by prevalent haemodialysis patients has been robustly evaluated with regard to the provision of outpatient haemodialysis; however, the impact of hospitalisation among such patients is poorly defined. Minimal information is available in the UK to estimate the health and economic burden associated with the inpatient management of prevalent haemodialysis patients. The aim of this study was to assess the pattern of hospitalisation among a cohort of haemodialysis patients, before and following their initiation of haemodialysis. In addition the study sought to assess the impact of their admissions on bed occupancy in a large tertiary referral hospital in a single region in the UK.

Methods: All admission episodes were reviewed and those receiving dialysis with the Belfast City Hospital Programme were identified over a 5 year period from January 2001 to December 2005. This tertiary referral centre provides dialysis services for a population of approximately 700?000 and additional specialist renal services for the remainder of Northern Ireland. The frequency and duration of hospitalisation, and contribution to bed day occupancy of haemodialysis patients, was determined and compared to other common conditions which are known to be associated with high bed occupancy. In addition, the pattern and timing of admissions in dialysis patients in relation to their dialysis initiation date was assessed.

Results: Over the 5 year study period, 798 haemodialysis patients were admitted a total of 2882 times. These accounted for 2.5% of all admissions episodes; the median number of admissions for these patients was 3 (2–5) which compared with 1 (1–2) for non-dialysis patients. The majority of first hospitalisations (54%) were within 100 days before or after commencement of maintenance dialysis therapy. In all clinical specialties the median length of stay for haemodialysis patients was significantly longer than for patients not on haemodialysis (p=0.004). In multivariate analysis with adjustment for age, gender, and other clinically relevant diagnostic codes, maintenance haemodialysis patients stayed on average 3.75 times longer than other patient groups (ratio of geometric means 3.75, IQR 3.46–4.06).

Conclusions: Maintenance haemodialysis therapy is an important risk factor for prolonged hospitalisation regardless of the primary reason for admission. Such patients require admission more frequently than the general hospital population, particularly within 100 days before and after initiation of their first dialysis treatment.