Performance of a low gain avalanche detector in a medical linac and characterisation of the beam profile.

Low gain avalanche detectors can measure charged particle fluences with high speed and spatial precision, and are a promising technology for radiation monitoring and dosimetry. A detector has been tested in a medical linac where single particles were observed with a time resolution of 50 ps. The integrated response is similar to a standard ionising chamber but with a spatial precision twenty times finer, and a temporal precision over 100 million times better, with the capability to measure the charge deposited by a single linac pulse. The unprecedented resolving power allows the structure of the ∼3 µs linac pulses to be viewed and the 350 ps sub-pulses in the train to be observed.

Small field detector correction factors kQclin,Qmsr (fclin,fmsr) for silicon-diode and diamond detectors with circular 6 MV fields derived using both empirical and numerical methods.

PURPOSE: The use of radiotherapy fields smaller than 3 cm in diameter has resulted in the need for accurate detector correction factors for small field dosimetry. However, published factors do not always agree and errors introduced by biased reference detectors, inaccurate Monte Carlo models, or experimental errors can be difficult to distinguish. The aim of this study was to provide a robust set of detector-correction factors for a range of detectors using numerical, empirical, and semiempirical techniques under the same conditions and to examine the consistency of these factors between techniques. METHODS: Empirical detector correction factors were derived based on small field output factor measurements for circular field sizes from 3.1 to 0.3 cm in diameter performed with a 6 MV beam. A PTW 60019 microDiamond detector was used as the reference dosimeter. Numerical detector correction factors for the same fields were derived based on calculations from a geant4 Monte Carlo model of the detectors and the Linac treatment head. Semiempirical detector correction factors were derived from the empirical output factors and the numerical dose-to-water calculations. RESULTS: The PTW 60019 microDiamond was found to over-respond at small field sizes resulting in a bias in the empirical detector correction factors. The over-response was similar in magnitude to that of the unshielded diode. Good agreement was generally found between semiempirical and numerical detector correction factors except for the PTW 60016 Diode P, where the numerical values showed a greater over-response than the semiempirical values by a factor of 3.7% for a 1.1 cm diameter field and higher for smaller fields. CONCLUSIONS: Detector correction factors based solely on empirical measurement or numerical calculation are subject to potential bias. A semiempirical approach, combining both empirical and numerical data, provided the most reliable results.

Analyses of ionizing radiation effects in vitro in peripheral blood lymphocytes with Raman spectroscopy.

The use of Raman spectroscopy to measure the biochemical profile of healthy and diseased cells and tissues may be a potential solution to many diagnostic problems in the clinic. Although extensively used to identify changes in the biochemical profiles of cancerous cells and tissue, Raman spectroscopy has been used less often for analyzing changes to the cellular environment by external factors such as ionizing radiation. In tandem with this, the biological impact of low doses of ionizing radiation remains poorly understood. Extensive studies have been performed on the radiobiological effects associated with radiation doses above 0.1 Gy, and are well characterized, but recent studies on low-dose radiation exposure have revealed complex and highly variable responses. We report here the novel finding that demonstrate the capability of Raman spectroscopy to detect radiation-induced damage responses in isolated lymphocytes irradiated with doses of 0.05 and 0.5 Gy. Lymphocytes were isolated from peripheral blood in a cohort of volunteers, cultured ex vivo and then irradiated. Within 1 h after irradiation spectral effects were observed with Raman microspectroscopy and principal component analysis and linear discriminant analysis at both doses relative to the sham-irradiated control (0 Gy). Cellular DNA damage was confirmed using parallel γ-H2AX fluorescence measurements on the extracted lymphocytes per donor and per dose. DNA damage measurements exhibited interindividual variability among both donors and dose, which matched that seen in the spectral variability in the lymphocyte cohort. Further evidence of links between spectral features and DNA damage was also observed, which may potentially allow noninvasive insight into the DNA remodeling that occurs after exposure to ionizing radiation.

Cell survival and DNA damage in normal prostate cells irradiated out-of-field.

Interest in out-of-field radiation dose has been increasing with the introduction of new techniques, such as volumetric modulated arc therapy (VMAT). These new techniques offer superior conformity of high-dose regions to the target compared to conventional techniques, however more normal tissue is exposed to low-dose radiation with VMAT. There is a potential increase in radiobiological effectiveness associated with lower energy photons delivered during VMAT as normal cells are exposed to a temporal change in incident photon energy spectrum. During VMAT deliveries, normal cells can be exposed to the primary radiation beam, as well as to transmission and scatter radiation. The impact of low-dose radiation, radiation-induced bystander effect and change in energy spectrum on normal cells is not well understood. The current study examined cell survival and DNA damage in normal prostate cells after exposure to out-of-field radiation both with and without the transfer of bystander factors. The effect of a change in energy spectrum out-of-field compared to in-field was also investigated. Prostate cancer (LNCaP) and normal prostate (PNT1A) cells were placed in-field and out-of-field, respectively, with the PNT1A cells being located 1 cm from the field edge when in-field cells were being irradiated with 2 Gy. Clonogenic and γ-H2AX assays were performed postirradiation to examine cell survival and DNA damage. The assays were repeated when bystander factors from the LNCaP cells were transferred to the PNT1A cells and also when the PNT1A cells were irradiated in-field to a different energy spectrum. An average out-of-field dose of 10.8 ± 4.2 cGy produced a significant reduction in colony volume and increase in the number of γ-H2AX foci/cell in the PNT1A cells compared to the sham-irradiated control cells. An adaptive response was observed in the PNT1A cells having first received a low out-of-field dose and then the bystander factors. The PNT1A cells showed a significant increase in γ-H2AX foci formation when irradiated to 20 cGy in-field in comparison to out-of-field. However, no significant difference in cell survival or colony volume was observed whether the PNT1A cells were irradiated in-field or out-of-field. Out-of-field radiation dose alone can have a damaging effect on the proliferation of PNT1A cells when a clinically relevant dose of 2 Gy is delivered in in-field. Out-of-field radiation with the transfer of bystander factors induces an adaptive response in the PNT1A cells.

Exosomes are involved in mediating radiation induced bystander signaling in human keratinocyte cells.

There is much evidence supporting the existence of bystander effects in cells that were never exposed to radiation. Directly irradiated cells and bystander cells can communicate with each other using gap junctional intercellular communication or by releasing soluble factors into the surrounding medium. Exosomes and microvesicles are also known to mediate communication between cells. The main aim of this study is to establish whether exosomes and microvesicles are involved in radiation induced bystander signaling. Human keratinocytes, HaCaT cells, were irradiated (0.005, 0.05 and 0.5 Gy) using γ rays produced from a cobalt 60 teletherapy unit. After irradiation, the cells were incubated for 1 h and the irradiated cell conditioned medium (ICCM) was harvested. Exosomes were isolated from the ICCM using ultracentrifugation. Exosomes were characterized using light scattering analysis (LSA) and scanning transmission electron microscopy (STEM). Cytotoxicity and reactive oxygen species assays and real time calcium imaging were performed either with ICCM from which exosomes and microvesicles were removed or with the exosome fraction resuspended in cell culture media. The characterization data showed a particle size distribution indicative of both exosomes (30-100 nm) and microvesicles (>100 nm) and the light scattering analysis showed increased concentration of both exosomes and microvesicles with increasing dose. Western blotting confirmed the presence of an exosomal protein marker, TSG 101. Treatment of unirradiated cells with ICCM in which exosomes and microvesicles were removed resulted in abrogation of ICCM induced effects such as reduction in viability, calcium influx and production of reactive oxygen species. Addition of exosomes to fresh media produced similar effects to complete ICCM. These results suggest a role for exosomes and microvesicles in radiation induced bystander signaling.

Bystander effect induced changes in apoptosis related proteins and terminal differentiation in in vitro murine bladder cultures.

PURPOSE: Radiation-induced bystander effects are now an established phenomenon seen in numerous cell and tissue culture models. The aim of this investigation was to examine the bystander signal and response in a multicellular primary tissue culture system in vitro. METHODS AND MATERIALS: Murine bladder samples were explanted and directly exposed to gamma radiation, or treated with irradiated tissue conditioned medium (ITCM) generated from the directly irradiated cultures. RESULTS: Results indicated that there was a strong bystander signal produced by the tissue that caused both dose-dependent and -independent changes in the ITCM treated tissue. Significantly increased B-cell lymphoma 2 (Bcl2) expression was noted after treatment with 0.5Gy and 5Gy ITCM (approximately 80%), while dose-dependent changes were observed in c-myelocytomatosis (cMyc) (39.48% at 0.5 Gy ITCM, 81.28% at 5 Gy ITCM) and the terminal differentiation marker uroplakin III (17.88% at 0.5 Gy). Nuclear fragmentation was also significantly increased at both doses of ITCM. CONCLUSION: These data suggest that the bystander signal produced in a multicellular environment induces complex changes in the ITCM-treated culture, and that these changes are reflective of a coordinated response to maintain integrity throughout the tissue.

A modified method of calculating the lateral build-up ratio for small electron fields.

This note outlines an improved method of calculating dose per monitor unit values for small electron fields using Khan's lateral build-up ratio (LBR). This modified method obtains the LBR directly from the ratio of measured, surface normalized, electron beam percentage depth dose curves. The LBR calculated using this modified method more accurately accounts for the change in lateral scatter with decreasing field size. The LBR is used along with Khan's dose per monitor unit formula to calculate dose per monitor unit values for a set of small fields. These calculated dose per monitor unit values are compared to measured values to within 3.5% for all circular fields and electron energies examined. The modified method was further tested using a small triangular field. A maximum difference of 4.8% was found.

The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects.

Much evidence now exists regarding radiation-induced bystander effects, but the mechanisms involved in the transduction of the signal are still unclear. The mitogen-activated protein kinase (MAPK) pathways have been linked to growth factor-mediated regulation of cellular events such as proliferation, senescence, differentiation and apoptosis. Activation of multiple MAPK pathways such as the ERK, JNK and p38 pathways have been shown to occur after exposure of cells to radiation and a variety of other toxic stresses. Previous studies have shown oxidative stress and calcium signaling to be important in radiation-induced bystander effects. The aim of the present study was to investigate MAPK signaling pathways in bystander cells exposed to irradiated cell conditioned medium (ICCM) and the role of oxidative metabolism and calcium signaling in the induction of bystander responses. Human keratinocytes (HPV-G cell line) were irradiated (0.005-5 Gy) using a cobalt-60 teletherapy unit. The medium was harvested 1 h postirradiation and transferred to recipient HPV-G cells. Phosphorylated forms of p38, JNK and ERK were studied by immunofluorescence 30 min-24 h after exposure to ICCM. Inhibitors of the ERK pathway (PD98059 and U0126), the JNK pathway (SP600125), and the p38 pathway (SB203580) were used to investigate whether bystander-induced cell death could be blocked. Cells were also incubated with ICCM in the presence of superoxide dismutase, catalase, EGTA, verapamil, nifedipine and thapsigargin to investigate whether bystander effects could be inhibited because of the known effects on calcium homeostasis. Activated forms of JNK and ERK proteins were observed after exposure to ICCM. Inhibition of the ERK pathway appeared to increase bystander-induced apoptosis, while inhibition of the JNK pathway appeared to decrease apoptosis. In addition, reactive oxygen species, such as superoxide and hydrogen peroxide, and calcium signaling were found to be important modulators of bystander responses. Further investigations of these signaling pathways may aid in the identification of novel therapeutic targets.

A method of predicting workload and staffing level for radiotherapy treatment planning as plan complexity changes.

When assessing the impact on workload from an expanding number of new patients and increasing treatment complexity, radiotherapy clinics find that oversimplified workload parameters, such as number of patients or number of fields, are not suitable for managing and predicting workload and organisational dimension. Although the basic treatment equivalent concept is available for predicting linear accelerator utilisation, no corresponding parameter has been available for radiotherapy treatment planning. In this study, we derive a simple workload indicator for treatment planning. The dose plan unit (DPU) takes the complexity of the treatment plan into account. Categorising plans according to complexity in their production, and measuring corresponding time for completing the plans in these categories, leads to the following baseline values for workload prediction: 1 DPU (non-computed tomography [CT]), 3 DPU (CT-contour) and 6 DPU (full-CT). The measured average productivity of 0.65 DPU per hour (1 standard deviation, SD = 0.08 DPU), or alternatively 1 DPU = 92 min, for a dosimetrist in this clinic indicates that 79.0 DPU can be produced by each dosimetrist per month within normal working hours. The predictive power of the DPU is shown in terms of using it to quantify the impact on workload in treatment planning of changing treatment protocols for a particular anatomic treatment site.

Dose escalation of chart in non-small cell lung cancer: is three-dimensional conformal radiation therapy really necessary?

PURPOSE: To evaluate, preclinically, the potential for dose escalation of continuous, hyperfractionated, accelerated radiation therapy (CHART) for non small-cell lung cancer (NSCLC), we examined the strategy of omission of elective nodal irradiation with and without the application of three-dimensional conformal radiation technology (3DCRT). METHODS AND MATERIALS: 2D, conventional therapy plans were designed according to the specifications of CHART for 18 patients with NSCLC (Stages Ib, IIb, IIIa, and IIIb). Further plans were generated with the omission of elective nodal irradiation (ENI) from the treatment portals (2D minus ENI plans [2D-ENI plans]). Both sets were inserted in the patient's planning computed tomographies (CTs). These reconstructed plans were then compared to alternative, three-dimensional treatment plans which had been generated de novo, with the omission of ENI: 3D minus elective nodal irradiation (3D-ENI plans). Dose delivery to the planning target volumes (PTVs) and to the organs at risk were compared between the 3 sets of corresponding plans. The potential for dose escalation of each patient's 2D-ENI and 3D-ENI plan beyond 54 Gy, standard to CHART, was also determined. RESULTS: PTV coverage was suboptimal in the 2D CHART and the 2D-ENI plans. Only in the 3D-ENI plans did 100% of the PTV get > or = 95% of the dose prescribed (i.e., 51.5 Gy [51.3-52.2]). Using 3D-ENI plans significantly reduced the dose received by the spinal cord, the mean and median doses to the esophagus and the heart. It did not significantly reduce the lung dose when compared to 2D-ENI plans. Escalation of the dose (minimum > or = 1 Gy) with optimal PTV coverage was possible in 55.5% of patients using 3D-ENI, but was possible only in 16.6% when using the 2D-ENI planning strategy. CONCLUSIONS: 3DCRT is fundamental to achieving optimal PTV coverage in NSCLC. A policy of omission of elective nodal irradiation alone (and using 2D technology) will not achieve optimal PTV coverage or dose escalation. 3DCRT with omission of ENI can achieve true escalation of CHART in 55.5% of tumors, depending on their site and N-stage.

An improved method for rebinning kernels from cylindrical to Cartesian coordinates.

This paper describes the errors in rebinning photon dose point spread functions and pencil beam kernels (PBKs) from cylindrical to Cartesian coordinates. An area overlap method, which assumes that the fractional energy deposited per unit volume remains constant within cylindrical voxels, provides large deviations (up to 20%) in rebinned Cartesian voxels while conserving the total energy. A modified area overlap method is presented that allows the fractional energy deposited per unit volume within cylindrical voxels to vary according to an interpolating function. This method rebins the kernels accurately in each Cartesian voxel while conserving the total energy. The dose distributions were computed for a partially blocked beam of uniform fluence using the Cartesian coordinate kernel and the kernels rebinned by both methods. The kernel rebinned by the modified area overlap method provided errors less than 1.7%, while the kernel rebinned by the area overlap method gave errors up to 4.4%.

Backscatter into the beam monitor chamber: implications for dosimetry of asymmetric collimators.

Backscatter from the asymmetric collimators of a linac into the beam monitor chamber (BMC) has been investigated for two accelerators having different BMC configurations. The effect has been quantified as a function of field size and collimator jaw position for 6 and 18 MV beams. The results indicate a maximum 2.5% (6 MV) and 4% (18 MV) decrease in output in one case and a negligible effect in the other case. The experiments indicate that the difference can be attributed to the different construction of the BMC's for the two accelerators.