A single ascending dose study of single-stranded oligodeoxyribonucleotide RO7062931 in Chinese healthy volunteers.

RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85-day follow-up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment-related) and seven of eight (87.5%) placebo recipients (n = 1 treatment-related). Apart from two moderate-intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection-related reactions, and headache. Dose-proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra-dose-proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well-tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first-in-human study of RO7062931.

Adrenomedullin and diabetes.

Adrenomedullin (ADM) is a peptide hormone widely expressed in different tissues, especially in the vasculature. Apart from its vasodilatatory and hypotensive effect, it plays multiple roles in the regulation of hormonal secretion, glucose metabolism and inflammatory response. ADM regulates insulin balance and may participate in the development of diabetes. The plasma level of ADM is increased in people with diabetes, while in healthy individuals the plasma ADM concentration remains low. Plasma ADM levels are further increased in patients with diabetic complications. In type 1 diabetes, plasma ADM level is correlated with renal failure and retinopathy, while in type 2 diabetes its level is linked with a wider range of complications. The elevation of ADM level in diabetes may be due to hyperinsulinemia, oxidative stress and endothelial injury. At the same time, a rise in plasma ADM level can trigger the onset of diabetes. Strategies to reduce ADM level should be explored so as to reduce diabetic complications.

Measuring solar UV radiation with EBT radiochromic film.

Ultraviolet radiation dosimetry has been performed with the use of a radiochromic film dosimeter called Gafchromic EBT for solar radiation exposure. The film changes from a clear colour to blue colour when exposed to ultraviolet radiation and results have shown that the colour change is reproducible within ±10% at 5 kJ m(-2) UV exposure under various conditions of solar radiation. Parameters tested included changes in season (summer versus winter exposure), time of day, as well as sky conditions such as cloudy skies versus clear skies. As the radiochromic films' permanent colour change occurs in the visible wavelengths the film can be analysed with a desktop scanner with the most sensitive channel for analysis being the red component of the signal. Results showed that an exposure of 5 kJ m(-2) (approximately 1 h exposure in full sun during summer) produced an approximate 0.28 change in the net OD when analysed in reflection mode on the desktop scanner which is significant darkening. The main advantages of this film type, and thus the new EBT2 film which has replaced EBT for measurement of UV exposure, is the visible colour change and thus easy analysis using a desktop scanner, its uniformity in response and its robust physical strength for use in outside exposure situations.

Scanning orientation and polarization effects for XRQA radiochromic film.

Gafchromic XRQA radiochromic film, is an effective tool for quality assurance and dose assessment in kilovoltage radiotherapy and diagnostic applications. Like other Gafchromic film products, XRQA film exhibits a variation in dose to reflected optical density response with angle of rotation when analysed with a light source that is partially or fully polarised such as a desktop scanner. Although warnings are not given on manufacturers specifications, this can affect dosimetry accuracy and we recommend that it is essential to scan all XRQA films in the same orientation. The effect is not as pronounced as EBT Gafchromic film. The magnitude of this variation has been measured and shown to be up to 16 ± 2% (1SD) using a fully linear polarised light source was seen with a 90° angle rotation. This would be the maximum variation seen on a desktop scanner with a fully polarised light source. For our standard desktop scanner (Epson v700) a mean variation of 2 ± 1% from 0 cGy to 20 cGy applied dose was measured as compared to 8 ± 2% for EBT Gafchromic. We recommend that to decrease uncertainty in dose measurement, accurate alignment of the calibration films to experimental films be performed on a regular basis. This is especially important if your desktop scanner has a high degree of polarization of its light source.

Measurement of dose reductions for superficial x-rays backscattered from bone interfaces.

Accurate measurement and knowledge of dose delivered during superficial x-ray radiotherapy is required for patient dose assessment. Some tumours treated near the surface (within the first few centimetres) can have large posterior bone structures. This can cause perturbations to dose delivered due to changed backscatter contributions from the bony structure as compared to full water or tissue scattering conditions. Measured results have shown that up to 7.5% of Dmax reductions in dose can occur near the water/bone interface for 100 kVp, using 10 cm diameter field sizes when a 1 cm thick slab of bone is located at 2 cm depth. At smaller field sizes such as 2 cm diameter these values reduce to 2% for the same energy. Larger variations (up to 12.5% of maximum) have been seen at the phantom surface when the bone layer is directly behind the point of interest (within 0.5 mm) and smaller effects (up to 5% of maximum) at depths down to 5 cm. Interesting to note is the fact that for larger field sizes, an increase in percentage dose is found at the water/bone interface due to the production of low energy backscattered electrons similar to the effect found in lead. However, they are much smaller in magnitude and thus would not cause any significant dosimetric effects. In the case where large bony structures lie relatively close to the surface and the tissue above this region is being treated, a dosimeter such as radiochromic film can be used to estimate the dose reduction that may occur due to the changed backscatter conditions.

Solid water phantom heat conduction: Heating and cooling rates.

Solid water is often the phantom material of choice for dosimetry procedures in radiotherapy high-energy X-ray and electron beam radiation calibration and quality assurance. This note investigates variation in heat conduction that can occur for a common commercially available solid water stack phantom when a temperature differential occurs between the phantom and ambient temperature. These variations in temperature can then affect radiation measurements and thus the accuracy of radiation dosimetry. In this manuscript, we aim to investigate the variations in temperature which can occur in radiation measurement incorporated (RMI) solid water phantoms, their thermal properties and the effects on radiation dosimetry which can occur because of temperature differentials. Results have shown that the rate of temperature change at a phantom center is a complex function but appears relatively proportional to the surface area of the phantom in normal clinical usage. It is also dependent on the thermal conductivity of any material in contact with the phantom; and the nature of the phantom construction, i.e., the number and thickness of slices within the phantom. A thermal time constant of approximately 20 min was measured for a 2-cm solid water phantom slice when located on a steel workbench in comparison to 60 min when located on a wooden workbench (linac couch insert). It is found that for larger solid water stack phantoms, a transient (within 1 degrees C) thermal equilibrium exists at the center for up to 2 h, before the temperature begins to change. This is assumed to be due to the insulating properties of multiple slices within the stack, whereby very small air spaces are introduced inhibiting the heat conduction through the phantom material. It is therefore recommended that the solid water/phantom material is kept within the treatment room for closest thermal accuracy conditions or at least placed within the room approximately 10 h before dosimetry measurements. If these options are not available, a standard linear interpolation method for calculation of temperature should be used to minimize uncertainty of temperature measurements.

Measurement of radiotherapy superficial X-ray dose under eye shields with radiochromic film.

Accurate measurement and knowledge of dose delivered under eye shield during superficial X-ray radiotherapy is required for patient peripheral dose assessment. Critical structures can include the cornea, lens and retina. Measurement of dose under eye shields has been historically performed with Thermoluminescent Dosimeters (TLD's) due to their small size and design. Restrictions include the energy dependence and the fact that they only provide a point dose assessment. This note investigates the use of a low energy dependence radiochromic thin film for measurement of dose under eye shields in a phantom and compares results to theoretical calculation of dose. Results have shown a good match between predicted and experimentally measured results at the centre of an eye shield irradiated with 50kVp and 150kVp beams. The added advantage of radiochromic film compared to TLD measurements is the two dimensional dose map which is recorded for the assessment of dose providing not only an assessment at the site of the cornea, lens and retina in a phantom but in other areas as well. Radiochromic film has been found to accurately measure dose under eye shield in phantom treatments.

Megavoltage x-ray skin dose variation with an angle using grid carbon fibre couch tops.

It is well known that a skin dose from high-energy x-ray radiation varies with the angle of beam incidence or the presence of a radiotherapy linear accelerator couch top material. This note investigates changes produced to the skin dose from a Varian carbon fibre grid couch top at differing angles of incidence for 6 MV x-rays as is often the case clinically. Results have shown that the skin dose can easily be measured using an EBT Gafchromic film whereby the delivered skin dose can be quantified to a high level of spatial resolution, not easily achieved with other skin dose detectors. Results have shown a significant increase in the skin dose specifically at the point of a cross-sectional carbon fibre grid. Values in % of the skin dose increased from approximately 27% (an open area within a 10 cm x 10 cm field) up to 55% (same field size) at the centre of the carbon fibre mesh strip (0 degrees incidence). This is compared to 19% of the skin dose for an open field of a 10 cm x 10 cm beam without the couch material present. At larger angles similar effects occur with values changing from 52% to 75% (60 degrees , 10 cm x 10 cm) in the open area and under the grid, respectively. This produces a wave effect for the skin dose. The average skin dose magnitude increases with the angle of incidence of the beam, ranging from 37.5% to 66% from 0 degrees to 60 degrees (10 x 10 cm), respectively. The symmetric wave nature of the skin dose profile skews to deliver an increased dose on the posterior side of the carbon fibre grid as the angle of incidence increases. Simulated fractional dose delivery on a phantom has shown that over 30 fractions the wave nature of the delivered skin dose is minimized due to the random nature of most patient positioning on the treatment couch. However, some variations are still present as the ratio of the open to grid area is approximately 4:1 and the dose spread is not necessarily completely averaged during a typical fractionated radiotherapy treatment. As such, if the treatment type results in a more rigorously positioned patient on the treatment couch, the wave nature of skin dose delivery may need to be taken into account.

X-Ray energy dependence of the dose response of SIRAD radiation dosimeters.

SIRADs (self-indicating instant radiation alert dosimeters) are designed to measure accident radiation doses. As the energy of radiation is usually unknown in such situations, a detector with a weak energy dependence of its response to dose would be ideal. We have studied the energy dependence of the dose response of SIRADs in the range from 50kVp to 10MV, which corresponds to photon equivalent energies from 25.5keV to 2.2MeV. The response to the same dose at 25.5keV is (29+/-4)%(+/-1s) lower than the response at 1.4MeV. The response to a dose slowly increases with radiation energy. This energy dependence is relatively weak in comparison with the dependence for radiographic films and similar in magnitude to the dependence for lithium fluoride thermoluminescence dosimeters. This energy dependence of the response diminishes the accuracy of dose assessments in radiation fields of unknown energy, but does not significantly compromise the core ability of the devices to provide visual estimates of radiation doses.

A practical method for determining organ dose during CT examination.

A practical method, based on depth dose, for determining organ dose during computed tomography (CT) examination is presented. For 4-slice spiral CT scans, performed at radii of 0, 37.5, 75.0, 112.5, and 150.0 mm, measurement of depth dose has been made using thermoluminescent dosimeters (TLDs) inserted into a modified International Electrotechnical Commission (IEC) standard dosimetry phantom and also additional TLDs placed on the surface of the phantom. A regression equation-linking dose with distance from the center of the phantom has been formulated, from which dose to a point of interest relative to the surface dose can also be calculated. The approximation reflects the attenuation properties of X-rays in the phantom. Using the equation, an estimate of organ dose can be ascertained for CT examination, assuming water equivalence of human tissue and a known organ position and volume. Using the 4-slice spiral scanner, relative doses to a patients' lung have been calculated, the location and size of the lung in vivo being found from the CT scan image, and the lung being divided into 38 segments to calculate the relative dose. Results from our test case show the dose to the lung to have been 69+/-13% of surface dose.

Visible absorption spectra of radiation exposed SIRAD dosimeters.

SIRAD badge dosimeters are a new type of personal dosimeter designed to measure radiation exposure up to 200 R and give a visual qualitative measurement of exposure. This is performed using the active dosimeter window, which contains a radiochromic material amalgamated in the badge assembly. When irradiated, the badges active window turns blue, which can be matched against the given colour chart for a qualitative assessment of the exposure received. Measurements have been performed to analyse the absorption spectra of the active window, and results show that the window automatically turns a blue colour upon irradiation and produces two peaks in the absorption spectra located at 617 nm and 567 nm. When analysed with a common computer desktop scanner, the optical density response of the film to radiation exposure is non-linear but reproducible. The net OD of the film was 0.21 at 50 R exposure and 0.31 at 200 R exposure when irradiated with a 6 MV x-ray energy beam. When compared to the calibration colour strips at 6 MV x-ray energy the film's OD response matches relatively well within 3.5%. An approximate 8% reduction in measured OD to exposure was seen for 250 kVp x-rays compared to 6 MV x-rays. The film provides an adequate measurement and visually qualitative assessment of radiation exposure for levels in the range of 0 to 200 R.

Measurement of high energy x-ray beam penumbra with Gafchromic EBT radiochromic film.

High energy x-ray beam penumbra are measured using Gafchromic EBT film. Gafchromic EBT, due to its limited energy dependence and high spatial resolution provide a high level of accuracy for dose assessment in penumbral regions. The spatial resolution of film detector systems is normally limited by the scanning resolution of the densitometer. Penumbral widths (80%/20%) measured at Dmax were found to be 2.8, 3.0, 3.2, and 3.4 mm (+/- 0.2 mm) using 5, 10, 20, and 30 cm square field sizes, respectively, for a 6 MV linear accelerator produced x-ray beam. This is compared to 3.2 mm +/- 0.2 mm (Kodak EDR2) and 3.6 mm +/- 0.2 mm (Kodak X-Omat V) at 10 cm x 10 cm measured using radiographic film. Using a zero volume extrapolation technique for ionization chamber measurements, the 10 cm X 10 cm field penumbra at Dmax was measured to be 3.1 mm, a close match to Gafchromic EBT results. Penumbral measurements can also be made at other depths, including the surface, as the film does not suffer significantly from dosimetric variations caused by changing x-ray energy spectra. Gafchromic EBT film provides an adequate measure of penumbral dose for high energy x-ray beams.

Measurement of energy dependence for XRCT radiochromic film.

Gafchromic XRCT, radiochromic film is assessed over a broad energy range, from kilovoltage to megavoltage x rays for variations in reflected optical density to dose response. A large energy dependence was found with reflected optical density output for the same delivered dose varying from 7.8 +/- 0.35 at 25.5 keV (50 kVp) peaking at 12.1 +/- 0.5 at 54 keV (125 kVp) to 0.975 +/- 0.03 at 2300 keV (10 MV) when normalized to 1 at 1400 keV (6 MV) energy. The response is constant (within 3%) in the 36-69 keV equivalent photon energy range, which corresponds to x-ray tube generating potentials of approximately 100-150 kVp. This matches well with beam qualities for diagnostic computed topography applications.

Absorption spectra of irradiated XRCT radiochromic film.

Gafchromic XRCT radiochromic film is a self-developing high sensitivity radiochromic film product which can be used for assessment of delivered radiation doses which could match applications such as computed tomography (CT) dosimetry. The film automatically changes colour upon irradiation changing from a yellow to green/brown colour. The absorption spectra of Gafchromic XRCT radiochromic film as measured with reflectance spectrophotometry have been investigated to analyse the dosimetry characteristics of the film. Results show two main absorption peaks produced from irradiation located at 636 nm and 585 nm. This is similar to EBT Gafchromic film. A high level of sensitivity is found for this film with a 1 cGy applied dose producing an approximate net optical density change of 0.3 at 636 nm. This high sensitivity combined with its relatively energy independent nature around the 100 kVp to 150 kVp x-ray energy range provides a unique enhancement in dosimetric measurement capabilities over currently available dosimetry films for CT applications.

Independence of calibration curves for EBT Gafchromic films of the size of high-energy X-ray fields.

The EBT Gafchromic radiochromic film is a relatively new product designed specifically for dosimetry in radiation therapy. Due to the weak dependence of its response on the photon energy (variations are below 10% in the 50 kVp-10 MVp range), the film is ideal for dosimetry when the photon energy spectrum may be changing or unknown. In order to convert a map of optical densities into a map of absorbed radiation doses, a calibration curve constructed on the basis of standard calibration films is necessary. Our results have shown that, with the EBT Gafchromic film, one can use the same calibration curve for 6-MV X-ray fields of any size in the range from 5 x 5 cm(2) up to 40 x 40 cm(2). This is not the case for radiographic films, such as Kodak X-Omat V, whose response to the same dose varies approximately by 10% depending on the field size in this range. This insensitivity of the EBT Gafchromic film to size of the radiation field makes it possible to assess doses delivered by small radiation fields. With the help of this film, it was shown that the output factor for a 0.5 x 0.5 cm(2) field is 0.60+/-0.03 (2SD) relative to the 10 x 10 cm(2) field.

Weak energy dependence of EBT gafchromic film dose response in the 50 kVp-10 MVp X-ray range.

The energy dependence of the dose response of EBT Gafchromic film is assessed over a broad energy range, from superficial to megavoltage X-rays. The film is auto-developing and sensitive, it provides accurate dose assessment of low doses (about 1-2 Gy) used in radiotherapy. The energy dependence of the response of EBT film was found to be very weak: the variations do not exceed 10% over the range from 50 kVp to 10 MVp X-rays. By contrast, variations of the response of Gafchromic HS film are as big as 30% over the same range, and variations of the response of Radiographic film exceed one order of magnitude. This weak dependence provides significantly higher accuracy of dose measurements under conditions of varying spectral quality of X-ray beams, which are common in radiation therapy.

Post-irradiation colouration of Gafchromic EBT radiochromic film.

Gafchromic EBT (International Specialty Products, NJ, USA), radiochromic film is one of the newest radiation-induced auto-developing x-ray analysis films available for therapeutic radiation dosimetry in radiotherapy applications. Part of any radiochromic film product which undergoes a polymerization reaction for automatic darkening is an associated post-irradiation colouration whereby the film continues to darken after irradiation has ceased. The Gafchromic EBT film has been shown to produce an approximate 6% to 9% increase in post-irradiation optical density within the first 12 h of irradiation within the 1 Gy to 5 Gy dose range. This is compared to approximately 13%, 15% and 19% for MD-55-2, XR type T and HS radiochromic film, respectively. It is also shown that the EBT film's post-irradiation growth stabilizes to within 1% within the first 6 h. Thus EBT provides a reduced post-irradiation growth effect. However, to increase the accuracy of the film analysis, it is recommended that films be left for a significant period (at least 6 h) before the analysis is performed to provide a high level of accuracy. Also, calibration films must be read out with the same post-irradiation time to further enhance the accuracy of dosimetry.

Fluorescent light effects on FWT-60 radiochromic film.

FWT-60 radiochromic film has been tested for colouration effects from fluorescent light sources and shown to produce a marked colouration when exposed to office fluorescent light sources showing an approximate 1 OD unit per 0.5 J m(-2) exposure to a broad ultraviolet (UV) UVA + UVB spectrum at the peak absorption wavelength. This produces a measurable and quantifiable response to UV exposure. By choosing an appropriate wavelength of readout or band pass, the level of sensitivity can be changed to match the application or exposure level measurement required. These levels of UV response are significantly higher in sensitivity than other radiochromic films such as Gafchromic MD-55 by an order of magnitude. This feature may be of use for measurement of integrated UV exposure from fluorescent lights when required and produces a quantifiable history of total exposure.

XR type-R radiochromic film x-ray energy response.

Gafchromic XR type-R radiochromic film is a relatively new product designed for use at clinical diagnostic x-ray energies both qualitatively and quantitatively. This short note investigates the energy response characteristics of this high-sensitivity radiochromic film for both diagnostic and therapeutic x-ray energies. Results are also compared to conventional silver halide x-ray film for energy response. Results show that the energy response of the new XR type-R film is minimal over the 75-125 kVp range (9% variation with +/-3% error in measurement to 1 SD). This is compared to a 27% variation for X-Omat V radiographic film for the same energy range. XR type-R film does, however, produce a larger energy response variation when compared over a larger therapeutic x-ray range (50 kVp superficial to 10 MV megavoltage) with a relative response of 10.4 at 125 kVp compared to 1 at 6 MV. This is significantly different to MD-55-2 and HS Gafchromic film which has a lower energy response at lower energies. XR type-R film is ideal for a quantitative dosimeter in the low energy range due to its relative energy independence and high sensitivity compared to conventional radiochromic film.