James L. Gräfe

The feasibility of in vivo detection of gadolinium by prompt gamma neutron activation analysis following gadolinium-based contrast-enhanced MRI

The feasibility of using the McMaster University in vivo prompt gamma neutron activation analysis system for the detection of gadolinium has been investigated. Phantoms have been developed for the kidney, liver, and the leg muscle. The initial detection limits are determined to be 7.2 ± 0.3 ppm for the kidney, 3.0 ± 0.1 ppm for the liver, and 2.33 ± 0.08 ppm for the lower leg muscle. A few system optimizations have been tested and show significant detection limit reduction from these initial values. The technique is promising and shows feasibility for in vivo studies of gadolinium retention.

Assessing the deviation from the inverse square law for orthovoltage beams with closed-ended applicators

In this report, we quantify the divergence from the inverse square law (ISL) of the beam output as a function of distance (standoff) from closed‐ended applicators for a modern clinical orthovoltage unit. The divergence is clinically significant exceeding 3% at a 1.2 cm distance for 4 × 4 and 10×10cm2 closed‐ended applicators. For all investigated cases, the measured dose falloff is more rapid than that predicted by the ISL and, therefore, causes a systematic underdose when using the ISL for dose calculations at extended SSD. The observed divergence from the ISL in closed‐ended applicators can be explained by the end‐plate scattering contribution not accounted for in the ISL calculation. The standoff measurements were also compared to the predictions from a home‐built kV dose computation algorithm, kVDoseCalc. The kVDoseCalc computation predicted a more rapid falloff with distance than observed experimentally. The computation and measurements agree to within 1.1% for standoff distances of 3 cm or less for 4×4cm2 and 10×10cm2 field sizes. The overall agreement is within 2.3% for all field sizes and standoff distances measured. No significant deviation from the ISL was observed for open‐ended applicators for standoff distances up to 10 cm. PACS numbers: 87.55.‐x, 87.55.khIn this report, we quantify the divergence from the inverse square law (ISL) of the beam output as a function of distance (standoff) from closed-ended applicators for a modern clinical orthovoltage unit. The divergence is clinically significant exceeding 3% at a 1.2 cm distance for 4 × 4 and 10×10cm2 closed-ended applicators. For all investigated cases, the measured dose falloff is more rapid than that predicted by the ISL and, therefore, causes a systematic underdose when using the ISL for dose calculations at extended SSD. The observed divergence from the ISL in closed-ended applicators can be explained by the end-plate scattering contribution not accounted for in the ISL calculation. The standoff measurements were also compared to the predictions from a home-built kV dose computation algorithm, kVDoseCalc. The kVDoseCalc computation predicted a more rapid falloff with distance than observed experimentally. The computation and measurements agree to within 1.1% for standoff distances of 3 cm or less for 4×4cm2 and 10×10cm2 field sizes. The overall agreement is within 2.3% for all field sizes and standoff distances measured. No significant deviation from the ISL was observed for open-ended applicators for standoff distances up to 10 cm. PACS numbers: 87.55.-x, 87.55.kh.

A phantom-based feasibility study for detection of gadolinium in bone in-vivo using X-ray fluorescence.

Gadolinium (Gd) based contrast agents have been commonly used over the past three decades to improve contrast in magnetic resonance imaging. These complexes, originally thought to be stable and clear from the body shortly after administration, have been shown to dissociate to a small extent and deposit in organs such as bone. A safe and non-invasive method for measuring Gd in bone is necessary for further exploring Gd retention in the body following the administration of a contrast agent. A feasibility study using a K x-ray fluorescence (K-XRF) system to measure Gd in human tibias was investigated. Bone phantoms mimicking human tibia were created with Gd concentrations ranging from 0 to 120ppm. The minimum detection limit (MDL) was calculated from 20-hour and 7-hour phantom measurements with a source activity of 0.11GBq. All MDL values were scaled to a more realistic measurement time of 30-minutes with a stronger source. Scaling arguments were based on activity ratio, measurement time, and system dead time. The MDL for a 1GBq source was estimated to be 3.60-3.64ppm, for an average range of tissue thicknesses overlaying a human tibia. For a stronger source of 5GBq and a four detector cloverleaf system, the MDL was estimated to be 1.49-1.52ppm. Determined and predicted MDLs are within the range of previous in-vitro Gd measurement data. The K-XRF system shows promising results for detecting Gd in bone and should be seriously considered for in-vivo measurements.

Gadolinium detection via in vivo prompt gamma neutron activation analysis following gadolinium-based contrast agent injection: a pilot study in 10 human participants

Gadolinium (Gd) based contrast agents are routinely used as part of many magnetic resonance imaging (MRI) procedures. The widespread use of these agents and concerns about Gd toxicity, motivated us to develop a monitoring procedure that could non-invasively measure quantitatively potential retention of toxic free Gd in tissues after use of the agent. We have been developing a method to measure Gd painlessly and non-invasively by prompt gamma neutron activation analysis. In this paper we present the results of a pilot study where we show that we can measure Gd, quantitatively in vivo, in the lower leg muscle of 10 participants. A series of three neutron leg scans were performed. The effective radiation dose for a single neutron leg scan was very low, 0.6 µSv, so multiple scans were possible. Calibration phantom and in vivo detection limits were determined to be identical: 0.58 ppm. Gd was not detectable in muscle prior to exposure to the contrast agent Gadovist(®). Gd was detected, at greater than 99% confidence, in 9 participants within 1 h of contrast administration and in 1 participant approximately 3.3 h post-contrast administration. The measured concentrations of Gd ranged from 2.0 to 17.3 ppm (6.9 to 56 uncertainties different from zero). No detectable Gd was measured in any participant in the third neutron scan (conducted 0.7 to 5.9 d post-contrast). The results of this study validate our new measurement technology. This technique could be used as a non-invasive monitoring procedure for exposure and retention of Gd from Gd-based chelates used in MRI.

Confirming improved detection of gadolinium in bone using in vivo XRF

The safety of using Gd in MRI contrast agents has recently been questioned, due to recent evidence of the retention of Gd in individuals with healthy renal function. Bone has proven to be a storage site for Gd, as unusually high concentrations have been measured in femoral heads of patients undergoing hip replacement surgery, as well as in autopsy samples. All previous measurements of Gd in bone have been invasive and required the bone to be removed from the body. X-ray fluorescence (XRF) offers a non-invasive and non-destructive method for carrying out in vivo measurements of Gd in humans. An updated XRF system provides improved detection limits in a short measurement time of 30-min. A new four-detector system and higher activity Cd-109 excitation source of 5GBq results in minimum detection limits (MDLs) of 1.64-1.72μgGd/g plaster for an average overlaying tissue thickness of the tibia. These levels are well within the range of previous in vitro Gd measurements. Additional validation through comparison with ICP-MS measurements has confirmed the ability of the XRF system for detecting Gd further, proving it is a feasible system to carry out human measurements.

Observed Deposition of Gadolinium in Bone Using a New Noninvasive in Vivo Biomedical Device: Results of a Small Pilot Feasibility Study

Purpose To perform a preliminary evaluation of a noninvasive measurement system to assess gadolinium deposition in bone and to investigate the relationship between the administration of gadolinium-based contrast agents (GBCAs) and gadolinium retention in bone. Materials and Methods In vivo measurement of gadolinium retention in tibia bones was performed in 11 exposed subjects who previously received GBCAs (six exposed subjects were from a study performed 5 years previously involving injection of GBCAs in healthy volunteers; five exposed subjects had self-reported GBCA exposure), and 11 sex- and age-matched control subjects without a history of GBCA exposure. Each subject underwent one measurement of gadolinium retention in the tibia with x-ray fluorescence in a laboratory at McMaster University. A one-tailed t test was performed to compare gadolinium concentration in the exposed group with that in the control group. The relationship between the dose of GBCA administered and the gadolinium concentration measured in bone was analyzed with linear regression. Results Gadolinium concentration in bone was significantly higher in exposed subjects (mean, 1.19 μg Gd/g bone mineral ± 0.73 [standard deviation]) than in control subjects (mean, -1.06 μg Gd/g bone mineral ± 0.71) (P = .01). There was also a positive correlation between the dose of GBCA administered and the gadolinium concentration measured in bone (R2 = 0.41); gadolinium concentration in bone increased by 0.39 μg Gd/g bone mineral ± 0.14 per 1 mL of GBCA administered. Gadolinium was detected in bone up to 5 years after one GBCA administration. Conclusion This x-ray fluorescence system is capable of measuring gadolinium deposition in bone noninvasively in vivo. Gadolinium can be retained in bone after one dose of GBCA in healthy subjects.

Coherent normalization for in vivo measurements of gadolinium in bone

OBJECTIVE Recent evidence of gadolinium (Gd) deposition in bones of healthy individuals who have previously received Gd-based contrast agents (GBCAs) for MRI has led to a demand for in vivo measurement techniques. The technique of x-ray fluorescence provides a low risk and painless method to assess Gd deposition in bone, and has the potential to be a useful clinical tool. However, interpatient variability creates a challenge while performing in vivo measurements. APPROACH We explored the use of coherent normalization, which involves normalizing the Gd K x-rays to the coherent scattered γ-ray from the excitation source, for bone Gd measurements through a series of phantom-based experiments and Monte Carlo simulations. MAIN RESULTS We found coherent normalization is able to correct for variation in overlying tissue thickness over a wide range (0-12.2 mm). The Gd signal to coherent signal ratio is independent of tissue thickness for both experiments and Monte Carlo simulations. SIGNIFICANCE Coherent normalization has been demonstrated to be used in practice with normal healthy adults to improve in vivo bone Gd measurements.

Characterization of a 2.5 MV inline portal imaging beam

A new megavoltage (MV) energy was recently introduced on Varian TrueBeam linear accelerators for imaging applications. This work describes the experimental characterization of a 2.5 MV inline portal imaging beam for commissioning, routine clinical use, and quality assurance purposes. The beam quality of the 2.5 MV beam was determined by measuring a percent depth dose, PDD, in water phantom for 10×10 cm2 field at source‐to‐surface distance 100 cm with a CC13 ion chamber, plane parallel Markus chamber, and GafChromic EBT3 film. Absolute dosimetric output calibration of the beam was performed using a traceable calibrated ionization chamber, following the AAPM Task Group 51 procedure. EBT3 film measurements were also performed to measure entrance dose. The output stability of the imaging beam was monitored for five months. Coincidence of 2.5 MV imaging beam with 6 MV therapy beam was verified with hidden‐target cubic phantom. Image quality was studied using the Leeds and QC3 phantom. The depth of maximum dose, dmax, and percent dose at 10 cm depth were, respectively, 5.7 mm and 51.7% for CC13, 6.1 mm and 51.9% for Markus chamber, and 5.1 mm and 51.9% for EBT3 film. The 2.5 MV beam quality is slightly inferior to that of a  60Co teletherapy beam; however, an estimated kQ of 1.00 was used for output calibration purposes. The beam output was found to be stable to within 1% over a five‐month period. The relative entrance dose as measured with EBT3 films was 63%, compared to 23% for a clinical 6 MV beam for a 10×10 cm2 field. Overall coincidence of the 2.5 MV imaging beam with the 6 MV clinical therapy beam was within 0.2 mm. Image quality results for two commonly used imaging phantoms were superior for the 2.5 MV beam when compared to the conventional 6 MV beam. The results from measurements on two TrueBeam accelerators show that 2.5 MV imaging beam is slightly softer than a therapeutic  60Co beam, it provides superior image quality than a 6 MV therapy beam, and has excellent output stability. These 2.5 MV beam characterization results can serve as reference for clinics planning to commission and use this novel energy‐image modality. PACS number(s): 87.57.‐s, 87.59.‐e, 06.20.fb, 87.53.BnA new megavoltage (MV) energy was recently introduced on Varian TrueBeam linear accelerators for imaging applications. This work describes the experimental characterization of a 2.5 MV inline portal imaging beam for commissioning, routine clinical use, and quality assurance purposes. The beam quality of the 2.5 MV beam was determined by measuring a percent depth dose, PDD, in water phantom for 10×10 cm2 field at source-to-surface distance 100 cm with a CC13 ion chamber, plane parallel Markus chamber, and GafChromic EBT3 film. Absolute dosimetric output calibration of the beam was performed using a traceable calibrated ionization chamber, following the AAPM Task Group 51 procedure. EBT3 film measurements were also performed to measure entrance dose. The output stability of the imaging beam was monitored for five months. Coincidence of 2.5 MV imaging beam with 6 MV therapy beam was verified with hidden-target cubic phantom. Image quality was studied using the Leeds and QC3 phantom. The depth of maximum dose, dmax, and percent dose at 10 cm depth were, respectively, 5.7 mm and 51.7% for CC13, 6.1 mm and 51.9% for Markus chamber, and 5.1 mm and 51.9% for EBT3 film. The 2.5 MV beam quality is slightly inferior to that of a  60Co teletherapy beam; however, an estimated kQ of 1.00 was used for output calibration purposes. The beam output was found to be stable to within 1% over a five-month period. The relative entrance dose as measured with EBT3 films was 63%, compared to 23% for a clinical 6 MV beam for a 10×10 cm2 field. Overall coincidence of the 2.5 MV imaging beam with the 6 MV clinical therapy beam was within 0.2 mm. Image quality results for two commonly used imaging phantoms were superior for the 2.5 MV beam when compared to the conventional 6 MV beam. The results from measurements on two TrueBeam accelerators show that 2.5 MV imaging beam is slightly softer than a therapeutic  60Co beam, it provides superior image quality than a 6 MV therapy beam, and has excellent output stability. These 2.5 MV beam characterization results can serve as reference for clinics planning to commission and use this novel energy-image modality. PACS number(s): 87.57.-s, 87.59.-e, 06.20.fb, 87.53.Bn.

In vivo detection of samarium by prompt gamma neutron activation analysis: a comparison between experiment and Monte-Carlo simulation

Building on previous simulation and experimental work on in vivo detection of gadolinium via PGNAA, we extend this work to incorporate the detection of samarium. Samarium, like gadolinium is a rare earth metal with an enormous cross section for neutron capture. The ab initio Monte-Carlo model agrees with experiment to within 2%. There is a wide discrepancy in the gamma emission probabilities for the 149Sm neutron capture reaction. Decision on the best agreement between simulation and experiment was compounded by a noticed loss in semiconductor detector efficiency due to prolonged neutron damage. We discuss some mechanisms for this loss and reason that the IAEA PGAA database has the most accurate Sm data. We also compare the energy dependence of neutron capture for the non-1/v absorbers, 149Sm and 157Gd, using the 238Pu/Be source. The initial in vivo detection limit for Sm in a shallow kidney or the human hand bones was found to be 5.5 parts per million (ppm; μg g−1). This work has applications to determining the feasibility of neutron activated imaging or for measuring the residual Sm concentration from medical, environmental, occupational, or accidental exposure.

Measurement of gadolinium retention: current status and review from an applied radiation physics perspective

OBJECTIVE This article briefly reviews the main measurement techniques for the non-invasive detection of residual gadolinium (Gd) in those exposed to gadolinium-based contrast agents (GBCAs). Approach and Main results: The current status of in vivo Gd measurement is discussed and is put into the context of concerns within the radiology community. The main techniques are based on applied atomic/nuclear medicine utilizing the characteristic atomic and nuclear spectroscopic signature of Gd. The main emission energies are in the 40-200 keV region and require spectroscopic detectors with good energy resolution. The two main techniques, prompt gamma neutron activation analysis and x-ray fluorescence, provide adequate detection limits for in vivo measurement, whilst delivering a low effective radiation dose on the order of a few µSv. SIGNIFICANCE Gadolinium is being detected in measureable quantities in people with healthy renal function who have received FDA approved GBCAs. The applied atomic/nuclear medicine techniques discussed in this review will be useful in determining the significance of this retention, and will help on advising future administration protocols.