Verification Study of Residual Activity Measurements After Yttrium-90 Radioembolization with Glass Microspheres.

OBJECTIVE: After yttrium-90 (90Y) radioembolization, residual activity and its consequences for dosimetric calculations are often not reported. The manufacturer for glass microspheres prescribes standard residual activity measurements by a survey meter, but the validity lacks evidence. This study aims to verify the accuracy of the survey meter approach for measuring residual activity of glass microspheres after treatment with glass microspheres. METHODS: To validate the accuracy of the survey meter approach, the measured residual activity of glass microspheres by survey meter was compared with measurements by PET. A sample of these waste containers was also measured by dose calibrator to confirm the accuracy of the PET. RESULTS: Twenty-four waste containers from glass microsphere treatments were prospectively scanned with 90Y-PET/CT. Bland-Altman plots showed substantial disagreement in residual activity measured by survey meter versus the residual activity measured by PET and dose calibrator, whereas the correlation between PET and dose calibrator was excellent (ρ = 0.99). CONCLUSION: This study found a significant disagreement between the residual activities measured by the survey meter, compared to measurements by PET and dose calibrator. If relatively high amounts of residual activity are encountered using the exposure rate measurement with a survey meter, additional quantification should be considered using either PET/CT or a dose calibrator measurement.

Rapid screening methods for beta-emitters in food samples.

In case of a nuclear emergency, many samples need to be measured in a short time period. Therefore, it is of vital importance to have a quick and reliable (screening)method. Most methods to determine total beta activity are time-consuming because of extensive sample preparation, such as ashing. In this article three different rapid screening methods for beta emitting nuclides in agriculture, livestock and fishery products were tested and compared to each other, and to an accurate but more time consuming reference method. The goal was to find the method with the optimal trade-off between accuracy, speed and minimal detectable activity (MDA). All of the methods rely on liquid scintillation counting (LSC) or Cerenkov counting, and differ mainly in sample preparation. For matrices with little or no colour, the direct LSC-method is the most accurate and fastest option, while for darker coloured samples this method is not suitable because of high colour quenching. For such samples, two additional methods using a microwave digestion during sample preparation, produced good results.

Holmium-166 poly(L-lactic acid) microsphere radioembolisation of the liver: technical aspects studied in a large animal model.

OBJECTIVE: To assess the accuracy of a scout dose of holmium-166 poly(L-lactic acid) microspheres ((166)Ho-PLLA-MS) in predicting the distribution of a treatment dose of (166)Ho-PLLA-MS, using single photon emission tomography (SPECT). METHODS: A scout dose (60 mg) was injected into the hepatic artery of five pigs and SPECT acquired. Subsequently, a 'treatment dose' was administered (540 mg) and SPECT, computed tomography (CT) and magnetic resonance imaging (MRI) of the total dose performed. The two SPECT images of each animal were compared. To validate quantitative SPECT an ex vivo liver was instilled with (166)Ho-PLLA-MS and SPECT acquired. The liver was cut into slices and planar images were acquired, which were registered to the SPECT image. RESULTS: Qualitatively, the scout dose and total dose images were similar, except in one animal because of catheter displacement. Quantitative analysis, feasible in two animals, tended to confirm this similarity (r(2) = 0.34); in the other animal the relation was significantly better (r(2) = 0.66). The relation between the SPECT and planar images acquired from the ex vivo liver was strong (r(2) = 0.90). CONCLUSION: In the porcine model a scout dose of (166)Ho-PLLA-MS can accurately predict the biodistribution of a treatment dose. Quantitative (166)Ho SPECT was validated for clinical application.

Toward prompt gamma spectrometry for monitoring boron distributions during extra corporal treatment of liver metastases by boron neutron capture therapy: a Monte Carlo simulation study.

A Monte Carlo calculation was carried out for boron neutron capture therapy (BNCT) of extra corporal liver phantom. The present paper describes the basis for a subsequent clinical application of the prompt gamma spectroscopy set-up aimed at in vivo monitoring of boron distribution. MCNP code was used first to validate the homogeneity in thermal neutron field in the liver phantom and simulate the gamma ray detection system (collimator and detector) in the treatment room. The gamma ray of 478 keV emitted by boron in small specific region can be detected and a mathematical formalism was used for the tomography image reconstruction.

Microspheres with ultrahigh holmium content for radioablation of malignancies.

PURPOSE: The aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter. METHODS: Microspheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT). RESULTS: Microspheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT. CONCLUSIONS: HoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

Neutron activation of holmium poly(L-lactic acid) microspheres for hepatic arterial radio-embolization: a validation study.

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (166Ho-PLLA-MS) are a novel microdevice for intra-arterial radio-embolization in patients with unresectable liver malignancies. The neutron activation in a nuclear reactor, in particular the gamma heating, damages the 166Ho-PLLA-MS. The degree of damage is dependent on the irradiation characteristics and irradiation time in a particular reactor facility. The aim of this study was to standardize and objectively validate the activation procedure in a particular reactor. The methods included light- and scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry, viscometry, thermal neutron flux measurements and energy deposition calculations. Seven hours-neutron irradiation results in sufficient specific activity of the 166Ho-PLLA-MS while structural integrity is preserved. Neutron flux measurements and energy deposition calculations are required in the screening of other nuclear reactors. For the evaluation of microsphere quality, light microscopy, SEM and particle size analysis are appropriate techniques.

On the beneficial role of silicon to organisms: a case study on the importance of silicon chemistry to metal accumulation in yeast.

Silicon is involved in numerous important structural and functional roles in a wide range of organisms, including diatoms, plants, and humans, but clear mechanisms have been discovered only in diatoms and sponges. Silicate availability influences metal concentrations within various cell- and tissue-types, but a mechanism has not been discovered so far. In an earlier study on Baker's yeast Saccharomyces cerevisiae it was proposed that a chemical mechanism, rather than a biological one, is important. In the present study, the interaction of silicon with Baker's yeast is further investigated by studying the influence of zinc and magnesium on Si accumulation both at a low and a high silicate concentration in the medium. Si accumulation fitted well with Freundlich adsorption and Si release followed depolymerization kinetics, indicating that silicate adsorbs to the surface of the cell rather than being transported over the cell membrane. Subsequently, adsorbed silicate interacts with metal ions and, therefore, alters the cell's affinity for these ions. Since several metals are nutritional, these Si interactions can significantly change the growth and viability of organisms. In conclusion, the results show that chemistry is important in Si and metal accumulation in Baker's yeast, and suggest that similar mechanisms should be studied in detail in other organisms to unravel essential roles of Si.

Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(L-lactic acid) microspheres in healthy pigs.

PURPOSE: The aim of this study is to evaluate the toxicity of holmium-166 poly(L-lactic acid) microspheres administered into the hepatic artery in pigs. METHODS: Healthy pigs (20-30 kg) were injected into the hepatic artery with holmium-165-loaded microspheres ((165)HoMS; n=5) or with holmium-166-loaded microspheres ((166)HoMS; n=13). The microspheres' biodistribution was assessed by single-photon emission computed tomography and/or MRI. The animals were monitored clinically, biochemically, and ((166)HoMS group only) hematologically over a period of 1 month ((165)HoMS group) or over 1 or 2 months ((166)HoMS group). Finally, a pathological examination was undertaken. RESULTS: After microsphere administration, some animals exhibited a slightly diminished level of consciousness and a dip in appetite, both of which were transient. Four lethal adverse events occurred in the (166)HoMS group due either to incorrect administration or comorbidity: inadvertent delivery of microspheres into the gastric wall (n=2), preexisting gastric ulceration (n=1), and endocarditis (n=1). AST levels were transitorily elevated post-(166)HoMS administration. In the other blood parameters, no abnormalities were observed. Nuclear scans were acquired from all animals from the (166)HoMS group, and MRI scans were performed if available. In pigs from the (166)HoMS group, atrophy of one or more liver lobes was frequently observed. The actual radioactivity distribution was assessed through ex vivo (166m)Ho measurements. CONCLUSION: It can be concluded that the toxicity profile of HoMS is low. In pigs, hepatic arterial embolization with (166)HoMS in amounts corresponding with liver-absorbed doses of over 100 Gy, if correctly administered, is not associated with clinically relevant side effects. This result offers a good perspective for upcoming patient trials.

Influence of silicon on cobalt, zinc, and magnesium in baker's yeast, Saccharomyces cerevisiae.

Silicon (Si, as silicate) is involved in numerous important structure and function roles in a wide range of organisms, including man. Silicate availability influences metal concentrations within various cell and tissue types, but, as yet, clear mechanisms for such an influence have been discovered only within the diatoms and sponges. In this study, the influence of silicate on the intracellular accumulation of metals was investigated in baker's yeast (Saccharomyces cerevisiae). It was found that at concentrations up to 10 mM, silicate did not influence the growth rate of S. cerevisiae within a standard complete medium. However, an 11% growth inhibition was observed when silicate was present at 100 mM. Intracellular metal concentrations were investigated in yeast cultures grown without added silicate (-Si) or with the addition of 10 mM silicate (+Si). Decreased amounts of Co (52%), Mn (35%), and Fe (20%) were found within +Sigrown yeast cultures as compared to -Si-grown ones, whereas increased amounts of Mo (56%) and Mg (38%) were found. The amounts of Zn and K were apparently unaffected by the presence of silicon. +Si enhanced the yeast growth rate for low-Zn2+ medium, but it decreased the growth rate under conditions of a low Mg2+ medium and did not alter the growth rates in high Zn2+ and Co2+ media. +Si doubled the uptake rate of Co2+ but did not influence that of Zn2+. We propose that a possible explanation for these results is that polysilicate formation at the cell wall changes the cell wall binding capacity for metal ions. The toxicity of silicate was compared to germanium (Ge, as GeO2), a member of the same group of elements as Si (group 14). Hence, Si and Ge are chemically similar, but silicate starts to polymerize to oligomers above 5 mM, whereas Ge salts remain as monomers at such concentrations. Ge proved to be far more toxic to yeast than Si and no influence of Si on Ge toxicity was found. We propose that these results relate to differences in cellular uptake.

Removal of chloroform from biodegradable therapeutic microspheres by radiolysis.

Radioactive holmium-166 loaded poly(l-lactic acid) microspheres are promising systems for the treatment of liver malignancies. These microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method using chloroform. After preparation the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. It was observed that relatively large amounts of residual chloroform (1000-6000 ppm) remained in the microspheres before neutron irradiation. Since it is known that chloroform is susceptible for high-energy radiation, we investigated whether neutron and gamma irradiation could result in the removal of residual chloroform in HoAcAc-loaded and placebo PLLA-MS by radiolysis. To investigate this, microspheres with relatively high and low amounts of residual chloroform were subjected to irradiation. The effect of irradiation on the residual chloroform levels as well as other microsphere characteristics (morphology, size, crystallinity, molecular weight of PLLA and degradation products) were evaluated. No chloroform in the microspheres could be detected after neutron irradiation. This was also seen for gamma irradiation at a dose of 200 kGy phosgene, which can be formed as the result of radiolysis of chloroform, was not detected with gas chromatography-mass spectrometry (GC-MS). A precipitation titration showed that radiolysis of chloroform resulted in the formation of chloride. Gel permeation chromatography and differential scanning calorimetry showed a decrease in molecular weight of PLLA and crystallinity, respectively. However, no differences were observed between irradiated microsphere samples with high and low initial amounts of chloroform. In conclusion, this study demonstrates that neutron and gamma irradiation results in the removal of residual chloroform in PLLA-microspheres.

Characterization of the NIST seaweed Standard Reference Material.

The National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) for seaweed was developed through an interlaboratory comparison with 24 participants from 16 countries. After evaluating different techniques to calculate certified values for the radionuclides, the median method was found to be the most representative technique. The certified values were provided for 13 radionuclides and information values were given for 15 more radionuclides. Results for the natural decay series showed disequilibrium in both the uranium and thorium series.

Production of GMP-grade radioactive holmium loaded poly(L-lactic acid) microspheres for clinical application.

Radioactive holmium-166 loaded poly(L-lactic acid) microspheres are promising systems for the treatment of liver malignancies. The microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method. After preparation, the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. In this paper, the aspects of the production of a (relatively) large-scale GMP batch (4 g, suitable for treatment of 5-10 patients) of Ho-PLLA-MS are described. The critical steps of the Ho-PLLA-MS production process (sieving procedure, temperature control during evaporation and raw materials) were considered and the pharmaceutical quality of the microspheres was evaluated. The pharmaceutical characteristics (residual solvents, possible bacterial contaminations and endotoxins) of the produced Ho-PLLA-MS batches were in compliance with the requirements of the European Pharmacopoeia. Moreover, neutron irradiated Ho-PLLA-MS retained their morphological integrity and the holmium remained stably associated with the microspheres; it was observed that after 270h (10 times the half-life of Ho-166) only 0.3+/-0.1% of the loading was released from the microspheres in an aqueous solution. In conclusion, Ho-PLLA-MS which are produced as described in this paper, can be clinically applied, with respect to their pharmaceutical quality.