Thyroid doses in Ukraine due to 131I intake after the Chornobyl accident. Report II: dose estimates for the Ukrainian population

This paper describes the revision of the thyroid dosimetry system in Ukraine using new, recently available data on (i) revised ¹³¹I thyroid activities derived from direct thyroid measurements done in May and June 1986 in 146,425 individuals; (ii) revised estimates of ¹³¹I ground deposition density in each Ukrainian settlement; and (iii) estimates of age- and gender-specific thyroid masses for the Ukrainian population. The revised dosimetry system estimates the thyroid doses for the residents of the settlements divided into three levels depending on the availability of measurements of ¹³¹I thyroid activity among their residents. Thyroid doses due to ¹³¹I intake were estimated in this study for different age and gender groups of residents of 30,353 settlements in 24 oblasts of Ukraine, Autonomous Republic Krym, and cities of Kyiv and Sevastopol. Among them, dose estimates for 835 settlements were based on ¹³¹I thyroid activities measured in more than ten residents (the first level), for 690 settlements based on such measurements done in neighboring settlements (the second level), and for 28,828 settlements based on a purely empirical relationship between the thyroid doses due to ¹³¹I intake and the cumulative ¹³¹I ground deposition densities in settlements (the third level). The arithmetic mean of the thyroid doses due to ¹³¹I intake among 146,425 measured individuals was 0.23 Gy (median of 0.094 Gy); about 99.8% of them received doses less than 5 Gy. The highest oblast-average population-weighted thyroid doses were estimated for residents of Chernihiv (0.15 Gy for arithmetic mean and 0.060 Gy for geometric mean), Kyiv (0.13 and 0.051 Gy) and Zhytomyr (0.12 and 0.049 Gy) Oblasts followed by Rivne (0.10 and 0.039 Gy) and Cherkasy (0.088 and 0.032 Gy) Oblasts, and Kyiv City (0.076 and 0.031 Gy). The geometric mean of thyroid doses estimated in this study for the entire Ukraine essentially did not change in comparison with a previous estimate, 0.020 vs. 0.021 Gy, respectively. The ratio of geometric mean of oblast-specific thyroid doses estimated in the present study to previously calculated doses varied from 0.51 to 3.9. The highest increase in thyroid doses was found in areas remote from the Chornobyl nuclear power plant with a low level of radioactive contamination: by 3.9 times for Zakarpatska Oblast, 3.5 times for Luhansk Oblasts and 2.9 times for Ivano-Frankivsk Oblast. The developed thyroid dosimetry system is being used to revise the thyroid doses due to ¹³¹I intake for the individuals of post-Chornobyl radiation epidemiological studies: the Ukrainian-American cohort of individuals exposed during childhood and adolescence, the Ukrainian in utero cohort, and the Chornobyl Tissue Bank.

     

Treatment and Prognosis of Anaplastic Thyroid Carcinoma: Experience from a Single Institution in China

Background

Anaplastic thyroid carcinoma (ATC), a highly aggressive malignancy, has a poor prognosis, and the consensus on the most effective treatment is needed.

Methods

Clinical data from all ATC patients treated in our institution over a 30-year period (between May 1980 and May 2010) were analyzed retrospectively with regard to mortality and survival rates (Kaplan–Meier). Multivariate analysis was performed using a Cox proportional hazards model.

Results

Sixty cases were analyzed. The overall 1- and 3-year survival rates were 35.0% and 22.9%, respectively. Univariate analysis showed that the best prognosis was seen in patients younger than 55 years, those without distant metastases, those with white blood cell (WBC) counts < 10.0 × 10⁹/L or blood platelet (PLT) counts < 300.0 × 10⁹/L at presentation, those who did not receive chemotherapy, and those who received radiotherapy doses ≥ 40 Gy or underwent surgery plus postoperative radiotherapy. According to multivariate analysis, the WBC count at first presentation and the type of therapeutic regimen independently influenced survival.

Conclusions

We found that the elevated peripheral PLT count may be an adverse prognostic factor of ATC patients. The prognosis for ATC is especially poor for patients with distant metastasis, a WBC count ≥ 10.0×10⁹/L, a PLT count ≥ 300.0 × 10⁹/L, or age ≥ 55 years. WBC count at presentation and surgery with or without postoperative radiotherapy independently influenced the prognosis. Intensive treatment combining surgery with postoperative radiotherapy is recommended for ATC patients with stage IVA/B disease.     

Biodosimetry and assessment of radiation dose

Aim

When investigating radiation accidents, it is very important to determine the exposition dose to the individuals. In the case of exposures over 1 Gy, clinicians may expect deterministic effects arising the following weeks and months, in these cases dose estimation will help physicians in the planning of therapy. Nevertheless, for doses below 1 Gy, biodosimetry data are important due to the risk of developing late stochastic effects. Finally, some accidental overexposures are lack of physical measurements and the only way of quantifying dose is by biological dosimetry.

Background

The analysis of chromosomal aberrations by different techniques is the most developed method of quantifying dose to individuals exposed to ionising radiations.^1,2 Furthermore, the analysis of dicentric chromosomes observed in metaphases from peripheral lymphocytes is the routine technique used in case of acute exposures to assess radiation doses.

Materials and methods

Solid stain of chromosomes is used to determine dicentric yields for dose estimation. Fluorescence in situ hybridization (FISH) for translocations analysis is used when delayed sampling or suspected chronically irradiation dose assessment. Recommendations in technical considerations are based mainly in the IAEA Technical Report No. 405.²

Results

Experience in biological dosimetry at Gregorio Marañón General Hospital is described, including own calibration curves used for dose estimation, background studies and real cases of overexposition.

Conclusion

Dose assessment by biological dosimeters requires a large previous standardization work and a continuous update. Individual dose assessment involves high qualification professionals and its long time consuming, therefore requires specific Centres. For large mass casualties cooperation among specialized Institutions is needed.     

Reticulocyte and micronucleated reticulocyte responses to gamma irradiation: dose–response and time-course profiles measured by flow cytometry

A flow cytometric, anti-CD71-based method was used to measure peripheral blood reticulocyte and micronucleated reticulocyte frequencies in response to ¹³⁷Cs total body irradiation (TBI). In three independent experiments, groups of five female C57BL/6N mice were irradiated at graded doses up to 3 Gy, and peripheral blood specimens were collected at 43 h post-irradiation. Whereas the frequency of reticulocytes declined over the range of doses studied, micronucleated reticulocyte incidence was observed to increase in a dose-dependent manner up to 1 Gy. At doses greater than approximately 1 Gy, micronucleated reticulocyte frequencies declined with increasing exposure. These responses were highly reproducible, with significant effects on reticulocyte and micronucleated reticulocyte frequencies observed for the lowest dose studied (0.125 Gy). A time-course experiment was performed to test whether radiation-induced cell cycle delay may explain saturation of the micronucleated reticulocyte endpoint at doses >1 Gy. For this experiment, groups of four female C57BL/6N mice were exposed to 1, 1.5, or 2 Gy TBI, and blood collection occurred at 12 h intervals from 43 to 115 h post-exposure. Reduced reticulocyte frequencies were observed for each dose studied, and the recovery of reticulocytes was increasingly delayed with higher radiation doses. Maximal micronucleated reticulocyte frequencies were observed at 43 or 55 h, with progressively lower values at later time points. At no time did micronucleated reticulocyte frequencies induced by 1.5 or 2 Gy significantly exceed that observed for 1 Gy at 43 h. These time-course data suggest that radiation-induced cell cycle delay cannot account for the micronucleated reticulocyte downturn phenomenon observed at doses greater than 1 Gy. An alternate hypothesis is discussed whereby apoptotic elimination of severely damaged bone marrow erythroid precursors plays a dominant role in saturating the radiation-induced micronucleated reticulocyte response observed for C57BL/6N mice.     

Consequences of Low Dose Ionizing Radiation Exposure on the Hippocampal Microenvironment

The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy), few studies have been conducted at much lower doses (≤ 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.     

Energy dependence of radiochromic dosimetry films for use in radiotherapy verification

Aim

The purpose of the study was to examine the energy dependence of Gafchromic EBT radiochromic dosimetry films, in order to assess their potential use in intensity-modulated radiotherapy (IMRT) verifications.

Materials and methods

The film samples were irradiated with doses from 0.1 to 12 Gy using photon beams from the energy range 1.25 MeV to 25 MV and the film response was measured using a flat-bed scanner. The samples were scanned and the film responses for different beam energies were compared.

Results

A high uncertainty in readout of the film response was observed for samples irradiated with doses lower than 1 Gy. The relative difference exceeds 20% for doses lower than 1 Gy while for doses over 1 Gy the measured film response differs by less than 5% for the whole examined energy range. The achieved uncertainty of the experimental procedure does not reveal any energy dependence of Gafchromic EBT film response in the investigated energy range.

Conclusions

Gafchromic EBT film does not show any energy dependence in the conditions typical for IMRT but the doses measured for pre-treatment plan verifications should exceed 1 Gy.     

Prematurely condensed chromosome fragments in human lymphocytes induced by high doses of high-linear-energy-transfer irradiation

This study provides a useful biodosimetry protocol for radiation accidents that involve high doses of heavy particle radiation. Human peripheral blood lymphocytes (PBLs) were irradiated in vitro with high doses (5–50 Gy) of charged heavy-ion particles (carbon ions, at an effective linear-energy-transfer (LET) of 34.6 keV/μm), and were then stimulated to obtain dividing cells. PBLs were treated with 100 nM calyculin A to force chromosomes to condense prematurely, and chromosome spreads were obtained and stained with Giemsa. The G2 prematurely condensed chromosome (G2-PCC) index and the number of G2-PCC including fragments (G2-PCC-Fs) per cell for each radiation dose point were scored. Dose-effect relationships were obtained by plotting the G2-PCC indices or G2-PCC-Fs numbers against radiation doses. The G2-PCC index was greater than 5% up to doses of 15 Gy; even after a 30 Gy radiation dose, the index was 1 to 2%. At doses higher than 30 Gy, however, the G2-PCC indices were close to zero. The number of G2-PCC-Fs increased steeply for radiation doses up to 30 Gy at a rate of 1.07 Gy⁻¹. At doses higher than 30 Gy, the numbers of G2-PCC-Fs could not be accurately indexed because of the limited numbers of cells for analysis. Therefore, the number of G2-PCC-Fs could be used to estimate radiation doses up to 30 Gy. In addition, a G2-PCC index close to zero could be used as an indicator for radiation doses greater than 40 Gy.     

Heavy Ion Radiation Exposure Triggered Higher Intestinal Tumor Frequency and Greater β-Catenin Activation than γ Radiation in APCMin/+ Mice

Risk of colorectal cancer (CRC) after exposure to low linear energy transfer (low-LET) radiation such as γ-ray is highlighted by the studies in atom bomb survivors. On the contrary, CRC risk prediction after exposure to high-LET cosmic heavy ion radiation exposure is hindered due to scarcity of in vivo data. Therefore, intestinal tumor frequency, size, cluster, and grade were studied in APC^Min/+ mice (n = 20 per group; 6 to 8 wks old; female) 100 to 110 days after exposure to 1.6 or 4 Gy of heavy ion ⁵⁶Fe radiation (energy: 1000 MeV/nucleon) and results were compared to γ radiation doses of 2 or 5 Gy, which are equitoxic to 1.6 and 4 Gy ⁵⁶Fe respectively. Due to relevance of lower doses to radiotherapy treatment fractions and space exploration, we followed 2 Gy γ and equitoxic 1.6 Gy ⁵⁶Fe for comparative analysis of intestinal epithelial cell (IEC) proliferation, differentiation, and β-catenin signaling pathway alterations between the two radiation types using immunoblot, and immunohistochemistry. Relative to controls and γ-ray, intestinal tumor frequency and grade was significantly higher after ⁵⁶Fe radiation. Additionally, tumor incidence per unit of radiation (per cGy) was also higher after ⁵⁶Fe radiation relative to γ radiation. Staining for phospho-histone H3, indicative of IEC proliferation, was more and alcian blue staining, indicative of IEC differentiation, was less in ⁵⁶Fe than γ irradiated samples. Activation of β-catenin was more in ⁵⁶Fe-irradiated tumor-free and tumor-bearing areas of the intestinal tissues. When considered along with higher levels of cyclin D1, we infer that relative to γ radiation exposure to ⁵⁶Fe radiation induced markedly reduced differentiation, and increased proliferative index in IEC resulting in increased intestinal tumors of larger size and grade due to preferentially greater activation of β-catenin and its downstream effectors.     

Stereotactic radiotherapy for bone oligometastases

About 60–90% of cancer patients are estimated to develop bone metastases, particularly in the spine.Bone scintigraphy, computed tomography (CT ) and magnetic resonance imaging (MRI ) are currently used to assess metastatic bone disease; positron emission tomography/computed tomography (PET-CT ) has become more widespread in clinical practice because of its high sensitivity and specificity with about 95% diagnostic accuracy. The most common and well-known radiotracer is 18F-fluorodeoxyglucose (¹⁸FDG); several other PET-radiotracers are currently under investigation for different solid tumors, such as ¹¹C or ¹⁸FDG-choline and prostate specific membrane antigen (PSMA)-PET/CT for prostate cancer. In treatment planning, standard and investigational imaging modalities should be registered with the planning CT so as to best define the bone target volume. For target volume delineation of spine metastases, the International Spine Radiosurgery Consortium (ISRC ) of North American experts provided consensus guidelines. Single fraction stereotactic radiotherapy (SRT ) doses ranged from 12 to 24 Gy; fractionated SRT administered 21–27 Gy in 3 fractions or 20–35 Gy in 5 fractions. After spine SRT, less than 5% of patients experienced grade ≥ 3 acute toxicity. Late toxicity included the extremely rare radiation-induced myelopathy and a 14% risk of de novo vertebral compression fractures.     

Toxicity outcome in patients treated with modulated arc radiotherapy for localized prostate cancer

Aim

This study evaluates the acute toxicity outcome in patients treated with RapidArc for localized prostate cancer.

Background

Modern technologies allow the delivery of high doses to the prostate while lowering the dose to the neighbouring organs at risk. Whether this dosimetric advantage translates into clinical benefit is not well known.

Materials and methods

Between December 2009 and May 2012, 45 patients with primary prostate adenocarcinoma were treated using RapidArc. All patients received 1.8 Gy per fraction, the median dose to the prostate gland, seminal vesicles, pelvic lymph nodes and surgical bed was 80 Gy (range, 77.4–81 Gy), 50.4 Gy, 50.4 Gy and 77.4 Gy (range, 75.6–79.2 Gy), respectively.

Results

The time between the last session and the last treatment follow up was a median of 10 months (range, 3–24 months). The incidence of grade 3 acute gastrointestinal (GI) and genitourinary (GU) toxicity was 2.2% and 15.5%, respectively. Grade 2 acute GI and GU toxicity occurred in 30% and 27% of patients, respectively. No grade 4 acute GI and GU toxicity were observed. Older patients (>median) or patients with V60 higher than 35% had significantly higher rates of grade ≥2 acute GI toxicity compared with the younger ones.

Conclusions

RapidArc in the treatment of localized prostate cancer is tolerated well with no Grade >3 GI and GU toxicities. Older patients or patients with higher V60 had significantly higher rates of grade ≥2 acute GI toxicity. Further research is necessary to assess definitive late toxicity and tumour control outcome.     

Local control of 1–5 fraction radiotherapy regimens for spinal metastases: an analysis of the impacts of biologically effective dose and primary histology

BackgroundThis analysis evaluates the impacts of biologically effective dose (BED) and histology on local control (LC) of spinal metastases treated with highly conformal radiotherapy to moderately-escalated doses.Materials and methodsPatients were treated at two institutions from 2010–2020. Treatments with less than 5 Gy per fraction or 8 Gy in 1 fraction were excluded. The dataset was divided into three RPA classes predictive of survival (1). The primary endpoint was LC.Results223 patients with 248 treatments met inclusion criteria. Patients had a median Karnofsky Performance Status (KPS ) of 80, and common histologies included breast (29.4%), non-small cell lung cancer (15.7%), and prostate (13.3%). A median 24 Gy was delivered in 3 fractions (BED: 38.4 Gy) to a median planning target volume (PTV) of 37.3 cc. 2-year LC was 75.7%, and 2-year OS was 42.1%. Increased BED was predictive of improved LC for primary prostate cancer (HR = 0.85, 95% CI: 0.74–0.99). Patients with favorable survival (RPA class 1) had improved LC with BED ≥ 40 Gy (p = 0.05), unlike the intermediate and poor survival groups. No grade 3–5 toxicities were reported.ConclusionsModerately-escalated treatments were efficacious and well-tolerated. BED ≥ 40 Gy may improve LC, particularly for prostate cancer and patients with favorable survival.     

A pilot study of a postal dosimetry system using the Fricke dosimeter for research irradiators

Cobalt-60 irradiators and soft X-ray machines are frequently used for research purposes, but the dosimetry is not always performed using the recommended protocols. This may lead to confusing and untrustworthy results within the conducted research. Postal dosimetry systems have already been approved by the IAEA, with thermoluminescence dosimeters (TLD) and optically stimulated luminescence (OSL) as the most commonly used dosimeter systems in these cases. The present study tests the Fricke dosimeter properties as a potential system to be used in postal dosimetry for a project using research irradiators. The Fricke solution was prepared according to the literature, and the linearity and fading tests were performed accordingly. All calculated doses were measured using a NE2571 Farmer ionization chamber as a reference. Doses ranging from 25 to 300 Gy were delivered by a research irradiator, with 150 kV and 22 mA to the Fricke solutions inside polyethylene (PE) bags (4 × 4 × 0.2 cm³). The results compared with the ionization chamber showed a linear response to the range of doses used. Fading tests showed no significant difference for the absorbed doses over 9 days, with a maximum difference of 1.5% found between days 0 and 3. The Fricke dosimeter presented good linearity, for low and high doses, and low uncertainties for the fading even for 9 days after irradiation. These preliminary results are motivating, and as the next step, we intend to design a postal dosimetry system using the PE bags of Fricke solution.     

Evaluation of volumetric modulated arc therapy (VMAT) — based total body irradiation (TBI) in pediatric patients

BackgroundThe dosimetric characterization of volumetric modulated arc therapy (VMAT)-based total-body irradiation (TBI) in pediatric patients is evaluated.Materials and methodsTwenty-two patients between the ages of 2 and 12 years were enrolled for VMAT-based TBI from 2018 to 2020. Three isocenters were irradiated over three overlapping arcs. While prescribing 90% of the TBI dose to the planning treatment volume (PTV), two fractions (2 Gy each) were delivered each day; hence 12 Gy was delivered in six fractions. During treatment optimization, the mean lung and kidney doses were set not to exceed 7 Gy and 7.5 Gy, respectively. The maximum lens dose was also set to less than 4 Gy. Patient quality assurance was carried out by comparing treatment planning system doses to the 3-dimensional measured doses by the ArcCHECK^® detector. The electronic portal imaging device (EPID) gamma indices were also obtained.ResultsThe average mean lung dose was 7.75 ± 0.18 Gy, mean kidney dose 7.63 ± 0.26 Gy, maximum lens dose 4.41 ± 0.39 Gy, and the mean PTV dose 12.69 ± 0.16 Gy. The average PTV heterogeneity index was 1.15 ± 0.03. Average differences in mean kidney dose, mean lung dose, and mean target dose were 2.79% ± 0.88, 0.84% ± 0.45 and 0.93% ± 0.47, respectively; when comparing planned and ArcCHECK^® measured doses. Only grade 1–2 radiation toxicities were recorded, based on CTCAE v5.0 scoring criteria.ConclusionsVMAT-TBI was characterized with good PTV coverage, homogeneous dose distribution, planned and measured dose agreement, and low toxicity.     

Altered Interactions between the Gut Microbiome and Colonic Mucosa Precede Polyposis in APCMin/+ Mice

Mutation of the adenomatous polyposis coli (APC gene), an early event in the adenoma-carcinoma sequence, is present in 70-80% of sporadic human colorectal adenomas and carcinomas. To test the hypothesis that mutation of the APC gene alters microbial interactions with host intestinal mucosa prior to the development of polyposis, culture-independent methods (targeted qPCR assays and Illumina sequencing of the 16S rRNA gene V1V2 hypervariable region) were used to compare the intestinal microbial composition of 30 six-week old C57BL/6 APC^Min/+ and 30 congenic wild type (WT) mice. The results demonstrate that similar to 12-14 week old APC^Min/+ mice with intestinal neoplasia, 6 week old APC^Min/+ mice with no detectable neoplasia, exhibit an increased relative abundance of Bacteroidetes spp in the colon. Parallel mouse RNA sequence analysis, conducted on a subset of proximal colonic RNA samples (6 APC^Min/+, 6 WT) revealed 130 differentially expressed genes (DEGs, fold change ≥ 2, FDR <0.05). Hierarchical clustering of the DEGs was carried out by using 1-r dissimilarity measurement, where r stands for the Pearson correlation, and Ward minimum variance linkage, in order to reduce the number of input variables. When the cluster centroids (medians) were included along with APC genotype as input variables in a negative binomial (NB) regression model, four of seven mouse gene clusters, in addition to APC genotype, were significantly associated with the increased relative abundance of Bacteroidetes spp. Three of the four clusters include several downregulated genes encoding immunoglobulin variable regions and non-protein coding RNAs. These results support the concept that mutation of the APC gene alters colonic-microbial interactions prior to polyposis. It remains to be determined whether interventions directed at ameliorating dysbiosis in APC^Min/+mice, such as through probiotics, prebiotics or antibiotics, could reduce tumor formation.     

Dose dependent pharmacokinetics,tissue distribution,and anti-tumor efficacy of a humanized monoclonal antibody against DLL4 in mice

Delta-like-4 ligand (DLL4) plays an important role in vascular development and is widely expressed on the vasculature of normal and tumor tissues. Anti-DLL4 is a humanized IgG1 monoclonal antibody against DLL4. The purpose of these studies was to characterize the pharmacokinetics (PK), tissue distribution, and anti-tumor efficacy of anti-DLL4 in mice over a range of doses. PK and tissue distribution of anti-DLL4 were determined in athymic nude mice after administration of single intravenous (IV) doses. In the tissue distribution study, radiolabeled anti-DLL4 (mixture of ¹²⁵Iodide and ¹¹¹Indium) was administered in the presence of increasing amounts of unlabeled anti-DLL4. Dose ranging anti-DLL4 anti-tumor efficacy was evaluated in athymic nude mice bearing MV522 human lung tumor xenografts. Anti-DLL4 had nonlinear PK in mice with rapid serum clearance at low doses and slower clearance at higher doses suggesting the involvement of target mediated clearance. Consistent with the PK data, anti-DLL4 was shown to specifically distribute to several normal tissues known to express DLL4 including the lung and liver. Maximal efficacy in the xenograft model was seen at doses ≥ 10 mg/kg when tissue sinks were presumably saturated, consistent with the PK and tissue distribution profiles. These findings highlight the importance of mechanistic understanding of antibody disposition to enable dosing strategies for maximizing efficacy.     

In vivo hepatic lipid quantification using MRS at 7 Tesla in a mouse model of glycogen storage disease type 1a

The assessment of liver lipid content and composition is needed in preclinical research to investigate steatosis and steatosis-related disorders. The purpose of this study was to quantify in vivo hepatic fatty acid content and composition using a method based on short echo time proton magnetic resonance spectroscopy (MRS) at 7 Tesla. A mouse model of glycogen storage disease type 1a with inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc^−/−) mice and control mice were fed a standard diet or a high-fat/high-sucrose (HF/HS) diet for 9 months. In control mice, hepatic lipid content was found significantly higher with the HF/HS diet than with the standard diet. As expected, hepatic lipid content was already elevated in L-G6pc^−/− mice fed a standard diet compared with control mice. L-G6pc^−/− mice rapidly developed steatosis which was not modified by the HF/HS diet. On the standard diet, estimated amplitudes from olefinic protons were found significantly higher in L-G6pc^−/− mice compared with that in control mice. L-G6pc^−/− mice showed no noticeable polyunsaturation from diallylic protons. Total unsaturated fatty acid indexes measured by gas chromatography were in agreement with MRS measurements. These results showed the great potential of high magnetic field MRS to follow the diet impact and lipid alterations in mouse liver.     

Dose uncertainty and resolution of polymer gel dosimetry using an MRI guided radiation therapy system’s onboard 0.35 T scanner

Magnetic Resonance Imaging (MRI) scanners are widely used for 3D gel dosimeters readout. However, limited access to MRI scanners is a challenge in MRI-based gel dosimetry. Recent clinical implementation of MRI-guided radiation therapy machines provides potential opportunities for onboard gel dosimetry using its MRI subsystem. The objective of this study was to investigate the feasibility of gel dosimetry using ViewRay’s onboard 0.35 T MRI scanner. A BANG® polymer gel dosimeter was irradiated by three beams of 3 × 3 cm² field size. The T₂ relaxation rate (R₂) of the irradiated gel was measured using a Philips 1.5 T Ingenia MRI and a ViewRay 0.35 T onboard MRI and spin-echo pulse sequences. The number of signal averages (NSA) was set to 16 for the ViewRay acquisitions and one for the Philips 1.5 T MRI to achieve similar signal-to-noise ratios. The in-plane spatial resolution was 1.5 × 1.5 mm² and the slice thickness was 5 mm. The relative dose uncertainty was obtained using R₂ versus dose curves to compare the performance of dosimetry using the two different MRIs and field strengths. The dose uncertainty decreased from 12% at 2 Gy to 3.5% at 7.5 Gy at 1.5 T. The dose uncertainty decreased from 13% at 2 Gy to 4% at 7.5 Gy with NSA = 16 and 3 × 3 mm² pixel size, and from 10.5% at 2 Gy to 3.2% at 7.5 Gy with NSA = 16 and denoised R₂ maps (1.5 × 1.5 mm² pixel size) at 0.35 T. The mean of dose resolution was 0.4 Gy at 1.5 T while the mean of dose resolution was 0.8 Gy and 0.64 Gy at 0.35 T by downsampling and denoising the R2 map, respectively. Therefore, comparable dose uncertainty was achievable using the ViewRay’s onboard 0.35 T and Philips 1.5 T MRI scanners. 3D gel dosimetry using onboard low-field MRI scanner provides ViewRay users a 3D high resolution dosimetry option besides film and ionization chamber.     

A Feasibility Study of Fricke Dosimetry as an Absorbed Dose to Water Standard for 192Ir HDR Sources

High dose rate brachytherapy (HDR) using ¹⁹²Ir sources is well accepted as an important treatment option and thus requires an accurate dosimetry standard. However, a dosimetry standard for the direct measurement of the absolute dose to water for this particular source type is currently not available. An improved standard for the absorbed dose to water based on Fricke dosimetry of HDR ¹⁹²Ir brachytherapy sources is presented in this study. The main goal of this paper is to demonstrate the potential usefulness of the Fricke dosimetry technique for the standardization of the quantity absorbed dose to water for ¹⁹²Ir sources. A molded, double-walled, spherical vessel for water containing the Fricke solution was constructed based on the Fricke system. The authors measured the absorbed dose to water and compared it with the doses calculated using the AAPM TG-43 report. The overall combined uncertainty associated with the measurements using Fricke dosimetry was 1.4% for k = 1, which is better than the uncertainties reported in previous studies. These results are promising; hence, the use of Fricke dosimetry to measure the absorbed dose to water as a standard for HDR ¹⁹²Ir may be possible in the future.     

NOD-Rag2null IL-2Rγnull Mice: An Alternative to NOG Mice for Generation of Humanized Mice

We have developed NOD-Rag2^null IL-2Rγ^null (NR2G) mice similar to NOD-scidIL-2Rγ^null (NOG) mice that are known as an excellent host to generate humanized mice. To evaluate the usefulness of NR2G mice as a host for humanized mice, the engraftment rates and differentiation of human cells after human hematopoietic stem cell (HSC) transplantation were compared among NR2G, NOG, and NOD-scid mice. For this purpose, the appropriate irradiation doses to expand the niche for human stem cells in the bone marrow were first determined. As a result, 8 and 2.5 Gy in adult, and 4 and 1 Gy in newborn NR2G and NOG mice, respectively, were found to be appropriate. Next, 5 × 10⁴ human umbilical cord blood CD34⁺ cells were intravenously inoculated into irradiated adult or newborn of the immunodeficient mice. These HSC transplantation experiments demonstrated that both NR2G and NOG mice showed high engraftment rates compared with NOD-scid mice, although NOG mice showed a slightly higher engraftment rate than that for NR2G mice. However, no difference was found in the human cell populations differentiated from HSCs between NR2G and NOG mice. The HSC transplantation experiments to adults and newborns of two immunodeficient mice also revealed that the HSC transplantation into newborn mice resulted in higher engraftment rate than those into adults. These results showed that NR2G mice could be used as an alternative host to NOG mice to generate humanized mice.