Radiation Dose Ratio Research Articles

Measurement of potassium in rats using an In vivo neutron activation analysis system

Abnormal levels of potassium are linked to several health conditions, including high blood pressure, cardiac dysfunction, kidney damage, and osteoporosis. Given the limited availability of in vivo measurement techniques, there is a need for novel methods to measure potassium to enhance the diagnosis and management of potassium metabolism related diseases. This study aimed to evaluate the feasibility of compact neutron generator based in vivo measurement system for quantification of potassium using rat carcasses. A cohort of thirty-nine rats (n = 20 males and 19 females, average weight 255 ± 15 and 163 ± 7 g) were sacrificed, and their carcasses were placed in polyethylene bottles. The rats were then positioned and irradiated in a carefully designed irradiation cave built alongside the neutron generator with an optimized thermal neutron flux and radiation dose ratio. The irradiation time was 10 min, followed by a 5-min decay and 2-h measurement using a high efficiency high purity germanium detector(HPGe). ResultsThe average potassium concentration in male and female rats was found to be comparable (male 2874 ± 161 and female 2866 ± 144 μg/g). A marginally positive correlation between potassium concentration and weight was found in female rats only (male(20) = 0.07, P = 0.76 and female r(19) = 0.34, P = 0.15). We assessed the influence of manganese toxicity on potassium levels and observed no significant impact. These results were consistent with our previous study in mice. ConclusionThis study suggests that in vivo neutron activation analysis could serve as a promising method to quantify potassium and to investigate the storage and metabolism of potassium in human and in animals.

Abstract A160: The FGFR axis is a potential radiosensitization target

Abstract Background: Establishing methods that sensitize cancers to photons is important for improving the treatment outcome of radiotherapy. Although sequencing has been widely used to identify druggable mutations in various cancers, this strategy have not been used extensively to identify new targets for radiotherapy sensitization. Thus, we performed clinical sequencing of radiotherapy-treated patient samples and investigated whether inhibition of the identified candidate targets resulted in radiosensitization in vitro and in vivo. Material and Methods: Ninety-eight patients with newly diagnosed and pathologically confirmed cervical cancer who had been treated with definitive radiotherapy were analyzed. DNA was extracted from formalin fixed and paraffin embedded pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next generation sequencer. Identified mutations were analyzed for correlations with clinical outcome. The radiosensitization induced by inhibition of the candidate target was investigated in in vitro clonogenic assays and nude mouse xenograft models using radioresistant cancer cell lines and small molecule inhibitors. The in vitro sensitizer enhancement ratio (SER) was calculated as the ratio of radiation dose required to reduce clonogenic cell survival by 50% without drug to that with drug. Results: Recurrent mutations were identified in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes combined (24.5%) was almost as high as that for well-studied PIK3CA and ARID1A. Fifty-five percent (21/38) of the identified FGFR mutations were located in the tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS, independent of clinicopathological variables. To investigate whether the FGFR axis can be targeted by drugs to increase radiosensitization, the radiosensitizing effect of a human-administrable selective pan-FGFR inhibitor LY2874455 was investigated. LY2874455 (at 100 nM) showed a potent in vitro radiosensitizing effect (SER: 1.62, 1.53, and 1.31 for A549, H1299, and H1703 cells, respectively). In A549 xenograft models, the combination of X-rays (10 Gy on day 1) and LY2874455 (3 mg/kg body weight, once daily, on Day 1–7) led to significantly greater suppression of tumor growth than either treatment with X-rays or LY2874455 alone, with no evidence of toxicities. LY2874455 treatment inhibited ERK signaling, the main target of the FGFR axis, both in vitro and in vivo. Conclusion: These data indicate that targeting the FGFR axis with LY2874455 could potentially be used to sensitize cancers to radiotherapy, which warrants clinical validation. Citation Format: Takahiro Oike, Eisuke Horigome, Akiko Adachi, Narisa Dewi Maulany Darwis, Atsushi Shibata, Tatsuya Ohno. The FGFR axis is a potential radiosensitization target [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A160.

Impact of pixel value truncation on image quality of low dose chest CT.

In some noisy low dose CT lung cancer screening images, we noticed that the CT density values of air were increased and the visibility of emphysema was distinctly decreased. By examining histograms of these images, we found that the CT density values were truncated at -1024 HU. The purpose of this study was to investigate the effect of pixel value truncation on the visibility of emphysema using mathematical models. Assuming CT noise follows a normal distribution, we derived the relationship between the mean CT density value and the standard deviation (SD) when the pixel values below -1024 HU are truncated and replaced by -1024 HU. To validate our mathematical model, 20 untruncated phantom CT images were truncated by simulation, and the mean CT density values and SD of air in the images were measured and compared with the theoretical values. In addition, the mean CT density values and SD of air were measured in 100 cases of real clinical images obtained by GE, Siemens, and Philips scanners, respectively, and the agreement with the theoretical values was examined. Next, the contrast-to-noise ratio (CNR) between air (-1000 HU) and lung parenchyma (-850 HU) was derived from the mathematical model in the presence and absence of truncation as a measure of the visibility of emphysema. In addition, the radiation dose ratios required to obtain the same CNR in the case with and without truncation were also calculated. The mathematical model revealed that when the pixel values are truncated, the mean CT density values are proportional to the noise magnitude when the magnitude exceeds a certain level. The mean CT density values and SD measured in the images with pixel values truncated by simulation and in the real clinical images acquired by GE and Philips scanners agreed well with the theoretical values from our mathematical model. In the Siemens images, the measured and theoretical values agreed well when a portion of the truncated values were replaced by random values instead of simply replacing by -1024 HU. The CNR of air and lung parenchyma was lowered by truncating CT density values compared to that of no truncation. Furthermore, it was found that higher radiation dose was required to obtain the same CNR with truncation as without. As an example, when the noise SD was 60 HU, the radiation dose required for the GE and Philips truncation method was about 1.2 times higher than that without truncation, and that for the Siemens truncation method was about 1.4 times higher. It was demonstrated mathematically that pixel value truncation causes a brightening of the mean CT density value and decreases the CNR of emphysema. Our results indicate that it is advisable to turn off truncation at -1024 HU, especially when scanning at low and ultra-low radiation doses in the thorax.

Evaluation of an 131I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers

Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[131I]iodobenzoate (iso-[131I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [131I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso-[131I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso-[131I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc2-iso-[131I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso-[131I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso-[131I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted.

Comparison of the effects of varying tube voltage and iodinated concentration on increasing the iodinated radiation dose in computed tomography

PurposeTo compare the effects of tube voltage and iodinated concentration on increasing the iodinated radiation dose in computed tomography (CT). Material and methodsWater and iodinated materials were inserted in an anthropomorphic thorax phantom. Helical CT scans were performed with tube voltages of 80 and 120 kV. Monte Carlo simulation of radiation doses in CT images was used to study the radiation dose profiles. The radiation doses at different iodine to water ratios in images were calculated from cumulative radiation doses for iodine and water at each iodine concentration, tube voltage, and peripheral/central location. A radiation dose ratio from 80 to 120 kV was calculated from cumulative radiation doses at the same iodine concentration. ResultsThe iodinated radiation doses with small and large phantoms were 1.56–2.04 and 1.61–1.82 times higher at 80 kV and 1.55–2.23 and 1.22–1.79 times higher at 120 kV than those in water. In the central portion, the iodinated radiation dose ratio decreased by 1.14–0.75 and 1.20–0.93 times at 80 kV and 1.29–1.23 and 1.17–1.23 times at 120 kV with increasing iodinated concentrations. In the peripheral portion, the iodinated radiation dose was slightly higher for 80 kV than for 120 kV. In the central portion, the ratio decreased with increasing iodinated concentration. ConclusionThe increase in iodinated radiation dose caused by photoelectric absorption was greater with increased iodine load than with lower tube voltage.

Optimal end-systolic cardiac phase prediction for low-dose ECG-synchronized cardiac CT

PurposeTo predict optimal end-systolic (ES) cardiac phase for low-dose ECG-synchronized cardiac computed tomography (CT). Materials and MethodsECG-synchronized ES cardiac CT examinations of 2441 patients from September 2010 to December 2016 were reviewed. Of them, 891 examinations acquired with an extended period of full tube current in a cardiac cycle (i.e., 10 % of RR interval or ≥100 ms) and adequate image quality (median patient age, 7 years; age range, 0 day‒60 years) were included. Absolute and relative delays (n = 861 and n = 30, respectively) of the cardiac CT were correlated with the heart rates. Best-fit equations were developed from the trend line with the highest coefficient of determination (R2) value for the two delays, and their success rates to obtain optimal ES phase in a padding with full tube current were calculated and compared with that of the T wave location method. CT radiation dose ratio was calculated as a width ratio of paddings with full tube current. ResultsThe absolute and relative delays in the Pearson correlation test demonstrated a strong negative correlation (R = -0.9, p < 0.001) and a nearly moderate positive correlation (R = 0.5, p < 0.001) with heart rates, respectively. Two best-fit equations could be developed separately for both relative (R2 = 0.3) and absolute delays (R2 = 0.8). When adjusting the period of full tube current to a 114 ms for absolute delay and a 17.4 % of RR interval for relative delay, success rates of 94.9 % and 95.1 %, respectively, could be achieved and were significantly higher than that determined by the T wave location (82.7 %, p < 0.001). ConclusionThe best-fit equations method has a higher success rate for predicting the optimal end-systolic phase of ECG-synchronized cardiac CT than the T wave location method.

The Effect of Radiation Protection Education for the Operators' Ocular Lens in Cardiac Catheterization

The purpose of this study was to educate operators regarding cardiac catheterization using radiation protection slides prepared for this study and to consider whether or not this radiation protection education contributes to reducing the exposure of the operator's ocular lens. Thermoluminescent dosimeter (TLD) was installed at the outside left, inside left, outside right, and inside right of the X-ray protective eyewear of the operators performing the cardiac catheterization. The exposure dose rate before and after radiation protection education for 3 operators performing cardiac catheterization was compared. The exposure dose ratio was defined by dividing the TLD measurement value, which is the air kerma calculated by the X-ray diagnosis apparatus for the angiography. In other words, this can calculate the ratio of how much the operators are exposed to radiation from the dose of the patient per examination. When comparing the radiation dose ratio obtained from the dosimeter installed on the right outer side before and after education, p-value was <0.05 in the left anterior oblique-cranial and right anterior oblique- cranial, and a significant difference was recognized. The radiation protection education carried out in this study contributes to a reduction in the exposure dose of the operators.

Increase in fluoroscopic radiation dose in successive sessions of multistage Onyx embolization of brain arteriovenous malformations compared with the first session

Background and purposeOnyx embolization is a treatment for brain arteriovenous malformations (AVMs). However, multistage embolization usually involves the presence of radiodense Onyx cast from the previous sessions, which may influence...

Imaging Factors Impacting on Accuracy and Radiation Dose in 3D Printing.

To compare reconstructed area and surface roughness of 3D models acquired using nine image acquisition protocols. Radiation dose was also compared among acquisition protocols. A dry craniofacial specimen was scanned using three CT devices (a cone beam CT, a 16-channel fan beam CT, and a 64-channel fan beam CT), with three different acquisition protocols each. Nine 3D models were manufactured using polylactic acid. Surface roughness and reconstructed area were determined for each 3D model. The radiation dose during acquisitions was measured using lithium crystals. ANOVA was used to compare the data among the 3D models. Linear function optimization techniques based on stochastic variables were applied to identify the most suitable protocol for use. For surface roughness, statistically significant differences were observed among all 3D models and the specimen. For reconstructed area, CBCT and one CT-16 channel protocols originated 3D models statistically significant different from the specimen. Higher radiation doses were observed with fan beam CT acquisitions. All three CT devices were suitable for 3D printing when used at full resolution. The highest reconstruct area vs. radiation dose ratio was found for 64-channel CT devices.

Improved chemoradiation treatment using trifluridine in human colorectal cancer cells in vitro

We aimed to assess the combined effect of trifluridine (FTD) and ionizing radiation (IR) on colorectal cancer cells in vitro. Colorectal cancer cells, HT-29, HCT-15, and HCT 116, showing low, medium, and high sensitivity to IR, respectively, were treated with the combinations of FTD and IR, and evaluated by the clonogenic survival assay. The radiation dose modification factors (DMFs) were calculated as the ratio of radiation doses producing equivalent surviving fractions following the FTD/IR treatment, or IR alone. DMFs of 4 μM FTD followed by 8 Gy of IR were 2.7, 1.5, and 1.2 for HT-29, HCT-15, and HCT 116, respectively, whereas those of 8 Gy of IR followed by FTD were 1.6, 1.4, and 1.0 for these cells, respectively. Intracellular DNA double-strand break levels after IR and FTD were significantly higher than those observed following the IR treatment alone, regardless of whether the IR was applied before or after FTD. RAD51 expression levels were shown to be increased in FTD and IR treated cells. Apoptotic proteins, such as cleaved PARP and cleaved caspase-3, were detected in cells treated with the combination of FTD and IR, while their expression was not significantly induced after IR or FTD treatment alone. These findings suggest that FTD enhances the efficacy of IR and provide a rationale for designing novel combination chemoradiotherapy regimens containing FTD for patients with rectal cancer that are insensitive to the radiation treatment.

Abstract 1055: Enhanced efficacy of trifluridine for ionizing radiation in human colorectal cancer cell lines

Abstract Background: Trifluridine/tipiracil is a combination of trifluridine (FTD), a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, in a molecular ratio of 1:0.5. Trifluridine/tipiracil is indicated for the treatment of patients with metastatic colorectal cancers refractory to standard chemotherapies. Chemotherapy can make radiation therapy more effective against some colorectal cancers. In this study, we investigated whether cytotoxicity was enhanced when FTD was sequentially used with ionizing radiation (IR). Method: The colorectal cancer cell lines HT-29, HCT-15, and HCT 116, showing low, middle and high sensitivity for IR, respectively, were treated with the combinations of FTD and IR as follows, 1) sequence 1 (pre-radiation): exposure to 2-8 Gy radiation alone and no treatment for 24 h followed by exposure to 0, 2.0, or 4.0 µM FTD for 24 h, 2) sequence 2 (post-radiation): exposure to 0, 2.0, or 4.0 µM FTD for 24 h followed by 2-8 Gy radiation alone and no treatment for 24 h. Cells were irradiated using a cabinet X-ray irradiation system and all treatments were evaluated by the clonogenic survival assay. The dose modification factors (DMFs) were calculated from clonogenic survival curves as the ratio of radiation doses (control radiation dose divided by the FTD-treated radiation dose). To evaluate DNA strand-breaks, alkaline comet assays were performed and the comet tail moment was determined. Results: DMFs of sequence 1 at 8 Gy for 2.0 µM FTD were 1.55, 1.24, and 1.03 and for 4.0 µM FTD were 1.75, 1.26, and 1.02 for HT-29, HCT-15, and HCT 116, respectively, and of sequence 2 at 8 Gy for 2.0 µM FTD were 1.82, 1.38, and 1.03 and for 4.0 µM FTD were 2.73, 1.41, and 1.09 for these cell lines, respectively. The DMFs increased in an FTD dose-dependent manner compared with IR-only treatment. In particular, FTD enhanced the efficacy of radiation in HT-29 and HCT-15 indicating low and middle sensitivity to IR. Compared with IR-only treatment, the median comet tail moments of sequence 1 at 8 Gy for 2.0 µM FTD, respectively, were 13.8-, 14.4-, and 2.0-fold and for 4.0 µM FTD were 16.6-, 12.6-, and 3.6-fold in HT-29, HCT-15, and HCT 116, respectively, and of sequence 2 at 8 Gy for 2.0 µM FTD were 4.8-, 4.3-, and 1.8-fold and for 4.0 µM were 7.5-, 14.3-, and 2.6-fold in these cell lines, respectively. Taken together, FTD promoted DNA strand-breaks and enhanced the efficacy of radiation in these three cell lines, regardless of both sequential treatments. Conclusion: Sequential combination of FTD and radiation was more effective than radiation alone against colorectal cancer cell lines with different radiosensitivities. These results suggest that combination therapy of radiation with trifluridine/tipiracil might be useful for colorectal cancer even with low sensitivity to radiation alone. Citation Format: Kazuaki Matsuoka, Mamoru Nukatsuka, Takashi Kobunai, Teiji Takechi. Enhanced efficacy of trifluridine for ionizing radiation in human colorectal cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1055. doi:10.1158/1538-7445.AM2017-1055

SU‐G‐TeP3‐05: In Vitro Demonstration of Endothelial Dose Enhancement Due to Gold Nanoparticles During Low‐Voltage Radiotherapy

Purpose:Oraya Therapy uses low‐voltage, stereotactic, highly targeted X‐rays for the treatment of wet age‐related macular degeneration (AMD) — offering a new option for patients worldwide. Neovascular endothelial cells play a crucial role in the pathogenesis of this disease. This in‐vitro study investigates the potential of gold nanoparticles (GNP) to enhance endothelial cell damage during low‐voltage radiotherapy towards potential applications in the treatment of wet‐AMD.Methods:Primary human umbilical cord vein endothelium cells (HUVEC) were treated with 1.4 nm sized GNPs for 24 hrs and then irradiated with variable X‐ray doses using an Oraya therapy system (100 kVp) or a Small Animal Radiation and Research platform (SARRP) at other beam qualities (up to 220 kVp). Radio‐sensitization was assessed by clonogenic assays. Variable concentrations of GNPs (0.05 mg/ml, 0.1 mg/ml, 0.25 mg/ml, 0.5 mg/ml, and 1 mg/ml) where employed. The dose enhancement factor (DEF) was calculated as the ratio of radiation doses required to give the same biological effect (survival factor, SF) with and without GNPs.Results:Preliminary results show DEFs of up to 2.62 for the different combinations of x‐ray doses and GNP concentrations and beam qualities. In general the DEF increased with increase in GNP concentration. However, for high doses the effect of GNP becomes less apparent likely due to already high cell kill by the radiation alone.Conclusion:The findings suggest that targeted GNPs can play a significant synergistic role in enhancing stereotactic radiosurgery for wet AMD. The results also provide impetus for ongoing studies to find the optimal synergy between the doses or beam energies and GNPs concentration. This will benefit in‐vivo studies towards development of nanoparticle‐aided radiotherapy for treatment of wet‐AMD and potentially ocular cancers.

양전자단층촬영(PET)시 환자의 특성에 따른 외부 방사선량률 측정

PET/CT Torso를 위해 방사성의약품(<TEX>$^{18}F$</TEX>-FDG) 투여 후 환자 개인의 특성에 따라 환자로부터 방출되는 외부 방사선량률을 여러 가지 방법으로 측정하여 방사선 선원으로부터 안전성을 확보하고, 경각심을 제공함으로서 방사선 노출에 의한 작업종사자와 환자 보호자, 수시출입자 등의 피폭선량을 저감하기 위함이다. 2013년1월에서 6월까지 PET Torso를 시행하는 환자들 중 80명을 대상으로 방사성의약품을 투여 후 환자의 체형(비만도), 수분 공급, 신장 상태, 방사성의약품 투여량에 따라 시간 변화에 의한 환자로부터 방출되는 외부 방사선량률을 각각 측정 하였다. 방사성의약품 투여 직후부터 환자 개인의 특성에 따라 외부 방사선량률을 측정한 결과 방사성의약품 투여량이 증가할수록 외부 방사선량률이 높았고, 환자 체형에 따른 외부 방사선량률은 유의한 차이가 없었다. 수분을 공급 했을 때와 신장이 정상일 때가 그렇지 않을 때 보다 외부 방사선량률이 낮았다. 방사선 안전관리를 준수하기 위하여 방사선 작업종사자는 선원을 취급하기 전 충분한 교육과 모의 훈련을 통해 작업시간을 최소화 할 수 있도록 노력해야 할 것이며, 개인 방사선 방호구를 착용하여 외부 방사선원으로부터 피폭을 최소화 시켜야 한다. The purpose of this study is to ensure safety by measuring External radiation dose ratio (ERDR) by traits of patients in many ways after administering radiopharmaceutical(<TEX>$^{18}F$</TEX>-FDG) for PET Torso scan, and to decrease ERDR of those to RI technologist, caretakers, and those who frequently exposed to radiation by arousing attention to radiation dose. Radiopharmaceutical was administered to 80 patients who conducted PET Torso from January to June, 2013. Radiation dose emitted from the patients was measured according to body shape(BMI), water hydration, height, amount of radiation administration. From the moment immediately after the radiopharmaceutical was administered, ERDR was measured by personal traits of patients. The radiation dose increased in proportion to the administered amount of the radiopharmaceutical, and there was no significant difference depending on the body shape of the patients. When water was supplied and the height was normal, the radiation dose was lower compared with the cases where water was not supplied and height was not normal. There is a need for making efforts to minimize the working time through sufficient education and mock training before those who RI technologist with sources of radiation for complying the radiation safety management rule. And they should minimize the ERDR by wearing a protective gear.

Gold nanoparticle enhancement of stereotactic radiosurgery for neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries for people over the age of 50. In this work, the dosimetric feasibility of using gold nanoparticles (AuNP) as radiosensitizers to enhance kilovoltage stereotactic radiosurgery for neovascular AMD is investigated. Microdosimetry calculations at the sub-cellular level were carried out to estimate the radiation dose enhancement to individual nuclei in neovascular AMD endothelial cells (nDEF) due to photon-induced photo-/Auger electrons from x-ray-irradiated AuNP. The nDEF represents the ratio of radiation doses to the endothelial cell nuclei with and without AuNP. The calculations were carried out for a range of feasible AuNP local concentrations using the clinically applicable 100 kVp x-ray beam parameters employed by a commercially available x-ray therapy system. The results revealed nDEF values of 1.30–3.26 for the investigated concentration range of 1–7 mg g−1, respectively. In comparison, for the same concentration range, nDEF values of 1.32–3.40, 1.31–3.33, 1.29–3.19, 1.28–3.12 were calculated for 80, 90, 110 and 120 kVp x-rays, respectively. Meanwhile, calculations as a function of distance from the AuNP showed that the dose enhancement, for 100 kVp, is markedly confined to the targeted neovascular AMD endothelial cells where AuNP are localized. These findings provide impetus for considering the application of AuNP to enhance therapeutic efficacy during stereotactic radiosurgery for neovascular AMD.

The effects of intraocular silicone oil placement prior to iodine 125 brachytherapy for uveal melanoma: a clinical case series

To investigate the role of silicone oil as an adjunct to iodine 125 ((125)I) brachytherapy in attenuating radiation dose and reducing radiation retinopathy. A 16-mm COMS plaque loaded with (125)I seeds was simulated in vitro on an eye model containing silicone oil as a vitreous substitute using BrachyDose. The radiation dose ratio of silicone oil vs water to ocular structures was calculated at angles subtended from the centre of the eye. Silicone oil was then used in three choroidal melanoma patients who underwent 23-gauge vitrectomy, silicone oil placement, and (125)I brachytherapy. Silicone oil reduced the ocular radiation dose in vitro to 65%. Radiation dose ratios on the retina increased from 0.45 to 0.99 when moving from points diametrically opposed to the plaque's central axis. In 10-24 months' follow-up, no patients have developed radiation retinopathy. Each patient required silicone oil removal and experienced cataract progression, and one also developed a retinal detachment. This study confirms that silicone oil attenuates radiation dose in vitro, and may protect against radiation retinopathy clinically in patients, however it requires extensive surgical interventions. Further studies in only very selected populations using silicone oil as an adjunct to (125)I brachytherapy will best elucidate its role in shielding radiation retinopathy.

Effects of Radiation and Lifestyle Factors on Risks of Urothelial Carcinoma in the Life Span Study of Atomic Bomb Survivors

Among the Life Span Study (LSS) of Atomic-bomb survivors, recent estimates showed that unspecified bladder cancer had high radiation sensitivity with a notably high female-to-male excess relative risk (ERR) per radiation dose ratio and were the only sites for which the ERR did not decrease with attained age. These findings, however, did not consider lifestyle factors, which could potentially confound or modify the risk estimates. This study estimated the radiation risks of the most prevalent subtype of urinary tract cancer, urothelial carcinoma, while accounting for smoking, consumption of fruit, vegetables, alcohol and level of education (a surrogate for socioeconomic status). Eligible study subjects included 105,402 (males = 42,890) LSS members who were cancer-free in 1958 and had estimated radiation doses. Members were censored due to loss of follow-up, incident cancer of another type, death, or the end of calendar year 2001. Surveys (by mail or clinical interview) gathered lifestyle data periodically for 1963-1991. There were 63,827 participants in one or more survey. Five hundred seventy-three incident urothelial carcinoma cases occurred, of which 364 occurred after lifestyle information was available. Analyses were performed using Poisson regression methods. The excess relative risk per weighted gray unit (the gamma component plus 10 times the neutron component, Gy(w)) was 1.00 (95% CI: 0.43-1.78) but the risks were not dependent upon age at exposure or attained age. Lifestyle factors other than smoking were not associated with urothelial carcinoma risk. Neither the magnitude of the radiation ERR estimate (1.00 compared to 0.96), nor the female-to-male (F:M) ERR/Gy(w) ratio (3.2 compared to 3.4) were greatly changed after accounting for all lifestyle factors. A multiplicative model of gender-specific radiation and smoking effects was the most revealing though there was no evidence of significant departures from either the additive or multiplicative joint effect models. Among the LSS cohort members with doses greater than 0.005 Gy(w) (average dose 0.21 Gy(w)), the attributable fraction of urothelial carcinoma due to radiation was 7.1% in males and 19.7% in females. Among current smokers, the attributable fraction of urothelial carcinoma due to smoking was 61% in males and 52% in females. Relative risk estimates of smoking risk were approximately two for smokers compared to nonsmokers. After adjustment for lifestyle factors, gender-specific radiation risks and the F:M ERR/Gy(w), the ratios of excess urothelial carcinoma risk were similar to the estimates without adjusting for lifestyle factors. Smoking was the primary factor responsible for excess urothelial carcinoma in this cohort. These findings led us to conclude that the radiation risk estimates of urothelial carcinoma do not appear to be strongly confounded or modified by smoking, consumption of alcohol, fruits, or vegetables, or level of education.

90Y labeled Phosphorodiamidate Morpholino Oligomer for Pretargeting Radiotherapy

While (188)Re has been used successfully in mice for tumor radiotherapy by MORF/cMORF pretargeting, previous radiolabeling of the amine-derivatized cMORF with (90)Y, a longer physical half-life nuclide, was not very successful. After developing a method involving a prepurification heating step during conjugation that increases labeling efficiency and label stability, the biodistribution of (90)Y-DOTA-Bn-SCN-cMORF ((90)Y-DOTA-cMORF) was measured in normal mice and in MORF-CC49 pretargeted mice that bear LS174T tumors. Absorbed radiation doses were then estimated and compared to those estimated for (188)Re. The pharmacokinetics of the (90)Y-DOTA-cMORF in normal mice and in the pretargeted nude mice was similar to that observed previously with (99m)Tc- and (188)Re-MAG(3)-cMORFs. While the (90)Y-DOTA-cMORF cleared rapidly from normal tissues, tumor clearance was very slow and tumor radioactivity accumulation was constant for at least 7 days such that the tumor/blood (T/B) ratio increased linearly from 6 to 25 over this period. Therefore, by extrapolation, normal tissue toxicities following administration of therapeutic doses of (90)Y may be comparable to that observed for (188)Re in which the T/B increased from 5 to 20. In conclusion, radiolabeling of DOTA-cMORF with (90)Y was improved by introducing a prepurification heating step during conjugation. The (90)Y-DOTA-cMORF provided a similar T/B ratio and biodistribution to that of (188)Re-MAG(3)-cMORF and was retained well in the tumor pretargeted with MORF-CC49. Because of the longer physical half-life, the T/NT absorbed radiation dose ratios were improved in most organs and especially in blood.

In vitro and In vivo Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor, AZD7762

Inhibition of checkpoint kinase 1 has been shown to enhance the cytotoxicity of DNA-damaging targeted chemotherapy through cell cycle checkpoint abrogation and impaired DNA damage repair. A novel checkpoint kinase 1/2 inhibitor, AZD7762, was evaluated for potential enhancement of radiosensitivity for human tumor cells in vitro and in vivo xenografts. Survival of both p53 wild-type and mutant human cell lines was evaluated by clonogenic assay. Dose modification factors (DMF) were determined from survival curves (ratio of radiation doses for control versus drug treated at 10% survival). Flow cytometry, Western blot, and radiation-induced tumor regrowth delay assays were conducted. AZD7762 treatment enhanced the radiosensitivity of p53-mutated tumor cell lines (DMFs ranging from 1.6-1.7) to a greater extent than for p53 wild-type tumor lines (DMFs ranging from 1.1-1.2). AZD7762 treatment alone exhibited little cytotoxicity to any of the cell lines and did not enhance the radiosensitivity of normal human fibroblasts (1522). AZD7762 treatment abrogated radiation-induced G(2) delay, inhibited radiation damage repair (assessed by gamma-H2AX), and suppressed radiation-induced cyclin B expression. HT29 xenografts exposed to five daily radiation fractions and to two daily AZD7762 doses exhibited significant radiation enhancement compared with radiation alone. AZD7762 effectively enhanced the radiosensitivity of mutated p53 tumor cell lines and HT29 xenografts and was without untoward toxicity when administered alone or in combination with radiation. The results of this study support combining AZD7762 with radiation in clinical trials.

Dosimetry study of a phase II multiple-dose intracavitary administration of 131I-TM601 in adult patients with recurrent high-grade glioma

e13006 Background: Postoperative radiotherapy for glioma has been shown to improve survival with increased radiation doses. Dose escalation of external beam radiotherapy or brachytherapy is limited by normal brain radionecrosis. Radiolabeled targeting molecules can deliver localized radiation to tumor and reduce normal brain radionecrosis. TM601, or synthetic Chlorotoxin, is a peptide derived from scorpion venom that specifically binds to tumor cells. Here we report dosimetry results of an imaging sub-study of a phase II trial, in which weekly doses of 131I-TM601 were infused into surgically created tumor resection cavities for 3 or 6 weeks. Methods: Five out of 76 patients treated in a phase II trial were imaged after receiving 1, 3, or 6 doses of 40 mCi/0.8 mg 131I-TM601 intracavitarily. For each imaging study, 5 sequential SPECT images (1–168 hour) were registered with MRI to determine the 131I-TM601 radiation dose to the 2-cm tumor cavity margin. Five sequential body scans were also acquired to determine 131I-TM601 radiation dose to extra-cranial organs. Results: 131I-TM601 is a rapidly penetrating and clearing radiolabeled peptide. The median residual activity in the cavity at 7 days post injection was 8.4%. Median radiation dose to the cavity margin was 121 cGy/mCi and ranged 52- 338 cGy/mCi in 5 subjects. The median coefficient of variation (intra-patient inter-fraction) for the 2-cm margin dose was 14.7% and ranged 7.1–18.9%. Median tumor cavity volume was 11.4 mL, and ranged 5.2 - 35.5 mL. There was no observed correlation between the 2-cm margin dose and the cavity volume. Median radiation dose to thyroid, kidneys, red marrow, and body was 8.3, 1.3, 0.4, and 0.6 cGy/mCi, respectively. Conclusions: Radiation dose ratio for 2-cm cavity margin-to-normal tissues was quite high. While intra-patient reproducibility was relatively good, cumulative effect of the residual activity was only meaningful within a week. These results support the multi-dose fractionation scheme for 131I-TM601 to minimize normal tissue toxicity, including radiation necrosis, and extend continuous irradiation to clinical or sub-clinical residual tumor cells after surgery. [Table: see text]

The Clinical Value of Radioembolization in the Treatment of Inoperable Liver Cancer

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. HCC-related mortality is high because most cases are diagnosed at an advanced stage. HCCs are relatively resistant to radiation and the liver is unable to tolerate the radiation doses required to achieve tumoricidal effects by standard external-beam radiation. Focal radiation techniques employing a 3D approach have been shown to safely permit higher levels of radiation to targeted regions within the liver. Delivery of therapy through hepatic artery branches preferentially affects HCC tumors and spares the surrounding liver parenchyma. Selective targeting of radionuclides to tumors has been shown to achieve high radiation dose ratios. Transarterial radionuclide therapies have been developed with the objective of achieving selective intra-arterial delivery of radiotherapy, including radioactive iodine-131 (131I), rhenium-188 (188Re), yttrium-90 (90Y) (resin or glass microspheres), and others. These treatments have been used to treat HCC via a selective transarterial approach as an alternative to TACE. Portal vein thrombosis (PVT) is a relative contraindication to transarterial chemoembolization (TACE); in contrast, high specific activity radiomicrospheres do not occlude a significant portion of the hepatic arterial vascular bed and can therefore be used in patients with PVT. The devices, toxicities, and results with use of the available radioembolic devices are reviewed in this article.