Noninvasive assessment of radiation-induced renal injury in mice.

PURPOSE: The kidney is a radiosensitive late-responding normal tissue. Injury is characterized by radiation nephropathy and decline of glomerular filtration rate (GFR). The current study aimed to compare two rapid and cost-effective methodologies of assessing GFR against more conventional biomarker measurements. METHODS: C57BL/6 mice were treated with bilateral focal X-irradiation (1x14Gy or 5x6Gy). Functional measurements of kidney injury were assessed 20 weeks post-treatment. GFR was estimated using a transcutaneous measurement of fluorescein-isothiocyanate conjugated (FITC)-sinistrin renal excretion and also dynamic contrast-enhanced CT imaging with a contrast agent (ISOVUE-300 Iopamidol). RESULTS: Hematoxylin and eosin (H&E) and Periodic acid-Schiff staining identified comparable radiation-induced glomerular atrophy and mesangial matrix accumulation after both radiation schedules, respectively, although the fractionated regimen resulted in less diffuse tubulointerstitial fibrosis. Albumin-to-creatinine ratios (ACR) increased after irradiation (1x14Gy: 100.4 ± 12.2 µg/mg; 6x5Gy: 80.4 ± 3.02 µg/mg) and were double that of nontreated controls (44.9 ± 3.64 µg/mg). GFR defined by both techniques was negatively correlated with BUN, mesangial expansion score, and serum creatinine. The FITC-sinistrin transcutaneous method was more rapid and can be used to assess GFR in conscious animals, dynamic contrast-enhanced CT imaging technique was equally safe and effective. CONCLUSION: This study demonstrated that GFR measured by dynamic contrast-enhanced CT imaging is safe and effective compared to transcutaneous methodology to estimate kidney function.

Assessment of Gadobutrol Safety in Combination with Ionizing Radiation Using a Preclinical MRI-Guided Radiotherapy Model.

MR-linac technology enhances the precision of therapeutic radiation by clarifying the tumor-normal tissue interface and provides the potential for adaptive treatment planning. Accurate delineation of tumors on diagnostic magnetic resonance imaging (MRI) frequently requires gadolinium-based contrast agents (GBCAs). Despite generally being considered safe, previous literature suggests that GBCAs are capable of contrast-induced acute kidney injury (AKI). It is unclear if the risk for AKI is enhanced when GBCAs are administered concurrently with ionizing radiotherapy. During irradiation, gadolinium may be liberated from its chelator which may induce AKI. The goal of this work was to determine if radiation combined with GBCAs increased the incidence of AKI. Using a preclinical MRI-guided irradiation system, where MRI acquisitions and radiation delivery are performed in rapid succession, tumor-bearing mice with normal kidney function were injected with GBCA and treated with 2, 8 or 18 Gy irradiation. Renal function was assessed on days three and seven postirradiation to assess for AKI. No clinically relevant changes in blood urea nitrogen and creatinine were observed in any combination of GBCA and radiation dose. From these data, we conclude that GBCA in combination with radiation does not increase the risk for AKI in mice. Additional investigation of multiple doses of GBCA administered concurrently with irradiation is warranted to evaluate the risk of chronic kidney injury.

Gonad dose assessment in paediatric kidney nuclear medicine test using Monte Carlo simulation.

In this study, we evaluated the effect of radiation dose on gonads during paediatric kidney nuclear medicine tests. Using Monte Carlo simulations, the distribution and effects of radiation were physically evaluated by displaying the distribution path of the source in the human body over time. In particular, the evaluation of doses in children, who are sensitive to radiation during nuclear medicine tests that use internal exposure among several types of medical exposures, was conducted to obtain data for the management of medical exposures. Our results indicated that under normal kidney function, the dose received by the target kidney was 0.430 mGy/mCi, which is ~6% higher than the dose suggested by the International Commission on Radiation Protection (ICRP). Furthermore, when kidney function was compromised, the dose estimated was 0.726 mGy/mCi, which is ~2% lower than the dose suggested by the ICRP. In the male and female gonads, namely the testicles and ovaries, the doses received were 0.359 mGy/mCi and 0.394 mGy/mCi, respectively, under normal kidney function. Similarly, under abnormal kidney function, the doses ranged from 0.187 to 0.353 mGy/mCi and 0.238 to 0.388 mGy/mCi in the male and female gonads, respectively.

An Assessment of Radiation Doses From Radon Exposures Using a Mouse Model System.

BACKGROUND: Radon and its progenies contribute significantly to the natural background radiation and cause several thousands of lung cancer cases per year worldwide. Moreover, patients with chronic inflammatory joint diseases are treated in radon galleries. Due to the complex nature of radon exposure, the doses associated with radon exposures are difficult to assess. Hence, there is a clear need to directly measure dose depositions from radon exposures to provide reliable risk estimates for radiation protection guidelines. OBJECTIVES: We aimed to assess tissue-specific radiation doses associated with radon activity concentrations, that deposit similar dose levels as the annual natural radon exposure or radon gallery visits. METHODS: We exposed mice to defined radon concentrations, quantified the number of 53BP1 foci as a measure of induced DNA damage, and compared it with the number of foci induced by known doses of reference-type radiations. An image-based analysis of the 3-dimensional foci pattern provided information about the radiation type inflicting the DNA damage. RESULTS: A 1-hour exposure to 440 kBq/m3 radon-induced DNA damage corresponding to a dose of ∼10 mGy in the lung and ∼3.3 mGy in the kidney, heart, and liver. A 1-hour exposure to 44 kBq/m3 provided values consistent with a linear relationship between dose and radon concentration. Two-thirds of the dose in the lung was caused by α-particles. The dose in the kidney, heart, and liver and one-third of the dose in the lung likely resulted from ß- and γ-rays. DISCUSSION: We found that radon exposures mainly lead to α-particle-induced DNA damage in the lung, consistent with the lung cancer risk obtained in epidemiologic studies. Our presented biodosimetric approach can be used to benchmark risk model calculations for radiation protection guidelines and can help to understand the therapeutic success of radon gallery treatments.

A microdosimetry model of kidney by GATE Monte Carlo simulation using a nonuniform activity distribution in digital phantom of nephron.

OBJECTIVES: As the main pathway for the clearance of radiopharmaceutical from the body, kidney is a dose-limiting organ in medical application of radionuclides. Because of its unique physiology, radioactivity is seen to concentrate on kidney nonuniformly. This nonuniformity can be considered in nephron microstructures. A microdosimetry model of kidney is necessary to include the nonuniform distribution in internal radiation dosimetry. METHOD: Implementing the microdosimetry model requires, first, a geometry phantom of nephrons. Stylized phantoms cannot distribute activities inside nephron compartments nonuniformly. A phantom of nephron was generated by a preliminary three-dimensional graphic model and was converted to a proper format of digital phantom. The phantom was fed to GATE Monte Carlo toolkits. Simulations were performed and S-values for five radionuclides (Tc-99m, In-111, Lu-177, Ac-225 and Bi-212) were calculated and compared with corresponding results published in the literature derived with a stylized phantom of nephron. Activity was distributed nonuniformly according to the kinetics of two mainly used diagnostic tracers (diethylenetriaminepetaacetate and ethylenedicysteine) and absorbed dose of nephron cells were calculated. RESULTS: A good correlation was shown between the generated phantom microdosimetry model and stylized model and revealed the phantom can be used for future microdosimetry studies of kidney to evaluate radiobiological effects of internal radiation from various diagnostic and therapeutic radiopharmaceuticals. Absorbed dose of cells for nonuniform distribution showed that some cells in a nephron compartment receive higher dose than (more than two-fold) that of compartment average dose. CONCLUSION: Average dose of nephron is not a reliable parameter for nephrotoxicity evaluation.

Optical Metabolic Imaging for Assessment of Radiation-Induced Injury to Rat Kidney and Mitigation by Lisinopril.

The kidney is one of the most radiosensitive organs; it is the primary dose-limiting organ in radiotherapies for upper abdominal cancers. The role of mitochondrial redox state in the development and treatment of renal radiation injury, however, remains ill-defined. This study utilizes 3D optical cryo-imaging to quantify renal mitochondrial bioenergetics dysfunction after 13 Gy leg-out partial body irradiation (PBI). Furthermore, the mitigating effects of lisinopril (lisino), an anti-hypertensive angiotensin converting enzyme inhibitor, is assessed in renal radiation-induced injuries. Around day 150 post-irradiation, kidneys are harvested for cryo-imaging. The 3D images of the metabolic indices (NADH, nicotinamide adenine dinucleotide, and FAD, flavin adenine dinucleotide) are acquired, and the mitochondrial redox states of the irradiated and irradiated + lisino kidneys are quantified by calculating the volumetric mean redox ratio (NADH/FAD). PBI oxidized renal mitochondrial redox state by 78%. The kidneys from the irradiated + lisino rats showed mitigation of mitochondrial redox state by 93% compared to the PBI group. The study provides evidence for an altered bioenergetics and energy metabolism in the rat model of irradiation-induced kidney damage. In addition, the results suggest that lisinopril mitigates irradiation damage by attenuating the oxidation of mitochondria leading to increase redox ratio.

Assessment of iterative image reconstruction on kidney and liver donors: Potential role of adaptive iterative dose reduction 3D (AIDR 3D) technology.

OBJECTIVE: The aim of this study was to evaluate the radiation exposure levels in two different types of subjects including liver and kidney donors in diagnostic assessment of transplant operation and also the significance of dose reduction on total effective dose. MATERIALS AND METHODS: A number of Sixty subjects (40 males and 20 females, average age of 35 ± 10 years) were randomly prospectively recruited and equally divided into two distinct groups namely kidney donors (KD, 24 M and 6 F) and liver donors (LD, 21 M and 9 female). Kidney donors were divided into full dose (KFD, n = 20) group and low dose (KLD, n = 10) group. They had undergone dynamic renal scan using Tc99 m-DTPA, CT renal angiography and x-ray plain radiograph. Liver donors were divided into full dose (LFD, n = 20) and low dose (LLD, n = 10) groups and performed CT liver volumetry. The CT dose index (CTDIvol), dose length product (DLP), total milli-ampere product time mAs, effective dose and image noise index were measured in all subjects of kidney and liver donors comparing full dose and low dose protocols. RESULTS: In comparison of all subjects of kidney donor groups (KFD vs KLD), the parameters (mAs = 16386.8 ± 3140.7 vs 2830.286 ± 831.676), (CTDIvol = 183.19 ± 32.58 mGy vs. 45.5 ± 13.3 mGy), DLP = 2884 ± 859.0 mGy.cm vs. 1437.5 ± 399 mGy.cm) and (effective dose = 49.0 ± 9.0 mSv vs. 18.9 mSv±5.7 mSv) were significant, p < 0.0005. Statistical evaluation of liver donors groups (LFD vs LLD) showed that (mAs = 14348.8 ± 4571.8 vs 3123.357 ± 794.5), (CTDIvol = 333.6 ± 59.5 mGy vs. 51.4 ± 13 mGy), (DLP = 3268.3 ± 604.3 mGy.cm vs 1260.5 ± 404.6 mGy.cm) and (effective dose = 43.3 mSv±12.9 mSv vs. 21.6 ± 5.9 mSv) are statistically significant, p < 0.0005. Nevertheless, the comparative evaluation of the image quality noise index of KFD vs KLD groups and LFD vs LLD showed a no statistical significance p > 0.05. CONCLUSION: Renal and liver donors bear a relatively significant radiation dose due to diagnostic evaluation and patient management. The CT iterative reconstruction using AIDR3D proved very valuable tool in dose reduction such that it can reduce 37% in kidney donors and 48% in liver donors while able to maintain an acceptable image quality. Monitoring of those subjects on the clinical and radiobiological levels are recommended.

A five-compartment biokinetic model for 90 Y-DOTATOC therapy.

PURPOSE: Neuroendocrine tumors (NETs) are now routinely treated by radiopeptide targeted therapy using somatostatin receptor-binding peptides such as 90 Y- and 177 Lu-DOTATOC. The objective of this work was to develop a biokinetics model of 90 Y labelled DOTATOC, which is applied in the therapy of NETs to estimate doses in kidney and tumor. METHODS: A multi-compartment model described by two sets of differential equations, one set for the actual 30-min infusion and the other set for the post-infusion period was developed and activities were measured by liquid scintillation counting in blood (compartment 1) and the urine (compartment 3). The inter-compartment transfer coefficients, λij , were varied to yield the best fit of the calculated to the measured time-activity data and the 90 Y-DOTATOC time-activity data in the five-compartments comprising the human body were thus determined. The resulting time-activity curves were integrated over the interval from 0 to 72 h post administration to obtain the number of radioactive decays in each compartment and, in case of the kidneys and tumor, then multiplied by the self-dose 90 Y beta particle absorbed fraction, determined by Monte Carlo (MC) simulation, the kidney and tumor absorbed doses. RESULTS: Transfer coefficients λij , were determined for five-compartments for all patients. Time- activity curves of 90 Y-DOTATOC in 14 patients were determined, and two typical ones are shown graphically. Absorbed doses in the tumor and kidneys, obtained by the developed method, were determined. The mean absorbed dose in a kidney per unit of administered activity is 1.43 mGy/MBq (range 0.73-2.42 mGy/MBq). The tumor dose was determined as 30.94 mGy/MBq (range 20.05-42.31 mGy/MBq). CONCLUSION: Analytical solution of a biokinetic model for 90 Y-DOTATOC therapy enabled determination of the transfer coefficients and derivation of time-activity curves and kidney and tumor absorbed doses for 14 treated patients. The model can be applied to other radionuclides where elimination is predominantly through urine, which is often the case in radiopharmaceuticals.

Effect of image registration on 3D absorbed dose calculations in 177Lu-DOTATOC peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) is an effective MRT (molecular radiotherapy) treatment, which consists of multiple administrations of a radiopharmaceutical labelled with 177Lu or 90Y. Through sequential functional imaging a patient specific 3D dosimetry can be derived. Multiple scans should be previously co-registered to allow accurate absorbed dose calculations. The purpose of this study is to evaluate the impact of image registration algorithms on 3D absorbed dose calculation. A cohort of patients was extracted from the database of a clinical trial in PRRT. They were administered with a single administration of 177Lu-DOTATOC. All patients underwent 5 SPECT/CT sequential scans at 1 h, 4 h, 24 h, 40 h, 70 h post-injection that were subsequently registered using rigid and deformable algorithms. A similarity index was calculated to compare rigid and deformable registration algorithms. 3D absorbed dose calculation was carried out with the Raydose Monte Carlo code. The similarity analysis demonstrated the superiority of the deformable registrations (p < .001). Average absorbed dose to the kidneys calculated using rigid image registration was consistently lower than the average absorbed dose calculated using the deformable algorithm (90% of cases), with percentage differences in the range [-19; +4]%. Absorbed dose to lesions were also consistently lower (90% of cases) when calculated with rigid image registration with absorbed dose differences in the range [-67.2; 100.7]%. Deformable image registration had a significant role in calculating 3D absorbed dose to organs or lesions with volumes smaller than 100 mL. Image based 3D dosimetry for 177Lu-DOTATOC PRRT is significantly affected by the type of algorithm used to register sequential SPECT/CT scans.

Internal dosimetry for radioembolization therapy with Yttrium-90 microspheres.

The absorbed doses in the liver and adjacent viscera in Yttrium-90 radioembolization therapy for metastatic liver lesions are not well-documented. We sought for a clinically practical way to determine the dosimetry of this advent treatment. Six different female XCAT BMIs and seven different male XCAT BMIs were generated. Using Monte Carlo GATE code simulation, the total of 100MBq 90 Y was deposited uniformly in the source organ, liver. Self-irradiation and absorbed doses in lung, kidney and bone marrow were calculated. The mean energy of Yittrium-90 (i.e., 0.937 MeV) was used. The S-values and equivalent doses in target organs were estimated. The dose absorbed in the liver was between 84 and 53 Gy and below the target of 80 to 150 Gy. The absorbed dose in the bone marrow, lungs, and kidneys are very low and below 0.1 , 0.4, and 0.5 Gy respectively. Our study indicates that larger activities than the conventional dose of 3 GBq may be both required and safe. Further confirmations in clinical settings are needed.

Assessment of Radiation Induced Therapeutic Effect and Cytotoxicity in Cancer Patients Based on Transcriptomic Profiling.

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and after radiation exposure. Bioinformatic tools were used for pathways, network, gene ontology and toxicity related studies. We found 429 differentially expressed genes at fold change >2 and p-value <0.05. The most significantly upregulated genes were synuclein alpha (SNCA), carbonic anhydrase I (CA1), X-linked Kx blood group (XK), glycophorin A and B (GYPA and GYPB), and hemogen (HEMGN), while downregulated ones were membrane-spanning 4-domains, subfamily A member 1 (MS4A1), immunoglobulin heavy constant mu (IGHM), chemokine (C-C motif) receptor 7 (CCR7), BTB and CNC homology 1 transcription factor 2 (BACH2), and B-cell CLL/lymphoma 11B (BCL11B). Pathway analysis revealed calcium-induced T lymphocyte apoptosis and the role of nuclear factor of activated T-cells (NFAT) in regulation of the immune response as the most inhibited pathways, while apoptosis signaling was significantly activated. Most of the normal biofunctions were significantly decreased while cell death and survival process were activated. Gene ontology enrichment analysis revealed the immune system process as the most overrepresented group under the biological process category. Toxicity function analysis identified liver, kidney and heart to be the most affected organs during and after radiation therapy. The identified biomarkers and alterations in molecular pathways induced by radiation therapy should be further investigated to reduce the cytotoxicity and development of fatigue.

Estimation of organ doses to patients undergoing hepatic chemoembolization procedures.

The aim of this study is to evaluate organ and tissue absorbed doses to patients undergoing hepatic chemoembolization procedures performed in two hospitals in the city of Recife, Brazil. Forty eight patients undergoing fifty hepatic chemoembolization procedures were investigated. For the 20 cases with PA projection only, organs and tissues dose to KAP conversion coefficients were calculated using the mesh-based anthropometric phantom series FASH and MASH coupled to the EGSnrc Monte Carlo code. Clinical, dosimetric and irradiations parameters were registered for all patients. The maximum organ absorbed doses found were 2.4 Gy, 0.85 Gy, 0.76 Gy and 0.44 Gy for skin, kidneys, adrenals and liver, respectively.

Comparison of internal dose estimates obtained using organ-level, voxel S value, and Monte Carlo techniques.

PURPOSE: The authors' objective was to compare internal dose estimates obtained using the Organ Level Dose Assessment with Exponential Modeling (OLINDA/EXM) software, the voxel S value technique, and Monte Carlo simulation. Monte Carlo dose estimates were used as the reference standard to assess the impact of patient-specific anatomy on the final dose estimate. METHODS: Six patients injected with 99mTc-hydrazinonicotinamide-Tyr3-octreotide were included in this study. A hybrid planar/SPECT imaging protocol was used to estimate 99mTc time-integrated activity coefficients (TIACs) for kidneys, liver, spleen, and tumors. Additionally, TIACs were predicted for 131I, 177Lu, and 90Y assuming the same biological half-lives as the 99mTc labeled tracer. The TIACs were used as input for OLINDA/EXM for organ-level dose calculation and voxel level dosimetry was performed using the voxel S value method and Monte Carlo simulation. Dose estimates for 99mTc, 131I, 177Lu, and 90Y distributions were evaluated by comparing (i) organ-level S values corresponding to each method, (ii) total tumor and organ doses, (iii) differences in right and left kidney doses, and (iv) voxelized dose distributions calculated by Monte Carlo and the voxel S value technique. RESULTS: The S values for all investigated radionuclides used by OLINDA/EXM and the corresponding patient-specific S values calculated by Monte Carlo agreed within 2.3% on average for self-irradiation, and differed by as much as 105% for cross-organ irradiation. Total organ doses calculated by OLINDA/EXM and the voxel S value technique agreed with Monte Carlo results within approximately ±7%. Differences between right and left kidney doses determined by Monte Carlo were as high as 73%. Comparison of the Monte Carlo and voxel S value dose distributions showed that each method produced similar dose volume histograms with a minimum dose covering 90% of the volume (D90) agreeing within ±3%, on average. CONCLUSIONS: Several aspects of OLINDA/EXM dose calculation were compared with patient-specific dose estimates obtained using Monte Carlo. Differences in patient anatomy led to large differences in cross-organ doses. However, total organ doses were still in good agreement since most of the deposited dose is due to self-irradiation. Comparison of voxelized doses calculated by Monte Carlo and the voxel S value technique showed that the 3D dose distributions produced by the respective methods are nearly identical.

Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with (177)Lu-octreotate.

PURPOSE: Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine-allowing only approximate estimates of GFR-the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. METHODS: Nephrotoxicity was analysed using (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with (177)Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by (99m)Tc-DTPA clearance versus serum creatinine. RESULTS: The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m(2) per year, relative yearly reduction -1.8 ± 18.9%). Fifteen patients (21%) experienced a mild (2-10 ml/min/m(2) per year) and 16 patients (22%) a significant (>10 ml/min/m(2) per year) decline of GFR following PRRT. However, 11 patients (15%) showed an increase of >10 ml/min/m(2) per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3%) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15% of the assessments and led to underestimation in 12% of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function. CONCLUSION: Serious nephrotoxicity after PRRT with (177)Lu-octreotate is rare (1.3%). However, slight renal impairment (GFR loss >2 ml/min/m(2) per year) can frequently (43%) be detected by (99m)Tc-DTPA clearance assessments. Cumulative administered activity of (177)Lu-octreotate is not a major determinant of renal impairment in our study.

Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response.

BACKGROUND: The kidneys are a principal dose-limiting organ in radiotherapy for upper abdominal cancers. The current understanding of kidney radiation dose response is rudimentary. More precise dose-volume response models that allow direct correlation of delivered radiation dose with spatio-temporal changes in kidney function may improve radiotherapy treatment planning for upper-abdominal tumours. METHODS/DESIGN: The Radiotherapy of Abdomen with Precise Renal Assessment with SPECT/CT Imaging (RAPRASI) is an observational clinical research study with participating sites at Sir Charles Gairdner Hospital (SCGH) in Perth, Australia and the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Eligible patients are those with upper gastrointestinal cancer, without metastatic disease, undergoing conformal radiotherapy that will involve incidental radiation to one or both kidneys. For each patient, total kidney function is being assessed before commencement of radiotherapy treatment and then at 4, 12, 26, 52 and 78 weeks after the first radiotherapy fraction, using two procedures: a Glomerular Filtration Rate (GFR) measurement using the 51Cr-ethylenediamine tetra-acetic acid (EDTA) clearance; and a regional kidney perfusion measurement assessing renal uptake of 99mTc-dimercaptosuccinic acid (DMSA), imaged with a Single Photon Emission Computed Tomography / Computed Tomography (SPECT/CT) system. The CT component of the SPECT/CT provides the anatomical reference of the kidney's position. The data is intended to reveal changes in regional kidney function over the study period after the radiotherapy. These SPECT/CT scans, co-registered with the radiotherapy treatment plan, will provide spatial correlation between the radiation dose and regional renal function as assessed by SPECT/CT. From this correlation, renal response patterns will likely be identified with the purpose of developing a predictive model. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000322235.

Can contrast media increase organ doses in CT examinations? A clinical study.

OBJECTIVE: The purpose of this article is to quantify the CT radiation dose increment in five organs resulting from the administration of iodinated contrast medium. MATERIALS AND METHODS: Forty consecutive patients who underwent both un-enhanced and contrast-enhanced thoracoabdominal CT were included in our retrospective study. The dose increase between CT before and after contrast agent administration was evaluated in the portal phase for the thyroid, liver, spleen, pancreas, and kidneys by applying a previously validated method. RESULTS: An increase in radiation dose was noted in all organs studied. Average dose increments were 19% for liver, 71% for kidneys, 33% for spleen and pancreas, and 41% for thyroid. Kidneys exhibited the maximum dose increment, whereas the pancreas showed the widest variance because of the differences in fibro-fatty involution. Finally, thyroids with high attenuation values on unenhanced CT showed a lower Hounsfield unit increase and, thus, a smaller increment in the dose. CONCLUSION: Our study showed an increase in radiation dose in several parenchymatous tissues on contrast-enhanced CT. Our method allowed us to evaluate the dose increase from the change in attenuation measured in Hounsfield units. Because diagnostic protocols require multiple acquisitions after the contrast agent administration, such a dose increase should be considered when optimizing these protocols.

Assessment of renal function after conformal radiotherapy and intensity-modulated radiotherapy by functional 1H-MRI and 23Na-MRI.

PURPOSE: Adjuvant radiochemotherapy (RCHT) improves survival of patients with locally advanced gastric cancer. Conventional three-dimensional conformal radiotherapy (3D-CRT) results in ablative doses to a significant amount of the left kidney, while image-guided intensity-modulated radiotherapy (IG-IMRT) provides excellent target coverage with improved kidney sparing. Few long-term results on IMRT for gastric cancer, however, have been published. Functional magnetic resonance imaging (fMRI) at 3.0 T including blood oxygenation-level dependent (BOLD) imaging, diffusion-weighted imaging (DWI) and, for the first time, (23)Na imaging was used to evaluate renal status after radiotherapy with 3D-CRT or IG-IMRT. PATIENTS AND METHODS: Four disease-free patients (2 after 3D-CRT and 2 after IMRT; FU for all patients > 5 years) were included in this feasibility study. Morphological sequences, axial DWI images, 2D-gradient echo (GRE)-BOLD images, and (23)Na images were acquired. Mean values/standard deviations for ((23)Na), the apparent diffusion coefficient (ADC), and R2* values were calculated for the upper/middle/lower parts of both kidneys. Corticomedullary (23)Na-concentration gradients were determined. RESULTS: Surprisingly, IG-IMRT patients showed no morphological alterations and no statistically significant differences of ADC and R2* values in all renal parts. Values for mean corticomedullary (23)Na-concentration matched those for healthy volunteers. Results were similar in 3D-CRT patients, except for the cranial part of the left kidney. This was atrophic and presented significantly reduced functional parameters (p = 0.001-p = 0.033). Reduced ADC values indicated reduced cell density and reduced extracellular space. Cortical and medullary R2* values of the left cranial kidney in the 3D-CRT group were higher, indicating more deoxygenated hemoglobin due to reduced blood flow/oxygenation. ((23)Na) of the renal cranial parts in the 3D-CRT group was significantly reduced, while the expected corticomedullary (23)Na-concentration gradient was partially conserved. CONCLUSIONS: Functional MRI can assess postradiotherapeutic renal changes. As expected, marked morphological/functional effects were observed in high-dose areas (3D-CRT), while, unexpectedly, no alteration in kidney function was observed in IG-IMRT patients, supporting the hypothesis that reducing total/fractional dose to the renal parenchyma by IMRT is clinically beneficial.

Combining the LKB NTCP model with radiosensitivity parameters to characterize toxicity of radionuclides based on a multiclonogen kidney model: a theoretical assessment.

The Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model is often used to estimate the damage level to normal tissue. However, it does not manifestly involve the influence of radiosensitivity parameters. This work replaces the generalized mean equivalent uniform dose (gEUD) with the equivalent uniform dose (EUD) in the LKB model to investigate the effect of a variety of radiobiological parameters on the NTCP to characterize the toxicity of five types of radionuclides. The dose for 50 % complication probability (D (50)) is replaced by the corresponding EUD for 50 % complication probability (EUD(50)). The properties of a variety of radiobiological characteristics, such as biologically effective dose (BED), NTCP, and EUD, for five types of radioisotope ((131)I, (186)Re, (188)Re, (90)Y, and (67)Cu) are investigated by various radiosensitivity parameters such as intrinsic radiosensitivity α, alpha-beta ratio α/ß, cell repair half-time, cell mean clonogen doubling time, etc. The high-energy beta emitters ((90)Y and (188)Re) have high initial dose rate and mean absorbed dose per injected activity in kidney, and their kidney toxicity should be of greater concern if they are excreted through kidneys. The radiobiological effect of (188)Re changes most sharply with the radiobiological parameters due to its high-energy electrons and very short physical half-life. The dose for a probability of 50% injury within 5y (D (50/5)) 28 Gy for whole-kidney irradiation should be adjusted according to different radionuclides and different radiosensitivity of individuals. The D (50/5) of individuals with low α/ß or low α, or low biological clearance half-time, will be less than 28 Gy. The 50 % complication probability dose for (67)Cu and (188)Re could be 25 Gy and 22 Gy. The same mean absorbed dose generally corresponds to different degrees of damage for tissues of different radiosensitivity and different radionuclides. The influence of various radiobiological parameters should be taken into consideration in the NTCP model.

Assessment of improved organ at risk sparing for advanced cervix carcinoma utilizing precision radiotherapy techniques.

PURPOSE: To evaluate the potential benefit of proton therapy and photon based intensity-modulated radiotherapy in comparison to 3-D conformal photon radiotherapy (3D-CRT) in locally advanced cervix cancer. PATIENTS AND METHODS: In five patients with advanced cervix cancer 3D-CRT (four-field box) was compared with intensity modulated photon (IMXT) and proton therapy (IMPT) as well as proton beam therapy (PT) based on passive scattering. Planning target volumes (PTVs) included primary tumor and pelvic and para-aortic lymph nodes. Dose-volume histograms (DVHs) were analyzed for the PTV and various organs at risk (OARs) (rectal wall, bladder, small bowel, colon, femoral heads, and kidneys). In addition dose conformity, dose inhomogeneity and overall volumes of 50% isodoses were assessed. RESULTS: All plans were comparable concerning PTV parameters. Large differences between photon and proton techniques were seen in volumes of the 50% isodoses and conformity indices. DVH for colon and small bowel were significantly improved with PT and IMPT compared to IMXT, with D(mean) reductions of 50-80%. Doses to kidneys and femoral heads could also be substantially reduced with PT and IMPT. Sparing of rectum and bladder was superior with protons as well but less pronounced. CONCLUSION: Proton beam RT has significant potential to improve treatment related side effects in the bowel compared to photon beam RT in patients with advanced cervix carcinoma.

Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.

PURPOSE: Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment. METHODS: Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2-172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t (2vo). In addition to standard toxicity assessment, the major inner organs were examined histologically. RESULTS: The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t (2vo)) and led to a lethality rate of 15-30%. Higher TPZ doses caused an increase in t (2vo), but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity. CONCLUSIONS: This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.