Radiation metabolomics. 5. Identification of urinary biomarkers of ionizing radiation exposure in nonhuman primates by mass spectrometry-based metabolomics

Mass spectrometry-based metabolomics has previously demonstrated utility for identifying biomarkers of ionizing radiation exposure in cellular, mouse and rat in vivo radiation models. To provide a valuable link from small laboratory rodents to humans, γ-radiation-induced urinary biomarkers were investigated using a nonhuman primate total-body-irradiation model. Mass spectrometry-based metabolomics approaches were applied to determine whether biomarkers could be identified, as well as the previously discovered rodent biomarkers of γ radiation. Ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry analysis was carried out on a time course of clean-catch urine samples collected from nonhuman primates (n = 6 per cohort) exposed to sham, 1.0, 3.5, 6.5 or 8.5 Gy doses of (60)Co γ ray (∼0.55 Gy/min) ionizing radiation. By multivariate data analysis, 13 biomarkers of radiation were discovered: N-acetyltaurine, isethionic acid, taurine, xanthine, hypoxanthine, uric acid, creatine, creatinine, tyrosol sulfate, 3-hydroxytyrosol sulfate, tyramine sulfate, N-acetylserotonin sulfate, and adipic acid. N-Acetyltaurine, isethionic acid, and taurine had previously been identified in rats, and taurine and xanthine in mice after ionizing radiation exposure. Mass spectrometry-based metabolomics has thus successfully revealed and verified urinary biomarkers of ionizing radiation exposure in the nonhuman primate for the first time, which indicates possible mechanisms for ionizing radiation injury.

Differences in Median Ultraviolet Light Transmissions of Serial Homeopathic Dilutions of Copper Sulfate, Hypericum perforatum, and Sulfur

Homeopathic remedies are produced by potentising, that is, the serial logarithmic dilution and succussion of a mother tincture. Techniques like ultraviolet spectroscopy, nuclear magnetic resonance, calorimetry, or thermoluminescence have been used to investigate their physical properties. In this study, homeopathic centesimal (c) potencies (6c to 30c) of copper sulfate, Hypericum perforatum, and sulfur as well as succussed water controls were prepared. Samples of these preparations were exposed to external physical factors like heat, pressure, ultraviolet radiation, or electromagnetic fields to mimic possible everyday storage conditions. The median transmissions from 190nm to 340nm and 220nm to 340nm were determined by ultraviolet light spectroscopy on five measurement days distributed over several months. Transmissions of controls and potencies of sulfur differed significantly on two of five measurement days and after exposure to physical factors. Transmissions of potencies exposed to ultraviolet light and unexposed potencies of copper sulfate and Hypericum perforatum differed significantly. Potency levels 6c to 30c were also compared, and wavelike patterns of higher and lower transmissions were found. The Kruskal-Wallis test yielded significant differences for the potency levels of all three substances. Aiming at understanding the physical properties of homeopathic preparations, this study confirmed and expanded the findings of previous studies.

The role of radiation therapy in resected T2 N0 esophageal cancer: a population-based analysis

The prognosis of even early-stage esophageal cancer is poor. Because there is not a consensus on how to manage T2 N0 disease, we examined survival after resection of T2 N0 esophageal cancer, with or without radiation therapy.

A high-resolution comparative radiation hybrid map of equine chromosome 4q12-q22

In this study, we present a comprehensive 5000-rad radiation hybrid map of a 40-cM region on equine chromosome 4 (ECA4) that contains quantitative trait loci for equine osteochondrosis. We mapped 29 gene-associated sequence tagged site markers using primers designed from equine expressed sequence tags or BAC clones in the ECA4q12-q22 region. Three blocks of conserved synteny, showing two chromosomal breakpoints, were identified in the segment of ECA4q12-q22. Markers from other segments of HSA7q mapped to ECA13p and ECA4p, and a region of HSA7p was homologous to ECA13p. Therefore, we have improved the resolution of the human-equine comparative map, which allows the identification of candidate genes underlying traits of interest.

Postoperative radiation therapy for T1 and T2 primary parotid carcinoma: is it useful?

OBJECTIVE: The benefit of postoperative radiation for advanced primary parotid carcinoma has been reported previously, whereas studies to evaluate the usefulness of postoperative radiation for T1 and T2 parotid carcinomas have never been performed. STUDY DESIGN AND SETTING: Retrospective analysis on 58 previously untreated patients with T1 and T2 parotid carcinomas. In 34 patients, postoperative radiation was included in the treatment protocol and in 24 patients, no postoperative radiation was applied. RESULTS: A local recurrence was observed in 8 of 24 (33%) patients without and in 1 of 34 (3%) patients with postoperative radiation (P < 0.5). The 5-year actuarial and disease-free survival rate was 83% and 70% for patients without postoperative radiation and 93% and 92% for patients with postoperative radiation. CONCLUSION AND SIGNIFICANCE: Local recurrence was less often observed in patients with postoperative radiation. Nevertheless, prospective randomized studies are needed to confirm the usefulness of postoperative radiation in early carcinomas. EBM rating: B-3b.

Effect of patient size on radiation dose for abdominal MDCT with automatic tube current modulation: phantom study

OBJECTIVE: The purpose of this study was to evaluate in a phantom study the effect of patient size on radiation dose for abdominal MDCT with automatic tube current modulation. MATERIALS AND METHODS: One or two 4-cm-thick circumferential layers of fat-equivalent material were added to the abdomen of an anthropomorphic phantom to simulate patients of three sizes: small (cross-sectional dimensions, 18 x 22 cm), average size (26 x 30 cm), and oversize (34 x 38 cm). Imaging was performed with a 64-MDCT scanner with combined z-axis and xy-axis tube current modulation according to two protocols: protocol A had a noise index of 12.5 H, and protocol B, 15.0 H. Radiation doses to three abdominal organs and the skin were assessed. Image noise also was measured. RESULTS: Despite increasing patient size, the image noise measured was similar for protocol A (range, 11.7-12.2 H) and protocol B (range, 13.9-14.8 H) (p > 0.05). With the two protocols, in comparison with the dose of the small patient, the abdominal organ doses of the average-sized patient and the oversized patient increased 161.5-190.6%and 426.9-528.1%, respectively (p < 0.001). The skin dose increased as much as 268.6% for the average-sized patient and 816.3% for the oversized patient compared with the small patient (p < 0.001). CONCLUSION: Oversized patients undergoing abdominal MDCT with tube current modulation receive significantly higher doses than do small patients. The noise index needs to be adjusted to the body habitus to ensure dose efficiency.

Dosimetric impact of geometric errors due to respiratory motion prediction on dynamic multileaf collimator-based four-dimensional radiation delivery

The synchronization of dynamic multileaf collimator (DMLC) response with respiratory motion is critical to ensure the accuracy of DMLC-based four dimensional (4D) radiation delivery. In practice, however, a finite time delay (response time) between the acquisition of tumor position and multileaf collimator response necessitates predictive models of respiratory tumor motion to synchronize radiation delivery. Predicting a complex process such as respiratory motion introduces geometric errors, which have been reported in several publications. However, the dosimetric effect of such errors on 4D radiation delivery has not yet been investigated. Thus, our aim in this work was to quantify the dosimetric effects of geometric error due to prediction under several different conditions. Conformal and intensity modulated radiation therapy (IMRT) plans for a lung patient were generated for anterior-posterior/posterior-anterior (AP/PA) beam arrangements at 6 and 18 MV energies to provide planned dose distributions. Respiratory motion data was obtained from 60 diaphragm-motion fluoroscopy recordings from five patients. A linear adaptive filter was employed to predict the tumor position. The geometric error of prediction was defined as the absolute difference between predicted and actual positions at each diaphragm position. Distributions of geometric error of prediction were obtained for all of the respiratory motion data. Planned dose distributions were then convolved with distributions for the geometric error of prediction to obtain convolved dose distributions. The dosimetric effect of such geometric errors was determined as a function of several variables: response time (0-0.6 s), beam energy (6/18 MV), treatment delivery (3D/4D), treatment type (conformal/IMRT), beam direction (AP/PA), and breathing training type (free breathing/audio instruction/visual feedback). Dose difference and distance-to-agreement analysis was employed to quantify results. Based on our data, the dosimetric impact of prediction (a) increased with response time, (b) was larger for 3D radiation therapy as compared with 4D radiation therapy, (c) was relatively insensitive to change in beam energy and beam direction, (d) was greater for IMRT distributions as compared with conformal distributions, (e) was smaller than the dosimetric impact of latency, and (f) was greatest for respiration motion with audio instructions, followed by visual feedback and free breathing. Geometric errors of prediction that occur during 4D radiation delivery introduce dosimetric errors that are dependent on several factors, such as response time, treatment-delivery type, and beam energy. Even for relatively small response times of 0.6 s into the future, dosimetric errors due to prediction could approach delivery errors when respiratory motion is not accounted for at all. To reduce the dosimetric impact, better predictive models and/or shorter response times are required.

[Radiation burden of organs in fluoroscopic studies]

Various conventional and modern fluoroscope units had been examined with an anthropomorphic phantom to determine the applied average organ doses. The aim of our investigation was to compare these doses with those normally delivered to the patients during a conventional X-ray examination of the thorax. As was to be expected, the doses resulting from conventional fluoroscopic units are much higher than the doses from modern units. As shown by means of our measurements, the efforts of advanced technology permit to reduce the dose rate up to a factor of 30. I.e., the doses resulting from modern fluoroscopic units are even smaller than the doses received during a conventional thoracic X-ray examination, what means a great improvement for this examination technic.

The double-stranded RNA-activated protein kinase mediates radiation resistance in mouse embryo fibroblasts through nuclear factor kappaB and Akt activation

PURPOSE: Activation of the double-stranded RNA-activated protein kinase (PKR) leads to the induction of various pathways including the down-regulation of translation through phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF-2alpha). There have been no reports to date about the role of PKR in radiation sensitivity. EXPERIMENTAL DESIGN: A clonogenic survival assay was used to investigate the sensitivity of PKR mouse embryo fibroblasts (MEF) to radiation therapy. 2-Aminopurine (2-AP), a chemical inhibitor of PKR, was used to inhibit PKR activation. Nuclear factor-kappaB (NF-kappaB) activation was assessed by electrophoretic mobility shift assay (EMSA). Expression of PKR and downstream targets was examined by Western blot analysis and immunofluorescence. RESULTS: Ionizing radiation leads to dose- and time-dependent increases in PKR expression and function that contributes to increased cellular radiation resistance as shown by clonogenic survival and terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) apoptosis assays. Specific inhibition of PKR with the chemical inhibitor 2-AP restores radiation sensitivity. Plasmid transfection of the PKR wild-type (wt) gene into PKR(-/-) MEFs leads to increased radiation resistance. The protective effect of PKR to radiation may be mediated in part through NF-kappaB and Akt because both NF-kappaB and Akt are activated after ionizing radiation in PKR+/+ but not PKR-/- cells. CONCLUSIONS: We suggest a novel role for PKR as a mediator of radiation resistance modulated in part through the protective effects of NF-kappaB and Akt activation. The modification of PKR activity may be a novel strategy in the future to overcome radiation resistance.

Abdominal multislice CT for obese patients: effect on image quality and radiation dose in a phantom study

RATIONALE AND OBJECTIVES: To evaluate the effect of a modified abdominal multislice computed tomography (CT) protocol for obese patients on image quality and radiation dose. MATERIALS AND METHODS: An adult female anthropomorphic phantom was used to simulate obese patients by adding one or two 4-cm circumferential layers of fat-equivalent material to the abdominal portion. The phantom was scanned with a subcutaneous fat thickness of 0, 4, and 8 cm using the following parameters (detector configuration/beam pitch/table feed per rotation/gantry rotation time/kV/mA): standard protocol A: 16 x 0.625 mm/1.75/17.5 mm/0.5 seconds/140/380, and modified protocol B: 16 x 1.25 mm/1.375/27.5 mm/1.0 seconds/140/380. Radiation doses to six abdominal organs and the skin, image noise values, and contrast-to-noise ratios (CNRs) were analyzed. Statistical analysis included analysis of variance, Wilcoxon rank sum, and Student's t-test (P < .05). RESULTS: Applying the modified protocol B with one or two fat rings, the image noise decreased significantly (P < .05), and simultaneously, the CNR increased significantly compared with protocol A (P < .05). Organ doses significantly increased, up to 54.7%, comparing modified protocol B with one fat ring to the routine protocol A with no fat rings (P < .05). However, no significant change in organ dose was seen for protocol B with two fat rings compared with protocol A without fat rings (range -2.1% to 8.1%) (P > .05). CONCLUSIONS: Using a modified abdominal multislice CT protocol for obese patients with 8 cm or more of subcutaneous fat, image quality can be substantially improved without a significant increase in radiation dose to the abdominal organs.

CT radiation dose for computer-assisted endoscopic sinus surgery: dose survey and determination of dose-reduction limits

BACKGROUND AND PURPOSE: Computer-assisted navigation is increasingly used in functional endoscopic sinus surgery (FESS) to prevent injury to vital structures, necessitating preparative CT and, thus, radiation exposure. The purpose of our study was to investigate currently used radiation doses for CT in computer-assisted navigation in sinus surgery (CAS-CT) and to assess minimal doses required. MATERIALS AND METHODS: A questionnaire inquiring about dose parameters used for CAS-CT was sent to 30 radiologic institutions. The feasibility of low-dose registration was tested with a phantom. The influence of CAS-CT dose on technical accuracy and on the practical performance of 5 ear, nose, and throat (ENT) surgeons was evaluated with cadaver heads. RESULTS: The questionnaire response rate was 63%. Variation between minimal and maximal dose used for CAS-CT was 18-fold. Phantom registration was possible with doses as low as 1.1 mGy. No dose dependence on technical accuracy was found. ENT surgeons were able to identify anatomic landmarks on scans with a dose as low as 3.1 mGy. CONCLUSIONS: The vast dose difference between institutions mirrors different attitudes toward image quality and radiation-protection issues rather than being technically founded, and many patients undergo CAS-CT at higher doses than necessary. The only limit for dose reduction in CT for computer-assisted endoscopic sinus surgery is the ENT surgeon's ability to cope with impaired image quality, whereas there is no technically justified lower dose limit. We recommend, generally, doses used for the typical diagnostic low-dose sinus CT (120 kV/20-50 mAs). When no diagnostic image quality is needed, even a reduction down to a third is possible.

Progress on BIG 1-02/IBCSG 27-02/NSABP B-37, a prospective randomized trial evaluating chemotherapy after local therapy for isolated locoregional recurrences of breast cancer

BACKGROUND: The utility of chemotherapy for women who experience a locoregional recurrence after primary treatment of early breast cancer remains an open question. An international collaborative trial is being conducted by the Breast International Group (BIG), the International Breast Cancer Study Group (IBCSG), and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine the effectiveness of cytotoxic therapy for these patients, either alone or in addition to selective use of hormonal therapy and trastuzumab. METHODS: The trial population includes women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery, but subsequently develop an isolated local and/or regional ipsilateral invasive recurrence. Excision of all macroscopic tumor without evidence of systemic disease is required for study entry. Patients are randomized to receive chemotherapy or no chemotherapy; type of chemotherapy is not protocol-specified. Radiation, hormonal therapy, and trastuzumab are given as appropriate. The primary endpoint is disease-free survival (DFS). Quality-of-life measurements are collected at baseline, and then at 9 and 12 months. The accrual goal is 977 patients. RESULTS: This report describes the characteristics of the first 99 patients. Sites of recurrence at study entry were: breast (56%), mastectomy scar/chest wall (35%), and regional lymph nodes (9%). Two-thirds of patients have estrogen-receptor-positive recurrences. CONCLUSION: This is the only trial actively investigating the question of "adjuvant" chemotherapy in locally recurrent breast cancer. The case mix of accrual to date indicates a broad representation of this patient population.