Abdominal imaging dose in radiology and radiotherapy – Phantom point dose measurements,effective dose and secondary cancer risk

PurposeTo compare abdominal imaging dose from 3D imaging in radiology (standard/low-dose/dual-energy CT) and radiotherapy (planning CT, kV cone-beam CT (CBCT)).MethodsDose was measured by thermoluminescent dosimeters (TLD’s) placed at 86 positions in an anthropomorphic phantom. Point, organ and effective dose were assessed, and secondary cancer risk from imaging was estimated.ResultsOverall dose and mean organ dose comparisons yield significantly lower dose for the optimized radiology protocols (dual-source and care kV), with an average dose of 0.34±0.01 mGy and 0.54±0.01 mGy (average ± standard deviation), respectively. Standard abdominal CT and planning CT involve considerably higher dose (13.58 ± 0.18 mGy and 18.78±0.27 mGy, respectively). The CBCT dose show a dose fall-off near the field edges. On average, dose is reduced as compared with the planning or standard CT (3.79 ± 0.21 mGy for 220° rotation and 7.76 ± 0.37 mGy for 360°), unless the high-quality setting is chosen (20.30 ± 0.96 mGy). The mean organ doses show a similar behavior, which translates to the estimated secondary cancer risk. The modelled risk is in the range between 0.4 cases per million patient years (PY) for the radiological scans dual-energy and care kV, and 300 cases per million PY for the high-quality CBCT setting.ConclusionsModern radiotherapy imaging techniques (while much lower in dose than radiotherapy), involve considerably more dose to the patient than modern radiology techniques. Given the frequency of radiotherapy imaging, a further reduction in radiotherapy imaging dose appears to be both desirable and technically feasible.     

Cytogenetic effect of low dose γ-radiation in Hordeum vulgare seedlings: non-linear dose–effect relationship

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10–1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed. An erratum to this article can be found at     

Characterization of binding mode of imatinib to human α1-acid glycoprotein

Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.     

A “quality-control-based correction method” for displayed dose indices on CT scanner consoles in patient dose surveys

PurposeA new quality-control-based (QC-based) method is introduced to obtain correction factors to be applied to displayed patient dose indices (CTDI_Vol and DLP) on CT scanner consoles to verify improvement of dose surveys for diagnostic reference levels (DRLs) determination.MethodAn available data-base of QC documents and reports of 57 CT scanners in Tehran, Iran was used to estimate CTDI_Vol, DLP and relevant correction factors for three CT examination types including head, chest and abdomen/pelvis. The correction factor is the ratio of QC-based estimated dose to displayed dose. A dose survey was performed by applying on-site “data collection method” and correction factors obtained in order to select CT scanners in three modes for determination of CT DRLs by inclusion of: (a) all CT scanners before displayed dose indices were corrected (57), (b) only CT scanners calibrated by QC experts (41) and (c) all CT scanners after displayed dose indices were corrected (57).ResultsFor the 41 CT scanners, correction factors of three examination types obtained in this study are within the acceptance tolerance of IAEA HHS-19. The correction factors range from 0.45 to 1.7 (average of 3 examinations) which is due to the change in the calibrated value of CTDI_Vol over extended time. The DRL differences in three modes are within ±1.0% for CTDI_Vol and ±12.4% for DLP.ConclusionsThe “QC-based correction method” applied to mode (c) has improved the DRLs obtained by other two modes. This method is a strong alternative to “direct dose measurement” with simplicity and cost effectiveness.     

Bladder dose–surface maps and urinary toxicity: Robustness with respect to motion in assessing local dose effects

The purpose of this study was to quantify the impact of inter-fraction modifications of bladder during RT of prostate cancer on bladder dose surface maps (DSM).Eighteen patients treated with daily image-guided Tomotherapy and moderate hypofractionation (70–72.8 Gy at 2.5–2.6 Gy/fr in 28 fractions and full bladder) were considered. Bladder contours were delineated on co-registered daily Megavoltage CT (MVCT) by a single observer and copied on the planning CT to generate dose–volume/surface histograms (DVH/DSH) and bladder DSMs. Discrepancies between planned and daily absorbed doses were analyzed through the average of individual systematic errors, the population systematic errors and the population random errors for the DVH/DSHs and DSMs.In total, 477 DVH/DSH and 472 DSM were available. DSH and DVH showed small population systematic errors of absolute surfaces (<3.4 cm²) and volumes (<8.4 cm³) at the highest doses.The dose to the posterior bladder base assessed on DSMs showed a mean systematic error below 1 Gy, with population systematic and random errors within 4 and 3 Gy, respectively. The region surrounding this area shows higher mean systematic errors (1–3 Gy), population systematic (8–11 Gy) and random (5–7 Gy) errors.In conclusion, DVH/DSH and DSMs are quite stable with respect to inter-fraction variations in the high-dose region, within about 2 cm from bladder base. Larger systematic variations occur in the anterior portion and cranially 2.5–3.5 cm from the base.Results suggest that dose predictors related to the high dose area (including the trigone dose) are likely to be sufficiently reliable with respect to the expected variations due to variable bladder filling.     

Is dose escalation achievable for esophageal carcinoma?

Aim

To investigate the feasibility of dose escalation using rapid arc (RA) and Helical Tomotherapy (HT) for patients with upper, middle and distal esophageal carcinomas, even for large tumor volumes.

Background

In esophageal cancer, for patients with exclusive radio-chemotherapy, local disease control remains poor. Planning study with dose escalation was done for two sophisticated modulated radiotherapy techniques: Rapid arc against Tomotherapy.

Materials and methods

Six patients treated with a RA simultaneous integrated boost (SIB) of 60 Gy were re-planned for RA and HT techniques with a SIB dose escalated to 70 Gy. Dose volume histogram statistics, conformity indices and homogeneity indices were analyzed. For a given set of normal tissue constraints, the capability of each treatment modality to increase the GTV dose to 70 Gy was investigated.

Results

Either HT or VMAT may be used to escalate the dose delivered in esophageal tumors while maintaining the spinal cord, lung and heart doses within tolerance. Adequate target coverage was achieved by both techniques. Typically, HT achieved better lung sparing and PTV coverage than did RA.

Conclusions

Dose escalation for esophageal cancer becomes clinically feasible with the use of RA and HT. This promising result could be explored in a carefully controlled clinical study which considered normal tissue complications and tumor control as endpoints.     

Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose–response relationships

Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional (3D) dose distributions for each individual patient. The dose distributions can be converted into organ equivalent doses to describe radiation-induced cancer after radiotherapy (OED_rad-ther) in the irradiated organs. The OED_rad-ther concept assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer risk. In this work, this concept is applied to dose–response relationships, which are leveling off at high dose. The organ-dependent operational parameter of this dose–response relationship was estimated by analyzing secondary cancer incidence data of patients with Hodgkin’s disease. The dose distributions of a typical radiotherapy treatment plan for treating Hodgkin’s disease was reconstructed. Dose distributions were calculated in individual organs from which cancer incidence data were available. The model parameter was obtained by comparing dose and cancer incidence rates for the individual organs.     

Hill coefficients,dose–response curves and allosteric mechanisms

Hill coefficients (n _H) derived from four parameter logistic fits to dose–response curves were compared to calculated realistic reaction schemes and related to experimental data: (1) Hill coefficients may give information on the number of interacting sites but cannot distinguish between competitive, non-competitive or ortho-, iso-, or allosteric mechanisms. (2) For enzymatic dose–inhibition curves, Hill coefficients smaller than one do not indicate anticooperative binding but show that at least one ternary complex has enzymatic activity. (3) Hill coefficients different from one are proof for multiple ligand binding. The large variations of reported Hill coefficients corresponds to multiple allosteric binding, where induced conformational changes cause loss of the active conformation. Such a denaturation mechanism is in stark contrast to the desired specificity of drugs. The discussion is open.     

The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian α-carbonic anhydrase isoforms

The protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition was recently shown to constitute a new modality for treating cancers. Two clinically used PTK inhibitors (PTKIs), imatinib (Glivec?/Gleevec?) and nilotinib (Tasigna?) were investigated for their effects on the zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1). The two PTKIs inhibited all 13 catalytically active mammalian isoforms CA I–XV with K_Is in the range of 4.1 nM–20.2 μM. CA I and CA II were the most potently inhibited isoforms (K_Is of 4–32 nM), whereas CA VA and VB showed the lowest affinity for these drugs (K_Is of 5.4–20.2 μM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs.     

The ΔT thermal dose concept 1: in vivo teratogenesis

This project was an initial test of the hypothesis that there would be a ΔT thermal dose relationship for birth defects in rats (Rattus norvegicus) during neural tube closure (NTC). Additionally, the same thermal dose as applied during NTC in utero in vivo, was also applied to exteriorized (i.e., ex vivo) in utero pregnant uterine horns at a comparable stage of organogenesis. Since the yields of the two regimens were comparable, the hyperthermia-induced teratogenic effects appear to result from the thermal dosing of the in utero embryos and not the elevated temperature of the mother. The hypothesis was supported.     

Low‐dose linearity: The rule or the exception?

In 1976, Crump, Hoel, Langley, and Peto described how almost any dose‐response relationship for carcinogens becomes linear at low doses when background cancers are taken into account. This has been used, by the U.S. Environmental Protection Agency, USEPA, as partial justification for a regulatory posture that assumes low‐dose linearity, as is illustrated by a discussion of regulation of benzene as a carcinogen. The argument depends critically on the assumption that the pollutant and the background proceed by the same biological mechanism. In this paper we show that the same argument applies to noncancer end points also. We discuss the application to a number of situations: reduction in lung function and consequent increase in death rate due to (particulate) air pollution; reduction in IQ and hence (in extreme cases) mental deficiency due to radiation in utero; reduction of sperm count and hence increase in male infertility due to DBCP exposure. We conclude that, although the biological basis for the health effect response is different, in each case low‐dose linearity might arise from the same mathematical effect discussed by Crump et al. (1976). We then examine other situations and toxic end points where low‐dose linearity might apply by the same argument. We urge that biologists and chemists should concentrate efforts on comparing the biological and pharmacokinetic processes that apply to the pollutant and the background. Finally, we discuss some public policy implications of the possibility that low dose linearity may be the rule rather than the exception for environmental exposures.     

Alleviation of salt stress by low dose γ-irradiation in rice

The effects of salt stress on the growth, photosynthesis, and antioxidative ability of the rice (Oryza sativa L.) plants raising from -irradiated seeds were investigated using two cultivars, Ilpumbyeo and Sanghaehyanghyella. The 50 and 100 mM NaCl solutions caused a remarkable decrease of the early germination rate and seedling growth. However, the salt stress-induced inhibition of the growth was significantly alleviated in the -irradiated plants. The chlorophyll contents and the effective quantum yield of photosystem 2 ( _{PS 2}) were lower in the NaCl-treated plants than in the control ones, while the non-photochemical quenching was higher in the former ones. Activities of the antioxidant enzymes such as superoxide dismutase (SOD) and ascorbate peroxidase (APX) increased with increasing NaCl concentrations, and the irradiated groups had even higher SOD and APX activities than the non-irradiated ones. These alleviation effects were observed similarly in both the cultivars tested.     

Selective binding of imatinib to the genetic variants of human α1-acid glycoprotein

Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to α₁-acid glycoprotein (AGP) component was found to inhibit the pharmacological activity. AGP shows genetic polymorphism and the two main genetic variants have different drug binding properties. The binding characteristics of imatinib to AGP genetic variants and the possibility of its binding interactions were investigated by various methods. The results proved that binding of imatinib to the two main genetic variants is very different, the high affinity binding belongs dominantly to the F1-S variant. This interaction is accompanied with specific spectral changes (induced circular dichroism, UV change, intrinsic fluorescence quenching), suggesting that the bound ligand has chiral conformation that would largely overlap with other ligands inside the protein cavity. Binding parameters of K_a = 1.7(± 0.2) × 10⁶ M^− 1 and n = 0.94 could be determined for the binding on the F1-S variant at 37°. Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nK_a ≈ 3 × 10⁴ M^− 1) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.     

A single dose of the DENV-1 candidate vaccine rDEN1Δ30 is strongly immunogenic and induces resistance to a second dose in a randomized trial

Dengue is an emerging infectious disease that has become the most important arboviral infection worldwide. There are four serotypes of dengue virus, DENV-1, DENV-2, DENV-3, and DENV-4, each capable of causing the full spectrum of disease. rDEN1Δ30 is a live attenuated investigational vaccine for the prevention of DENV-1 illness and is also a component of an investigational tetravalent DENV vaccine currently in Phase I evaluation. A single subcutaneous dose of rDEN1Δ30 was previously shown to be safe and immunogenic in healthy adults. In the current randomized placebo-controlled trial, 60 healthy flavivirus-naive adults were randomized to receive 2 doses of rDEN1Δ30 (N = 50) or placebo (N = 10), either on study days 0 and 120 (cohort 1) or 0 and 180 (cohort 2). We sought to evaluate the safety and immunogenicity of this candidate vaccine in 50 additional vaccinees and to test whether the humoral immune response could be boosted by a second dose administered 4 or 6 months after the first dose. The first dose of vaccine was well tolerated, infected 47/50 vaccinees and induced seroconversion in 46/50 vaccinees. Irrespective of dosing interval, the second dose of vaccine was also well tolerated but did not induce any detectable viremia or ≥4-fold rise in serum neutralizing antibody titer.Only five subjects had an anamnestic antibody response detectable by ELISA following a second dose of vaccine, demonstrating that the vaccine induced sterilizing humoral immunity in most vaccinees for at least six months following primary vaccination.The promising safety and immunogenicity profile of this vaccine confirms its suitability for inclusion in a tetravalent dengue vaccine.     

How does radiation damage in protein crystals depend on X-ray dose?

Is radiation damage to cryopreserved protein crystals strictly proportional to accumulated dose at the high-flux density of beams from undulators at third-generation synchrotron sources? The answer is "yes," for overall damage to several different kinds of protein crystals at flux densities up to 10(15) ph/sec/mm(2) (APS beamline 19-ID). We find that, at 12 keV (1 A wavelength), about ten absorbed photons are sufficient to "kill" a unit cell. As this corresponds to about one elastically scattered photon, each unit cell can contribute only about one photon to total Bragg diffraction. The smallest crystal that can yield a full data set to 3.5 A resolution has a diameter of about 20 microm (100 A unit cell).     

Micro‐dose placement of phosphorus induces deep rooting of upland rice

Plant and Soil - Upland rice production is often constrained by phosphorus deficiency (P) and drought events. Methods are needed to maximize P use efficiency, while promoting deep root development...