Dose and litter allocations in the design of teratological studies for detecting hormesis

BACKGROUND: Hormesis is being recognized in the field of toxicology due to the stimulating effects of some toxic compounds at low exposure levels. Therefore, it is desirable that experimental designs for toxicological studies be flexible enough to aid in the detection of hormetic effects. Current designs may still not have enough power to do this. METHODS: A simulation study was conducted to determine teratological study designs that would yield more power over standard designs in detecting hormesis. Developmental toxicity endpoints of interest are the number of dead/resorbed or malformed fetuses in a litter. The simulation designs mimic teratological experiments in terms of sample size and number of dose levels. Modified designs with even dose spacing at low levels and reallocated litters are investigated to determine the power of hormetic detection. RESULTS: Designs with reallocated litters (with more litters at low exposure levels than at high levels) and even dose spacing have more power than those with equal litters per group and uneven dose spacing. CONCLUSIONS: Through appropriate modifications of current experimental designs, such as reallocation of litters and even dose spacing, we can better detect hormetic effects.     

Dose optimization in cardiac CT

Rapid progress in the field of Cardiac CT is fostered by the advances in CT scanner technology as well as multiple clinical trials demonstrating its role in coronary artery disease and other indications like congenital heart disease, pulmonary vein assessment and pre transcatheter aortic valve replacement. The cardiovascular imager today is responsible for delivering diagnostic image quality while striking a balance with optimized radiation dose. Radiation dose is the result of multiple scanner and patient related factors. Achieving a justifiable radiation dose according to the ALARA principle requires an adept understanding of the factors affecting radiation dose. We review different scan factors and their effect on radiation dose and present strategies for radiation dose optimization in cardiac CT.     

Dose response in neutral filter elution

In neutral filter elution a nonlinear relationship between fraction of eluted DNA and dose is usually observed, which is often interpreted as a nonlinear induction of DNA double-strand breaks (DSBs) with dose. The conclusiveness of this hypothesis is questioned here on the basis of theoretical considerations regarding the size distribution of DNA fragments. A simple hydrodynamic model is proposed which generates the typical features of the dose response of neutral filter elution: (1) the shoulder at low doses, (2) a quasilinear correlation in an intermediate dose range, (3) a saturation at high doses, and (4) a linearization of the curve in the intermediate and higher dose range in a semilogarithmic plot. These features were derived even with the assumption of a linear induction of DSBs with dose. Thus it is demonstrated that the fraction of eluted DNA could conceivably be a nonlinear function of dose even if the induction of DSBs is directly proportional to the radiation dose.     

Dose distribution of modified heyman packing

Introduction. One of the treatment modalities of brachytherapy of endometrial carcinomas is the modified Heyman packing technique.The aim of the study is to assess the dose distributions of regular arrangements of modified Heyman packings.Materials and Methods. We reconstructed the catheters with biplane X-ray images and optimised the dose distribution with defining‘dose points’ the uterine wall thickness apart from the outermost left and right catheters. We fitted the reconstructed catheters with the diagnostic sagittal MR scan obtained prior to the first insertion. We checked the dose distribution defining ‘patients points’ on sagittal contour of the uterus.Results and Conclusions. The treatment plans optimised ‘on dose points and geometry’ resulted in a satisfactory dose distribution, however systematic overdosed and under-dosed regions have been experienced.     

Routine High Dose Excretory Urography

Radiologic evaluation of 316 excretory urograms utilizing a single 50 ml injection of a 50 to 60 per cent tri-iodinated contrast medium indicated that these studies are of better quality than those previously obtained with the injection of 30 ml. The low incidence of side effects coincides with recent reports in the literature that this dosage level is safe. High dose intravenous drip infusion pyelography was necessary only in selected cases. High dose excretory urography is recommended for routine use.     

Dose response of a radiophotoluminescent glass dosimeter for TomoTherapy,CyberKnife, and flattening-filter-free linear accelerator output measurements in dosimetry audit

PurposeWe experimentally determined the radiophotoluminescent glass dosimeter (RPLD) dose responses for TomoTherapy, CyberKnife, and flattening-filter-free (FFF) linear accelerator (linac) outputs for dosimetry audits in Japan.MethodsA custom-made solid phantom with a narrow central-axis spacing of three RPLD elements was used for output measurement to minimise the dose-gradient effect of the non-flattening filter beams. For RPLD dose estimation, we used the ISO 22127 formalism. Additional unit-specific correction factors were introduced and determined via the measured data. For TomoTherapy (7 units) and CyberKnife (4 units), the doses were measured under machine-specific reference fields. For FFF linac (5 units), in addition to the reference condition, we obtained the field-size effects for the range from 5×5 cm to 25×25 cm.ResultsThe correction factors were estimated as 1.008 and 0.999 for TomoTherapy and CyberKnife, respectively. For FFF linac, they ranged from 1.011 to 0.988 for 6 MV and from 1.011 to 0.997 for 10 MV as a function of the side length of the square field from 5 to 25 cm. The estimated uncertainties of the absorbed dose to water measured by RPLD for the units were 1.32%, 1.35%, and 1.30% for TomoTherapy, CyberKnife, and FFF linac, respectively. A summary of the dosimetry audits of these treatment units using the obtained correction factors is also presented. The average percentage differences between the measured and hospital-stated doses were <1% under all conditions.ConclusionRPLD can be successfully used as a dosimetry audit tool for modern treatment units.     

Dose finding - a challenge in statistics

A good understanding and characterization of the dose response relationship of any new compound is an important and ubiquitous problem in many areas of scientific investigation. This is especially true in the context of pharmaceutical drug development, where it is mandatory to launch safe drugs which demonstrate a clinically relevant effect. Selecting a dose too high may result in unacceptable safety problems, while selecting a dose too low may lead to ineffective drugs. Dose finding studies thus play a key role in any drug development program and are often the gate-keeper for large confirmatory studies. In this overview paper we focus on definitive and confirmatory dose finding studies in Phase II or III, reviewing relevant statistical design and analysis methods. In particular, we describe multiple comparison procedures, modeling approaches, and hybrid methods combining the advantages of both. An outlook to adaptive dose finding methods is also given. We use a real data example to illustrate the methods, together with a brief overview of relevant software.     

Dose finding in the Ames Salmonella assay

Threshold dose/concentration values, such as the lowest effective dose, minimum effective dose or the lowest effective concentration (LED, MED or LEC, respectively) are in use as an alternative to the mutagen potency measures based on the 'rate' measurements (e.g., the slope of the initial part of the dose-response curve). In this respect, several statistical procedures for the corresponding so-called 'dose finding' were proposed during the last decades. However, most of them disregard the discrete nature of responses such as the plate colony count in the Ames Salmonella assay. When the plate counts agree with the Poisson assumption, two procedures considered here seem to be appropriate for the dose finding. One is based on the stepwise collapsing of the homogeneous control and dose counts; another consists of constructing the confidence limits for the mutation induction factor (MIF). When the dose and control counts are non-overlapping, the simple 'visual' non-parametric estimation of LED is possible. Applicability and validity of the methods is demonstrated with the two data sets on the mutagenicity of the beta-carboline alkaloid, harmine, and one of the oxidation products of apomorphine.     

低剂量与常规剂量扫描在CT引导下经皮穿刺肺活检术中的临床应用价值对比研究

摘要 目的：比较低剂量与常规剂量扫描在CT引导下经皮穿刺肺活检术中的临床应用价值。方法：选择2018年1月至2019年12月我院行CT引导下经皮穿刺肺活检术的患者96例,采用随机数字表法分为低剂量组和常规剂量组,每组48例,两组分别在低剂量扫描、常规剂扫描下行CT引导下经皮穿刺肺活检术,比较两组扫描范围、X射线剂量、图像质量、穿刺成功率及并发症发生情况。结果：低剂量组CT吸收剂量加权指数（CTDIw）、平均剂量长度乘积（DLP）显著低于常规剂量组（P<0.05）,两组扫描范围比较无统计学差异（P>0.05）。低剂量组图像质量1级1例、2级1例、3级46例;常规剂量组1级0例、2级1例、3级47例,两组图像质量比较无统计学差异（P>0.05）。低剂量组穿刺成功率87.50%,常规剂量组穿刺成功率89.58%,两组穿刺成功率比较无统计学差异（P>0.05）。低剂量组并发症发生率为12.50%,常规剂量组并发症发生率为10.42%,两组并发症发生率比较差异无统计学意义（P>0.05）。结论：与常规剂量扫描相比,在CT引导下经皮穿刺肺活检术中应用低剂量扫描可以有效降低辐射剂量,但不影响图像质量和穿刺成功率,患者并发症发生率也未增加,具有较好的临床价值。     

Multiple Testing for Detecting Efficient Dose Steps

In the comparison of various dose levels it can often be assumed that the parameters to be tested follow an order restriction. Two closed multiple test procedures for detecting the highest dose level still providing a shift in the response distribution as compared to the adjacent lower dose level is proposed. One is based on one sided comparisons between neighbouring doses, the other uses Helmert-type contrast statistics. If a sequence of testing is fixed in advance the multiple test can be suitably modified. The power of the procedures is simulated under the assumption of normally distributed responses for various constellations of the dose means. It is compared with the power of a general Holm-type procedure discussed in BUDDE & BAUER (1989).     

Dose responses of gibberellins

To determine the response type, published data for the most widely used bioassays for gibberellins have been analyzed by means of a computer program for estimating sensitivity parameters, or by interpolation. The dose response data are almost uniformly subsensitive, i. e. more than an 81-fold increase in external gibberellin concentration is required for a change from 10 to 90% of maximal response (S₉₀/S₁₀). Data for the interaction of gibberellins with artificial membranes are, in contrast, markedly ultrasensitive (S₉₀/S₁₀± 10). This difference further strengthens the view that lipid structures do not function as receptors for gibberellins. Most of the subsensitive dose responses for gibberellins can be quite precisely represented by cooperative isotherms. However, available data are insufficiently detailed for an unequivocal choice among cooperative, multiphasic or more complex kinetics.     

Monte Carlo Study of Radiation Dose Enhancement by Gadolinium in Megavoltage and High Dose Rate Radiotherapy

MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.     

On the Definition of Internal Dose Metrics

Internal dose metrics, as computed with pharmacokinetic models, are increasingly used as a means for extrapolating animal toxicological data to humans and to extrapolate across routes of administration. These internal dose metrics are thought to provide a more scientific means of comparing toxicological effects across animal species. The use of internal dose metrics is based on the universal assumption that toxic effects are equal across species if and only if the concentration of the toxic moieties in the target tissue is equal across species. Herein it is shown that this assumption is inconsistent with empirical toxicological data. It is shown that measurement of internal dose metrics in chronological time, as is done for AUC (Area under the concentration curve) and rate of metabolite production per kg of target tissue, does not produce equal toxic effects across species. A consequence of this observation is that the application of pharmacokinetics in risk assessments for such important chemicals as trichloroethylene, vinyl chloride, perchloroethylene, and perchlorate may need reassessment.     

Enhanced Activity of Deoxycytidine Kinase After Pulsed Low Dose Rate and Single Dose Gamma Irradiation

In both pulsed low dose rate (LDR) and single high dose radiation schedules, gemcitabine pretreatment sensitizes tumor cells to radiation. These radiosensitizing effects could be the result of decreased DNA repair. In this study, the effect of irradiation on the deoxycytidine kinase (dCK) needed for DNA repair was investigated. The activity of dCK, a deoxynucleoside analogue-activating enzyme was increased upon irradiation in both schedules. No change in dCK protein expression was observed that indicates a post-translational regulation. The benefit of this increased activity induced by irradiation should be further investigated in combination with deoxynucleoside analogues activated by this enzyme.     

On dose cube pixel spacing pre-processing for features extraction stability in dosiomic studies

PurposeDosiomics allows to parameterize regions of interest (ROIs) and to produce quantitative dose features encoding the spatial and statistical distribution of radiotherapy dose. The stability of dosiomics features extraction on dose cube pixel spacing variation has been investigated in this study.Material and MethodsBased on 17 clinical delivered dose distributions (P_n), dataset has been generated considering all the possible combinations of four dose grid resolutions and two calculation algorithms. Each dose voxel cube has been post-processed considering 4 different dose cube pixel spacing values: 1x1x1, 2x2x2, 3x3x3 mm³ and the one equal to the planning CT. Dosiomics features extraction has been performed from four different ROIs. The stability of each extracted dosiomic feature has been analyzed in terms of coefficient of variation (CV) intraclass correlation coefficient (ICC).ResultsThe highest CV mean values were observed for PTV ROI and for the grey level size zone matrix features family. On the other hand, the lowest CV mean values have been found for RING ROI for the grey level co-occurrence matrix features family. P₃ showed the highest percentage of CV >1 (1.14%) followed by P₁₅ (0.41%), P₁ (0.29%) and P13 (0.19%). ICC analysis leads to identify features with an ICC >0.95 that could be considered stable to use in dosiomic studies when different dose cube pixel spacing are considered, especially the features in common among the seventeen plans.ConclusionConsidering the observed variability, dosiomic studies should always provide a report not only on grid resolution and algorithm dose calculation, but also on dose cube pixel spacing.     

低水平辐射诱导的细胞遗传学适应性反应

先用0.01GY x-射线(剂量率:0.01GY/分)体外照射人、兔外周血,经不同时间后再用1.5GY X-射线(0.44GY/分)照射,发现在G_0、G_1、S和G_2期受0.01GY X-射线照射后再给大剂量照射者,其染色体畸变率明显低于单纯受1.5GY X-射线照射组(P<0.01)。这一适应性反应能持续3个细胞周期,在接受小剂量照射后超过3个细胞周期再受大剂量照射者,染色体畸变率未见减少。若在第三细胞周期以后再次给予小剂量照射,可再次诱导适应性反应。用小鼠整体小剂量照射后骨髓细胞和生殖细胞亦出现这种适应性反应。另外也探讨了不同剂量和不同剂量率的预先照射对适应性反应的影响。     

Single Daily Dose Methimazole Treatment of Hyperthyroidism

The effectiveness of methimazole used in a single daily dose was studied in 47 patients during their initial episode of hyperthyroidism, and in an additional eight patients during a relapse of hyperthyroidism. All patients become euthyroid using this method. Mean time required to achieve a euthyroid state was 16.7±1.1 weeks in the former group, and 14.9±2.9 weeks in the latter. In one patient there was an initial response to single daily dose therapy, but subsequently split dosage was required for control. The single daily dose regimen of antithyroid drugs will control hyperthyroidism in most patients. We have found that propylthiouracil will achieve this more rapidly than methimazole.     

Pilot Study on Image Quality and Radiation Dose of CT Colonography with Adaptive Iterative Dose Reduction Three-Dimensional

Objective

To investigate image quality and radiation dose of CT colonography (CTC) with adaptive iterative dose reduction three-dimensional (AIDR3D).

Methods

Ten segments of porcine colon phantom were collected, and 30 pedunculate polyps with diameters ranging from 1 to 15 mm were simulated on each segment. Image data were acquired with tube voltage of 120 kVp, and current doses of 10 mAs, 20 mAs, 30 mAs, 40 mAs, 50 mAs, respectively. CTC images were reconstructed using filtered back projection (FBP) and AIDR3D. Two radiologists blindly evaluated image quality. Quantitative evaluation of image quality included image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). Qualitative image quality was evaluated with a five-score scale. Radiation dose was calculated based on dose-length product. Ten volunteers were examined supine 50 mAs with FBP and prone 20 mAs with AIDR3D, and image qualities were assessed. Paired t test was performed for statistical analysis.

Results

For 20 mAs with AIDR3D and 50 mAs with FBP, image noise, SNRs and CNRs were (16.4 ± 1.6) HU vs. (16.8 ± 2.6) HU, 1.9 ± 0.2 vs. 1.9 ± 0.4, and 62.3 ± 6.8 vs. 62.0 ± 6.2, respectively; qualitative image quality scores were 4.1 and 4.3, respectively; their differences were all not statistically significant. Compared with 50 mAs with FBP, radiation dose (1.62 mSv) of 20 mAs with AIDR3D was decreased by 60.0%. There was no statistically significant difference in image noise, SNRs, CNRs and qualitative image quality scores between prone 20 mAs with AIDR3D and supine 50 mAs with FBP in 10 volunteers, the former reduced radiation dose by 61.1%.

Conclusion

Image quality of CTC using 20 mAs with AIDR3D could be comparable to standard 50 mAs with FBP, radiation dose of the former reduced by about 60.0% and was only 1.62 mSv.     

Estimating Growth Reduction Dose for Polynomial Response Relationships

Mutation breeders often estimate an irradiation dose which causes a specified reduction in growth of a biological material. In this paper, we estimate the growth reduction dose (GRD) and its confidence interval, when the dose-response relationship is of a general polynomial form. We make a realistic assumption that the response at the control dose is a random variable. We compare the estimates, standard error and confidence intervals of GRD with those obtained under a situation where response at control dose is a known constant. We illustrate the procedure with data on the effect of gamma irradiation and Ethylmethane sulphate on shoot lengths of chickpea genotypes.     

The Perils of Adapting to Dose Errors in Radiation Therapy

We consider adaptive robust methods for lung cancer that are also dose-reactive, wherein the treatment is modified after each treatment session to account for the dose delivered in prior treatment sessions. Such methods are of interest because they potentially allow for errors in the delivered dose to be corrected as the treatment progresses, thereby ensuring that the tumor receives a sufficient dose at the end of the treatment. We show through a computational study with real lung cancer patient data that while dose reaction is beneficial with respect to the final dose distribution, it may lead to exaggerated daily underdose and overdose relative to non-reactive methods that grows as the treatment progresses. However, by combining dose reaction with a mechanism for updating an estimate of the uncertainty, the magnitude of this growth can be mitigated substantially. The key finding of this paper is that reacting to dose errors – an adaptation strategy that is both simple and intuitively appealing – may backfire and lead to treatments that are clinically unacceptable.