[en] In the frame of a study about the feasibility of an underground storage of radioactive wastes, we focused on the role of degraded natural organic matter in the eventual transport of radionuclides in the environment. We are more interested by the determination of electro kinetic properties of these humic substances rather than the description of speciation reaction already widely discussed in the literature. We chose to determine the size and the charge of these humic substances thanks to an original method: high precision conductometry. This technique, associated to a suited transport theory, allows to describe the mobility of charged species in solution when taking into account the pairs interactions. We have participated in the development of this transport theory and we use it in order to determine the size and the charge of humic substances and a reference polyelectrolyte in different conditions of pH and ionic strength. All these experimental results obtained by conductometry were correlated with other experimental and theoretical methods: Atomic Force Microscopy, dynamic light scattering, laser zeta-metry and Monte-Carlo simulations. The obtained results confirm the generally admitted idea that humic substances are nano-metric entities having complexing properties towards cations and that can aggregate to form supra molecular structures. The effect of the ions present in the environment (sodium, calcium, magnesium) has been investigated. Finally the complexation of europium (which is considered as a good analogue of americium 241) has also been analysed by square wave voltammetry. (author)

[en] Positron emission tomography (PET) is a high-resolution, sensitive, molecular, and functional imaging technique. It permits repeated, noninvasive assessment and quantification of specific biological and pharmacological processes and is the most advanced technology currently available for studying in vivo molecular interactions. Radioligands labeled with the positron-emitters carbon-11 (half-life: 20.4 minutes) or with fluorine-18 (half-life: 109.8 minutes) have been developed in this thesis to image the N-Methyl-D-Aspartate (NMDA) receptor NR2B subunit (part one) or image the nAChR a4b2 subunit (part two) with PET. In the first part, two antagonists have been synthesized and labeled with carbon-11: the 6-[3-[4-(4-fluoro-benzyl)piperidino]propionyl]-³H-benzoxazole-2-[¹¹C]one ([¹¹C]EMD-95885) and the 5-[3-(4-benzyl-piperidine-1-yl)prop-1-ynyl] - 1,3-dihydro-benzo-imidazole-2-[¹¹C]one. In the second part, four agonists have been synthesised and labeled with fluor-18 or with carbon-11: the 2-exo - (2'-[¹⁸F]fluoro-3'-phenyl-pyridine-5'-yl) - 7-azabicyclo[2.2.1]heptane, the 2-exo - (2'-[¹⁸F]fluoro-3'-(4-fluoro-phenyl)-pyridine-5'-yl) - 7 -azabicyclo[2.2.1]heptane, the (-)-9-(2-[¹⁸F]fluoro-pyridyl)cytisine and the [(R)-2-[6-chloro-5-((E)-2-pyridine-4-yl-vinyl) - pyridine-3-yl-oxy]-1-methyl-ethyl]-[¹¹C] methyl-amine. Pharmacological profile were assessed using biodistribution studies, brain radioactivity monitoring using intracerebral radiosensitive beta-microprobes in rat and finally brain PET imaging in non-humans primates. (author)

[en] Purpose: To examine how the long-term costs of radiation therapy may be influenced by modifications to fractionation schemes, and how any improvements in tumor control might, in principle, be translated into a potential cost saving for the responsible healthcare organization. Methods and Materials: Standard radiobiological modeling based on the linear-quadratic (LQ) model is combined with financial parameters relating to the estimated costs of different aspects of radiotherapy treatment delivery. The cost model includes provision for the long-term costs of treatment failure and enables the extra costs of near optimal radiotherapy to be balanced against suboptimal alternatives, which are more likely to be associated with further radiotherapy, salvage surgery, and continuing care. Results: A number of caveats are essential in presenting a model such as this for the first time, and these are clearly stated. However, a recurring observation is that, in terms of the whole cost of supporting a patient from first radiotherapy treatment onwards, high quality radiotherapy (i.e., based on individual patterns of fractionation that are near optimal for particular subpopulations of tumor) will frequently be associated with the lowest global cost. Conclusions: This work adds weight to the case for identifying fast and accurate predictive assay techniques, and supports the argument that suboptimal radiotherapy is usually more costly in the long term. Although the article looks only at the cost-benefit consequences of altered patterns of fractionation, the method will, in principle, have application to other changes in the way radiotherapy can be performed, e.g., to examining the cost-benefit aspects of tumor dose escalation as a consequence of using advanced conformal treatment planning

[en] Purpose: To modify existing linear-quadratic (LQ) equations in order to take account of relative biological effectiveness (RBE) using the concept of biologically effective dose (BED). Methods and Materials: Clinically useful forms of the LQ model have been modified to incorporate RBE effects in such a way as to allow comparison between high- and low-LET (linear energy transfer) radiations in terms of similar biological dose units. The new parameter in the formulation is RBE_M, the intrinsic (or maximum) RBE at zero dose. The principal assumption (following Kellerer and Rossi; ref. ) is that high-LET radiation modifies the α-coefficient of damage while leaving the β-coefficient unaltered. Results: The equations allow a quantitative estimation of how the apparent RBE will change with changes in dose/fraction or dose-rate and of how the magnitude and rate of change is governed by the low-LET α/β ratio of the irradiated tissue. The modifications are applicable to all types of radiotherapy (fractionated, continuous low dose-rate, therapy with decaying sources, etc.). In cases where the normal tissue RBE_M is greater than that for the tumor, the revised formulation helps explain why there will be situations where therapeutic index will be adversely affected by use of high-LET radiation. Such clinical advantages as have been observed are more likely to result from favorable geometrical sparing of critical normal tissues and/or the fact that slowly growing tumors may have α/β values more typical of late-responding normal tissues. Conclusions: The incorporation of RBE into existing LQ methodology allows quantitative assessment of clinical applications of high-LET radiations via an examination of the associated BEDs. On the basis of such assessments high-LET radiations are shown to confer few advantages

[en] Purpose: Standard clinical trial designs can lead to restrictive conclusions: the 'best recommended treatments' based on trial results, although generally applicable to patient populations, do not necessarily apply to individual patients. In theory, radiobiological modeling, coupled with reliable predictive assays, can be used to rationalize the selection of patients for particular schedules in trials. Materials and Methods: Linear-quadratic modeling of radiotherapy can be used to simulate a clinical trial. This is achieved by random sampling techniques where the key radiobiological parameters (α, β, T_pot and clonogen number) are selected from known or expected ranges. Clinical trial design in radiotherapy may be improved by formal radiobiological assessment designed to estimate the likely changes in tumor cure probability (TCP) and the likely normal tissue biologically effective dose (BED). Modeling may also be used to rationalize the allocation of patients to a test or standard schedule or for individual optimization of a treatment schedule. Such approaches depend on there being reliable predictive assays of the radiobiological parameters in individual patients. The influence of variations in predictive assay accuracy on the improved outcomes are assessed. Results: Clinical trials, which have been preceded by modeling simulation, offer potentially substantial improvements in the results of cancer treatment by radiotherapy. These exceed the usual gains found in standard clinical trials. Conclusion: Future preclinical trial design should include modeling assessments that indicate how best to structure the trial

[en] Purpose: To investigate the potential for mathematic modeling in the assessment of symptom relief in palliative radiotherapy and cytotoxic chemotherapy. Methods: The linear quadratic model of radiation effect with the overall treatment time and the daily dose equivalent of repopulation is modified to include the regrowth time after completion of therapy. Results: The predicted times to restore the original tumor volumes after treatment are dependent on the biological effective dose (BED) delivered and the repopulation parameter (K); it is also possible to estimate K values from analysis of palliative treatment response durations. Hypofractionated radiotherapy given at a low total dose may produce long symptom relief in slow-growing tumors because of their low α/β ratios (which confer high fraction sensitivity) and their slow regrowth rates. Cancers that have high α/β ratios (which confer low fraction sensitivity), and that are expected to repopulate rapidly during therapy, are predicted to have short durations of symptom control. The BED concept can be used to estimate the equivalent dose of radiotherapy that will achieve the same duration of symptom relief as palliative chemotherapy. Conclusion: Relatively simple radiobiologic modeling can be used to guide decision-making regarding the choice of the most appropriate palliative schedules and has important implications in the design of radiotherapy or chemotherapy clinical trials. The methods described provide a rationalization for treatment selection in a wide variety of tumors

[en] Purpose: For high linear energy transfer (LET) radiations, the relative biologic effect (RBE) changes with dose per fraction. Methods for calculating the optimum dose per fraction for high LET radiations should therefore include an allowance for RBE. Methods and Materials: The linear-quadratic (LQ) model, and the associated biologic effective dose (BED) concept, has previously been extended to incorporate the RBE effect. Differential calculus is now used to calculate the optimum dose per fraction (z), when high-LET radiation is used, which is given by the solution for z of g-((_LATE(α/β)_L)/(_TUM(α/β)_L)) ·RBE_Mz²-2·f·g·K·z-_LATE(α/β)_L·f·K·RBE_M=0 where g is the normal tissue sparing factor, RBE_M is the maximum RBE value, f the mean interfraction interval, K the daily low-LET BED equivalent dose for clonogen repopulation and _LATE(α/β)_L and _TUM(α/β)_L are the respective late reacting normal tissue and tumor fractionation sensitivities for low-LET radiation. Results: The optimum dose per fraction for proton therapy is generally lower than that calculated for photons but there is not a simple relationship between the magnitude of the reduction and the assumed value of RBE_M. Thus_, generic values of RBE_M cannot always be used in such calculations. In some cases, where tumor α/β ratios are low (around 5-6 Gy) and where there is good normal tissue sparing, the optimum dose per fraction is relatively large, typically 4-8 Gy. Conclusion: BED equations that include the RBE parameter, together with low-LET α/β ratios and repopulation dose equivalents, constitute a rational model of high-LET radiotherapy. In the case of proton beam therapy, a wide range of optimum dose per fraction is predicted.

[en] Purpose: To assess the potential changes in the net costs of focal radiotherapy techniques at differing doses per fraction and interfraction intervals. Methods: Linear quadratic radiobiological modeling is used with appropriate variations in the radiosensitivity and tumor cell proliferation parameters. The notional cost of treatment is calculated from the number of fractions, cost per fraction and the cost of treatment failure, which is itself related to (1-TCP) where TCP is the tumor cure probability. Additional Monte Carlo calculations from ranges of radiobiological parameters have been used to simulate the cost of treatment of tumor populations. Results: The optimum dose per fraction (and optimum overall cost) for conventional (nonfocal) radiotherapy is generally at low doses of around 2 Gy per fraction. The use of hyperfractionated and accelerated radiotherapy in addition to focal radiotherapy techniques appear to be indicated for more radioresistant tumors and if tumor proliferation is extremely rapid, but the need for treatment acceleration is much reduced where effective focal techniques are used. Conclusions: Radiobiological and economic modeling can be used to guide clinical choices of dose fractionation techniques providing the key radiobiological parameters are known or if the ranges of likely parameters in a tumor population are known. Focal radiotherapy, by the introduction of changes in the physical dose distribution, produces an upward shift in the optimum dose per fraction and a reduced dependency on overall treatment time

[en] Purpose: The use of molecular biology based therapies concurrently with radical radiotherapy is likely to offer potential benefits, but there is relatively little use of classical radiobiology in the rationale for such applications. The biological mechanisms that govern the outcomes of radiotherapy need to be completely understood before rational application and optimization of such adjuvant biotherapies with radiotherapy. Methods and Materials: Existing biomathematical models of radiotherapy can be used to explore the possible impact of biotherapies that modify tumor proliferation rates and/or radiosensitivity parameters during radiotherapy. Equations that show how to incorporate biotherapies with the linear-quadratic model of radiation cell kill are presented. Also considered are changes in tumor physiology, such as improved blood flow with enhanced delivery of biotherapy to the tumor cells and accelerated clonogen repopulation during radiotherapy. Monte Carlo random sampling methods are used to simulate these effects in heterogenous tumor populations with variation in radiosensitivities, clonogen numbers, and doubling times, as well as variations in repopulation onset rates and in vascular perfusion rates with time. Results: The time onset and duration of exposure of each type of biotherapy during radical radiotherapy can influence the predicted tumor cure probabilities in subtle ways. In general, the efficacy of biotherapies that radiosensitize will depend upon the number of radiotherapy fractions that are sensitized and the change in blood flow with time during radiotherapy. Biotherapies that control repopulation will depend not only on the duration of exposure but also, where accelerated repopulation occurs, on the time at which biotherapy is initiated during radiotherapy. From the ranges of radiobiological parameters and biotherapy efficacies assumed for exploratory examples, large changes of tumor control probability (TCP) are encountered in individual tumors from the application of cytostatic therapy. There are predictions of smaller increments in TCP in heterogenous tumor populations from the application of cytostatic and radiosensitizing biotherapies in combination. Conclusions: The exercises show how the scheduling of biotherapies may critically influence tumor cure probabilities in subtle ways and give considerable insight into the interacting biological mechanisms that influence these changes. Future therapeutic developments should be guided by these principles

[en] Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal β-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPARα activation, although signaling through other receptors (e.g. PPARγ, RXR) or through non-receptor pathways cannot be excluded