Comparison of four-year toxicities and local control of ultra-hypofractionated vs moderate-hypofractionated image guided prostate radiation with HDR brachytherapy boost: A phase I-II single institution trial.

Purpose/Objectives: To analyze the long term efficacy and safety of an ultra-hypofractionated (UHF) radiation therapy prostate treatment regimen with HDR brachytherapy boost (BB) and compare it to moderate-hypofractionated regimens (MHF). Materials/Methods: In this single arm, prospective monocentric study, 28 patients with intermediate risk prostate cancer were recruited in an experimental treatment arm of 25 Gy in 5 fractions plus a 15 Gy HDR BB. They were then compared to two historical control groups, treated with either 36 Gy in 12 fractions or 37.5 Gy in 15 fractions with a similar HDR BB. The control groups included 151 and 311 patients respectively. Patient outcomes were reported using the International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC-26) questionnaires at baseline and at each follow-up visit. Results: Median follow-up for the experimental arm was 48.5 months compared to 47 months and 60 months compared to the 36/12 and 37,5/15 groups respectively. The IPSS and EPIC scores did not demonstrate any significant differences in the gastrointestinal or genitourinary domains between the three groups over time. No biochemical recurrence occurred in the UHF arm as defined by the Phoenix criterion. Conclusion: The UHF treatment scheme with HDR BB seems equivalent to standard treatment arms in terms of toxicities and local control. Randomized control trials with larger cohorts are ongoing and needed to further confirm our findings.

Evidence of coprostanol estrogenicity to the freshwater mussel Elliptio complanata.

Coprostanol (5 beta (H)-cholestan-3 beta ol) is a reduced metabolite of cholesterol produced by micro-organisms found in the intestinal tract of mammals. This substance abounds in urban effluents and is accumulated by organisms living in the vicinity of municipal effluent outfalls. In an earlier study, freshwater mussels exposed to contaminated river water for 62 days accumulated large quantities of coprostanol (Cop) in their soft tissues (16 micrograms/g dry wt.). Moreover, these mussels were found to have elevated levels of vitellin in their hemolymphs, suggesting estrogenic effects. Although municipal wastewaters are known to contain other estrogenic compounds capable of inducing Vn synthesis in mussels, the estrogenic potential of coprostanol was singled out for examination. To this end, mussels were first injected with concentrations of coprostanol via the abductor muscle route, and allowed to stand in aerated water for 72 h at 15 degrees C. The levels of Vn in mussel hemolymph were assayed using the organic alkali-labile phosphate method. A competitive estradiol-binding assay was then devised to measure the ability of coprostanol to compete in the binding of fluorescein-labeled estradiol-albumin to cytosolic proteins. Coprostanol partially reversed the binding of labeled estradiol-albumin to cytosolic proteins with an EC50 of 1 mM. In addition, injections of coprostanol and estradiol-17 beta led to increased levels of vitellins in the hemolymph of treated mussels. Moreover, incubation of cop in gonad homogenate extracts in the presence of NADPH led to the formation of two compounds, as determined by high-performance thin-layer chromatography. One of these compounds appears to be the C17 oxidation product of coprostanol, whose polarity is similar to that of estradiol. The results present evidence that coprostanol is estrogenic to freshwater mussels.

Cytotoxic and genotoxic effects of energetic compounds on bacterial and mammalian cells in vitro.

The mutagenicity and toxicity of energetic compounds such as 2,4, 6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), hexahydro-1,3, 5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3, 5,7-tetrazocine (HMX), and of amino/nitro derivatives of toluene were investigated in vitro. Mutagenicity was evaluated with the Salmonella fluctuation test (FT) and the V79 Chinese hamster lung cell mutagenicity assay. Cytotoxicity was evaluated using V79 and TK6 human lymphoblastic cells. For the TK6 and V79 assays, TNB and 2, 4,6-triaminotoluene were more toxic than TNT, whereas RDX and HMX were without effect at their maximal aqueous solubility limits. The primary TNT metabolites (2-amino-4,6-dinitrotoluene, 4-amino-2, 6-dinitrotoluene, 2,4-diamino-6-nitrotoluene and 2, 6-diamino-4-nitrotoluene) were generally less cytotoxic than the parent compound. The FT results indicated that TNB, TNT and all the tested primary TNT metabolites were mutagenic. Except for the cases of 4-amino-2,6-dinitrotoluene and 2,4-diamino-6-nitrotoluene in the TA98 strain, addition of rat liver S9 resulted in either no effect, or decreased activity. None of the tested compounds were mutagenic for the V79 mammalian cells with or without S9 metabolic activation. Thus, the FT assay was more sensitive to the genotoxic effects of energetic compounds than was the V79 test, suggesting that the FT might be a better screening tool for the presence of these explosives. The lack of mutagenicity of pure substances for V79 cells under the conditions used in this study does not preclude that genotoxicity could actually exist in other mammalian cells. In view of earlier reports and this study, mutagenicity testing of environmental samples should be considered as part of the hazard assessment of sites contaminated by TNT and related products.

A new penumbra generator for electron fields matching.

Abutment of two or more electron fields to irradiate extended areas may lead to significant dose inhomogeneities in the junction region. This paper describes the geometric and dosimetric characteristics of a device developed to modify the penumbra of an electron beam and thereby improve the dose uniformity in the overlap region when fields are abutted. The device is a Lipowitz metal block placed on top of the electron applicator's insertion plate and positioned to stop part of the electron beam on the side of field abutment. The air-scattered electrons beyond the block increase the penumbra width from about 1.4 to 2.7-3.4 cm with an SSD of 100 cm. The modified penumbra is broad and almost linear at all depths for the 9 and 12 MeV electron beams used in this study. Film dosimetry was used to obtain beam profiles and isodose distributions of single modified beams and matched fields of 9 and 12 MeV as well as matched fields of both energies. Computer simulation was used to optimize the skin gap to be used and to quantify the dose uniformity as a function of the field separation for both modified and nonmodified beams. Results are presented for various field configurations. Without the penumbra generator, lateral setup errors of 2-3 mm may introduce dose variations of 20% or more in the junction region. Similar setup errors cause less than 5% dose variations when the penumbra generator is used to match the fields. The potential of the technique for the irradiation of curved surfaces is presented. A possible method for implementing the modified penumbra into a conventional treatment planning system is evaluated.

Activation of cyclic GMP-binding and cyclic AMP-specific phosphodiesterases of rat platelets by a mechanism involving cyclic AMP-dependent phosphorylation.

We have previously reported that the cAMP-specific phosphodiesterase activity in washed rat platelets is increased by a short exposure of platelet suspension to PGE1 and 1-methyl-3-isobutyl-xanthine (MIX). We report here that the incubation of washed platelets with forskolin resulted in an increase in the binding of cGMP and the activity of cGMP-phosphodiesterase as well as that of cAMP-specific phosphodiesterase. As for PGE1, MIX potentiated the stimulatory effect of forskolin. The maximal activation of phosphodiesterases by forskolin and MIX occurred after 30 sec of incubation of platelets (with a slow decline thereafter). The activation of phosphodiesterases in intact platelets by forskolin occurred in parallel with the dissociation of a cAMP-dependent protein kinase. Prior incubation of a platelet supernatant with Mg-ATP and cAMP had only a slight effect on cAMP- or cGMP-phosphodiesterase activities, but the presence of MIX during the prior incubation, followed by appropriate dilution, greatly enhanced the activity of the two phosphodiesterases. The phosphodiesterase activation in vitro was inhibited by a non-hydrolysable analogue of ATP, AMP-PNP. Since the cGMP-binding phosphodiesterase activity is enhanced by the catalytic subunit of cAMP-dependent protein kinase in the presence of MIX and absence of cAMP, the effect of MIX cannot be explained in terms of the protection of cAMP from hydrolysis. It is possible that the xanthine increases the susceptibility of the cAMP-specific and cGMP-binding phosphodiesterases to phosphorylation.