Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

BACKGROUND. Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy. METHODS. Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. RESULTS. Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis. CONCLUSIONS. A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.

Modern cataract surgery for radiation-induced cataracts in retinoblastoma.

Background Surgery of radiation-induced cataracts in children with retinoblastoma (RB) is a challenge as early intervention is weighted against the need to delay surgery until complete tumour control is obtained. This study analyses the safety and functional results of such surgery. Methods In a retrospective, non-comparative, consecutive case series, we reviewed medical records of RB patients </=14 y of age who underwent either external beam radiotherapy or plaque treatment and were operated for radiation-induced cataract between 1985 and 2008. Results In total, 21 eyes of 20 RB patients were included and 18 out of the 21 eyes had Reese-Ellsworth stage V or ABC classification group D/E RB. Median interval between last treatment for RB and cataract surgery was 21.5 months, range 3-164 months. Phacoaspiration was performed in 13 eyes (61%), extra-capsular cataract extraction in 8 (39%) and intraocular lens implantation in 19 eyes (90%). The majority of cases, 11/21 (52%), underwent posterior capsulorhexis or capsulotomy and 6/21 (28%) an anterior vitrectomy. Postoperative visual acuity was >/=20/200 in 13 eyes and <20/200 in 5 eyes. Intraocular tumour recurrence was noted in three eyes. Mean postoperative follow up was 90 months+/-69 months. Conclusions Modern cataract surgery, including clear cornea approach, lens aspiration with posterior capsulotomy, anterior vitrectomy and IOL implantation is a safe procedure for radiation-induced cataract as long as RB is controlled. The visual prognosis is limited by initial tumour involvement of the macula and by corneal complications of radiotherapy. We recommend a minimal interval of 9 months between completion of treatment of retinoblastoma and cataract surgery.

Intérêt des marqueurs sanguins dans la prédiction de la toxicité radio-induite [Interest of blood markers in predicting radiation-induced toxicity].

The oncologic outcome and the total dose are highly correlated with the treatment by ionizing radiation. The dose increase (total or per fraction) may provoke late-side effects that are potentially irreversible. The radiation-induced CD8 lymphocyte apoptotic value and the molecular modifications within the lymphocyte are capable of predicting the level of risk of developing late-side effects after curative intent radiotherapy. In this review, we present the different blood assays in this setting and discuss the current possibilities of researches, namely those involving the proteomic process.

Bitumens in the late Variscan hydrothermal vein-type uranium deposit of Pribram, Czech Republic: Sources, radiation-induced alteration, and relation to mineralization

The late Variscan (275-278 Ma) Pribram uranium deposit is one of the largest known accumulations of uraniferous bitumens in hydrothermal veins. The deposit extends along the northwestern boundary of the Central Bohemian pluton (345-335 Ma) with low-grade metamorphosed Late Proterozoic and unmetamorphosed Cambrian rocks. From a net uranium production of 41,742 metric tons (t), more than 6,000 t were extracted from bitumen-uraninite ores during 43 years of exploration and mining. Three morphological varieties of solid bitumen are recognized: globular, asphaltlike, and cokelike. While the globular bitumen is uranium free, the other two types are uraniferous. The amount of bitumen in ore veins gradually decreases toward the contact with the plutonic body and increases with depth. Two types of bitumen microtextures are recognized using high-resolution transmission electron microscopy: amorphous and microporous, the former being less common in uraniferous samples. A lower Raman peak area ratio (1,360/1,575 cm(-1)) in mineralized bitumens (0.9) compared with uranium-free samples (2.0) indicates a lower degree of microtextural organization in the latter The H/C and O/C atomic ratios in uranium-free bitumens (0.9-1.1 and 0.09, respectively) are higher than those in mineralized samples (H/C = 0.3-0.8, O/C = 0.03-0.09). The chloroform extractable matter yield is Very low in uranium-free bitumens (0.30-0.35% of the total organic carbon,TOC) and decreases with uranium content increase. The extracted solid uraniferous bitumen infrared spectra show depletion in aliphatic CH2 and CH3 groups compared to uranium-free samples. The concentration of oxygen-bearing functional groups relative to aromatic bonds in the IR spectra of uranium-free and mineralized bitumen, however, do not differ significantly. C-13 NMR confirmed than the aromaticity of a uraniferous sample is higher (F-ar = 0.61) than in the uranium-free bitumen (F-ar = 0.51). Pyrolysates from uraniferous and nonuraniferous bitumens do not differ significantly, being predominantly cresol, alkylphenols, alkylbenzenes, and alkylnaphthalenes. The liquid pyrolysate yield decreases significantly with increasing uranium content. The delta(13)C Values of bulk uranium-free bitumens and low-grade uraniferous, asphaltlike bitumens range from -43.6 to 52.3 per mil. High-grade, cokelike, uraniferous bitumens are more C-13 depleted (54.5 to -58.4 parts per thousand). In contrast to the very light isotopic ratios of the high-grade uraniferous cokelike bitumen bulk carbon, the individual n-alkanes and isoprenoids (pristane and phytane) extracted from the same sample are significantly C-13 enriched. The isotopic composition of the C13-24 n-alkanes extracted from the high-grade uraniferous sample (delta(13)C = -28.0 to 32.6 parts per thousand) are heavier compared with the same compounds in a uranium-free sample (delta(13)C = 31.9 to 33.8 parts per thousand). It is proposed that the bitumen source was the isotopically light (delta(13)C = 35.8 to 30.2 parts per thousand) organic matter of the Upper Proterozoic host rocks that were pyrolyzed during intrusion of the Central Bohemian pluton. The C-13- depleted pyrolysates were mobilized from the innermost part of the contact-metamorphic aureole, accumulated in structural traps in less thermally influenced parts of the sedimentary complex and were later extracted by hydrothermal fluids. Bitumens at the Pribram deposit are younger than the main part of the uranium mineralization and were formed through water-washing and radiation-induced polymerization of both the gaseous and liquid pyrolysates. Direct evidence for pyrolysate reduction of uranium in the hydrothermal system is difficult to obtain as the chemical composition of the original organic fluid phase was modified during water-washing and radiolytic alteration. However, indirect evidence-e.g., higher O/C atomic ratios in uranium-free bitumens (0.1) relative to the Upper Proterozoic source rocks (0.02-0.05), isotopically very light carbon in associated whewellite (delta(13)C = 31.7 to -28.4 parts per thousand), and the striking absence of bitumens in the pre-uranium, hematite stage of the mineralization-indicates that oxidation of organic fluids may have contributed to lowering of aO(2) and uraninite precipitation.

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

Late Onset Cystoid Macular Oedema Following Surgery for Radiation Induced Cataract in Patient With Retinoblastoma

Purpose: Cystoid macular oedema (CMO) is a very rare condition following cataract surgery in paediatric population. Nevertheless, we report a case series of patients with radiation induced cataract after retinoblastoma (Rb) treatment that underwent cataract surgery and developed subsequently late onset CMO. Methods: Between January 1984 and December 2009, 25 consecutive eyes (25 patients) with Rb presented with radiation induced cataract surgery at the Jules Gonin Eye Hospital. Sixteen eyes (16 patients) had prior radiation induced retinopathy and maculopathy (IRM). Out of these, 3 eyes (3 patients) developed CMO after cataract surgery. Results: One eye had Rb stage B, and 2 eyes had stage D International classification. All of them developed IRM following brachytherapy and/or external beam irradiation. Patients underwent phako-aspiration and in bag intraocular lens implantation after IRM had resolved. Mean age at cataract surgery was 10.7 ± 2.8 (SEM) (range 5-14) years old. Mean time between resolution of IRM and cataract surgery was 76.0 ± 27.2 (SEM) (range 24-116) months. Mean time of onset CMO after cataract surgery was 81.0 ± 34.4 (SEM) (range 13-124) months. There was no other underlying vascular or tractional factor for CMO development. All of them were treated with a combination of oral carbonic anhydrase inhibitor, topical steroid and topical non-steroid. Mean macular thickness pre-, during-, and post CMO were 134.0 ± 10.3, 298.0 ± 37.1, and 154.0 ± 4.0 (SEM) µm, respectively. Mean best corrected visual acuity pre-, during-, and post CMO were 0.31 ± 0.19, 0.46 ± 0.12, and 0.34 ± 0.18 (SEM) LogMAR, respectively. Mean time for CMO reabsorption was 17.0 ± 9.8 (SEM) months. Conclusions: To the best of our knowledge, CMO following paediatric cataract surgery is a very uncommon condition. Moreover, late onset CMO after phako-aspiration for radiation induced cataract in Rb patients has never been described. It is a rare complication but can be treated successfully.

Radiation-induced modifications of the tumor microenvironment promote metastasis.

Radiotherapy is successfully used to treat cancer. Emerging evidence, however, indicates that recurrences after radiotherapy are associated with increased local invasion, metastatic spreading and poor prognosis. Radiation-induced modifications of the tumor microenvironment have been proposed to contribute to increased aggressive tumor behavior, an effect also referred to as tumor bed effect, but the putative mechanisms involved have remained largely elusive. We have recently demonstrated that irradiation of the prospective tumor stroma impairs de novo angiogenesis through sustained inhibition of proliferation, migration and sprouting of endothelial cells. Experimental tumors growing within a pre-irradiated field have reduced tumor angiogenesis and tumor growth, increased hypoxia, necrosis, local invasion and distant metastasis. Mechanisms of progression involve adaptation of tumor cells to local hypoxic conditions as well as selection of cells with invasive and metastatic capacities. The matricellular protein CYR61 and integrin αVβ5 emerged as molecules that cooperate to mediate lung metastasis. Cilengitide, a small molecular inhibitor of αV integrins prevented lung metastasis formation. These results represent a conceptual advance to the understanding of the tumor bed effect and indicate that αV integrin inhibition might be a potential therapeutic approach for preventing metastasis in patients at risk for post-radiation recurrences.

Light induced defects in thermal annealed hydrogenated amorphous silicon

The metastable defects of a-Si:H samples annealed at temperatures in the 300-550°C range have been studied by photothermal deflection spectroscopy (PDS). The light-soaked samples show an increase in optical absorption in the 0.8 to 1.5 eV range. The metastable defect density decreases when the annealing temperature increases, while the defect density increases. This decrease in the metastable defect density shows an almost linear correlation with the decrease in the hydrogen content of the samples, determined by IR transmission spectroscopy and thermal desorption spectroscopy.

Séquelles radio-induites et tests prédictifs [Radiation-induced sequelae: toward an individual profile]

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivery is limited by the tolerated dose of the surrounding healthy tissues. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced sequelae due to their irreversibility and the potential impact on daily quality of life. In a population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, lymphocytes seem to be the tissue of choice due to easy accessibility. Recently, low percentage of CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of sequelae. In addition, recent data suggest that patients with severe radiation-induced late side effects possess four or more SNP in candidate genes (ATM, SOD2, TGFB1, XRCC1 et XRCC3) and low radiation-induced CD8 lymphocyte apoptosis in vitro.

Effects of vacancy-type defects in silicon based particle detectors

The semiconductor particle detectors used at CERN experiments are exposed to radiation. Under radiation, the formation of lattice defects is unavoidable. The defects affect the depletion voltage and leakage current of the detectors, and hence affect on the signal-to-noise ratio of the detectors. This shortens the operational lifetime of the detectors. For this reason, the understanding of the formation and the effects of radiation induced defects is crucial for the development of radiation hard detectors. In this work, I have studied the effects of radiation induced defects-mostly vacancy related defects-with a simulation package, Silvaco. Thus, this work essentially concerns the effects of radiation induced defects, and native defects, on leakage currents in particle detectors. Impurity donor atom-vacancy complexes have been proved to cause insignificant increase of leakage current compared with the trivacancy and divacancy-oxygen centres. Native defects and divacancies have proven to cause some of the leakage current, which is relatively small compared with trivacancy and divacancy-oxygen.