Assessment of combined use of ArcCheck® detector and portal dosimetry for delivery quality assurance of head and neck and prostate volumetric-modulated arc therapy.

PURPOSE: To assess the efficiency of combined use of ArcCheck® detector (AC) and portal dosimetry (PDIP) for delivery quality assurance of head and neck and prostate volumetric-modulated arc therapy. MATERIALS AND METHODS: Measurement processes were studied with the Gamma index method according to three analysis protocols. The detection sensitivity to technical errors of each individual or combined measurement processes was studied by inserting collimator, dose and MLC opening error into five head and neck and five prostate initial treatment plans. A total of 220 plans were created and 660 analyses were conducted by comparing measurements to error free planned dose matrix. RESULTS: For head and neck localization, collimator errors could be detected from 2° for AC and 3° for PDIP. Dose and MLC errors could be detected from 2% and 0.5 mm for AC and PDIP. Depending on the analysis protocol, the detection sensitivity of total simulated errors ranged from 54% to 88% for AC vs 40% to 74% for PDIP and 58% to 92% for the combined process. For the prostate localization, collimator errors could be detected from 4° for AC while they could not be detected by PDIP. Dose and MLC errors could be detected from 3% and 0.5 mm for AC and PDIP. The detection sensitivity of total simulated errors ranged from 30% to 56% for AC vs 16% to 38% for PDIP and 30% to 58% for combined process. CONCLUSION: The combined use of the two measurement processes did not statistically improve the detectability of technical errors compared to use of single process.

From the target cell theory to a more integrated view of radiobiology in Targeted radionuclide therapy: The Montpellier group's experience.

Targeted radionuclide therapy (TRT) is used to treat disseminated or metastatic tumours in which conventional external beam radiotherapy (EBRT) would have unacceptable side effects. Unlike EBRT, TRT delivers low doses at a continuous low dose rate. In EBRT, the effect increases progressively with the dose rate, and biological effects (tumour control and normal tissue damage) are related to the dose according to a sigmoid curve model. This model is part of the so-called quantitative radiobiology that is mostly based on the target cell theory, according to which cell death is due to (lethal) radiation hits to vital cellular targets. This model was developed for EBRT, but was adapted to low dose-rate situations by including a parameter that reflects the time needed to repair tissue damage. However, a growing body of evidence indicates that the model should take into account also the biological effects, which are due to intercellular communications (bystander effects) and amplify the effects of radiation, as well as the immune system. Moreover, extranuclear targets must be considered, although induced intracellular and intercellular signalling pathways may ultimately result in DNA damage. It is likely that bystander effects and immune response always contribute to the overall response to TRT at different levels, and that dose and dose rate are key parameters in controlling their real contribution. We hypothesize that the dose rate is the key determinant in the balance between the physical and DNA-centred response on one side, and the biological response that integrates all subcellular compartments and intercellular signalling pathways on the other side.

DNA damage-centered signaling pathways are effectively activated during low dose-rate Auger radioimmunotherapy.

INTRODUCTION: Low dose-rate radioimmunotherapy (RIT) using (125)I-labelled monoclonal antibodies ((125)I-mAbs) is associated with unexpected high cytotoxicity per Gy. METHODS: We investigated whether this hypersensitivity was due to lack of detection of DNA damage by the targeted cells. DNA damage was measured with the alkaline comet assay, gamma-H2AX foci and the micronucleus test in p53(-/-) and p53(+/+) HCT116 cells exposed to increasing activities of internalizing anti-HER1 (125)I-mAbs or non-internalizing anti-CEA (125)I-mAbs. The expression of proteins involved in radiation response and progression of cells through the cycle were determined. RESULTS: Cell hypersensitivity to low absorbed doses of anti-CEA (125)I-mAbs was not due to defect in DNA damage detection, since ATM (ataxia telangiectasia mutated gene), gamma-H2AX, p53 and p21 were activated in RIT-treated HCT116 cells and G2/M cell cycle arrest was observed. Moreover, the alkaline comet assay showed that DNA breaks accumulated when cells were placed at 4°C during exposure but were repaired under standard RIT conditions (37°C), suggesting that lesions detected under alkaline conditions (mostly DNA single strand breaks and alkali-labile sites) are efficiently repaired in treated cells. The level of gamma-H2AX protein corroborated by the level of foci measured in nuclei of treated cells was shown to accumulate with time thereby suggesting the continuous presence of DNA double strand breaks. This was accompanied by the formation of micronuclei. CONCLUSION: Hypersensitivity to non-internalizing (125)I-mAbs is not due to lack of detection of DNA damage after low absorbed dose-rates. However, DNA double strand breaks accumulate in cells exposed both to internalizing and non-internalizing (125)I-mAbs and lead to micronuclei formation. These results suggest impairment in DNA double strand breaks repair after low absorbed doses of (125)I-mAbs.

Apoptosis and p53 are not involved in the anti-tumor efficacy of ¹²5I-labeled monoclonal antibodies targeting the cell membrane.

INTRODUCTION: (125)I-labeled monoclonal antibodies ((125)I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in (125)I-mAb toxicity in p53(-/-) and p53(+/+) cancer cells. METHODS: We exposed p53(-/-) and p53(+/+) HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 (125)I-mAbs, or non-internalizing (cell surface location) anti-CEA (125)I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism. RESULTS: In both p53(-/-) and p53(+/+) HCT116 cells, anti-CEA (125)I-mAbs were more cytotoxic per Gy than anti-HER1 (125)I-mAbs. Sensitivity to anti-CEA (125)I-mAbs was p53-independent, while sensitivity to anti-HER1 (125)I-mAbs was higher in p53(-/-) HCT 116 cells, suggesting that they act through different signaling pathways. Apoptosis was only induced in p53(+/+) HCT116 cells and could not explain cell membrane radiation sensitivity. Inhibition of autophagy did not modify the cell response to (125)I-mAbs. By contrast, mitotic death was similarly induced in both p53(-/-) and p53(+/+) HCT116 cells by the two types of (125)I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells. CONCLUSION: Cell membrane sensitivity to (125)I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of (125)I-mAbs binding cell surface receptors.

Determination of the lesion size in Laser-induced Interstitial Thermal Therapy (LITT) using a low-field MRI.

This study aimed to compare MR thermal mapping during Laser-induced Interstitial Thermal Therapy (LITT) to thermal lesions observed macroscopically, in order to estimate the 3D size of the coagulative necrosis. Laser irradiation was performed ex-vivo with a 980 nm laser in pig liver in a open low-magnetic field (0.2T) scanner. The laser light was transmitted through a 1040/600 microm (outer/core diameter) bare-tip silica fiber. The laser energy was applied on a pulsed mode (10 s laser-on, 10 s laser-off) for 12 minutes, power: 6W, energy: 2160 J. MR thermal mapping used T1 method for its simplicity and its efficiency at low magnetic field.