High dose bystander effects in spatially fractionated radiation therapy

Traditional radiotherapy of bulky tumors has certain limitations. Spatially fractionated radiation therapy (GRID) and intensity modulated radiotherapy (IMRT) are examples of advanced modulated beam therapies that help in significant reductions in normal tissue damage. GRID refers to the delivery of a single high dose of radiation to a large treatment area that is divided into several smaller fields, while IMRT allows improved dose conformity to the tumor target compared to conventional three-dimensional conformal radiotherapy. In this review, we consider spatially fractionated radiotherapy approaches focusing on GRID and IMRT, and present complementary evidence from different studies which support the role of radiation induced signaling effects in the overall radiobiological rationale for these treatments.

Accelerated partial breast irradiation (APBI): Are breath-hold and volumetric radiation therapy techniques useful?

Background: In a selective group of patients accelerated partial breast irradiation (APBI) might be applied after conservative breast surgery to reduce the amount of irradiated healthy tissue. The role of volumetric modulated arc therapy (VMAT) and voluntary moderately deep inspiration breath-hold (vmDIBH) techniques in further reducing irradiated healthy – especially heart – tissue is investigated.

Material and methods: For 37 partial breast planning target volumes (PTVs), three-dimensional conformal radiotherapy (3D-CRT) (3 – 5 coplanar or non-coplanar 6 and/or 10 MV beams) and VMAT (two partial 6 MV arcs) plans were made on CTs acquired in free-breathing (FB) and/or in vmDIBH. Dose-volume parameters for the PTV, heart, lungs, and breasts were compared. 

Results: Better dose conformity was achieved with VMAT compared to 3D-CRT (conformity index 1.24 0.09 vs. 1.49 0.20). Non-PTV ipsilateral breast receiving 50% of the prescribed dose was on average reduced by 28% in VMAT plans compared to 3D-CRT plans. Mean heart dose (MHD) reduced from 2.0 (0.1 – 5.1) Gy in 3D-CRT(FB) to 0.6 (0.1 – 1.6) Gy in VMAT(vmDIBH). VMAT is benefi cial for MHD reduction if MHD with 3D-CRT exceeds 0.5Gy. Cardiac dose reduction as a result of VMAT increases with increasing initial MHD, and adding vmDIBH reduces the cardiac dose further. Mean dose to the ipsilateral lung decreased from 3.7 (0.7 – 8.7) to 1.8 (0.5 – 4.0) Gy with VMAT(vmDIBH) compared to 3D-CRT(FB). VMAT resulted in a slight increase in the contralateral breast dose (DMean ) always remaining 1.9 Gy). 

Conclusions: For APBI patients, VMAT improves PTV dose conformity and delivers lower doses to the ipsilateral breast and lung compared to 3D-CRT. This goes at the cost of a slight but acceptable increase of the contralateral breast dose. VMAT reduces cardiac dose if MHD exceeds 0.5 Gy for 3D-CRT. Adding vmDIBH results in a further reduction of heart and ipsilateral lung dose. 

Near-monochromatic high-harmonic radiation from relativistic laser-plasma interactions with blazed grating surfaces

Intense, femtosecond laser interactions with blazed grating targets are studied through experiment and particle-in-cell (PIC) simulations. The high harmonic spectrum produced by the laser is angularly dispersed by the grating leading to near-monochromatic spectra emitted at different angles, each dominated by a single harmonic and its integer-multiples. The spectrum emitted in the direction of the third-harmonic diffraction order is measured to contain distinct peaks at the 9th and 12th harmonics which agree well with two-dimensional PIC simulations using the same grating geometry. This confirms that surface smoothing effects do not dominate the far-field distributions for surface features with sizes on the order of the grating grooves whilst also showing this to be a viable method of producing near-monochromatic, short-pulsed extreme-ultraviolet radiation.

Generation of 10μW relativistic surface high-harmonic radiation at a repetition rate of 10 Hz

Experimental results on relativistic surface HHG at a repetition rate of 10 Hz are presented. Average powers in the 10?W range are generated in the spectral range of 51 to 26 nm (24-48 eV). The surface harmonic radiation is produced by focusing the second-harmonic of a high-power laser onto a rotating glass surface to moderately relativistic intensities of 3×10 ¹⁹Wcm ^?2. The harmonic emission exhibits a divergence of 26 mrad. Together with absolute photon numbers recorded by a calibrated spectrometer, this allows for the determination of the extreme ultraviolet (XUV) yield. The pulse energies of individual harmonics are reaching up to the μJ level, equivalent to an efficiency of 10 ^?5. The capability of producing stable and intense high-harmonic radiation from relativistic surface plasmas may facilitate experiments on nonlinear ionization or the seeding of free-electron lasers. © IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.

Application of laser radiation for the treatment of waste materials using a photocatalyst

One effective approach is to destroy industrial waste and pollution is the use of a semiconductor photocatalysis system. To date such, photocatalysis systems have employed conventional linear light sources. Initial results from a study of a photocatalysis system incorporating a tripled Nd:YAG laser are reported. The laser light not only played a roll as a light source for activating the photocatalyst(TiO₂), but also destroyed the organic species directly via a photochemical process. The reaction intermediates and changes in their concentrations are monitored using HPLC. The relationship between the power of laser and kinetics of photoreaction are discussed.

Photo-ionized neon plasmas induced by radiation pulses of a laser-plasma EUV source and a free electron laser FLASH

In this work, a laser-produced plasma extreme ultraviolet source and a free electron laser were used to create Ne photo-ionized plasmas. In both cases, a radiation beam was focused onto a gas stream injected into a vacuum chamber synchronously with the radiation pulse. Extreme ultraviolet radiation from the plasma spanned a wide spectral range with pronounced maximum centered at lambda = 11 +/- 1 nm while the free electron laser pulses were emitted at a wavelength of 32 nm. The power density of the focused plasma radiation was approximately 2 x 10(7) W/cm(2) and was seven orders of magnitude lower compared with the focused free electron laser beam. Radiation fluences in both experimental conditions were comparable. Despite quite different spectral characteristics and extremely different power densities, emission spectra of both photo-ionized plasmas consist of the same spectral lines within a wavelength range of 20 to 50 nm, however, with different relative intensities of the corresponding lines. The dominating spectral lines originated from singly charged ions (Ne II); however, Ne III lines were also detected. Additionally, computer simulations of the emission spectra, obtained for photo-ionized plasmas, driven by the plasma extreme ultraviolet source, were performed. The corresponding measured and calculated spectra are presented. An electron temperature and ionic composition were estimated. Differences between the experimental spectra, obtained for both irradiation conditions, were analyzed. The differences were attributed mainly to different energies of driving photons.

A novel experimental approach to investigate radiolysis processes in liquid samples using collimated radiation sources

Here is detailed a novel and low-cost experimental method for high-throughput automated fluid sample irradiation. The sample is delivered via syringe pump to a nozzle, where it is expressed in the form of a hanging droplet into the path of a beam of ionising radiation. The dose delivery is controlled by an upstream lead shutter, which allows the beam to reach the droplet for a user defined period of time. The droplet is then further expressed after irradiation until it falls into one well of a standard microplate. The entire system is automated and can be operated remotely using software designed in-house, allowing for use in environments deemed unsafe for the user (synchrotron beamlines, for example). Depending on the number of wells in the microplate, several droplets can be irradiated before any human interaction is necessary, and the user may choose up to 10 samples per microplate using an array of identical syringe pumps, the design of which is described here. The nozzles consistently produce droplets of 25.1 ± 0.5 μl.

Radiation responses of stem cells: targeted and not-targeted effects

Stem cells are fundamental to the development of any tissue or organism via their ability to self-renew, which is aided by their unlimited proliferative capacity and their ability to produce fully differentiated offspring, often from multiple lineages. Stems cells are long lived and have the potential to accumulate mutations, including in response to radiation exposure. It is thought that stem cells have the potential to be induced into a cancer stem cell phenotype and that these may play an important role in resistance to radiotherapy. For radiation-induced carcinogenesis, the role of targeted and non-targeted effects is unclear with tissue or origin being important. Studies of genomic instability and bystander responses have shown consistent effects in haematopoietic models. Several models of radiation have predicted that stem cells play an important role in tumour initiation and that bystander responses could play a role in proliferation and self-renewal.

Time and Cell Type Dependency of Survival Responses in Co-cultured Tumor and Fibroblast Cells after Exposure to Modulated Radiation Fields

Advanced radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) achieve high levels of conformity to the target volume through the sequential delivery of highly spatially and temporally modulated radiation fields, which have been shown to impact radiobiological response. This study aimed to characterize the time and cell type dependency of survival responses to modulated fields using single cell type (SCT) and mixed cell type (MCT) co-culture models of transformed fibroblast (AG0-1522b) cells, and prostate (DU-145) and lung (H460) cancer cells. In SCT cultures, in-field responses showed no significant time dependency while out-of-field responses occurred early, and plateaued 6 h after irradiation in both DU-145 and H460 cells. Under modulated beam configurations MCT co-cultures showed cell-specific, differential out-of-field responses depending on the irradiated in-field and responding out-of-field cell type. The observed differential out-of-field responses may be due to the genetic background of the cells, in particular p53 status, which has been shown to mediate radiation-induced bystander effects (RIBEs). These data provide further insight into the radiobiological parameters that influence out-of-field responses, which have potential implications for advanced radiotherapy modalities and may provide opportunities for biophysical optimization in radiotherapy treatment planning.

(223)Ra and other bone-targeting radiopharmaceuticals-the translation of radiation biology into clinical practice

Osseous metastases are a source of significant morbidity for patients with a variety of cancers. Radiotherapy is well established as an effective means of palliating symptoms associated with such metastases. The role of external beam radiotherapy is limited where sites of metastases are numerous and widespread. Low linear energy transfer (LET) radionuclides have been utilized to allow targeted delivery of radiotherapy to disparate sites of disease, with evidence of palliative benefit. More recently, the bone targeting, high LET radionuclide (223)Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration-resistant prostate cancer with bone metastases. This article reviews the different radionuclide-based approaches for targeting bone metastases, with an emphasis on (223)Ra, and key elements of the underlying radiobiology of these that will impact their clinical effectiveness. Consideration is given to the remaining unknowns of both the basic radiobiological and applied clinical effects of (223)Ra as targets for future research.

Clinical potential of gene-directed enzyme prodrug therapy to improve radiation therapy in prostate cancer patients

Despite the advances in prostate cancer diagnosis and treatment, current therapies are not curative in a significant proportion of patients. Gene-directed enzyme prodrug therapy (GDEPT), when combined with radiation therapy, could improve the outcome of treatment for prostate cancer, the second leading cause of cancer death in the western world. GDEPT involves the introduction of a therapeutic transgene, which can be targeted to the tumour cells. A prodrug is administered systemically and is converted to its toxic form only in those cells containing the transgene, resulting in cell kill. This review will discuss the clinical trials which have investigated the potential of GDEPT at various stages of prostate cancer progression. The advantages of using GDEPT in combination with radiotherapy will be examined, as well as some of the recent advances which enhance the potential utility of GDEPT.

DNA mismatch repair and the DNA damage response to ionizing radiation:making sense of apparently conflicting data

The DNA mismatch repair (MMR) pathway detects and repairs DNA replication errors. While DNA MMR-proficiency is known to play a key role in the sensitivity to a number of DNA damaging agents, its role in the cytotoxicity of ionizing radiation (IR) is less well characterized. Available literature to date is conflicting regarding the influence of MMR status on radiosensitivity, and this has arisen as a subject of controversy in the field. The aim of this paper is to provide the first comprehensive overview of the experimental data linking MMR proteins and the DNA damage response to IR. A PubMed search was conducted using the key words "DNA mismatch repair" and "ionizing radiation". Relevant articles and their references were reviewed for their association between DNA MMR and IR. Recent data suggest that radiation dose and the type of DNA damage induced may dictate the involvement of the MMR system in the cellular response to IR. In particular, the literature supports a role for the MMR system in DNA damage recognition, cell cycle arrest, DNA repair and apoptosis. In this review we discuss our current understanding of the impact of MMR status on the cellular response to radiation in mammalian cells gained from past and present studies and attempt to provide an explanation for how MMR may determine the response to radiation.