Enhanced production of reactive oxygen species by gadolinium oxide nanoparticles under core-inner-shell excitation by proton or monochromatic X-ray irradiation: implication of the contribution from the interatomic de-excitation-mediated nanoradiator effect to dose enhancement.

Core-inner-valence ionization of high-Z nanoparticle atomic clusters can de-excite electrons through various interatomic de-excitation processes, thereby leading to the ionization of both directly exposed atoms and adjacent neutral atoms within the nanoparticles, and to an enhancement in photon-electron emission, which is termed the nanoradiator effect. To investigate the nanoradiator-mediated dose enhancement in the radio-sensitizing of high-Z nanoparticles, the production of reactive oxygen species (ROS) was measured in a gadolinium oxide nanoparticle (Gd-oxide NP) solution under core-inner-valence excitation of Gd with either 50 keV monochromatic synchrotron X-rays or 45 MeV protons. This measurement was compared with either a radiation-only control or a gadolinium-chelate magnetic resonance imaging contrast agent solution containing equal amounts of gadolinium as the separate atomic species in which Gd-Gd interatomic de-excitations are absent. Ionization excitations followed by ROS measurements were performed on nanoparticle-loaded cells or aqueous solutions. Both photoexcitation and proton impact produced a dose-dependent enhancement in the production of ROS by a range of factors from 1.6 to 1.94 compared with the radiation-only control. Enhanced production of ROS, by a factor of 1.83, was observed from Gd-oxide NP atomic clusters compared with the Gd-chelate molecule, with a Gd concentration of 48 µg/mL in the core-level photon excitation, or by a factor of 1.82 under a Gd concentration of 12 µg/mL for the proton impact at 10 Gy (p < 0.02). The enhanced production of ROS in the irradiated nanoparticles suggests the potential for additional therapeutic dose enhancements in radiation treatment via the potent Gd-Gd interatomic de-excitation-driven nanoradiator effect.

Position statement on ethics, equipoise and research on charged particle radiation therapy.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

Improved calibration of mass stopping power in low density tissue for a proton pencil beam algorithm.

Dose distributions for proton therapy treatments are almost exclusively calculated using pencil beam algorithms. An essential input to these algorithms is the patient model, derived from x-ray computed tomography (CT), which is used to estimate proton stopping power along the pencil beam paths. This study highlights a potential inaccuracy in the mapping between mass density and proton stopping power used by a clinical pencil beam algorithm in materials less dense than water. It proposes an alternative physically-motivated function (the mass average, or MA, formula) for use in this region. Comparisons are made between dose-depth curves calculated by the pencil beam method and those calculated by the Monte Carlo particle transport code MCNPX in a one-dimensional lung model. Proton range differences of up to 3% are observed between the methods, reduced to <1% when using the MA function. The impact of these range errors on clinical dose distributions is demonstrated using treatment plans for a non-small cell lung cancer patient. The change in stopping power calculation methodology results in relatively minor differences in dose when plans use three fields, but differences are observed at the 2%-2 mm level when a single field uniform dose technique is adopted. It is therefore suggested that the MA formula is adopted by users of the pencil beam algorithm for optimal dose calculation in lung, and that a similar approach is considered when beams traverse other low density regions such as the paranasal sinuses and mastoid process.

Feasibility study for a biomedical experimental facility based on LEIR at CERN.

In light of the recent European developments in ion beam therapy, there is a strong interest from the biomedical research community to have more access to clinically relevant beams. Beamtime for pre-clinical studies is currently very limited and a new dedicated facility would allow extensive research into the radiobiological mechanisms of ion beam radiation and the development of more refined techniques of dosimetry and imaging. This basic research would support the current clinical efforts of the new treatment centres in Europe (for example HIT, CNAO and MedAustron). This paper presents first investigations on the feasibility of an experimental biomedical facility based on the CERN Low Energy Ion Ring LEIR accelerator. Such a new facility could provide beams of light ions (from protons to neon ions) in a collaborative and cost-effective way, since it would rely partly on CERN's competences and infrastructure. The main technical challenges linked to the implementation of a slow extraction scheme for LEIR and to the design of the experimental beamlines are described and first solutions presented. These include introducing new extraction septa into one of the straight sections of the synchrotron, changing the power supply configuration of the magnets, and designing a new horizontal beamline suitable for clinical beam energies, and a low-energy vertical beamline for particular radiobiological experiments.

Data-driven Markov models and their application in the evaluation of adverse events in radiotherapy.

Decision-making processes in medicine rely increasingly on modelling and simulation techniques; they are especially useful when combining evidence from multiple sources. Markov models are frequently used to synthesize the available evidence for such simulation studies, by describing disease and treatment progress, as well as associated factors such as the treatment's effects on a patient's life and the costs to society. When the same decision problem is investigated by multiple stakeholders, differing modelling assumptions are often applied, making synthesis and interpretation of the results difficult. This paper proposes a standardized approach towards the creation of Markov models. It introduces the notion of 'general Markov models', providing a common definition of the Markov models that underlie many similar decision problems, and develops a language for their specification. We demonstrate the application of this language by developing a general Markov model for adverse event analysis in radiotherapy and argue that the proposed method can automate the creation of Markov models from existing data. The approach has the potential to support the radiotherapy community in conducting systematic analyses involving predictive modelling of existing and upcoming radiotherapy data. We expect it to facilitate the application of modelling techniques in medical decision problems beyond the field of radiotherapy, and to improve the comparability of their results.

Hadron therapy information sharing prototype.

The European PARTNER project developed a prototypical system for sharing hadron therapy data. This system allows doctors and patients to record and report treatment-related events during and after hadron therapy. It presents doctors and statisticians with an integrated view of adverse events across institutions, using open-source components for data federation, semantics, and analysis. There is a particular emphasis upon semantic consistency, achieved through intelligent, annotated form designs. The system as presented is ready for use in a clinical setting, and amenable to further customization. The essential contribution of the work reported here lies in the novel data integration and reporting methods, as well as the approach to software sustainability achieved through the use of community-supported open-source components.