Deforming a planning CT to match a daily CBCT provides the tools needed for the calculation of the "dose of the day" without the need to acquire a new CT. The initial clinical application of our method will be weekly offline calculations of the "dose of the day," and use this information to inform adaptive radiotherapy (ART). The work here presented is a first step into a full implementation of a "dose-driven" online ART.

X-ray fluorescence techniques have proven beneficial for identifying and quantifying trace elements in biological tissues. A novel approach is being developed that employs x-ray fluorescence with an aim to locate heavy nanoparticles, such as gold, which are embedded into tissues. Such nanoparticles can be functionalized to act as markers for tumour characteristics to map the disease state, with the future aim of imaging them to inform cancer therapy regimes. The uptake of functionalized nanoparticles by cancer cells will also enable detection of small clusters of infiltrating cancer cells which are currently missed by commonly used imaging modalities. The novel system, consisting of an energy-resolving silicon drift detector with high spectral resolution, shows potential in both quantification of and sensitivity to nanoparticle concentrations typically found in tumours. A series of synchrotron measurements are presented; a linear relationship between fluorescence intensity and gold nanoparticle (GNP) concentration was found down to 0.005 mgAu ml(-1), the detection limit of the system. Successful use of a bench-top source, suitable for possible future clinical use, is also demonstrated, and found not to degrade the detection limit or accuracy of the GNP concentration measurement. The achieved system sensitivity suggests possible future clinical usefulness in measuring tumour uptake in vivo, particularly in shallow tumour sites and small animals, in ex vivo tissue and in 3D in vitro research samples.

High-Z nano materials have been previously shown to increase the amount of dose deposition within the tumour due to an increase in secondary electrons.This study evaluates the effects of high-Z nano materials in combination with protons, and the impact of proton energy, nanoparticle material and concentration. These effects were studied in silico through Monte Carlo simulation and experimentally through a phantom study, with particular attention to macroscale changes to the Bragg peak in the presence of nanoparticles. Three nanoparticle materials were simulated (gold, silver and platinum) at three concentrations (0.01, 0.1 and 6.5 mg ml−1) at two clinical proton energies (60 and 226 MeV). Simulations were verified experimentally using Gafchromic film measurements of gold nanoparticles suspended in water at two available high concentrations (5.5 mg ml−1 and 1.1 mg ml−1). A significant change to Bragg peak features was evident, where at 226 MeV and 6.5 mg ml−1, simulations of gold showed a 4.7 mm longitudinal shift of the distal edge and experimentally at 5.5 mg ml−1, a shift of 2.2 mm. Simulations showed this effect to be material dependent, where platinum having the highest physical density caused the greatest shift with increasing concentration. A dose enhancement of 6%  ±  0.05 and 5%  ±  0.15 (60 MeV and 226 MeV, respectively) was evident with gold at 6.5 mg ml−1 to water alone, compared to the 21%  ±  0.53 observed experimentally as dose to film with 5.5 mg ml−1 of gold nanoparticles suspended in water at 226 MeV. The introduction of nanoparticles has strong potential to enhance dose in proton therapy, however the changes to the Bragg peak distribution that occur with high concentrations need to be accounted for to ensure tumour coverage.

Gold nanoparticles (GNPs) may be used as a contrast agent to identifytumour location and can be modified to target-and image-specific tumour biological parameters. There are currently no imaging systems in the literature that have sufficient sensitivity to GNP concentration and distribution measurement at sufficient tissue depth for use in in vivo and in vitro studies. We have demonstrated that high detecting sensitivity of GNPs can be achieved using x-ray fluorescence; furthermore this technique enables higher depth imaging in comparison to optical modalities. Two x-ray fluorescence systems were developed and used to image a range of GNP imaging phantoms. The first system consisted of a 10 mm 2 silicon drift detector coupled to a slightly focusing polycapillary optic which allowed 2D energy resolved imaging in step and scan mode. The system has sensitivity to GNP concentrations as low as 1 ppm. GNP concentrations different by a factor of 5 could be resolved, offering potential to distinguish tumour from non-tumour. The second system was designed to avoid slow step and scan image acquisition; the feasibility of excitation of the whole specimen with a wide beam and detection of the fluorescent x-rays with a pixellated controlled drift energy resolving detector without scanning was investigated. A parallel polycapillary optic coupled to the detector was successfully used to ascertain the position where fluorescence was emitted. The tissue penetration of the technique was demonstrated to be sufficient for nearsurface small-animal studies, and for imaging 3D in vitro cellular constructs. Previous work demonstrates strong potential for both imaging systems to form quantitative images of GNP concentration.

A multi-disciplinary cooperative for nanoparticle-enhanced radiotherapy (NERT) has been formed to review the current status of the field and identify key stages towards translation. Supported by the Colorectal Cancer Healthcare Technologies Cooperative, the cooperative comprises a diverse cohort of key contributors along the translation pathway including academics of physics, cancer and radio-biology, chemistry, nanotechnology and clinical trials, clinicians, manufacturers, industry, standards laboratories, policy makers and patients. Our aim was to leverage our combined expertise to devise solutions towards a roadmap for translation and commercialisation of NERT, in order to focus research in the direction of clinical implementation, and streamline the critical pathway from basic science to the clinic. A recent meeting of the group identified barriers to and strategies for accelerated clinical translation. This commentary reports the cooperative's recommendations. Particular emphasis was given to more standardised and cohesive research methods, models and outputs, and reprioritised research drivers including patient quality of life following treatment. Nanoparticle design criteria were outlined to incorporate scalability of manufacture, understanding and optimisation of biological mechanisms of enhancement and in vivo fate of nanoparticles, as well as existing design criteria for physical and chemical enhancement. In addition, the group aims to establish a long-term and widespread international community to disseminate key findings and create a much-needed cohesive body of evidence necessary for commercial and clinical translation.

In order to maximize the potential of nanoparticles (NPs) in cancer imaging and therapy, their mechanisms of interaction with host tissue need to be fully understood. NP uptake is known to be dramatically influenced by the tumor microenvironment, and an imaging platform that could replicate in vivo cellular conditions would make big strides in NP uptake studies. Here, a novel NP uptake platform consisting of a tissue-engineered 3D in vitro cancer model (tumoroid), which mimics the microarchitecture of a solid cancer mass and stroma, is presented. As the tumoroid exhibits fundamental characteristics of solid cancer tissue and its cellular and biochemical parameters are controllable, it provides a real alternative to animal models. Furthermore, an X-ray fluorescence imaging system is developed to demonstrate 3D imaging of GNPs and to determine uptake efficiency within the tumoroid. This platform has implications for optimizing the targeted delivery of NPs to cells to benefit cancer diagnostics and therapy.

clinically due to the number of variables that need to be investigated to control and optimize the effect. Various groups have investigated different aspects, such as varying NP size or radiation beam energy. Even with knowledge from these studies, there is still a considerable amount of variability in reported findings. Differences are caused by the diversity in cell lines, NPs with their respective coatings, incubated NP concentrations, incubation times, irradiation parameters, as well as the assays used to demonstrate the effects. This has led to variations in the results, where significant enhancements of a factor of 25 were shown by Rahman et al., with Aurovist 1.9 nm gold nanoparticles (AuNPs) at a concentration of 1 mm with bovine aortic endothelial cells (BAEC) and 80 kV X-rays, [3] compared to smaller enhancements shown by Chithrani et al., where they synthesized 50 nm AuNPs at a concentration of approximately 1 nm in HeLa cells and found an enhancement factor of 1.17 with 6 MV X-rays. [4] As well as this, there are also differences in protocols between research groups, in both maintenance of cells and assays reported.A review by Her et al. reported on the different mechanisms associated with NP-enhanced radiotherapy, where the overall effect is a combination of physical, chemical, and biological -7 and U87) and three commercially available nanoparticles (gold, gadolinium, and iron oxide) irradiated by 6 MV X-rays. To assess cell survival, clonogenic assays are carried out for all variables considered, with a concentration of 0.5 mg mL -1 for each nanoparticle material used. This study demonstrates differences in cell survival between nanoparticles and cell line. U87 shows the greatest enhancement with gadolinium nanoparticles (2.02 ± 0.36), whereas MCF-7 cells have higher enhancement with gold nanoparticles (1.74 ± 0.08). Materials with a high atomic number (Z) are shown to cause an increase in the level of cell kill by ionizing radiation when introduced into tumor cells. This study uses in vitro experiments to investigate the differences in radiosensitization between two cell lines (MCFMass spectrometry, however, shows highest elemental uptake with iron oxide and U87 cells with 4.95 ± 0.82 pg of iron oxide per cell. A complex relationship between cellular elemental uptake is demonstrated, highlighting an inverse correlation with the enhancement, but a positive relation with DNA damage when comparing the same nanoparticle between the two cell lines.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

We have demonstrated that our algorithm can be used to automate the interpretation of routine datasets to extract survival information for this sample of patients. It currently underestimates recurrence rates due to many patients not being well-enough to be treated for recurrent disease. With some further optimisation, this technique could be extended to a national level, providing a new approach to measuring outcomes on a larger scale than is currently possible. This could have implications for healthcare provision and policy for a range of different disease types.