Giuseppe Schettino

Professor Giuseppe Schettino


Professor of Medical Physics
+44 (0)1483 689320
14 BC 04

Biography

Research

Research interests

My publications

Publications

Mohajer Jonathan Kim, Nisbet Andrew, Velliou Eirini, Ajaz Mazhar, Schettino Giuseppe (2018) Biological effects of static magnetic field exposure in the context of MR-guided radiotherapy,British Journal of Radiation 92 (1094) British Institute of Radiology

The clinical introduction of magnetic resonance imaging guided radiotherapy has
prompted consideration of the potential impact of the static magnetic field on biological
responses to radiation. This review provides an introduction to the mechanisms of
biological interaction of radiation and magnetic fields individually, in addition to a
description of the magnetic field effects on megavoltage photon beams at the
macroscale, microscale and nanoscale arising from the Lorentz force on secondary
charged particles.

A relatively small number of scientific studies have measured the impact of combined
static magnetic fields and ionising radiation on biological endpoints of relevance to
radiotherapy. Approximately half of these investigations found that static magnetic
fields in combination with ionising radiation produced a significantly different outcome
compared with ionising radiation alone. MRI strength static magnetic fields appear to
modestly influence the radiation response via a mechanism distinct from modification
to the dose distribution. This review intends to serve as a reference for future biological
studies, such that understanding of static magnetic field plus ionising radiation
synergism may be improved, and if necessary, accounted for in magnetic resonance
imaging guided radiotherapy treatment planning.

Kokurewicz K., Brunetti E., Welsh G. H., Wiggins S. M., Boyd M., Sorensen A., Chalmers A. J., Schettino G., Subiel A., DesRosiers C., Jaroszynski D. A. (2019) Focused very high-energy electron beams as a novel radiotherapy modality for producing high-dose volumetric elements,Scientific Reports 9 10837 pp. 1-10 Nature Research
The increased inertia of very high-energy electrons (VHEEs) due to relativistic effects reduces scattering and enables irradiation of deep-seated tumours. However, entrance and exit doses are high for collimated or diverging beams. Here, we perform a study based on Monte Carlo simulations of focused VHEE beams in a water phantom, showing that dose can be concentrated into a small, well-defined volumetric element, which can be shaped or scanned to treat deep-seated tumours. The dose to surrounding tissue is distributed over a larger volume, which reduces peak surface and exit doses for a single beam by more than one order of magnitude compared with a collimated beam.
Hanton F., Chaudhary P., Doria D., Gwynne D., Maiorino C., Scullion C., Ahmed H., Marshall T., Naughton K., Romagnani L., Kar S., Schettino G., McKenna P., Botchway S., Symes D. R., Rajeev P. P., Prise K. M., Borghesi M. (2019) DNA DSB Repair Dynamics following Irradiation with Laser-Driven Protons at Ultra-High Dose Rates,Scientific Reports 9 4471 pp. 1-10 Nature Research
Protontherapy has emerged as more effective in the treatment of certain tumors than photon based therapies. However, significant capital and operational costs make protontherapy less accessible. This has stimulated interest in alternative proton delivery approaches, and in this context the use of laser-based technologies for the generation of ultra-high dose rate ion beams has been proposed as a prospective route. A better understanding of the radiobiological effects at ultra-high dose-rates is important for any future clinical adoption of this technology. In this study, we irradiated human skin fibroblasts-AG01522B cells with laser-accelerated protons at a dose rate of 109 Gy/s, generated using the Gemini laser system at the Rutherford Appleton Laboratory, UK. We studied DNA double strand break (DSB) repair kinetics using the p53 binding protein-1(53BP1) foci formation assay and observed a close similarity in the 53BP1 foci repair kinetics in the cells irradiated with 225 kVp X-rays and ultra- high dose rate protons for the initial time points. At the microdosimetric scale, foci per cell per track values showed a good correlation between the laser and cyclotron-accelerated protons indicating similarity in the DNA DSB induction and repair, independent of the time duration over which the dose was delivered.
Soultanidis George, Subiel Anna, Renard Isaline, Reinhart Anna Merle, Green Victoria L, Oelfke Uwe, Archibald Stephen J, Greenman John, Tulk Amanda, Walker Adrian, Schettino Giuseppe, Cawthorne Christopher J (2019) Development of an anatomically correct mouse phantom for dosimetry measurement in small animal radiotherapy research,Physics in Medicine & Biology 64 (12) 12NT02 pp. 1-11 IOP Publishing

Significant improvements in radiotherapy are likely to come from biological rather than technical optimization, for example increasing tumour radiosensitivity via combination with targeted therapies. Such paradigms must first be evaluated in preclinical models for efficacy, and recent advances in small animal radiotherapy research platforms allow advanced irradiation protocols, similar to those used clinically, to be carried out in orthotopic models. Dose assessment in such systems is complex however, and a lack of established tools and methodologies for traceable and accurate dosimetry is currently limiting the capabilities of such platforms and slowing the clinical uptake of new approaches. Here we report the creation of an anatomically correct phantom, fabricated from materials with tissue-equivalent electron density, into which dosimetry detectors can be incorporated for measurement as part of quality control (QC). The phantom also allows training in preclinical radiotherapy planning and cross-institution validation of dose delivery protocols for small animal radiotherapy platforms without the need to sacrifice animals, with high reproducibility.

Mouse CT data was acquired and segmented into soft tissue, bone and lung. The skeleton was fabricated using 3D printing, whilst lung was created using computer numerical control (CNC) milling. Skeleton and lung were then set into a surface-rendered mould and soft tissue material added to create a whole-body phantom. Materials for fabrication were characterized for atomic composition and attenuation for x-ray energies typically found in small animal irradiators. Finally cores were CNC milled to allow intracranial incorporation of bespoke detectors (alanine pellets) for dosimetry measurement.

Newpower Mark, Patel Darshana, Bronk Lawrence, Guan Fada, Chaudhary Pankaj, McMahon Stephen J., Prise Kevin M., Schettino Giuseppe, Grosshans David R., Mohan Radhe (2019) Using the Proton Energy Spectrum and Microdosimetry to Model Proton Relative Biological Effectiveness,International Journal of Radiation Oncology*Biology*Physics 104 (2) pp. 316-324 Elsevier

Purpose

We introduce a methodology to calculate the microdosimetric quantity dose-mean lineal energy for input into the microdosimetric kinetic model (MKM) to model the relative biological effectiveness (RBE) of proton irradiation experiments.

Methods and Materials

The data from 7 individual proton RBE experiments were included in this study. In each experiment, the RBE at several points along the Bragg curve was measured. Monte Carlo simulations to calculate the lineal energy probability density function of 172 different proton energies were carried out with use of Geant4 DNA. We calculated the fluence-weighted lineal energy probability density function , based on the proton energy spectra calculated through Monte Carlo at each experimental depth, calculated the dose-mean lineal energy for input into the MKM, and then computed the RBE. The radius of the domain (rd) was varied to reach the best agreement between the MKM-predicted RBE and experimental RBE. A generic RBE model as a function of dose-averaged linear energy transfer (LETD) with 1 fitting parameter was presented and fit to the experimental RBE data as well to facilitate a comparison to the MKM.

Results

Both the MKM and LETD-based models modeled the RBE from experiments well. Values for rd were similar to those of other cell lines under proton irradiation that were modeled with the MKM. Analysis of the performance of each model revealed that neither model was clearly superior to the other.

Conclusions

Our 3 key accomplishments include the following: (1) We developed a method that uses the proton energy spectra and lineal energy distributions of those protons to calculate dose-mean lineal energy. (2) We demonstrated that our application of the MKM provides theoretical validation of proton irradiation experiments that show that RBE is significantly greater than 1.1. (3) We showed that there is no clear evidence that the MKM is better than LETD-based RBE models.

Gupta Priyanka, Perez-Mancera Pedro A., Kocher Hemant, Nisbet Andrew, Schettino Giuseppe, Velliou Eirini (2020) A novel scaffold based hybrid multicellular model for pancreatic ductal adenocarcinoma ? towards a better mimicry of the in vivo tumour microenvironment,Frontiers in Bioengineering and Biotechnology Frontiers Media
With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to ? (i) its late diagnosis and (ii) its high resistance to current treatment methods. The later, specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumour niche. Advancements in the field of Tissue Engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, poly- urethane (PU) scaffold based, long term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells and stellate cells. Recognising the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumour compartment consisting of cancer cells (fibronectin coated) and a surrounding stromal compartment consisting of stellate and endothelial cells (collagen I coated). Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported time frame in vitro. Furthermore, the hybrid model showed extensive collagen I production by the cells, mimicking desmoplasia, one of PDAC?s hallmark features. Fibril alignment of the stellate cells was observed, which attested for their activated state. All three cell types expressed various cell specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low cost tool for in vitro studies of PDAC as well as for treatment screening.
Subiel Anna, Silvestre Patallo Ileana, Palmans Hugo, Barry Miriam, Tulk Amanda, Soultanidis Georgios, Greenman John, Green Victoria L, Cawthorne Christopher, Schettino Giuseppe (2020) The influence of lack of reference conditions on dosimetry in pre-clinical radiotherapy with medium energy x-ray beams,Physics in Medicine & Biology 65 (8) 085016 IOP Publishing
Despite well-established dosimetry in clinical radiotherapy, dose measurements in pre-clinical and radiobiology studies are frequently inadequate, thus undermining the reliability and reproducibility of published findings. The lack of suitable dosimetry protocols, coupled with the increasing complexity of pre-clinical irradiation platforms, undermines confidence in preclinical studies and represents a serious obstacle in the translation to clinical practice. To accurately measure output of a pre-clinical radiotherapy unit, appropriate Codes of Practice (CoP) for medium energy x-rays needs to be employed. However, determination of absorbed dose to water (Dw) relies on application of backscatter factor (Bw) employing in-air method or carrying out in-phantom measurement at the reference depth of 2 cm in a full backscatter (i.e. 30 × 30 × 30 cm3) condition. Both of these methods require thickness of at least 30 cm of underlying material, which are never fulfilled in typical pre-clinical irradiations. This work is focused on evaluation the effects of the lack of recommended reference conditions in dosimetry measurements for pre-clinical settings and is aimed at extending the recommendations of the current CoP to practical experimental conditions and highlighting the potential impact of the lack of correct backscatter considerations on radiobiological studies.
Silvestre Patallo Ileana, Subiel Anna, Westhorpe Adam, Gouldstone Clare, Tulk Amanda, Sharma Ricky A., Schettino Giuseppe (2020) Development and Implementation of an End-To-End Test for Absolute Dose Verification of Small Animal Preclinical Irradiation Research Platforms,International Journal of Radiation Oncology*Biology*Physics 107 (3) pp. 587-596 Elsevier
Purpose

Lack of standardization and inaccurate dosimetry assessment in preclinical research is hampering translational opportunities for new radiation therapy interventions. The aim of this work was to develop and implement an end-to-end dosimetry test for small animal radiation research platforms to monitor and help improve accuracy of dose delivery and standardization across institutions.
Methods and Materials

The test is based on a bespoke zoomorphic heterogeneous mouse and WT1 Petri dish phantoms with alanine as a reference detector. Alanine measurements within the mouse phantom were validated with Monte Carlo simulations at 0.5 mm Cu x-ray reference beam. Energy dependence of alanine in medium x-ray beam qualities was taken into consideration. For the end-to-end test, treatment plans considering tissue heterogeneities were created in Muriplan treatment planning systems (TPS) and delivered to the phantoms at 5 institutions using Xstrahl's small animal irradiation platforms. Mean calculated dose to the pellets were compared with alanine measured dose.
Results

Monte Carlo simulations and in phantom alanine measurements in NPL's reference beam were in excellent agreement, validating the experimental approach. At 1 institute, initial measurements showed a larger than 12% difference between calculated and measured dose caused by incorrect input data. The physics data used by the calculation engine were corrected, and the TPS was recommissioned. Subsequent end-to-end test measurements showed differences Conclusions

An end-to-end dosimetry test was developed and implemented for dose evaluation in preclinical irradiation with small animal irradiation research platforms. The test was capable of detecting treatment planning commissioning errors and highlighted critical elements in dose calculation. Absolute dosimetry with alanine in relevant preclinical irradiation conditions showed reasonable levels of accuracy compared with TPS calculations. This work provides an independent and traceable dosimetric validation in preclinical research involving small animal irradiation.

Barry Miriam A., Hussein Mohammad, Schettino Giuseppe (2020) Evaluating the Propagation of Uncertainties in Biologically Based Treatment Planning Parameters,Frontiers in Oncology 10 Frontiers Media
Biologically based treatment planning is a broad term used to cover any instance in radiotherapy treatment planning where some form of biological input has been used. This is wide ranging, and the simpler forms (e.g., fractionation modification/optimization) have been in use for many years. However, there is a reluctance to use more sophisticated methods that incorporate biological models either for plan evaluation purposes or for driving plan optimizations. This is due to limited data available regarding the uncertainties in these model parameters and what impact these have clinically. This work aims to address some of these issues and to explore the role that uncertainties in individual model parameters have on the overall tissue control probability (TCP)/normal tissue control probability (NTCP) calculated, those parameters that have the largest influence and situations where extra care must be taken. In order to achieve this, a software tool was developed, which can import individual clinical DVH's for analysis using a range of different TCP/NTCP models. On inputting individual model parameters, an uncertainty can be applied. Using a normally distributed random number generator, distributions of parameters can be generated, from which TCP/NTCP values can be calculated for each parameter set for the DVH in question. These represent the spread in TCP/NTCP parameters that would be observed for a simulated population of patients all being treated with that particular dose distribution. A selection of clinical DVHs was assessed using published parameters and their associated uncertainties. A range of studies was carried out to determine the impact of individual parameter uncertainties including reduction of uncertainties and assessment of what impact fractionation and dose have on these probabilities.
Ahmad Reem, Schettino Giuseppe, Royle Gary, Barry Miriam, Pankhurst Quentin A., Tillement Olivier, Russell Ben, Ricketts Kate (2020) Radiobiological Implications of Nanoparticles Following Radiation Treatment,Particle & Particle Systems Characterization 37 (4) 1900411 Wiley
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 (MCF?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). Mass 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
Brown Kathryn H., Ghita Mihaela, Schettino Giuseppe, Prise Kevin M., Butterworth Karl T. (2020) Evaluation of a Novel Liquid Fiducial Marker, BioXmark®, for Small Animal Image-Guided Radiotherapy Applications,Cancers 12 (5) 1276 MDPI
BioXmark®(Nanovi A/S, Denmark) is a novel fiducial marker based on a liquid, iodine-basedand non-metallic formulation. BioXmark®has been clinically validated and reverse translated topreclinical models to improve cone-beam CT (CBCT) target delineation in small animal image-guidedradiotherapy (SAIGRT). However, in phantom image analysis andin vivoevaluation of radiobiologicalresponse after the injection of BioXmark®are yet to be reported. In phantom measurements wereperformed to compare CBCT imaging artefacts with solid fiducials and determine optimum imagingparameters for BioXmark®.In vivostability of BioXmark®was assessed over a 5-month period, andthe impact of BioXmark®onin vivotumour response from single-fraction and fractionated X-rayexposures was investigated in a subcutaneous syngeneic tumour model. BioXmark®was stable, welltolerated and detectable on CBCT at volumesd10¼L. Our data showed imaging artefacts reduced byup to 84% and 89% compared to polymer and gold fiducial markers, respectively. BioXmark®wasshown to have no significant impact on tumour growth in control animals, but changes were observedin irradiated animals injected with BioXmark®due to alterations in dose calculations induced by thesharp contrast enhancement. BioXmark®is superior to solid fiducials with reduced imaging artefactson CBCT. With minimal impact on the tumour growth delay, BioXmark®can be implemented inSAIGRT to improve target delineation and reduce set-up errors
Price Gareth, Biglin Emma R, Collins Sean, Aitkinhead Adam, Subiel Anna, Chadwick Amy L, Cullen David, M, Kirkby Karen J, Schettino Giuseppe, Tipping Jill, Robinson Andrew (2020) An open source heterogeneous 3D printed mouse phantom utilising a novel bone representative thermoplastic,Physics in Medicine & Biology 65 (10) 10NT02 IOP Publishing
The lack of rigorous quality standards in pre-clinical radiation dosimetry has renewed interest in the development of anthropomorphic phantoms. Using 3D printing customisable phantoms can be created to assess all parts of pre-clinical radiation research: planning, image guidance and treatment delivery. We present the full methodology, including material development and printing designs, for the production of a high spatial resolution, anatomically realistic heterogeneous small animal phantom. A methodology for creating and validating tissue equivalent materials is presented. The technique is demonstrated through the development of a bone-equivalent material. This material is used together with a soft-tissue mimicking ABS plastic filament to reproduce the corresponding structure geometries captured from a CT scan of a nude mouse. Air gaps are used to represent the lungs. Phantom validation was performed through comparison of the geometry and x-ray attenuation of CT images of the phantom and animal images. A 6.6% difference in the attenuation of the bone-equivalent material compared to the reference standard in softer beams (0.5 mm Cu HVL) rapidly decreases as the beam is hardened. CT imaging shows accurate (sub-millimetre) reproduction of the skeleton (Distance-To-Agreement 0.5 mm ± 0.4 mm) and body surface (0.7 mm ± 0.5 mm). Histograms of the voxel intensity profile of the phantom demonstrate suitable similarity to those of both the original mouse image and that of a different animal. We present an approach for the efficient production of an anthropomorphic phantom suitable for the quality assurance of pre-clinical radiotherapy. Our design and full methodology are provided as open source to encourage the pre-clinical radiobiology community to adopt a common QA standard.

Additional publications