 So, welcome to this special issue on flash. My name is Jonathan far, and I work for applications of detectors and accelerators to medicine spin off from CERN, and I'm based in Geneva, Switzerland. And my name is the Katya Parody, I'm a professor at chair of medical physics at Ludwig Maximilian University in Munich. My name is David Carlson, I'm an associate professor of medical physics at the University of Pennsylvania in Philadelphia. As we look at the exciting topic of flash research and flash radiotherapy, we see that in the history of radiotherapy, going back decades, flash radiation is potentially the most interesting new development that we've seen. In fact, flash radiation flash radiotherapy has the potential to change practice to either allow higher doses of radiation, or additional sparing to patients. In fact, though, there are many things that we don't understand about flash that we the underlying science remains to be fully explored. And we see this as an opportunity now to assess. What do we know about flash. What don't we know about flash. Where is there additional work to be done before we can see a translation to human use. We've named our special issue flash current status and the transition to clinical use. We'd like to take this opportunity to thank the medical physics editors who have supported this project over the past couple of years. To the content organization for this flash special issue. It occurred to us to divide it into four categories. The first one being the physics of flash technology and asymmetry. And finally, the underlying mechanisms of flash, followed by the pre clinical investigations that have been conducted for flash effects. And lastly and maybe most importantly, the preparation for a translation to clinical use. The first special issue is formed by a number of invited contributions, mostly from senior leaders in the field, but also include some exciting results from early career investigators. Looking at the first section on flash physics so we have a set of companion papers there. We have ultra high dose rate radiation production and delivery systems intended for flash so that covers the state of the art of accelerators today, used in radiotherapy and some indeed use for flash investigations. And what the roadmap looks like to improve those systems to come up with new systems new delivery mechanisms to produce ultra high dose rates. The paper in this section focuses on flash dosimetry and setup for experimental investigations into flash. I'd like to turn over now to Dave who will tell us about the next section. Thank you Jonathan. In the second section of our special issue, we were fortunate to have several key expert authors, explore the potential underlying physical chemical and biological mechanisms of the flash effects, which are not yet fully understood. Crucial to our understanding of the physical chemical effects is the manuscript on model studies of the role of oxygen in the flash effect, where competing but related hypotheses are proposed, compared and contrasted with published results. Subsequent paper on the radiobiology of the flash effect. Additional biological mechanisms such as inflammatory processes DNA damage and repair, altered metabolic and detoxification pathways and repair pathways used by tumor cells are also fully explored. In the next section, we asked authors to present a critical review of the pre clinical evidence for the flash effect using existing radiation modalities, while also providing a vision of what future experiments must be performed to advance our scientific understanding in this field. Subsequent was to be inclusive of all modalities relevant to current clinical practice, including electrons x rays protons and carbon ions, where there's a paper summarizing the results from each of these modalities and really highlighting the potential physical and biological advantages and disadvantages of each approach. So with that I'll turn it over to Katya. Thank you so much for the update and indeed facing the next step of translating this intriguing findings into a possible future clinical routine of flesh radiotherapy requires innovations at several levels of our current chain of radiation therapy. So the next part of the special issue addresses when you're exciting developments of treatment planning system, which will have to include the new optimization tools to take into account the complexity of understanding of a fresh effect, and it's delivery. And these internal require advancement beyond state of the art in image guidance techniques, not only for proper planning, but also for safe delivery and ideally treatment response assessment. And as described in the related paper, the unique nature of ultra high dose rate pulse beams, not only poses several dosimetric challenges but also opens new opportunities of verifying the treatment delivery on a single pulse level. So finally, in the last contribution of a specialist shoe, a word of caution is given on the roadmap to save an effective prospective clinical trials, including a list of issues that have to be critically addressed before those trials can be performed now the technology is mature to bring fresh delivery into the clinical reach for more indications. So summarizing the fresh radiotherapy is an exciting treatment modality that promises to change and not only the practice of radiotherapy but also it's a true one role in the field of oncology. However, it's full fledged application radiotherapy will require further developments beyond state of the art. And especially should provide the detail and multidisciplinary insight on the current state of knowledge, the critical needs and new developments in the field, and the soon to be realized methods and system, leading possibly to a safe and effective application of flash in clinical practice. Right, so I'd like to thank our co editors for the nice introduction to the flash special issue. And we'd like to close out by mentioning that we thought it would also be interesting to the viewers to hear specific introductions by the authors themselves for certain papers and so those segments will be following this video. Thank you very much. My name is Jonathan far. I work at the application of detectors and accelerators to medicine, a spin off from CERN located in Geneva, Switzerland, where we're developing a proton therapy lineup called light based on CERN technology. Today I'd like to introduce two papers to the special issue flash current status and the transition to clinical use. The papers are the ultra high dose rate radiation production and delivery systems intended for flash, as well as a practical guide to flash irradiations and dosimetry. I have the question, what are the challenges and ongoing new developments for the production and delivery of flash radiotherapy. Well, first of all, we have to ask ourselves, what is flash. But more specifically, with regard to this topic, what are the observed correlations between ultra high dose rate radiation types and flash. I have the question, what are the challenges and ongoing new developments for their production and delivery of flash radiotherapy. Well, first of all, we have to ask ourselves a question, what is flash and more specifically in this context. What are the observed correlations between ultra high dose rate radiation type and flash. As we investigated this question, the co authors and I put together the results in figure one of this publication. Another aspect that became clear to us is that as flash is an evolving field, the terminology of flash is also growing. Pertaining to ultra high dose rate systems, we've developed a glossary of flash terminology also included as part of this paper. And specifically with regard to flash systems, we ask ourselves, what are the requirements for flash systems. We must first start with all of the unknowns, which are many. What are the flash differences between x rays, electrons, ions. How is it related to the average dose rate, the pulse dose rate, the beam on time, dose rate variations. What's the optimal dose rate or range of dose rates. What are the flash differences, including let in the brag peak for ions. What are the timing matters of being micro and macro structure. What is the need for dose conformity or the lack thereof. What about dose distributions overlapping in space and time. And what about the time interval between these overlapping or non overlapping doses. Although we don't have good answers to those questions today. Regardless, making reasonable assumptions and specifying design choices where possible. We consider here the existing technology and how to move it forward to ultra high dose rate performance. Both readily achievable and long term developments. We look at two specific aspects of ultra high dose rate systems. First of all, the so called ultra high dose rate drivers, the accelerators, cyclotrons, synchro cyclotrons, linux lasers. Also with regard to the radiation type x rays, electrons and protons. Furthermore, we look at ultra high dose rate delivery systems. The question about transmission versus conformal flash irradiation. The question about transmission versus conformal flash irradiation. The needed detector development and beam diagnostics for the control systems. Following in the companion paper, the practical guide to flash irradiations and dosimetry. The authors looked at ultra high dose rate detector types and techniques and ongoing developments in the field. Dear colleagues, my name is Vincent Favaudon. I'm a radiation biologist at the crossroads between physical chemistry and molecular biology. My lab is located in Institue Curie at Orsay inside the campus of Paris-Saclay University. With Marie-France Poupon, Jean-Jacques Fontaine and Marie-Catherine Vozna, we discovered the flash effect. Namely, specific sparing of normal tissue from late complications upon exposure to ultra high dose rate irradiation without compromising the anti-tumor efficiency. This year, I participated in two review papers published in the Flash Special Issue of Medical Physics Journal. The first one is with Anna Friedel, Kevin Price, Karl Butterworth and Pierre Montagruel and deals with the radiobiology of the flash effect in vivo and in vitro, including molecular pathways, tumor responses, immunological modulation and effects from radiation quality. The second review paper is with Rodilla Barbe and Charles Limoy and deals with the various theoretical models proposed to explain normal tissue sparing by ultra high dose rate irradiation as well as differential responses of normal tissues versus tumors. The kinetic model we published two years ago in the Green Journal with Rodilla Barbe and colleagues from IBA Company is discussed in this review paper. This model supports termination of peroxidative chain reactions through bimolecular recombination of intermediate peroxyl radicals as a likely source of the flash effect. Actually, I am fully convinced that recombination of peroxyl radicals drives the flash effect. It depends on three factors. Firstly, the square of the local radical concentration at the sub-mini-second time scale. Secondly, lateral or rotational diffusion. And thirdly, the accessibility of the substrates within membrane bilayers or chromatin structure. I am quite sure that studies in this field will shed light onto the origin of the flash effect in various organs, depending on their chemical composition and marginally on the availability of oxygen. Thank you for your attention. Hi, my name is Eric Diffenberfer. I am an assistant professor of medical physics at the University of Pennsylvania. My primary area of expertise is in proton therapy physics. I think that protons have advantages over other ultra high dose rate treatment modalities because they can treat deep targets with a conformal dose distribution using fewer beams. Preclinical evidence of the flash effect indicates that dose rate is an important factor for optimizing the flash effect. And using fewer beams is one way to optimize the average dose rate of a treatment fraction. Proton treatments can be designed with a single conformal field using either passive or active range modulation devices and existing clinical accelerator systems. However, significant challenges remain as bounds or thresholds on the treatment parameters needed to realize the flash effect have not been determined. Many preclinical studies are needed, and additional complications are introduced with proton beam therapy as the spatial and temporal variation of dose delivery with scanned proton beams also needs to be studied for its influence on the flash effect. Thank you. Hello, my name is Marco Schwarz, and together with four colleagues, I am the author of the paper on treatment planning for flash. And if we consider that treatment planning is the step in the radiation oncology process, where we find a compromise between what we would like to do, and what we can actually do given the constraints of patient anatomy, and the radiation physics, and the beam delivery system that we have available. It becomes quite clear that treatment planning for flash will become the more important, the more we will concentrate on the translation of what we are learning what we learn from radio biological studies into clinical practice. This is particularly true in the early phase of flash clinical application, when we will be using radiation oncology equipment that has not been designed with flash in mind, and that as a consequence may be quite suboptimal in that respect. Therefore, address two questions that we think are important concerning the relation between flash and treatment planning. And these two questions are, can we generate given current radiotherapy equipment, those distributions that are clinically meaningful, and that can both take advantage of flash and still take advantage also of those shaping capabilities of current systems. The assumption here is that flash alone will not be sufficient to generate good dose distribution and that we have to combine these two properties. What we were interested in is to assess what kind of flash specific planning tools are needed when it comes to both plan optimization and plan evaluation. We focus on proton therapy because we think that among the equipment that we are currently using in in radiotherapy is the one that is the closest to what is needed to achieve the flash regime. We think that proton therapies are important therapy systems are the best possible. And, but the analysis of what are the properties of future in production and delivery system is discussed in other, in other papers of this special issue. There's three different sites disease sites three different dosimetric protocols and three different planning techniques and two beam delivery systems, one based on the cyclotron and one on a on a linear. And we generated those distributions and we assess what is, if you will, the flash potential of such distributions. What we learn is that, given some assumptions some hypothesis on what is needed in order to achieve flash. It is possible to generate flashes distributions with current equipment, even though the amount of flash that one can get is heavily dependent on some assumptions on both a dose rates, how we are we define the dose rate, and what is the minimum that has to be achieved in order for the flesh effect to occur. And these also outline how we need from radio biology, the results from some experiments that will be aimed at the specific application of flash in clinical practice with current clinical protocols. We also show that even the operative therapy Kennedy deliver flesh those distributions, in order to do that we have to develop training planning approaches that are completely different to what we are doing right now. And as a consequence, these approaches have to be possible in terms of planning systems which is not the case right now at least when it comes to commercial systems. We also think that we are at the very beginning of training planning for flash so somehow this mismatch between what we have and what we need is totally understandable. And as a consequence, based on our results, we also propose a list of developments that we think are needed so that training planning will really help in maximise the benefits we can get from flash for patients. This article focuses on image guidance for flash radio therapy as part of the special issue on flash. It's co-authored by myself as Salman Naga, Brian Pog, Rong Chao, Zang, Ibrahim Arakad and Katya Parady. The main topics covered in this article include imaging for treatment planning, for delivery, for in vivo asymmetry as well as response assessment. Starting by imaging for treatment planning follows the conventional radio therapy planning using CT MRI but with more special focus on flash delivery. More related to this is the utilisation of functional imaging with PET, not only for target delineation of the metabolic volume but also for assessing areas within the tumour or the normal tissue of hypoxia which could be relevant given the oxygen dependence of flash using tracer like f-myzofasa and ATSM among others. Another area covered in the article focuses on imaging for setup correction, delivery and adaptation using combim CT or integrated linear accelerator with MR or PET imaging. Online imaging and in vivo asymmetry received special attention in this article reviewing emerging technology using optical imaging or acoustic imaging. This is an example on utilisation of optical imaging for in vivo asymmetry done at Dartmouth showing Shrinkov in water phantom with its ability to distinguish pulse-to-pulse doses. Another example showing the dose distribution on the surface with another example showing Shrinkov's emission of breast cancer case. The utilisation of acoustic imaging adds more ability to measure dose at depth. This is work done at the University of Michigan. This is the phantom setup shown here as well as the attachment of an ultrasound transducer. Again, acoustic imaging as in the case of optics is able to discriminate between pulse-to-pulse doses and resolve these in a time dependent matter as well as showing a linear relationship with dose as measured by conventional film techniques. This is an example using the bottom showing a rabbit model and an ex vivo model showing how this acoustic imaging could actually track movement and motion related to anatomy and the beam making sure that there is good alignment. An area of strong interest is the understanding of mechanisms of flash radiotherapy and imaging again can help in that regard. Whether it's using phosphorescent quenching oxygen type measurements or in the case of particle therapy using prompt gamma spectroscopy, here are some results showing oxygen measurements as well as calcium measurements using gamma prompt gamma techniques. So in conclusion, image guidance is important and necessary for safe and flash radiotherapy. Current and emerging imaging technologies are being for the current one repurposed and for emerging one being developed for planning delivery and response assessment of flash radiotherapy. This is also adjuvant to other technologies such AI, faster electronics and advanced beam control that could help many of the impending issues confronting getting a better image equality, especially for emerging technologies as well. Thank you. Hi, MedFizz readers. My name is Paige Taylor. I'm a medical physicist at Iraq in Houston, Texas. My specialty is clinical trial QA specifically for radiation therapy. I'm going to be talking about a paper called a roadmap to clinical trials for flash, which I wrote with Jeff Bucksbaum, David Jaffrey and Jean Moran. So what is still needed? Well, we break this roadmap into three sections. The first section is technology that's needed to move forward with flash trials. So that's everything from beam technology, the delivery, we want the patient safety mechanisms that stop and start the beam when we want it to. We also need things like dye contacts to be developed for all the parameters that we think might be pertinent for flash. So things like dose rate, pulse rate and beam delivery time. Once all of these tools have been built out, that will really help with a multi institutional framework for clinical trials. Next, we want to look at preclinical data. We know a lot of places are doing preclinical trials, but we haven't seen very uniform or consistent or reproducible data across these institutions. So some things we want to look at are complex flash in a preclinical setting. So what does flash look like if it's multi field or multi modality or multi fraction? We want to look at the biological effect of flash. We want to look at flash plus other types of treatment. So how does flash interact with immunotherapy or chemotherapy or other types of radiation? Last, when we're thinking about these multi institutional clinical trials, we want to make sure that we have thought of everything ahead of time, come up with a really great prescription for how to do these trials. So we need standardized protocols. We need to think about what our constraints will be. We need to build out a structure for credentialing institutions for these flash trials and think about whether we would allow multiple modalities like protons and electrons on the same trial or how we would credential for something like that. We're really excited for trials to move forward with flash, but we want to make sure we do so cautiously and carefully using all the tools we have available and the smarts we have as medical physicists and radiation oncologists. Initial trials have begun in human patients in Cincinnati. Are we ready for widespread clinical trials? Well in our paper we lay out some ideas of how we can get ready. We don't think we're quite there yet. Thank you.