Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of "big data" and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal "focused biology." Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

An Exploration of the Rs of Radiobiology in Prostate Cancer.

OBJECTIVES: To explore the four Rs of radiobiology (Repair, Reoxygenation, Reassortment, and Repopulation) as a means to understand the effects of ionising radiation on biological tissue and subsequently as the basis for conventional fractionated treatment schedules. These radiobiological principles will form a rationale for combined regimens in prostate cancer treatment involving androgen deprivation therapy and radiation therapy and the associated toxicities of this approach will be discussed. DATA SOURCES: Electronic databases including CINAHL, MEDLINE, Scopus, professional websites, books and grey literature were searched using Google Scholar. CONCLUSION: It is important for nurses to understand the four Rs of radiobiology to grasp the effects of ionising radiation on biological tissue as the basis for conventional fractionated treatment schedules in prostate cancer. Men can experience a sequalae of physical and psychological side effects of treatment that can negatively impact quality of life. IMPLICATIONS FOR NURSING PRACTICE: Men can experience a range of unmet supportive care needs particularly related to informational, sexual, and psychological needs. For men affected by prostate cancer opting for radiation therapy (+/-) androgen deprivation therapy, nurses should ask targeted questions based on the Common Terminology Criteria for Adverse Events related to urinary and bowel function, potency and fatigue, and sexual health. We also recommend the use of holistic needs assessments to tailor self-management care plans. Evidence-based self-management advice should be provided in response to each man's unique needs.

An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses.

For decades the field of radiation oncology has sought to improve the therapeutic ratio through innovations in physics, chemistry, and biology. To date, technological advancements in image guided beam delivery techniques have provided clinicians with their best options for improving this critical tool in cancer care. Medical physics has focused on the preferential targeting of tumors while minimizing the collateral dose to the surrounding normal tissues, yielding only incremental progress. However, recent developments involving ultra-high dose rate irradiation termed FLASH radiotherapy (FLASH-RT), that were initiated nearly 50 years ago, have stimulated a renaissance in the field of radiotherapy, long awaiting a breakthrough modality able to enhance therapeutic responses and limit normal tissue injury. Compared to conventional dose rates used clinically (0.1-0.2 Gy/s), FLASH can implement dose rates of electrons or X-rays in excess of 100 Gy/s. The implications of this ultra-fast delivery of dose are significant and need to be re-evaluated to appreciate the fundamental aspects underlying this seemingly unique radiobiology. The capability of FLASH to significantly spare normal tissue complications in multiple animal models, when compared to conventional rates of dose-delivery, while maintaining persistent growth inhibition of select tumor models has generated considerable excitement, as well as skepticism. Based on fundamental principles of radiation physics, radio-chemistry, and tumor vs. normal cell redox metabolism, this article presents a series of testable, biologically relevant hypotheses, which may help rationalize the differential effects of FLASH irradiation observed between normal tissue and tumors.

Targets, pools, shoulders, and communication - a reflection on the evolution of low-dose radiobiology.

This reflection aims to look at the evolution of thinking about radiation dose response relationships from the early years of the journal when target theory prevailed to the present day when dose response is seen as a more holistic process involving multiple levels of organization and communication. The review is structured to consider how the old ideas evolved leading to apparently abrupt paradigm shifts. The odd data leading to these conceptual shifts are reviewed. Topics, which are currently still not mainstream are considered with a view to how they may change the future of radiobiology. Finally some personal reflections on the insights gained during the writing of the review are presented. The major conclusion from this study is that ideas concerning survival curves and radiation dose responses evolved and (epi)mutated gradually, driven in a large part by the techniques available for studying radiobiological processes. The illusion of abrupt paradigm shifts is not really borne out by the history when primary references are studied rather than textbooks or reviews. The textbooks necessarily simplify and distil complex data to provide a 'take-home message' while reviews are usually very personal collations selected among the vast amount of scientific literature. Primary references reveal the context of the discussion and the caveats and uncertainties of the authors.

Dosimetry and characterization of a 25-MeV proton beam line for preclinical radiobiology research.

PURPOSE: With the increase in proton therapy centers, there is a growing need to make progress in preclinical proton radiation biology to give accessible data to medical physicists and practicing radiation oncologists. METHODS: A cyclotron usually producing radioisotopes with a proton beam at an energy of about 25 MeV after acceleration, was used for radiobiology studies. Depleted silicon surface barrier detectors were used for the beam energy measurement. A complementary metal oxide semiconductor (CMOS) sensor and a plastic scintillator detector were used for fluence measurement, and compared to Geant4 and an in-house analytical dose modeling developed for this purpose. Also, from the energy measurement of each attenuated beam, the dose-averaged linear energy transfer (LETd ) was calculated with Geant4. RESULTS: The measured proton beam energy was 24.85 ± 0.14 MeV with an energy straggling of 127 ± 22 keV before scattering and extraction in air. The measured flatness was within ± 2.1% over 9 mm in diameter. A wide range of LETd is achievable: constant between the entrance and the exit of the cancer cell sample ranging from 2.2 to 8 keV/µm, beyond 20 keV/µm, and an average of 2-5 keV/µm in a scattering spread-out Bragg peak calculated for an example of a 6-mm-thick xenograft tumor. CONCLUSION: The dosimetry and the characterization of a 25-MeV proton beam line for preclinical radiobiology research was performed by measurements and modeling, demonstrating the feasibility of delivering a proton beam for preclinical in vivo and in vitro studies with LETd of clinical interest.

Chemical radiosensitizers: the Journal history.

Purpose: To review the Journal's coverage of chemical radiosensitizers. Methods: I have reviewed all the possibly-relevant papers that appeared in the Journal prior to 1970 and since 2010, plus the most highly-cited papers from the intervening years. I excluded papers that dealt only with oxygen as a sensitizer, that referred to sensitization of phototoxicity or hyperthermia, or that described interactions with antineoplastic agents unless they clearly distinguish between additive toxicity and radiosensitization. My definition of 'chemical' was very broad, so the coverage includes everything from classical hypoxic cell sensitizers to gold nanoparticles. Results: A literature search identifies ∼600 Journal articles as involving 'radiation sensitizing agents'; these articles are not common in Journals' first years but take off after 1970 with a peak in the late 1980s. Half of the highly-cited radiosensitizer papers were published between 1969 and 1974; the two most-cited radiosensitizer papers were 1969 and 1979 papers on hypoxic cell sensitizers. The third most-cited radiosensitizer paper would not come for two more decades, and it would use a physical rather than a chemical approach to radiosensitization. Conclusion: The development of an agent that would differentially sensitize tumors to irradiation remains a 'holy grail' of clinically-oriented radiobiology. Approaches to this goal have been a major feature of the Journal since its first decade, but we have yet to find such an agent. Perhaps we should be discouraged, but personally, I remain optimistic that we (or our students) will succeed.

The influence of ketogenic therapy on the 5 R's of radiobiology.

PURPOSE: Radiotherapy (RT) is a mainstay in the treatment of solid tumors and works by inducing free radical stress in tumor cells, leading to loss of reproductive integrity. The optimal treatment strategy has to consider damage to both tumor and normal cells and is determined by five factors known as the 5 R's of radiobiology: Reoxygenation, DNA repair, radiosensitivity, redistribution in the cell cycle and repopulation. The aim of this review is (i) to present evidence that these 5 R's are strongly influenced by cellular and whole-body metabolism that in turn can be modified through ketogenic therapy in form of ketogenic diets and short-term fasting and (ii) to stimulate new research into this field including some research questions deserving further study. CONCLUSIONS: Preclinical and some preliminary clinical data support the hypothesis that ketogenic therapy could be utilized as a complementary treatment in order to improve the outcome after RT, both in terms of higher tumor control and in terms of lower normal tissue complication probability. The first effect relates to the metabolic shift from glycolysis toward mitochondrial metabolism that selectively increases ROS production and impairs ATP production in tumor cells. The second effect is based on the differential stress resistance phenomenon, which is achieved when glucose and growth factors are reduced and ketone bodies are elevated, reprogramming normal but not tumor cells from proliferation toward maintenance and stress resistance. Underlying both effects are metabolic differences between normal and tumor cells that ketogenic therapy seeks to exploit. Specifically, the recently discovered role of the ketone body ß-hydroxybutyrate as an endogenous class-I histone deacetylase inhibitor suggests a dual role as a radioprotector of normal cells and a radiosensitzer of tumor cells that opens up exciting possibilities to employ ketogenic therapy as a cost-effective adjunct to radiotherapy against cancer.

Standards and Methodologies for Characterizing Radiobiological Impact of High-Z Nanoparticles.

Research on the application of high-Z nanoparticles (NPs) in cancer treatment and diagnosis has recently been the subject of growing interest, with much promise being shown with regards to a potential transition into clinical practice. In spite of numerous publications related to the development and application of nanoparticles for use with ionizing radiation, the literature is lacking coherent and systematic experimental approaches to fully evaluate the radiobiological effectiveness of NPs, validate mechanistic models and allow direct comparison of the studies undertaken by various research groups. The lack of standards and established methodology is commonly recognised as a major obstacle for the transition of innovative research ideas into clinical practice. This review provides a comprehensive overview of radiobiological techniques and quantification methods used in in vitro studies on high-Z nanoparticles and aims to provide recommendations for future standardization for NP-mediated radiation research.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

Influence of quasi-spherical polarization on results of bioelectromagnetic studies.

One of the most interesting questions in bioelectromagnetic and compatibility studies is differences between results of experiments performed in different labs in "identical" conditions, especially in bioelectromagnetics studies. A reason of these differences may be due to differences in investigated objects, particularly in in vivo experiments. However, the author, as engineer, would like to focus the readers' attention on the technical aspects of exposure systems namely: presence and role of mutual interaction between the object under test and the exposure system, interaction between exposure objects, the role of polarization and the similarity of real-life exposure to those applied in experiments, etc. All these factors may change the results of experiments and lead to false conclusions.

Exposure systems for bioelectromagnetic experiments.

One of the most interesting questions in bioelectromagnetics is why there is a difference between results of experiments performed in various labs in "identical" conditions. One of the possible reasons is the difference of investigated objects, especially while performing experiments in vivo. However, the authors, as engineers, would like to focus readers' attention on the technical aspects of exposure systems, especially the presence and role of mutual interaction between biological objects under test (OUT) and the exposure system, the interactions between the objects, the role of polarization, the similarity of real exposure to that applied in experiments etc. All these factors may alter the results of experiments and lead to false conclusions.

Online training on the safe use of fluoroscopy can result in a significant decrease in patient dose.

RATIONALE AND OBJECTIVES: Concerns over medical radiation exposure have received national press in recent years, and training in the appropriate use of radiation has become an essential component of every radiology residency program. Appropriate training is particularly important in fluoroscopy because it is commonly used by inexperienced radiology residents and has the potential to impart relatively high patient radiation doses. In an effort to minimize the radiation doses received by patients, our institution has recently initiated an online training program in the safe use of fluoroscopy. This course is required and must be completed by new radiology residents before their first fluoroscopy rotation. The goal of this study was to determine if the use of an online course in the safe use of fluoroscopy could result in decreased patient dose without affecting diagnostic quality. MATERIALS AND METHODS: Four years of retrospective procedural data for residents performing gastrointestinal and genitourinary fluoroscopic procedures without specialized training were reviewed. Incoming residents took an American Medical Association-accredited online training program in the safe use of fluoroscopy the week before their first fluoroscopy rotation. Patient dose and diagnostic quality data, inferred from the frequency of attending physician intervention necessary to complete the procedure, were collected for all exams performed by the new group of residents after completion of the training course. This was then compared to data from prior classes and stratified by procedure type. RESULTS: Statistically significant reductions in both average fluoroscopy time (FT) or dose-area-product (DAP) were found for many of the fluoroscopic procedures performed by residents who participated in the online fluoroscopy training program. Specifically, statistically significant reductions in FT for barium enema, cystogram, defecogram, and esophagram procedures (P < .001) were found. Esophagram and upper gastrointestinal studies were completed with a significantly lower DAP (P < .001). The average reduction in DAP across all procedures performed by first-year residents was 38%, whereas the average reduction in FT was 25%. Based on a review of data from all procedures performed, there was no statistically significant loss in diagnostic quality. CONCLUSION: An online training program can be effectively used to provide radiation safety instruction immediately before the start of a resident's fluoroscopy rotation, decreasing patient dose without affecting diagnostic quality.

Toxicity of irradiated advanced heavy water reactor fuels.

The good neutron economy and online refueling capability of the CANDU® heavy water moderated reactor (HWR) enable it to use many different fuels such as low enriched uranium (LEU), plutonium, or thorium, in addition to its traditional natural uranium (NU) fuel. The toxicity and radiological protection methods for these proposed fuels, unlike those for NU, are not well established. This study uses software to compare the fuel composition and toxicity of irradiated NU fuel against those of two irradiated advanced HWR fuel bundles as a function of post-irradiation time. The first bundle investigated is a CANFLEX® low void reactor fuel (LVRF), of which only the dysprosium-poisoned central element, and not the outer 42 LEU elements, is specifically analyzed. The second bundle investigated is a heterogeneous high-burnup (LEU,Th)O(2) fuelled bundle, whose two components (LEU in the outer 35 elements and thorium in the central eight elements) are analyzed separately. The LVRF central element was estimated to have a much lower toxicity than that of NU at all times after shutdown. Both the high burnup LEU and the thorium fuel had similar toxicity to NU at shutdown, but due to the creation of such inhalation hazards as (238)Pu, (240)Pu, (242)Am, (242)Cm, and (244)Cm (in high burnup LEU), and (232)U and (228)Th (in irradiated thorium), the toxicity of these fuels was almost double that of irradiated NU after 2,700 d of cooling. New urine bioassay methods for higher actinoids and the analysis of thorium in fecal samples are recommended to assess the internal dose from these two fuels.

[The problems of radioecology and radiation safety of the former uranium production in Kyrgyzstan].

The article summarizes the history and problems of the former uranium production (tailing and waste dumps), the current status and their possible impact on the environment. Also given are the priority radio-ecological and radiobiogeohemichal problems for the medium term, as well as legal and regulatory framework.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach.

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

Cytokines in radiobiological responses: a review.

Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). "Self" molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, "driver" cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly affect intrinsic cellular radiosensitivity, the incidence and type of radiation tissue complications, bystander effects, genomic instability and cancer. Minor and not so minor, polymorphisms in cytokine genes give considerable diversity within populations and are relevant to causation of disease. Therapeutic intervention is made difficult by such complexity; but the potential prize is great.

[Gamma knife radiosurgery]. / La radiochirurgie par Gamma Knife.

Gamma Knife radiosurgery can be used as an alternative or complementary therapy to neurosurgery or radiotherapy for the treatment of some brain disorders or tumors of small volume. The most frequent indications are brain metastases, vestibular schwannomas, meningiomas, trigeminal neuralgia, arteriovenous malformations, some gliomas, and pituitary adenomas. Created in 1999, the Gamma Knife Center of the ULB remains currently the unique center in Belgium where a Gamma Knife radiosurgery treatment can be performed.

Boron analysis and boron imaging in biological materials for Boron Neutron Capture Therapy (BNCT).

Boron Neutron Capture Therapy (BNCT) is based on the ability of the stable isotope 10B to capture neutrons, which leads to a nuclear reaction producing an alpha- and a 7Li-particle, both having a high biological effectiveness and a very short range in tissue, being limited to approximately one cell diameter. This opens the possibility for a highly selective cancer therapy. BNCT strongly depends on the selective uptake of 10B in tumor cells and on its distribution inside the cells. The chemical properties of boron and the need to discriminate different isotopes make the investigation of the concentration and distribution of 10B a challenging task. The most advanced techniques to measure and image boron are described, both invasive and non-invasive. The most promising approach for further investigation will be the complementary use of the different techniques to obtain the information that is mandatory for the future of this innovative treatment modality.