Machine learning to determine optimal conditions for controlling the size of elastin-based particles.

This paper evaluates the aggregation behavior of a potential drug and gene delivery system that combines branched polyethyleneimine (PEI), a positively-charged polyelectrolyte, and elastin-like polypeptide (ELP), a recombinant polymer that exhibits lower critical solution temperature (LCST). The LCST behavior of ELP has been extensively studied, but there are no quantitative ways to control the size of aggregates formed after the phase transition. The aggregate size cannot be maintained when the temperature is lowered below the LCST, unless the system exhibits hysteresis and forms irreversible aggregates. This study shows that conjugation of ELP with PEI preserves the aggregation behavior that occurs above the LCST and achieves precise aggregate radii when the solution conditions of pH (3, 7, 10), polymer concentration (0.1, 0.15, 0.3 mg/mL), and salt concentration (none, 0.2, 1 M) are carefully controlled. K-means cluster analyses showed that salt concentration was the most critical factor controlling the hydrodynamic radius and LCST. Conjugating ELP to PEI allowed crosslinking the aggregates and achieved stable particles that maintained their size below LCST, even after removal of the harsh (high salt or pH) conditions used to create them. Taken together, the ability to control aggregate sizes and use of crosslinking to maintain stability holds excellent potential for use in biological delivery systems.

First benchmarking of the BIANCA model for cell survival prediction in a clinical hadron therapy scenario.

In the framework of RBE modelling for hadron therapy, the BIANCA biophysical model was extended to O-ions and was used to construct a radiobiological database describing the survival of V79 cells as a function of ion type (1 ⩽ Z ⩽ 8) and energy. This database allowed performing RBE predictions in very good agreement with experimental data. A method was then developed to construct analogous databases for different cell lines, starting from the V79 database as a reference. Following interface to the FLUKA Monte Carlo radiation transport code, BIANCA was then applied for the first time to predict cell survival in a typical patient treatment scenario, consisting of two opposing fields of range-equivalent protons or C-ions. The model predictions were found to be in good agreement with CHO cell survival data obtained at the Heidelberg ion-beam therapy (HIT) centre, as well as predictions performed by the local effect model (version LEM IV). This work shows that BIANCA can be used to predict cell survival and RBE not only for V79 and AG01522 cells, as shown previously, but also, in principle, for any cell line of interest. Furthermore, following interface to a transport code like FLUKA, BIANCA can provide predictions of 3D biological dose distributions for hadron therapy treatments, thus laying the foundations for future applications in clinics.

ENLIGHT: European network for Light ion hadron therapy.

The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 following various European particle therapy network initiatives during the 1980s and 1990s (e.g. EORTC task group, EULIMA/PIMMS accelerator design). ENLIGHT started its work on major topics related to hadron therapy (HT), such as patient selection, clinical trials, technology, radiobiology, imaging and health economics. It was initiated through CERN and ESTRO and dealt with various disciplines such as (medical) physics and engineering, radiation biology and radiation oncology. ENLIGHT was funded until 2005 through the EC FP5 programme. A regular annual meeting structure was started in 2002 and continues until today bringing together the various disciplines and projects and institutions in the field of HT at different European places for regular exchange of information on best practices and research and development. Starting in 2006 ENLIGHT coordination was continued through CERN in collaboration with ESTRO and other partners involved in HT. Major projects within the EC FP7 programme (2008-2014) were launched for R&D and transnational access (ULICE, ENVISION) and education and training networks (Marie Curie ITNs: PARTNER, ENTERVISION). These projects were instrumental for the strengthening of the field of hadron therapy. With the start of 4 European carbon ion and proton centres and the upcoming numerous European proton therapy centres, the future scope of ENLIGHT will focus on strengthening current and developing European particle therapy research, multidisciplinary education and training and general R&D in technology and biology with annual meetings and a continuously strong CERN support. Collaboration with the European Particle Therapy Network (EPTN) and other similar networks will be pursued.

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure.

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 µM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 µM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 µM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire.

BACKGROUND: We performed a survey using the modified EORTC Facility questionnaire (pFQ) to evaluate the human, technical and organizational resources of particle centers in Europe. MATERIAL AND METHODS: The modified pFQ consisted of 235 questions distributed in 11 sections accessible on line on an EORTC server. Fifteen centers from 8 countries completed the pFQ between May 2015 and December 2015. RESULTS: The average number of patients treated per year and per particle center was 221 (range, 40-557). The majority (66.7%) of centers had pencil beam or raster scanning capability. Four (27%) centers were dedicated to eye treatment only. An increase in the patients-health professional FTE ratio was observed for eye tumor only centers when compared to other centers. All centers treated routinely chordomas/chondrosarcomas, brain tumors and sarcomas but rarely breast cancer. The majority of centers treated pediatric cases with particles. Only a minority of the queried institutions treated non-static targets. CONCLUSIONS: As the number of particle centers coming online will increase, the experience with this treatment modality will rise in Europe. Children can currently be treated in these facilities in a majority of cases. The majority of these centers provide state of the art particle beam therapy.

Charged-particle therapy in cancer: clinical uses and future perspectives.

Radiotherapy with high-energy charged particles has become an attractive therapeutic option for patients with several tumour types because this approach better spares healthy tissue from radiation than conventional photon therapy. The cost associated with the delivery of charged particles, however, is higher than that of even the most elaborate photon-delivery technologies. Reliable evidence of the relative cost-effectiveness of both modalities can only come from the results of randomized clinical trials. Thus, the hurdles that currently limit direct comparisons of these two approaches in clinical trials, especially those related to insurance coverage, should be removed. Herein, we review several randomized trials of charged-particle therapies that are ongoing, with results that will enable selective delivery to patients who are most likely to benefit from them. We also discuss aspects related to radiobiology, including the immune response and hypoxia, which will need to be taken into consideration in future randomized trials to fully exploit the potential of charged particles.

NanOx, a new model to predict cell survival in the context of particle therapy.

Particle therapy is increasingly attractive for the treatment of tumors and the number of facilities offering it is rising worldwide. Due to the well-known enhanced effectiveness of ions, it is of utmost importance to plan treatments with great care to ensure tumor killing and healthy tissues sparing. Hence, the accurate quantification of the relative biological effectiveness (RBE) of ions, used in the calculation of the biological dose, is critical. Nevertheless, the RBE is a complex function of many parameters and its determination requires modeling. The approaches currently used have allowed particle therapy to thrive, but still show some shortcomings. We present herein a short description of a new theoretical framework, NanOx, to calculate cell survival in the context of particle therapy. It gathers principles from existing approaches, while addressing some of their weaknesses. NanOx is a multiscale model that takes the stochastic nature of radiation at nanometric and micrometric scales fully into account, integrating also the chemical aspects of radiation-matter interaction. The latter are included in the model by means of a chemical specific energy, determined from the production of reactive chemical species induced by irradiation. Such a production represents the accumulation of oxidative stress and sublethal damage in the cell, potentially generating non-local lethal events in NanOx. The complementary local lethal events occur in a very localized region and can, alone, lead to cell death. Both these classes of events contribute to cell death. The comparison between experimental data and model predictions for the V79 cell line show a good agreement. In particular, the dependence of the typical shoulders of cell survival curves on linear energy transfer are well described, but also the effectiveness of different ions, including the overkill effect. These results required the adjustment of a number of parameters compatible with the application of the model in a clinical scenario thereby showing the potential of NanOx. Said parameters are discussed in detail in this paper.

The relative biological effectiveness of antiprotons.

BACKGROUND AND PURPOSE: Aside from the enhancement of physical dose deposited by antiprotons annihilating in tissue-like material compared to protons of the same range a further increase of biological effective dose has been demonstrated. This enhancement can be expressed in an increase of the relative biological effectiveness (RBE) of antiprotons near the end of range. We have performed the first-ever direct measurement of the RBE of antiprotons both at rest and in flight. MATERIALS AND METHODS: Experimental data were generated on the RBE of an antiproton beam entering a tissue-like target consisting of V79 cells embedded in gelatin with an energy providing a range of approximately 10cm. RESULTS: The RBE in the entrance channel (the "plateau") is only slightly above the value for a comparable proton beam, and remains low until the proximal edge of the spread-out Bragg peak (SOBP). A steep increase of RBE is seen starting from the onset of the SOBP. CONCLUSIONS: This paper reports the final results of the experiment AD-4/ACE at CERN on the first-ever direct measurement of RBE of antiprotons and constitutes the first step toward developing treatment plans.

Production of the PET isotope 11C in hadron therapy via neutron knockout.

PURPOSE: Positron emitting isotopes such as 11C and 10C can be used for vital dose verification in hadron therapy. These isotopes are produced when the high energy 12C primary beam particles undergo nuclear reactions within the patient. METHODS: We discuss a model for calculating cross sections for the production 11C in 12C+12C collisions, applicable at hadron therapy energies. RESULTS: Good agreement with the available cross section measurements is found for 12C(-1n), though more detailed, systematic measurements would be very valuable. CONCLUSIONS: Nuclear structure plays a crucial role in the reactions of light nuclei, particularly when those reactions are peripheral and involve only a few nucleons. For such reactions, nuclear structure has a strong influence on the energy and angular distribution of the cross section, and is an important consideration for reliable dose verification using 11C in hadron therapy.

MCNP6 model of the University of Washington clinical neutron therapy system (CNTS).

A MCNP6 dosimetry model is presented for the Clinical Neutron Therapy System (CNTS) at the University of Washington. In the CNTS, fast neutrons are generated by a 50.5 MeV proton beam incident on a 10.5 mm thick Be target. The production, scattering and absorption of neutrons, photons, and other particles are explicitly tracked throughout the key components of the CNTS, including the target, primary collimator, flattening filter, monitor unit ionization chamber, and multi-leaf collimator. Simulations of the open field tissue maximum ratio (TMR), percentage depth dose profiles, and lateral dose profiles in a 40 cm × 40 cm × 40 cm water phantom are in good agreement with ionization chamber measurements. For a nominal 10 × 10 field, the measured and calculated TMR values for depths of 1.5 cm, 5 cm, 10 cm, and 20 cm (compared to the dose at 1.7 cm) are within 0.22%, 2.23%, 4.30%, and 6.27%, respectively. For the three field sizes studied, 2.8 cm × 2.8 cm, 10.4 cm × 10.3 cm, and 28.8 cm × 28.8 cm, a gamma test comparing the measured and simulated percent depth dose curves have pass rates of 96.4%, 100.0%, and 78.6% (depth from 1.5 to 15 cm), respectively, using a 3% or 3 mm agreement criterion. At a representative depth of 10 cm, simulated lateral dose profiles have in-field (⩾ 10% of central axis dose) pass rates of 89.7% (2.8 cm × 2.8 cm), 89.6% (10.4 cm × 10.3 cm), and 100.0% (28.8 cm × 28.8 cm) using a 3% and 3 mm criterion. The MCNP6 model of the CNTS meets the minimum requirements for use as a quality assurance tool for treatment planning and provides useful insights and information to aid in the advancement of fast neutron therapy.

The National Centre for Oncological Hadrontherapy (CNAO): Status and perspectives.

The National Centre for Oncological Hadrontherapy (CNAO, sited in Pavia, Italy) completed at the end of 2013 the clinical trial phase achieving the CE label from the notified body of the Italian Health Ministry and obtained the authorisation to treat patients within the national health system. Nowadays more than 400 patients completed the treatments, two thirds of them with carbon ions, and recently started the treatment of pathologies located within moving organs. For the first time in the world carbon ions delivered with active scanning, coupled with breathing synchronisation and rescanning modalities have been applied to treat patients affected by tumours of the liver and by pancreatic cancers. The path to reach the final CE label required a wide-ranging experimental activity that went through dosimetry measurements of the hadron beams, in-vitro and in-vivo radiobiology essays and treatments of 150 patients, all enrolled in one of the 23 clinical trials approved by the Ethical Committee of CNAO and then authorized by the Italian Ministry of Health. The results of the trials were very positive in terms of safety and reliability of the procedures. The follow-up period is still short, but preliminary good results are observed in particular in terms of limited toxicity, that on the whole is less than expected. The paper gives a status report on the experimental phase that completed the CE certification process and then outlines the ongoing activities with also indications on the future trends and the most interesting R&D programmes pursued at CNAO.

History of hadron therapy accelerators.

In the last 60 years, hadron therapy has made great advances passing from a stage of pure research to a well-established treatment modality for solid tumours. In this paper the history of hadron therapy accelerators is reviewed, starting from the first cyclotrons used in the thirties for neutron therapy and passing to more modern and flexible machines used nowadays. The technical developments have been accompanied by clinical studies that allowed the selection of the tumours which are more sensitive to this type of radiotherapy. This paper aims at giving a review of the origin and the present status of hadron therapy accelerators, describing the technological basis and the continuous development of this application to medicine of instruments developed for fundamental science. At the end the present challenges are reviewed.

ENLIGHT and LEIR biomedical facility.

Particle therapy (including protons and carbon ions) allows a highly conformal treatment of deep-seated tumours with good accuracy and minimal dose to surrounding tissues, compared to conventional radiotherapy using X-rays. Following impressive results from early phase trials, over the last decades particle therapy in Europe has made considerable progress in terms of new institutes dedicated to charged particle therapy in several countries. Particle therapy is a multidisciplinary subject that involves physicists, biologists, radio-oncologists, engineers and computer scientists. The European Network for Light Ion Hadron Therapy (ENLIGHT) was created in response to the growing needs of the European community to coordinate such efforts. A number of treatment centres are already operational and treating patients across Europe, including two dual ion (protons and carbon ions) centres in Heidelberg (the pioneer in Europe) and Pavia. However, much more research needs to be carried out and beamtime is limited. Hence there is a strong interest from the biomedical research community to have a facility with greater access to relevant beamtime. Such a facility would facilitate research in radiobiology and the development of more accurate techniques of dosimetry and imaging. The Low Energy Ion Ring (LEIR) accelerator at CERN presents such an opportunity, and relies partly on CERN's existing infrastructure. The ENLIGHT network, European Commission projects under the ENLIGHT umbrella and the future biomedical facility are discussed.

Dreams, themes and particle beams--an oncologist's perspective on technology trickle-down from the LHC.

11 years ago, the European Network for Light Ion Therapy (ENLIGHT) was established as a multidisciplinary network of engineers, physicists and clinicians with a common interest in the development of hadron therapy in Europe. ENLIGHT is coordinated from the European Centre for Nuclear Research (CERN), the home of the Large Hadron Collider. The network has evolved into a mature platform for research, with more than 100 researchers working in CERN and its allied research centres. One of the benefits of hosting this network at CERN is the ability to translate hardware and software developments, originally developed in the High Energy Physics domain, into clinical applications. From the perspective of a clinical radiation oncologist within the network, this commentary reviews the ways in which leading edge technological developments in detectors and solid state physics, Monte-Carlo simulation, grid computing and accelerator design have trickled down into real-world clinical applications.

Charged particle therapy--optimization, challenges and future directions.

The use of charged particle therapy to control tumours non-invasively offers advantages over conventional radiotherapy. Protons and heavy ions deposit energy far more selectively than X-rays, allowing a higher local control of the tumour, a lower probability of damage to healthy tissue, low risk of complications and the chance for a rapid recovery after therapy. Charged particles are also useful for treating tumours located in areas that surround tissues that are radiosensitive and in anatomical sites where surgical access is limited. Current trial outcomes indicate that accelerated ions can potentially replace surgery for radical cancer treatments, which might be beneficial as the success of surgical cancer treatments are largely dependent on the expertise and experience of the surgeon and the location of the tumour. However, to date, only a small number of controlled randomized clinical trials have made comparisons between particle therapy and X-rays. Therefore, although the potential advantages are clear and supported by data, the cost:benefit ratio remains controversial. Research in medical physics and radiobiology is focusing on reducing the costs and increasing the benefits of this treatment.

Physical interactions of charged particles for radiotherapy and space applications.

In this paper, the basic physics by which energetic charged particles deposit energy in matter is reviewed. Energetic charged particles are used for radiotherapy and are encountered in spaceflight, where they pose a health risk to astronauts. They interact with matter through nuclear and electromagnetic forces. Deposition of energy occurs mostly along the trajectory of the incoming particle, but depending on the type of incident particle and its energy, there is some nonzero probability for energy deposition relatively far from the nominal trajectory, either due to long-ranged knock-on electrons (sometimes called delta rays) or from the products of nuclear fragmentation, including neutrons. In the therapy setting, dose localization is of paramount importance, and the deposition of energy outside nominal treatment volumes complicates planning and increases the risk of secondary cancers as well as noncancer effects in normal tissue. Statistical effects are also important and will be discussed. In contrast to radiation therapy patients, astronauts in space receive comparatively small whole-body radiation doses from energetic charged particles and associated secondary radiation. A unique aspect of space radiation exposures is the high-energy heavy-ion component of the dose. This is not present in terrestrial exposures except in carbon-ion radiotherapy. Designers of space missions must limit exposures to keep risk within acceptable limits. These limits are, at present, defined for low-Earth orbit, but not for deep-space missions outside the geomagnetosphere. Most of the uncertainty in risk assessment for such missions comes from the lack of understanding of the biological effectiveness of the heavy-ion component, with a smaller component due to uncertainties in transport physics and dosimetry. These same uncertainties are also critical in the therapy setting.

Lauriston S. Taylor Lecture on radiation protection and measurements: what makes particle radiation so effective?

The scientific basis for the physical and biological effectiveness of particle radiations has emerged from many decades of meticulous basic research. A diverse array of biologically relevant consequences at the molecular, cellular, tissue, and organism level have been reported, but what are the key processes and mechanisms that make particle radiation so effective, and what competing processes define dose dependences? Recent studies have shown that individual genotypes control radiation-regulated genes and pathways in response to radiations of varying ionization density. The fact that densely ionizing radiations can affect different gene families than sparsely ionizing radiations, and that the effects are dose- and time-dependent, has opened up new areas of future research. The complex microenvironment of the stroma and the significant contributions of the immune response have added to our understanding of tissue-specific differences across the linear energy transfer (LET) spectrum. The importance of targeted versus nontargeted effects remains a thorny but elusive and important contributor to chronic low dose radiation effects of variable LET that still needs further research. The induction of cancer is also LET-dependent, suggesting different mechanisms of action across the gradient of ionization density. The focus of this 35th Lauriston S. Taylor Lecture is to chronicle the step-by-step acquisition of experimental clues that have refined our understanding of what makes particle radiation so effective, with emphasis on the example of radiation effects on the crystalline lens of the human eye.

NCI support for particle therapy: past, present, future.

In light of the rising worldwide interest in particle therapy, and proton therapy specifically in the United States, the National Cancer Institute (NCI) is being asked more often about funding for such research and facilities. Many of the questions imply that NCI is naive to the exciting possibilities inherent in particle therapies, and thus they wish to encourage NCI to initiate and underwrite such programs. In fact, NCI has a long track record of support for the translation of hadrons from the physics laboratory to the therapy clinic by way of technology development and scientific investigations of physical and biological processes as well as clinical outcomes. Early work has included continuous funding since 1961 of proton treatments for more than 15,000 patients and facility construction at the Harvard/Massachusetts General Hospital (MGH) site; treatment of 227 patients with the pi-meson facility at Los Alamos between 1974 and 1981; funding of more than $69M for seven neutron therapy centers between 1971 and 1989; many funded projects in boron neutron capture radiation therapy through the present time; and numerous radiobiology projects over the past 50 y. NCI continues to play an active role in the incorporation of protons into randomized clinical trials through the Children's Oncology Group, Radiation Therapy Oncology Group, and the Program Project Grant (P01), which is co-directed by the MGH and MD Anderson Cancer Center. This has required funding development and implementation of guidelines that enable intercomparison of dosimetry and treatment between facilities. NCI has also funded recent efforts to develop new physical processes for the production of particles such as protons. With regard to the future, while it is true that there are no specific funding opportunity announcements directed to particle therapy research, it is also true that NCI remains open to reviewing any research that is compatible with an established mechanism. However, given the very substantial resources that these facilities currently require along with the highly competitive economic environment that now exists, it is clear that scientific review of such grant applications will look to leverage the scientific pursuits that are the NCI mandate with the reality of the clinical practices, just as is the case for photon radiation research. Such leveraging should be enhanced by the growing opportunities and need for international collaborations. On the other hand, these collaborations are complicated by the fact that these particle therapies are now fully reimbursable modalities, which makes it difficult to separate research (the NCI mission) from clinical practice development. This paper seeks to illuminate these new realities in order to encourage the pursuit and funding of the scientific underpinnings of physical methods, radiobiology, and clinical practice with particle therapy.

Accelerators for America's Future Workshop: Medicine and Biology.

"Medicine and Biology" was one of five working groups of the "Accelerators for America's Future" Workshop held October 2009. The recently-released workshop report stresses that the leadership position of the United States in fields where accelerators play an important part is being seriously eroded because of lack of coordinated agency support for accelerator research and development. This is particularly true for biology and medicine. Radiation therapy with beams of protons and light ions was pioneered in the United States and has proven successful in the treatment of several different tumor sites in the body. Proton therapy is available in the United States in a number of centers; however, all but one contain accelerator and beam-delivery components manufactured abroad. Light-ion therapy is only available overseas. Why has the United States lost its lead in this field? The Working Group noted that in other countries, central governments are subsidizing construction and technology development by their industries, whereas in the United States funding for purchasing and building clinical facilities must be raised from private sources. As a result, most proton facilities in the United States, by virtue of having to recover investment costs, favor reimbursable treatments, detracting from the development of research protocols. The financial hurdle for starting a light-ion facility in the United States has been totally prohibitive for the private-equity market. While technological advances are being made that will provide some reduction in capital costs, the field will not flourish in the United States until effective funding means are developed that do not put the full burden on the private sector.

ENLIGHT: The European Network for Light Ion Hadron Therapy.

The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 to coordinate European efforts on hadron therapy (radiotherapy performed with protons and light ions instead of high-energy photons). The ENLIGHT network is formed by the European Hadron Therapy Community, with more than 300 participants from 20 different countries. A major success of ENLIGHT has been uniting traditionally separate communities so that clinicians, physicists, biologists, and engineers with experience and interest in particle therapy work together. ENLIGHT has been a successful initiative in forming a common European platform and bringing together people from diverse disciplines. ENLIGHT demonstrates the advantages of regular and organized exchanges of data, information, and best practices, as well as determining and following strategies for future needs in research and technological development in the hadron therapy field.