Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint.Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on sub-cellular damage and repair effects are discussed.Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of ~1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from ~1.1 in the entrance region, to ~1.15 in the center, ~1.35 at the distal edge and ~1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (α/β)x decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (α/β)x. Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of ~1.1.This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels.

https://iopscience.iop.org/article/10.1088/0031-9155/59/22/R419/pdf

Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer

The bone marrow niche has mystified scientists for many years, leading to widespread investigation to shed light into its molecular and cellular composition. Considerable efforts have been devoted toward uncovering the regulatory mechanisms of hematopoietic stem cell (HSC) niche maintenance. Recent advances in imaging and genetic manipulation of mouse models have allowed the identification of distinct vascular niches that have been shown to orchestrate the balance between quiescence, proliferation and regeneration of the bone marrow after injury. Here we highlight the recently discovered intrinsic mechanisms, microenvironmental interactions and communication with surrounding cells involved in HSC regulation, during homeostasis and in regeneration after injury and discuss their implications for regenerative therapy.

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Hematopoietic stem cell niche maintenance during homeostasis and regeneration

High-energy beams of charged nuclear particles (protons and heavier ions) offer significant advantages for the treatment of deep-seated local tumors in comparison to conventional megavolt photon therapy. Their physical depth-dose distribution in tissue is characterized by a small entrance dose and a distinct maximum (Bragg peak) near the end of range with a sharp fall-off at the distal edge. Taking full advantage of the well-defined range and the small lateral beam spread, modern scanning beam systems allow delivery of the dose with millimeter precision. In addition, projectiles heavier than protons such as carbon ions exhibit an enhanced biological effectiveness in the Bragg peak region caused by the dense ionization of individual particle tracks resulting in reduced cellular repair. This makes them particularly attractive for the treatment of radio-resistant tumors localized near organs at risk. While tumor therapy with protons is a well-established treatment modality with more than 60 000 patients treated worldwide, the application of heavy ions is so far restricted to a few facilities only. Nevertheless, results of clinical phase I-II trials provide evidence that carbon-ion radiotherapy might be beneficial in several tumor entities. This article reviews the progress in heavy-ion therapy, including physical and technical developments, radiobiological studiesmore » and models, as well as radiooncological studies. As a result of the promising clinical results obtained with carbon-ion beams in the past ten years at the Heavy Ion Medical Accelerator facility (Japan) and in a pilot project at GSI Darmstadt (Germany), the plans for new clinical centers for heavy-ion or combined proton and heavy-ion therapy have recently received a substantial boost.« less

Heavy-ion tumor therapy: Physical and radiobiological benefits

Radiotherapy is one of the most common and effective therapies for cancer. Generally, patients are treated with X-rays produced by electron accelerators. Many years ago, researchers proposed that high-energy charged particles could be used for this purpose, owing to their physical and radiobiological advantages compared with X-rays. Particle therapy is an emerging technique in radiotherapy. Protons and carbon ions have been used for treating many different solid cancers, and several new centers with large accelerators are under construction. Debate continues on the cost:benefit ratio of this technique, that is, on whether the high costs of accelerators and beam delivery in particle therapy are justified by a clear clinical advantage. This Review considers the present clinical results in the field, and identifies and discusses the research questions that have resulted with this technique.

Charged particles in radiation oncology

The effect of ionising radiation is influenced by the dose, the dose rate, and the quality of the radiation. Before 1990, dose-equivalent quantities were defined in terms of a quality factor, Q(L), that was applied to the absorbed dose at a point in order to take into account the differences in the effects of different types of radiation. In its 1990 recommendations, the ICRP introduced a modified concept. For radiological protection purposes, the absorbed dose is averaged over an organ or tissue, T, and this absorbed dose average is weighted for the radiation quality in terms of the radiation weighting factor, wR, for the type and energy of radiation incident on the body. The resulting weighted dose is designated as the organ- or tissue-equivalent dose, HT. The sum of the organ-equivalent doses weighted by the ICRP organ-weighting factors, wT, is termed the effective dose, E. Measurements can be performed in terms of the operational quantities, ambient dose equivalent, and personal dose equivalent. These quantities continue to be defined in terms of the absorbed dose at the reference point weighted by Q(L). The values for wR and Q(L) in the 1990 recommendations were based on a review of the biological and other information available, but the underlying relative biological effectiveness (RBE) values and the choice of wR values were not elaborated in detail. Since 1990, there have been substantial developments in biological and dosimetric knowledge that justify a re-appraisal of wR values and how they may be derived. This re-appraisal is the principal objective of the present report. The report discusses in some detail the values of RBE with regard to stochastic effects, which are central to the selection of wR and Q(L). Those factors and the dose-equivalent quantities are restricted to the dose range of interest to radiation protection, i.e. to the general magnitude of the dose limits. In special circumstances where one deals with higher doses that can cause deterministic effects, the relevant RBE values are applied to obtain a weighted dose. The question of RBE values for deterministic effects and how they should be used is also treated in the report, but it is an issue that will demand further investigations. This report is one of a set of documents being developed by ICRP Committees in order to advise the ICRP on the formulation of its next Recommendations for Radiological Protection. Thus, while the report suggests some future modifications, the wR values given in the 1990 recommendations are still valid at this time. The report provides a scientific background and suggests how the ICRP might proceed with the derivation of wR values ahead of its forthcoming recommendations.

https://journals.sagepub.com/doi/pdf/10.1016/S0146-6453%2803%2900024-1

Relative biological effectiveness(RBE), quality factor(Q), and radiation weighting factor(WR)

Purpose: The LET position of the RBE maximum and its dependence on the cellular repair capacity was determined for carbon ions. Hamster celllines of differing repair capacity were irradiated with monoenergetic carbon ions. RBE values for cell inactivation at different survival levels were determined and the differences in the RBE-LET patterns were compared with the individual sensitivity to photon irradiation of the different cell lines. Material and methods: Three hamster cell lines, the wild-type cell lines V79 and CHO-K1 and the radiosensitive CHO mutant xrs5, were irradiated with carbon ions of different energies (2.4-266.4MeV/u) and LET values (13.7-482.7keV/mum) and inactivation data were measured in comparison to 250kV x-rays. Results: For the repair-proficient cell lines a RBE maximum was found at LET values between 150 and 200keV/mum. For the repair-deficient cell line the RBE failed to show a maximum and decreased continuously for LET values above 100keV/mum. Conclusions: The carbon RBE-LET rela...

RBE for carbon track-segment irradiation in cell lines of differing repair capacity

Heavy-ion radiobiology is attracting increasing interest for its implications in radiation oncology and space radiation protection. The analysis of chromosome aberrations induced by heavy-ions started already in the 1960s, but the new FISH-painting methodologies are revealing unique features of the action of the heavy charged particles. Heavy-ions induce a high fraction of complex-type exchanges, and possibly unique chromosome rearrangements. The relative biological effectiveness for the induction of cytogenetic damage is strongly dependent on the time between irradiation and chromosome harvest, due to cell-cycle delays and loss of heavily damaged cells. In this review we will concentrate on recent data obtained with multicolor FISH methods in mammalian chromosomes exposed to heavy-ions, and the open questions that remain to be addressed.

Heavy-ion induced chromosomal aberrations: A review

human lymphocytes, heavy ions, time-course of aberrations, calyculin A, apoptosis The time-course of Fe-ion (200 MeV/u, 440 keV/µm) and X-ray induced chromosomal damage was investigated in human lymphocytes. After cells were exposed in G0 and stimulated to grow, aberrations were measured in first-cycle metaphases harvested 48, 60 and 72h post-irradiation. Additionally, lesions were analysed in G2 and mitotic (M) cells collected at 48h using calyculin A-induced premature chromosome condensation (PCC). Following X-irradiation, similar aberration yields were found in all of the samples scored. In contrast, after Fe-ion exposure a drastic increase in the aberration frequency with sampling time was observed, i.e. cells arriving late at the first mitosis carried more aberrations than those arriving at earlier times. The PCC data indicate that the delayed entry of heavily damaged cells into mitosis observed after Fe-ion irradiation resulted from a prolonged arrest in G2. Altogether these experiments provide further evidence that in the case of high-LET exposure cell-cycle delays of severely damaged cells have to be taken into account for any meaningful quantification of chromosomal damage and, consequently, for an accurate estimate of the RBE.

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Relationship between aberration yield and mitotic delay in human lymphocytes exposed to 200 MeV/u Fe-ions or X-rays.

Fournier, C., Barberet, P., Pouthier, T., Ritter, S., Fischer, B., Voss, K. O., Funayama, T., Hamada, N., Kobayashi, Y. and Taucher-Scholz, G. No Evidence for DNA and Early Cytogenetic Damage in Bystander Cells after Heavy-Ion Microirradiation at Two Facilities. Radiat. Res. 171, 530–540 (2009). The occurrence of bystander effects has challenged the evaluation of risk for heavy ions, mainly in the context of space exploration and the increasing application of carbon ions in radiotherapy. In the present study, we addressed whether heavy-ion-induced DNA and cytogenetic damage is detectable in bystander cells. The formation of γ-H2AX foci, sister chromatid exchanges and micronuclei were used as markers of damage to DNA. Normal human fibroblasts were exposed to low fluences of carbon and uranium ions, and alternatively single cells were targeted with heavy ions using the GSI microbeam. We did not observe a significant increase in the bystander formation of γ-H2AX foci, sister chromatid exchanges or m...

No Evidence for DNA and Early Cytogenetic Damage in Bystander Cells after Heavy-Ion Microirradiation at Two Facilities

Purpose: To examine the relationship between cell proliferation and the expression of chromosomal damage in normal human skin fibroblasts after X‐ray and particle irradiation.Materials and methods: Confluent G0/G1 AG1522B cells were exposed to X‐rays or 195 MeV u−1 C ions with a linear energy transfer of 16.6 keV µm−1 in the dose range 1–4 Gy. Directly after irradiation, cells were reseeded at a low density in medium containing 5‐bromo‐2′‐deoxyuridine. At multiple time points post‐irradiation, the cumulative BrdU‐labelling index, mitotic index and aberration frequency were measured. Based on these data, the total amount of damage induced within the entire cell population was estimated by means of mathematical analysis.Results: Both types of radiation exposure exert a pronounced effect on the cell cycle progression of fibroblasts. They result in delayed entry of cells into S‐phase and into the first mitosis, and cause a dramatic reduction in mitotic activity. Measurement of chromosomal damage in first‐cycl...

Sylvia Ritter

Papers

RBE for carbon track-segment irradiation in cell lines of differing repair capacity

Heavy-ion induced chromosomal aberrations: A review

Relationship between aberration yield and mitotic delay in human lymphocytes exposed to 200 MeV/u Fe-ions or X-rays.

No Evidence for DNA and Early Cytogenetic Damage in Bystander Cells after Heavy-Ion Microirradiation at Two Facilities

Cell cycle arrest and aberration yield in normal human fibroblasts. I. Effects of X-rays and 195 MeV u(-1) C ions.