The innovative 52g Mn for positron emission tomography (PET) imaging: Production cross section modeling and dosimetric evaluation.

BACKGROUND: Manganese is a paramagnetic element suitable for magnetic resonance imaging (MRI) of neuronal function. However, high concentrations of Mn2 + can be neurotoxic. 52g Mn may be a valid alternative as positron emission tomography (PET) imaging agent, to obtain information similar to that delivered by MRI but using trace levels of Mn2 + , thus reducing its toxicity. Recently, the reaction n a t $^{nat}$ V(α,x)52g Mn has been proposed as a possible alternative to the standard n a t $^{nat}$ Cr(p,x)52g Mn one, but improvements in the modeling were needed to better compare the two production routes. PURPOSE: This work focuses on the development of precise simulations and models to compare the 52g Mn production from both reactions in terms of amount of activity and radionuclidic purity (RNP), as well as in terms of dose increase (DI) due to the co-produced radioactive contaminants, versus pure 52g MnCl2 . METHODS: The nuclear code Talys has been employed to optimize the n a t $^{nat}$ V(α,x)52g Mn cross section by tuning the parameters of the microscopic level densities. Thick-target yields have been calculated from the expression of the rates as energy convolution of cross sections and stopping powers, and finally integrating the time evolution of the relevant decay chains. Dosimetric assessments of [ x x $^{xx}$ Mn]Cl2 have been accomplished with OLINDA software 2.2.0 using female and male adult phantoms and biodistribution data for 52g MnCl2 in normal mice. At the end, the yield of x x $^{xx}$ Mn radioisotopes estimated for the two production routes have been combined with the dosimetric results, to assess the DI at different times after the end of the irradiation. RESULTS: Good agreement was obtained between cross-section calculations and measurements. The comparison of the two reaction channels suggests that n a t $^{nat}$ V(α,x)52g Mn leads to higher yield and higher purity, resulting in more favorable radiation dosimetry for patients. CONCLUSIONS: Both n a t $^{nat}$ V(α,x) and n a t $^{nat}$ Cr(p,x) production routes provide clinically acceptable 52g MnCl2 for PET imaging. However, the n a t $^{nat}$ V(α,x)52g Mn reaction provides a DI systematically lower than the one obtainable with n a t $^{nat}$ Cr(p,x)52g Mn and a longer time window in which it can be used clinically (RNP ≥ 99%).

PREDICTING BIOLOGICAL EFFECTS ALONG HADRONTHERAPY DOSE PROFILES BY THE BIANCA BIOPHYSICAL MODEL.

The BIANCA biophysical model of cell death and chromosome aberrations was further refined and applied to predict the biological effectiveness along Spread-Out Bragg Peaks used in hadrontherapy. The simulation outcomes were compared with in vitro survival data on protons, He-ions and C-ions over a wide LET range, and the particle- and LET-dependence of the DNA Cluster Lesions (CLs) yields used as input parameters was investigated. For each particle type, the CL yield was found to increase with LET in a linear-quadratic fashion; fitting the CL yields allowed to predict cell death and chromosome aberrations in principle at any depth along a longitudinal proton dose profile used at CNAO. A clear increase in effectiveness was found in the SOBP distal region, supporting the idea that, in some cases, the constant proton RBE usually applied in clinics may be a sub-optimal solution.

Proximity effects in chromosome aberration induction: Dependence on radiation quality, cell type and dose.

It is widely accepted that, in chromosome-aberration induction, the (mis-)rejoining probability of two chromosome fragments depends on their initial distance, r. However, several aspects of these "proximity effects" need to be clarified, also considering that they can vary with radiation quality, cell type and dose. A previous work performed by the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model has suggested that, in human lymphocytes and fibroblasts exposed to low-LET radiation, an exponential function of the form exp(-r/r0), which is consistent with free-end (confined) diffusion, describes proximity effects better than a Gaussian function. Herein, the investigation was extended to intermediate- and high-LET. Since the r0 values (0.8 µm for lymphocytes and 0.7 µm for fibroblasts) were taken from the low-LET study, the results were obtained by adjusting only one model parameter, i.e. the yield of "Cluster Lesions" (CLs), where a CL was defined as a critical DNA damage producing two independent chromosome fragments. In lymphocytes, the exponential model allowed reproducing both dose-response curves for different aberrations (dicentrics, centric rings and excess acentrics), and values of F-ratio (dicentrics to centric rings) and G-ratio (interstitial deletions to centric rings). In fibroblasts, a good correspondence was found with the dose-response curves, whereas the G-ratio (and, to a lesser extent, the F-ratio) was underestimated. With increasing LET, F decreased and G increased in both cell types, supporting their role as "fingerprints" of high-LET exposure. A dose-dependence was also found at high LET, where F increased with dose and G decreased, possibly due to inter-track effects. We therefore conclude that, independent of radiation quality, in lymphocytes an exponential function can describe proximity effects at both inter- and intra-chromosomal level; on the contrary, in fibroblasts further studies (experimental and theoretical) are needed to explain the strong bias for intra-arm relative to inter-arm exchanges.

BIANCA, a biophysical model of cell survival and chromosome damage by protons, C-ions and He-ions at energies and doses used in hadrontherapy.

An upgraded version of the BIANCA II biophysical model, which describes more realistically interphase chromosome organization and the link between chromosome aberrations and cell death, was applied to V79 and AG01522 cells exposed to protons, C-ions and He-ions over a wide LET interval (0.6-502 keV µm-1), as well as proton-irradiated U87 cells. The model assumes that (i) ionizing radiation induces DNA 'cluster lesions' (CLs), where by definition each CL produces two independent chromosome fragments; (ii) fragment (distance-dependent) mis-rejoining, or un-rejoining, produces chromosome aberrations; (iii) some aberrations lead to cell death. The CL yield, which mainly depends on radiation quality but is also modulated by the target cell, is an adjustable parameter. The fragment un-rejoining probability, f, is the second, and last, parameter. The value of f, which is assumed to depend on the cell type but not on radiation quality, was taken from previous studies, and only the CL yield was adjusted in the present work. Good agreement between simulations and experimental data was obtained, suggesting that BIANCA II is suitable for calculating the biological effectiveness of hadrontherapy beams. For both V79 and AG01522 cells, the mean number of CLs per micrometer was found to increase with LET in a linear-quadratic fashion before the over-killing region, where a less rapid increase, with a tendency to saturation, was observed. Although the over-killing region deserves further investigation, the possibility of fitting the CL yields is an important feature for hadrontherapy, because it allows performing predictions also at LET values where experimental data are not available. Finally, an approach was proposed to predict the ion-response of the cell line(s) of interest from the ion-response of a reference cell line and the photon response of both. A pilot study on proton-irradiated AG01522 and U87 cells, taking V79 cells as a reference, showed encouraging results.

Proximity effects in chromosome aberration induction by low-LET ionizing radiation.

Although chromosome aberrations are known to derive from distance-dependent mis-rejoining of chromosome fragments, evaluating whether a certain model describes such "proximity effects" better than another one is complicated by the fact that different approaches have often been tested under different conditions. Herein, a biophysical model ("BIANCA", i.e. BIophysical ANalysis of Cell death and chromosome Aberrations) was upgraded, implementing explicit chromosome-arm domains and two new models for the dependence of the rejoining probability on the fragment initial distance, r. Such probability was described either by an exponential function like exp(-r/r0), or by a Gaussian function like exp(-r2/2σ2), where r0 and σ were adjustable parameters. The second, and last, parameters was the yield of "Cluster Lesions" (CL), where "Cluster Lesion" defines a critical DNA damage producing two independent chromosome fragments. The model was applied to low-LET-irradiated lymphocytes (doses: 1-4Gy) and fibroblasts (1-6.1Gy). Good agreement with experimental yields of dicentrics and centric rings, and thus their ratio ("F-ratio"), was found by both the exponential model (with r0=0.8µm for lymphocytes and 0.7µm for fibroblasts) and the Gaussian model (with σ=1.1µm for lymphocytes and 1.3µm for fibroblasts). While the former also allowed reproducing dose-responses for excess acentric fragments, the latter substantially underestimated the experimental curves. Both models provided G-ratios (ratio of acentric to centric rings) higher than those expected from randomness, although the values calculated by the Gaussian model were lower than those calculated by the exponential one. For lymphocytes the calculated G-ratios were in good agreement with the experimental ones, whereas for fibroblasts both models substantially underestimated the experimental results, which deserves further investigation. This work suggested that, although both models performed better than a step model (which previously allowed reproducing the F-ratio but underestimated the G-ratio), an exponential function describes proximity effects better than a Gaussian one.

Calculating Variations in Biological Effectiveness for a 62 MeV Proton Beam.

A biophysical model of radiation-induced cell death and chromosome aberrations [called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA)] was further developed and applied to therapeutic protons. The model assumes a pivotal role of DNA cluster damage, which can lead to clonogenic cell death following three main steps: (i) a DNA "cluster lesion" (CL) produces two independent chromosome fragments; (ii) fragment mis-rejoining within a threshold distance d gives rise to chromosome aberrations; (iii) certain aberration types (dicentrics, rings, and large deletions) lead to clonogenic inactivation. The yield of CLs and the probability, f, that a chromosome fragment remains un-rejoined even if other fragment(s) are present within d, were adjustable parameters. The model, implemented as a MC code providing simulated dose-responses directly comparable with experimental data, was applied to pristine and modulated Bragg peaks of the proton beam used to treat eye melanoma at INFN-LNS in Catania, Italy. Experimental survival curves for AG01522 cells exposed to the Catania beam were reproduced, supporting the model assumptions. Furthermore, cell death and chromosome aberrations at different depths along a spread-out Bragg peak (SOBP) dose profile were predicted. Both endpoints showed an increase along the plateau, and high levels of damage were found also beyond the distal dose fall-off, due to low-energy protons. Cell death and chromosome aberrations were also predicted for V79 cells, in the same irradiation scenario as that used for AG01522 cells. In line with other studies, this work indicated that assuming a constant relative biological effectiveness (RBE) along a proton SOBP may be sub-optimal. Furthermore, it provided qualitative and quantitative evaluations of the dependence of the beam effectiveness on the considered endpoint and dose. More generally, this work represents an example of therapeutic beam characterization avoiding the use of experimental RBE values, which can be source of uncertainties.