Microdosimetry of a 62-MeV clinical proton beam with five detectors.

In proton therapy, most treatment planning systems (TPS) use a fixed relative biological effectiveness (RBE) of 1.1 all along the depth-dose profile. Innovative TPS are now investigated considering the variability of RBE with radiation quality. New TPS need an experimental verification in the quality assurance (QA) routine in clinics, but RBE data are usually obtained with radiobiological measurements that are time consuming and not suitable for daily QA. Microdosimetry is a useful tool based on physical measurements which can monitor the radiation quality. Several microdosimeters are available in different research institutions, which could potentially be used for the QA in TPS. In this study, the response functions of five detectors in the same 62-MeV proton Spread Out Bragg Peak is compared in terms of spectral distributions and their average values and microdosimetric RBE. Their different response function has been commented and must be considered in the clinical practice.

Microdosimetric analysis of the radiation quality of two different proton beams in the distal edge of the depth-dose profile.

Proton-therapy exploits the advantageous depth-dose profile of protons to induce the highest damage to tumoral cells in the last millimetres of their range in sharp Bragg Peak. To cover the whole tumoral volume, beams of different energies are combined to create the Spread Out Bragg Peak (SOBP). In passive modulated beams, the energy spread is created with modulators in which the highest energy beam is degraded through different thicknesses of calibrated plastic materials. The highest energy is chosen depending on the deepest point that needs to be treated. This study aims to investigate differences in the radiation quality in the distal edge of SOBP beams with different initial energy and modulation techniques based on microdosimetric measurements with mini Tissue-Equivalent Proportional Counters. The beams investigated are the 62 MeV proton SOBP of the clinical facility of CATANA and the 148 MeV proton SOBP of the research beam line of the proton-therapy centre of Trento.

Interaction of therapeutic12C ions with bone-like targets: physical characterization and dosimetric effect at material interfaces.

Carbon therapy is a promising treatment option for cancer. The physical and biological properties of carbon ions can theoretically allow for the delivery of curative doses to the tumor, while simultaneously limiting risks of toxicity to adjacent healthy structures. The treatment effectiveness can be further improved by decreasing the uncertainties stemming from several sources, including the modeling of tissue heterogeneity. Current treatment plans employ density-based conversion methods to translate patient-specific anatomy into a water system, where dose distribution is calculated. This approach neglects differences in nuclear interactions stemming from the elemental composition of each tissue. In this work, we investigated the interaction of therapeutic carbon ions with bone-like materials. The study concentrated on nuclear interactions and included attenuation curves of 200 and 400 AMeV beams in different types of bones, as well as kinetic energy spectra of all charged fragments produced up to 29 degrees from the beam direction. The comparison between measurements and calculations of the treatment planning system TRiP98 indicated that bone tissue causes less fragmentation of carbon ions than water. Overall, hydrogen and helium particles were found to be the most abundant species, while heavier fragments were mostly detected within 5 degrees from the beam direction. We also investigated how the presence of a soft tissue-bone interface could affect the depth-dose profile. The results revealed a dose spike in the transition region, that extended from the entry channel to the target volume. The findings of this work indicated that the tissue-to-water conversion method based only on density considerations can result in dose inaccuracies. Tissue heterogeneity regions containing bones can potentially produce dose spikes, whose magnitude will depend on the patient anatomy. Dose uncertainties can be decreased by modeling nuclear interactions directly in bones, without applying the tissue-to-water conversion.

Generalized stochastic microdosimetric model: The main formulation.

The present work introduces a rigorous stochastic model, called the generalized stochastic microdosimetric model (GSM^{2}), to describe biological damage induced by ionizing radiation. Starting from the microdosimetric spectra of energy deposition in tissue, we derive a master equation describing the time evolution of the probability density function of lethal and potentially lethal DNA damage induced by a given radiation to a cell nucleus. The resulting probability distribution is not required to satisfy any a priori conditions. After the initial assumption of instantaneous irradiation, we generalized the master equation to consider damage induced by a continuous dose delivery. In addition, spatial features and damage movement inside the nucleus have been taken into account. In doing so, we provide a general mathematical setting to fully describe the spatiotemporal damage formation and evolution in a cell nucleus. Finally, we provide numerical solutions of the master equation exploiting Monte Carlo simulations to validate the accuracy of GSM^{2}. Development of GSM^{2} can lead to improved modeling of radiation damage to both tumor and normal tissues, and thereby impact treatment regimens for better tumor control and reduced normal tissue toxicities.

Microdosimetric measurements as a tool to assess potential in-field and out-of-field toxicity regions in proton therapy.

Relative biological effectiveness (RBE) variations are thought to be one of the primary causes of unexpected normal-tissue toxicities during tumor treatments with charged particles. Unlike carbon therapy, where treatment planning is optimized on the basis of the RBE-weighted dose, a constant RBE value of 1.1 is currently used in proton therapy. Assuming a uniform value can lead to under- or over-dosage, not just to the tumor but also to surrounding normal tissue. RBE changes have been linked with dose/fraction, the biological endpoint and beam properties. Understanding radiation quality and the associated RBE can improve the prediction of normal-tissue toxicities. In this study, we exploited microdosimetry for characterizing radiation quality in proton therapy in-field, and off-beam at 20 (beam edge), 50 (close out-of-field) and 100 (far out-of-field) mm from the beam center. We measured the lineal energy y spectra in a water phantom irradiated with 152 MeV protons, from which beam quality as well as the physical dose could be obtained. Taking advantage of the linear quadratic model and a modified version of the microdosimetric kinetic model, the microdosimetric data were combined with radiobiological parameters (α and ß) of human salivary gland tumor cells for assessing cell survival RBE and RBE-weighted dose. The results indicate that if a dose of 60 Gy is delivered to the peak, the beam edge receives up to 6 Gy while the close and far out-of-field regions receive doses on the order of 10-3 Gy and 10-4 Gy, respectively. The RBE estimate in-beam shows large variations, ranging from 1.0 ± 0.2 at the entrance channel to 2.51 ± 0.15 at the tail. The beam edge follows a similar trend but the RBE calculated at the Bragg peak depth is 2.27 ± 0.17, i.e. twice the RBE in-beam (1.05 ± 0.15). Out-of-field, the estimated RBE is always significantly higher than 1.1 and increases with increasing lateral distance, reaching the overall highest value of 3.4 ± 0.3 at a depth of 206 mm and a lateral distance of 10 mm. The combination of RBE and dose into the biological dose points to the beam edge and the end-of-range in-beam as the areas with the highest risk of potential toxicities.

STUDY FOR A PASSIVE SCATTERING LINE DEDICATED TO RADIOBIOLOGY EXPERIMENTS AT THE TRENTO PROTON THERAPY CENTER.

The recent worldwide spread of Proton Therapy centers paves the way to new opportunities for basic and applied research related to the use of accelerated proton beams. Clinical centers make use of proton beam energies up to about 230 MeV. This represents an interesting energy range for a large spectrum of applications, including detector testing, radiation shielding and space research. Additionally, radiobiology research might benefit for a larger availability of proton beams, especially in those centers where a room dedicated to research activities also exists. Here, we describe the initial activities for the setup of a radiobiology irradiation facility at the Trento Proton Therapy Center. Data referring to the characterization of the beam in air are essential to that purpose and will be presented. A basic setup for large field irradiation will be also proposed, which is needed for the majority of in vitro and in vivo radiobiology experiments.

Fragmentation of 120 and 200 MeV u-14He ions in water and PMMA targets.

Recently, the use of 4He particles in cancer radiotherapy has been reconsidered as they potentially represent a good compromise between protons and 12C ions. The first step to achieve this goal is the development of a dedicated treatment planning system, for which basic physics information such as the characterization of the beam lateral scattering and fragmentation cross sections are required. In the present work, the attenuation of 4He primary particles and the build-up of secondary charged fragments at various depths in water and polymethyl methacrylate were investigated experimentally for 120 and 200 MeV u-1 beams delivered by the synchrotron at the Heidelberg Ion-Beam Therapy Center, Heidelberg. Species and isotope identification was accomplished combining energy loss and time-of-flight measurements. Differential yields and energy spectra of all fragments types were recorded between 0° and 20° with respect to the primary beam direction.

Absolute prompt-gamma yield measurements for ion beam therapy monitoring.

Prompt-gamma emission detection is a promising technique for hadrontherapy monitoring purposes. In this regard, obtaining prompt-gamma yields that can be used to develop monitoring systems based on this principle is of utmost importance since any camera design must cope with the available signal. Herein, a comprehensive study of the data from ten single-slit experiments is presented, five consisting in the irradiation of either PMMA or water targets with lower and higher energy carbon ions, and another five experiments using PMMA targets and proton beams. Analysis techniques such as background subtraction methods, geometrical normalization, and systematic uncertainty estimation were applied to the data in order to obtain absolute prompt-gamma yields in units of prompt-gamma counts per incident ion, unit of field of view, and unit of solid angle. At the entrance of a PMMA target, where the contribution of secondary nuclear reactions is negligible, prompt-gamma counts per incident ion, per millimetre and per steradian equal to (124 ± 0.7stat ± 30sys) × 10(-6) for 95 MeV u(-1) carbon ions, (79 ± 2stat ± 23sys) × 10(-6) for 310 MeV u(-1) carbon ions, and (16 ± 0.07stat ± 1sys) × 10(-6) for 160 MeV protons were found for prompt gammas with energies higher than 1 MeV. This shows a factor 5 between the yields of two different ions species with the same range in water (160 MeV protons and 310 MeV u(-1) carbon ions). The target composition was also found to influence the prompt-gamma yield since, for 300/310 MeV u(-1) carbon ions, a 42% greater yield ((112 ± 1stat ± 22sys) × 10(-6) counts ion(-1) mm(-1) sr(-1)) was obtained with a water target compared to a PMMA one.

Complicated diverticulitis in kidney transplanted patients: analysis of 717 cases.

INTRODUCTION: This study aims to investigate possible risk factors for diverticulitis in kidney transplant recipients affected by colonic diverticulosis. METHODS AND RESULTS: We investigated 717 patients transplanted between 2000 and 2010. Diverticular disease was endoscopically diagnosed in 17 of 717 examined patients. Eight patients were diagnosed with autosomal dominant polycystic kidney disease (ADPKD); 9 of 17 patients underwent emergency surgery. We performed Hartmann's procedure on all patients, with a second stage performed at least 6 months later. DISCUSSION: Although the incidence of colonic diverticular perforation in kidney transplanted patients is similar to that observed in the general population, perforation in immunosuppressed patients is associated with a higher morbidity/mortality rate. In our study, the incidence of perforation is 1.25% (9 of 717), with almost half of the cases observed in patients with ADPKD (4 of 9). Such an observation is consistent with published data, in which patients with ADPKD are reported to more frequently develop colonic diverticulosis and its complications. One possible explanation might be related to a belated diagnosis of diverticulitis, which could initially simulate an inflammatory disease as a consequence of renal cysts. Also, steroids seem to be a predisposing factor for colonic perforation in these patients. CONCLUSIONS: A timely surgery can significantly reduce mortality. In cases of elective surgery, mortality and morbidity are similar to those of immunocompetent patients; accordingly, this is the goal to be pursued. Early signs and symptoms are often masked by immunosuppressive therapy. In these patients, surgeons should always perform (1) abdominal computed tomography scanning and, in the presence of diverticulitis, reduce or withdraw immunosuppressive therapy; and (2) early surgery, with Hartmann's procedure being, in our opinion, the best choice. Before transplantation, elective surgery for colonic resection should be considered in patients with ADPKD or with a history of 1 or more episodes of acute diverticulitis who then regressed with medical therapy.

Measurement of charged particle yields from PMMA irradiated by a 220 MeV/u (12)C beam.

The radiation used in hadrontherapy treatments interacts with the patient body producing secondary particles, either neutral or charged, that can be used for dose and Bragg peak monitoring and to provide a fast feedback on the treatment plans. Recent results obtained from the authors on simplified setups (mono-energetic primary beams interacting with homogeneous tissue-like target) have already indicated the correlation that exists between the flux of these secondaries coming from the target (e.g. protons and photons) and the position of the primary beam Bragg peak. In this paper, the measurements of charged particle fluxes produced by the interaction of a 220 MeV/u carbon ion beam at GSI, Darmstadt, with a polymethyl methacrylate target are reported. The emission region of protons (p), deuterons (d) and tritons (t) has been characterized using a drift chamber while the particle time-of-flight, used to compute the kinetic energy spectra, was measured with a LYSO scintillator. The energy released in the LYSO crystal was used for particle identification purposes. The measurements were repeated with the setup at 60° and 90° with respect to the primary beam direction. The accuracy on the fragments emission profile reconstruction and its relationship with the Bragg peak position have been studied. Based on the acquired experimental evidence, a method to monitor the dose profile and the position of the Bragg peak inside the target is proposed.

Out-of-field dose measurements in a water phantom using different radiotherapy modalities.

This investigation focused on the characterization of the lateral dose fall-off following the irradiation of the target with photons, protons and carbon ions. A water phantom was irradiated with a rectangular field using photons, passively delivered protons as well as scanned protons and carbon ions. The lateral dose profile in the depth of the maximum dose was measured using an ion chamber, a diamond detector and thermoluminescence detectors TLD-600 and TLD-700. The yield of thermal neutrons was estimated for all radiation types while their complete spectrum was measured with bubble detectors during the irradiation with photons. The peripheral dose delivered by photons is significantly higher compared to both protons and carbon ions and exceeds the latter by up to two orders of magnitude at distances greater than 50 mm from the field. The comparison of passive and active delivery techniques for protons shows that, for the chosen rectangular target shape, the former has a sharper penumbra whereas the latter has a lower dose in the far-out-of-field region. When comparing scanning treatments, carbon ions present a sharper dose fall-off than protons close to the target but increasing peripheral dose with increasing incident energy. For photon irradiation, the contribution to the out-of-field dose of photoneutrons appears to be of the same order of magnitude as the scattered primary beam. Charged particles show a clear supremacy over x-rays in achieving a higher dose conformality around the target and in sparing the healthy tissue from unnecessary radiation exposure. The out-of-field dose for x-rays increases with increasing beam energy because of the production of biologically harmful neutrons.

Heavy-ion anisotropy measured by ALTEA in the International Space Station.

The uneven shielding of the International Space Station from the vessel hull, racks and experiments produces a modulation of the internal radiation environment. A detailed knowledge of this environment, and therefore of the Station's shielding effectiveness, is mandatory for an accurate assessment of radiation risk. We present here the first 3D measurements of the Station's radiation environment, discriminating particle trajectories and LET, made possible using the detection capability of the ALTEA-space detector. We provide evidence for a strong (factor ≈ 3) anisotropy in the inner integral LET for high-LET particles (LET > 50 keV/µm) showing a minimum along the longitudinal station axis (most shielded) and a maximum normal to it. Integrating over all measured LETs, the anisotropy is strongly reduced, showing that unstopped light ions plus the fragments produced by heavier ions approximately maintain flux/LET isotropy. This suggests that, while changing the quality of radiation, the extra shielding along the station main axis is not producing a benefit in terms of total LET. These features should be taken into account (1) when measuring radiation with detectors that cannot distinguish the direction of the impinging radiation or that are unidirectional, (2) when planning radiation biology experiments on the ISS, and (3) when simulating the space radiation environment for experiments on the ground. A novel analysis technique that fully exploits the ability to retrieve the angular distribution of the radiation is also presented as well as the angular particle flux and LET characteristic of three geomagnetic zones measured during 2009 by the ALTEA-space detector. This technique is applied to the ALTEA-space detector, but a wider applicability to other detectors is suggested.

Wound complications after kidney transplantation in nondiabetic patients.

INTRODUCTION: Impaired wound healing represents a common operative complication after kidney transplantation. This problem seems to be affected by factors related to surgical technique, drugs, and patient/graft peculiarities. PATIENTS AND METHODS: From January 2000 to December 2007, 350 consecutive kidney transplantations were performed in a population of nondiabetic patients. We evaluated the influence of various factors on impaired wound healing. RESULTS: Among 350 kidney transplantation patients, we observed 54 cases (15.43%) of impaired healing of the surgical incision: 36 (10.29%) with first level and 18 (5.14%) with second level wound complications. Factors related to complications were overweight and delayed graft function. Cyclosporine and tacrolimus had similar effects. However, all patients developing second level complications showed more risk factors. In our experience, postoperative lymphocele did not occur as an unique factor but became a significant risk factor when associated with another one. Patients who did not have reconstruction of the muscle layers showed a greater incidence of incisional complications. CONCLUSION: Impaired healing of the surgical incision more or less seriously influenced outcomes of transplanted patients. This complication was common and usually related to the presence of more than one risk factor.

The finding of vascular and urinary anomalies in the harvested kidney for transplantation.

INTRODUCTION: In kidney transplantation, anatomical vascular and excretory anomalies may represent causes of failure. Today's surgical techniques have made the most of the organs with anatomic anomalies and iatrogenic injury successfully used for transplantation. MATERIALS AND METHODS: From January 2000 to June 2006, we harvested 230 kidneys, of including 88 kidneys (20%) with vascular, urinary, or vascular-urinary anomalies; 64 kidneys were implanted and 15 were sent to other transplantation centers. Only 9 kidneys were not appropriate for transplantation. RESULTS: All patients who received kidneys with the above-mentioned anomalies were carefully examined after the transplantation and short-term and long-term complications were evaluated with respect to controls without anomalies. DISCUSSION: Renal anatomic anomalies are frequently observed during kidney transplantation and may produce postsurgical complications. However, the presence of these anomalies does not necessarily imply the impossibility of using the kidney for a transplant, especially because of improved surgical techniques. Our experience in transplantation procedures showed that even if kidneys present the above-mentioned anomalies they can still be considered appropriate for transplantation when we perform a correct harvesting/back-table transplant surgery. So vascular and urinary anomalies have to be considered always an incentive to research new surgical solutions and to perform a careful surgical technique.

Cytogenetic effects of high-energy iron ions: dependence on shielding thickness and material.

We report results for chromosomal aberrations in human peripheral blood lymphocytes after they were exposed to high-energy iron ions with or without shielding at the HIMAC, AGS and NSRL accelerators. Isolated lymphocytes were exposed to iron ions with energies between 200 and 5000 MeV/nucleon in the 0.1-1-Gy dose range. Shielding materials consisted of polyethylene, lucite (PMMA), carbon, aluminum and lead, with mass thickness ranging from 2 to 30 g/cm2. After exposure, lymphocytes were stimulated to grow in vitro, and chromosomes were prematurely condensed using a phosphatase inhibitor (calyculin A). Aberrations were scored using FISH painting. The yield of total interchromosomal exchanges (including dicentrics, translocations and complex rearrangements) increased linearly with dose or fluence in the range studied. Shielding decreased the effectiveness per unit dose of iron ions. The highest RBE value was measured with the 1 GeV/nucleon iron-ion beam at NSRL. However, the RBE for the induction of aberrations apparently is not well correlated with the mean LET. When shielding thickness was increased, the frequency of aberrations per particle incident on the shield increased for the 500 MeV/nucleon ions and decreased for the 1 GeV/nucleon ions. Maximum variation at equal mass thickness was obtained with light materials (polyethylene, carbon or PMMA). Variations in the yield of chromosomal aberrations per iron particle incident on the shield follow variations in the dose per incident particle behind the shield but can be modified by the different RBE of the mixed radiation field produced by nuclear fragmentation. The results suggest that shielding design models should be benchmarked using both physics and biological data.

Fragmentation of 1 GeV/nucleon iron ions in thick targets relevant for space exploration.

We have measured charged nuclear fragments produced by 1 GeV/nucleon 56Fe ions interacting with aluminium, polyethylene and lead. These materials are relevant for assessment of radiation risk for manned space flight. The data will be presented in a form suitable for comparison with models of nuclear fragmentation and transport, including linear energy transfer (LET) spectrum, fluence for iron and fragments, event-tack- and event-dose-averaged LET, total dose and iron contribution to dose.