In-vivo dose determination in a human after radon exposure: proof of principle.

Radon-222 is pervasive in our environment and the second leading cause of lung cancer induction after smoking while it is simultaneously used to mediate anti-inflammatory effects. During exposure, radon gas distributes inhomogeneously in the body, making a spatially resolved dose quantification necessary to link physical exposure conditions with accompanying risks and beneficial effects. Current dose predictions rely on biokinetic models based on scarce input data from animal experiments and indirect exhalation measurements of a limited number of humans, which shows the need for further experimental verification. We present direct measurements of radon decay in the abdomen and thorax after inhalation as proof of principle in one patient. At both sites, most of the incorporated radon is removed within ~ 3 h, whereas a smaller fraction is retained longer and accounts for most of the deposited energy. The obtained absorbed dose values were [Formula: see text] µGy (abdomen, radon gas) and [Formula: see text] µGy (thorax, radon and progeny) for a one-hour reference exposure at a radon activity concentration of 55 kBq m-3. The accumulation of long-retained radon in the abdomen leads to higher dose values at that site than in the thorax. Contrasting prior work, our measurements are performed directly at specific body sites, i.e. thorax and abdomen, which allows for direct spatial distinction of radon kinetics in the body. They show more incorporated and retained radon than current approaches predict, suggesting higher doses. Although obtained only from one person, our data may thus represent a challenge for the barely experimentally benchmarked biokinetic dose assessment model.

Radon Exposure-Therapeutic Effect and Cancer Risk.

Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.

Radon progeny measurements in a ventilated filter system to study respiratory-supported exposure.

Radon (222Rn) and its progeny are responsible for half of the annual dose from natural radiation and the most frequent cause for lung cancer induction after smoking. During inhalation, progeny nuclides accumulate in the respiratory tract while most of the radon gas is exhaled. The decay of progeny nuclides in the lung together with the high radiosensitivity of this tissue lead to equivalent doses implying a significant cancer risk. Here, we use gamma spectroscopy to measure the attachment of radon progeny on an air-ventilated filter system within a radon enriched atmosphere, mimicking the respiratory tract. A mathematical model was developed to describe the measured time-dependent activities of radon progeny on the filter system. We verified a linear relation between the ambient radon activity concentration during exposure and the amount of decay products on the filter system. The measured activities on the filters and its mathematical description are in good agreement. The developed experimental set-up can thus serve to further investigate the deposition of radon progeny in the respiratory tract under varying conditions for determination of dose conversion factors in radiation protection, which we demonstrate by deriving dose estimations in mouse lung.

Radon Solubility in Different Tissues after Short Term Exposure.

Radon, a naturally occurring radioactive noble gas, contributes significantly to lung cancer when incorporated from our natural environment. However, despite having unknown underlying mechanisms, radon is also used for therapeutic purposes to treat inflammatory diseases such as rheumatoid arthritis. Data on the distribution and accumulation of radon in different tissues represent an important factor in dose determination for risk estimation, the explanation of potential therapeutic effects and the calculation of doses to different tissues using biokinetic dosimetry models. In this paper, radon's solubility in bones, muscle tissue, adipose tissue, bone marrow, blood, a dissolved gelatin and oleic acid were determined. In analogy to current radon use in therapies, samples were exposed to radon gas for 1 h using two exposure protocols combined with established γ-spectroscopic measurements. Solubility data varied over two orders of magnitude, with the lowest values from the dissolved gelatin and muscle tissue; radon's solubility in flat bones, blood and adipose tissue was one order of magnitude higher. The highest values for radon solubility were measured in bone marrow and oleic acid. The data for long bones as well as bone marrow varied significantly. The radon solubility in the blood suggested a radon distribution within the body that occurred via blood flow, reaching organs and tissues that were not in direct contact with radon gas during therapy. Tissues with similar compositions were expected to reveal similar radon solubilities; however, yellow bone marrow and adipose tissue showed differences in solubility even though their chemical composition is nearly the same-indicating that interactions on the microscopic scale between radon and the solvent might be important. We found high solubility in bone marrow-where sensitive hematopoietic cells are located-and in adipose tissue, where the biological impact needs to be further elucidated.

The history of ion beam therapy in Germany.

The advantageous depth dose profile of ion beams together with state of the art beam delivery and treatment planning systems allow for highly conformal tumor treatments in patients. First treatments date back to 1954 at the Lawrence Berkeley Laboratory (LBL) and in Europe, ion beam therapy started in the mid-1990s at the Paul-Scherrer Institute (PSI) with protons and at the Helmholtz Center for Heavy Ion Research (GSI) with carbon ions, followed by the Heidelberg Ion Therapy Center (HIT) in Heidelberg. This review describes the historical development of ion beam therapy in Germany based on the pioneering work at LBL and in the context of simultaneous developments in other countries as well as recent developments.

Radon Progeny Adsorption on Facial Masks.

The radioactive noble gas radon and its short-living progeny are inhaled during respiration, depositing their decay energies in the lungs. These progeny are considered responsible for more than 95% of the total effective dose and are, together with radon, classified as carcinogenic for lung cancer. Consequently, filtration of the progeny could reduce the dose to the lungs. In our study, we investigated the filtration properties of FFP2 versus surgical masks (II R) for radon and its decay products. The masks were attached to a measurement device, which enabled determination of the size distribution of radon progeny, ranging from unattached to clustered progeny. In parallel, it measured the radon activity concentration during experiments. By comparing background measurements without mask and experiments with masks, the percentage of retained unattached radon progeny was determined for FFP2 (98.8 ± 0.6%) and II R masks (98.4 ± 0.7%). For clustered progeny, the retained fraction was 85.2 ± 18.1% for FFP2 and 79.5 ± 22.1% for II R masks while radon was not filtered. We can show that masks are effective in filtering radon progeny and thus are capable of reducing the total effective dose to the lungs.

Radon Adsorption in Charcoal.

Radon is pervasive in our environment and the second leading cause of lung cancer induction after smoking. Therefore, the measurement of radon activity concentrations in homes is important. The use of charcoal is an easy and cost-efficient method for this purpose, as radon can bind to charcoal via Van der Waals interaction. Admittedly, there are potential influencing factors during exposure that can distort the results and need to be investigated. Consequently, charcoal was exposed in a radon chamber at different parameters. Afterward, the activity of the radon decay products 214Pb and 214Bi was measured and extrapolated to the initial radon activity in the sample. After an exposure of 1 h, around 94% of the maximum value was attained and used as a limit for the subsequent exposure time. Charcoal was exposed at differing humidity ranging from 5 to 94%, but no influence on radon adsorption could be detected. If the samples were not sealed after exposure, radon desorbed with an effective half-life of around 31 h. There is also a strong dependence of radon uptake on the chemical structure of the recipient material, which is interesting for biological materials or diffusion barriers as this determines accumulation and transport.

Ion beam radiobiology and cancer: time to update ourselves.

High-energy protons and carbon ions exhibit an inverse dose profile allowing for increased energy deposition with penetration depth. Additionally, heavier ions like carbon beams have the advantage of a markedly increased biological effectiveness characterized by enhanced ionization density in the individual tracks of the heavy particles, where DNA damage becomes clustered and therefore more difficult to repair, but is restricted to the end of their range. These superior biophysical and biological profiles of particle beams over conventional radiotherapy permit more precise dose localization and make them highly attractive for treating anatomically complex and radioresistant malignant tumors but without increasing the severe side effects in the normal tissue. More than half a century since Wilson proposed their use in cancer therapy, the effects of particle beams have been extensively investigated and the biological complexity of particle beam irradiation begins to unfold itself. The goal of this review is to provide an as comprehensive and up-to-date summary as possible of the different radiobiological aspects of particle beams for effective application in cancer treatment.

α-Irradiation setup for primary human cell cultures.

Purpose: We present an α-irradiation setup for the irradiation of primary human cell cultures under controlled conditions using 241Am α-particles.Materials and Methods: To irradiate samples with α-particles in a valid manner, a reliable dosimetry is a great challenge because of the short α-range and the complex energy spectrum. Therefore, the distance between α-source and sample must be minimal. In the present setup, this is achieved by cells growing on a 2 µm thick biaxially-oriented polyethylene terephthalate (boPET) foil which is only 2.7 mm apart from the source. A precise and reproducible exposure time is realized through a mechanical shutter. The fluence, energy spectra and the corresponding linear energy transfer are determined by the source geometry and the material traversed. They were measured and calculated, yielding a dose rate of 8.2 ± 2.4 Gy/min. To improve cell growth on boPET foils, they were treated with air plasma. This treatment increased the polarity and thus the ability of cells attaching to the surface of the foil. Several tests including cell growth, staining for a marker of DNA double-strand breaks and a colony-forming assay were performed and confirm our dosimetry.Conclusion: With our setup, it is possible to irradiate cell cultures under defined conditions with α-particles. The plasma-treated foil is suitable for primary human cell cultures as shown in cell experiments, confirming also the expected number of particle traversals.

[Heavy ion tumor therapy]. / Tumortherapie mit Schwerionenstrahlen.

Heavy ion tumor therapy can reach a millimeter precision everywhere in the body and a greater biological effectiveness in radioresistant tumors compared to the normal tissue. Therefore it is possible to treat mainly resistant or otherwise inoperable tumors with ion beams with great success. In line with the excellent results achieved in a pilot project at GSI several new centers are under construction. In this article, basics of heavy ion tumor therapy are given and the clinical results of the pilot project are described.

A combined experimental and theoretical study of radon solubility in fat and water.

Radon is a radioactive noble gas that can enter the human body, thus increasing the risk of lung cancer. But it is also used for treatment of various ailments, most notably rheumatoid arthritis. The accumulation of radon differs between tissues, with particularly high concentrations in fat tissue. To understand the underlying mechanisms, a combination of γ-spectroscopy and molecular dynamics simulations were performed, to study the accumulation of radon gas in contact with several liquids (water, fatty acids). The solubilities, specific for a defined radon activity concentration, are in good agreement and differ by two orders of magnitude between water and fat, caused by radon disrupting the hydrogen bond network of water. In contrast, the energy cost of introducing radon atoms into fat is low due to the dispersive interaction between radon and fat, which is a non-polar solvent. This correlation was also explicitly demonstrated in our simulations by changing the polarization of the solvent.

The absence of an early calcium response to heavy-ion radiation in Mammalian cells.

Intracellular calcium is an important second messenger that regulates many cell functions. Recent studies have shown that calcium ions can also regulate the cellular responses to ionizing radiation. However, previous data are restricted to cells treated with low-LET radiations (X rays, gamma rays and beta particles). In this work, we investigated the calcium levels in cells exposed to heavy-ion radiation of high LET. The experiments were performed at the single ion hit facility of the GSI heavy-ion microprobe. Using a built-in online calcium imaging system, the intracellular calcium concentrations were examined in HeLa cells and human foreskin fibroblast AG1522-D cells before and after irradiation with 4.8 MeV/nucleon carbon or argon ions. Although the experiment was sensitive enough to detect the calcium response to other known stimuli, no response to heavy-ion radiation was found in these two cell types. We also found that heavy-ion radiation has no impact on calcium oscillation induced by hypoxia stress in fibroblast cells.

Modulation power of porous materials and usage as ripple filter in particle therapy.

Porous materials with microscopic structures like foam, sponges, lung tissues and lung substitute materials have particular characteristics, which differ from those of solid materials. Ion beams passing through porous materials show much stronger energy straggling than expected for non-porous solid materials of the same thickness. This effect depends on the microscopic fine structure, the density and the thickness of the porous material. The beam-modulating effect from a porous plate enlarges the Bragg peak, yielding similar benefits in irradiation time reduction as a ripple filter. A porous plate can additionally function as a range shifter, which since a higher energy can be selected for the same penetration depth in the body reduces the scattering at the beam line and therefore improves the lateral fall-off. Bragg curve measurements of ion beams passing through different porous materials have been performed in order to determine the beam modulation effect of each. A mathematical model describing the correlation between the mean material density, the porous pore structure size and the strength of the modulation has been developed and a new material parameter called 'modulation power' is defined as the square of the Gaussian sigma divided by the mean water-equivalent thickness of the porous absorber. Monte Carlo simulations have been performed in order to validate the model and to investigate the Bragg peak enlargement, the scattering effects of porosity and the lateral beam width at the end of the beam range. The porosity is found to only influence the lateral scattering in a negligible way. As an example of a practical application, it is found that a 20 mm and 50 mm plate of Gammex LN300 performs similar to a 3 mm and 6 mm ripple filter, respectively, and at the same time can improve the sharpness of the lateral beam due to its multifunctionality as a ripple filter and a range shifter.

Simulations to design an online motion compensation system for scanned particle beams.

Respiration-induced target motion is a major problem in intensity-modulated radiation therapy. Beam segments are delivered serially to form the total dose distribution. In the presence of motion, the spatial relation between dose deposition from different segments will be lost. Usually, this results in over- and underdosage. Besides such interplay effects between target motion and dynamic beam delivery as known from photon therapy, changes in internal density have an impact on delivered dose for intensity-modulated charged particle therapy. In this study, we have analysed interplay effects between raster scanned carbon ion beams and target motion. Furthermore, the potential of an online motion strategy was assessed in several simulations. An extended version of the clinical treatment planning software was used to calculate dose distributions to moving targets with and without motion compensation. For motion compensation, each individual ion pencil beam tracked the planned target position in the lateral as well as longitudinal direction. Target translations and rotations, including changes in internal density, were simulated. Target motion simulating breathing resulted in severe degradation of delivered dose distributions. For example, for motion amplitudes of +/-15 mm, only 47% of the target volume received 80% of the planned dose. Unpredictability of resulting dose distributions was demonstrated by varying motion parameters. On the other hand, motion compensation allowed for dose distributions for moving targets comparable to those for static targets. Even limited compensation precision (standard deviation approximately 2 mm), introduced to simulate possible limitations of real-time target tracking, resulted in less than 3% loss in dose homogeneity.

Radiotherapy for chordomas and low-grade chondrosarcomas of the skull base with carbon ions.

PURPOSE: Compared to photon irradiation, carbon ions provide physical and biologic advantages that may be exploited in chordomas and chondrosarcomas. METHODS AND MATERIALS: Between August 1998 and December 2000, 37 patients with chordomas (n = 24) and chondrosarcomas (n = 13) were treated with carbon ion radiotherapy within a Phase I/II trial. Tumor conformal application of carbon ion beams was realized by intensity-controlled raster scanning with pulse-to-pulse energy variation. Three-dimensional treatment planning included biologic plan optimization. The median tumor dose was 60 GyE (GyE = Gy x relative biologic effectiveness). RESULTS: The mean follow-up was 13 months. The local control rate after 1 and 2 years was 96% and 90%, respectively. We observed 2 recurrences outside the gross tumor volume in patients with chordomas. Progression-free survival was 100% for chondrosarcomas and 83% for chordomas at 2 years. Partial remission after carbon ion radiotherapy was observed in 6 patients. Treatment toxicity was mild. CONCLUSION: These are the first data demonstrating the clinical feasibility, safety, and effectiveness of scanning beam delivery of ion beams in patients with skull base tumors. The preliminary results in patients with skull base chordomas and low-grade chondrosarcomas are encouraging, although the follow-up was too short to draw definite conclusions concerning outcome. In the absence of major toxicity, dose escalation might be considered.

Feasibility and toxicity of combined photon and carbon ion radiotherapy for locally advanced adenoid cystic carcinomas.

PURPOSE: To investigate clinical feasibility and toxicity of combined photon and carbon ion radiotherapy in locally advanced adenoid cystic carcinomas (ACC) within a prospective Phase I/II trial. METHODS AND MATERIALS: Between September 1998 and April 2002, 16 patients with histopathologically proven ACC and residual macroscopic tumor were treated with combined photon RT and a carbon ion boost to the macroscopic tumor. Median total tumor dose within the gross tumor volume (GTV) was 72 GyE. Photon radiation therapy (RT) consisted of fractionated stereotactic RT in 7 patients; 9 patients received stereotactic intensity-modulated RT. Carbon ion boost was delivered by intensity-controlled raster scanning at the heavy ion synchrotron (SIS) at the Heavy Ion Research Center (GSI) in Darmstadt. RESULTS: Median follow-up was 12 months. Three patients developed locoregional recurrences 9, 11, and 24 months after RT, respectively. Actuarial local control rates were 80.8% and 64.6% at 1 and 3 years, respectively. Overall survival rates were 100% and 83.3% at 1 and 3 years, respectively. Acute side effects greater than Common Toxicity Criteria (CTC) Grade 2 were observed in 2 patients; no patient developed late effects > CTC Grade 2. CONCLUSIONS: Combined photon and carbon ion RT is feasible and effective in patients with locally advanced ACC. Acute and late toxicity is moderate with respect to the delivered tumor doses and in accordance with the radiobiologic modeling. A Phase III trial is designed.

Results of carbon ion radiotherapy in 152 patients.

PURPOSE: This study summarizes the experience with raster scanned carbon ion radiation therapy (RT) at the Gesellschaft für Schwerionenforschung (GSI), Darmstadt, Germany since 1997. METHODS AND MATERIALS: Between December 1997 and December 2002, 152 patients were treated at GSI with carbon ion RT. Eighty-seven patients with chordomas and low-grade chondrosarcomas of the skull base received carbon ion RT alone (median dose 60 GyE); 21 patients with unfavorable adenoid cystic carcinomas and 17 patients with spinal (n = 9) and sacrococcygeal (n = 8) chordomas and chondrosarcomas were treated with combined photon and carbon ion RT. Twelve patients received reirradiation with carbon ions with or without photon RT for recurrent tumors. Furthermore, 15 patients with skull base tumors other than chordoma and low-grade chondrosarcoma were treated with carbon ions. RESULTS: Actuarial 3-year local control was 81% for chordomas, 100% for chondrosarcomas, and 62% for adenoid cystic carcinomas. Local control was obtained in 15/17 patients with spinal (8/9) and sacral (7/8) chordomas or chondrosarcomas and in 11/15 patients with skull base tumors other than chordomas and low-grade chondrosarcomas, respectively. Six of 12 patients who received reirradiation are still alive without signs of tumor progression. Common Toxicity Criteria Grade 4 or Grade 5 toxicity was not observed. CONCLUSION: Carbon ion therapy is safe with respect to toxicity and offers high local control rates for skull base tumors such as chordomas, low-grade chondrosarcomas, and unfavorable adenoid cystic carcinomas.

3D online compensation of target motion with scanned particle beam.

Intensity modulated, active beam delivery, like magnetic raster scanning, strongly relies on target immobilisation. If target motion cannot be avoided, interferences between the scanning procedure and the tumour displacement destroy the volume conformity. A prototype setup for 3D online motion compensation (3D-OMC) with a scanned particle beam is described, transferring the full potential of volume conformal irradiation to moving targets.