Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

Background Medium-dose (25 gray) x-ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x-ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium-dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3-month or 6-month follow-up, the animals underwent an open-chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium-dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

Heavy charged particle beam therapy and related new radiotherapy technologies: The clinical potential, physics and technical developments required to deliver benefit for patients with cancer.

In the UK, one in two people will develop cancer during their lifetimes and radiotherapy (RT) plays a key role in effective treatment. High energy proton beam therapy commenced in the UK National Health Service in 2018. Heavier charged particles have potential advantages over protons by delivering more dose in the Bragg peak, with a sharper penumbra, lower oxygen dependence and increased biological effectiveness. However, they also require more costly equipment including larger gantries to deliver the treatment. There are significant uncertainties in the modelling of relative biological effectiveness and the effects of the fragmentation tail which can deliver dose beyond the Bragg peak. These effects need to be carefully considered especially in relation to long-term outcomes.In 2019, a group of clinicians, clinical scientists, engineers, physical and life scientists from academia and industry, together with funding agency stakeholders, met to consider how the UK should address new technologies for RT, especially the use of heavier charged particles such as helium and carbon and new modes of delivery such as FLASH and spatially fractionated radiotherapy (SFRT).There was unanimous agreement that the UK should develop a facility for heavier charged particle therapy, perhaps constituting a new National Ion Research Centre to enable research using protons and heavier charged particles. Discussion followed on the scale and features, including which ions should be included, from protons through helium, boron, and lithium to carbon, and even oxygen. The consensus view was that any facility intended to treat patients must be located in a hospital setting while providing dedicated research space for physics, preclinical biology and clinical research with beam lines designed for both in vitro and in vivo research. The facility should to be able to investigate and deliver both ultra-high dose rate FLASH RT and SFRT (GRID, minibeams etc.). Discussion included a number of accelerator design options and whether gantries were required. Other potential collaborations might be exploited, including with space agencies, electronics and global communications industries and the nuclear industry.In preparation for clinical delivery, there may be opportunities to send patients overseas (for 12C or 4He ion therapy) using the model of the National Health Service (NHS) Proton Overseas Programme and to look at potential national clinical trials which include heavier ions, FLASH or SFRT. This could be accomplished under the auspices of NCRI CTRad (National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group).The initiative should be a community approach, involving all interested parties with a vision that combines discovery science, a translational research capability and a clinical treatment facility. Barriers to the project and ways to overcome them were discussed. Finally, a set of different scenarios of features with different costs and timelines was constructed, with consideration given to the funding environment (prer-Covid-19) and need for cross-funder collaboration.

Experimental investigation of the characteristics of radioactive beams for heavy ion therapy.

PURPOSE: This work has two related objectives. The first is to estimate the relative biological effectiveness of two radioactive heavy ion beams based on experimental measurements, and compare these to the relative biological effectiveness of corresponding stable isotopes to determine whether they are therapeutically equivalent. The second aim is to quantitatively compare the quality of images acquired postirradiation using an in-beam whole-body positron emission tomography scanner for range verification quality assurance. METHODS: The energy deposited by monoenergetic beams of 11 C at 350 MeV/u, 15 O at 250 MeV/u, 12 C at 350 MeV/u, and 16 O at 430 MeV/u was measured using a cruciform transmission ionization chamber in a water phantom at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Dose-mean lineal energy was measured at various depths along the path of each beam in a water phantom using a silicon-on-insulator mushroom microdosimeter. Using the modified microdosimetric kinetic model, the relative biological effectiveness at 10% survival fraction of the radioactive ion beams was evaluated and compared to that of the corresponding stable ions along the path of the beam. Finally, the postirradiation distributions of positron annihilations resulting from the decay of positron-emitting nuclei were measured for each beam in a gelatin phantom using the in-beam whole-body positron emission tomography scanner at HIMAC. The depth of maximum positron-annihilation density was compared with the depth of maximum dose deposition and the signal-to-background ratios were calculated and compared for images acquired over 5 and 20 min postirradiation of the phantom. RESULTS: In the entrance region, the h b o x RBE 10 was 1.2 ± 0.1 for both 11 C and 12 C beams, while for 15 O and 16 O it was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. At the Bragg peak, the RBE 10 was 2.7 ± 0.4 for 11 C and 2.9 ± 0.4 for 12 C, while for 15 O and 16 O it was 2.7 ± 0.4 and 2.8 ± 0.4, respectively. In the tail region, RBE 10 could only be evaluated for carbon; the RBE 10 was 1.6 ± 0.2 and 1.5 ± 0.1 for 11 C and 12 C, respectively. Positron emission tomography images obtained from gelatin targets irradiated by radioactive ion beams exhibit markedly improved signal-to-background ratios compared to those obtained from targets irradiated by nonradioactive ion beams, with 5-fold and 11-fold increases in the ratios calculated for the 15 O and 11 C images compared with the values obtained for 16 O and 12 C, respectively. The difference between the depth of maximum dose and the depth of maximum positron annihilation density is 2.4 ± 0.8 mm for 11 C, compared to -5.6 ± 0.8 mm for 12 C and 0.9 ± 0.8 mm for 15 O vs -6.6 ± 0.8 mm for 16 O. CONCLUSIONS: The RBE 10 values for 11 C and 15 O were found to be within the 95% confidence interval of the RBEs estimated for their corresponding stable isotopes across each of the regions in which it was evaluated. Furthermore, for a given dose, 11 C and 15 O beams produce much better quality images for range verification compared with 12 C and 16 O, in particular with regard to estimating the location of the Bragg peak.

Investigation of single carbon ion fragmentation in water and PMMA for hadron therapy.

Carbon ion radiotherapy is an attractive alternative to conventional radiotherapy, especially in case of deep-seated and radio-resistant tumors. As a consequence of inelastic nuclear reactions between primary particles and patient's tissues, the primary carbon ions may undergo nuclear fragmentation. The resulting decrease of primary ions and production of secondary fragments have to be carefully considered for accurate dose calculations in the treatment planning systems. The experimental data currently available provide only general information on carbon ion fragmentation and are not sufficient to cover the entire range of beam energies, target configurations and compositions relevant for radiotherapy. Therefore, new investigations were carried out to analyse the outcomes of the inelastic nuclear reaction processes on a single-ion-based approach. Measurements were performed at HIT, using 430 MeV/u carbon ion beams crossing water and PMMA targets. Unique in this method is the possibility of measuring number and type of fragments produced from each single carbon ion, provided that they are within the acceptance of the experimental apparatus. Concerning the amount of residual carbon ions behind water and PMMA targets with the same water equivalent thickness (WET), no significant differences were found. The experimental attenuation curve was well reproduced by the simulations. However, in the experiments, differences were observed regarding the amount of secondary fragments produced in water and in PMMA targets with the same WET. Differences were also found between experiments and simulations. These findings should be considered when dosimetric measurements are performed with PMMA instead of water phantoms. The found differences between experiments and simulations may contribute to improve the nuclear interaction and fragmentation models in Monte Carlo codes.

Effect of respiratory guidance on internal/external respiratory motion correlation for synchrotron-based pulsed heavy-ion radiotherapy.

Having implemented an audio-visual biofeedback (BFB) method for respiratory-gated radiotherapy of synchrotron-based pulsed heavy-ion beam delivery with tracking of external abdominal wall motion, this study evaluated the feasibility of the respiratory guidance method on thoracic and abdominal cancer patients, and the internal/external respiratory motion consistency under respiratory guidance maneuvers due to its interactive intervention in free breathing (FB). A total of 42 breathing traces from seven lung and breast cancer patients and corresponding fluoroscopy movies under FB, standard breath hold (stBH) and representative breath hold (reBH) guidance maneuvers were analyzed. Diaphragm motions were measured manually on a frame-by-frame basis. Mean absolute deviation (MAD) values of the measured external motion curves were calculated for the FB and guidance maneuvers, and the internal/external motion consistencies were compared with a linear fit. Compared with FB, the MAD values were reduced significantly with respiratory guidance maneuvers. The mean internal/external correlations of the first treatment fraction were determined to be 0.96 ± 0.03, 0.97 ± 0.02, and 0.97 ± 0.03 for the FB, stBH and reBH guidance maneuvers, respectively, and were 0.95 ± 0.03, 0.97 ± 0.03, and 0.98 ± 0.02 for the second treatment fraction. No phase shift between the two breathing signals was observed, and good reproducibility of consistency of breathing guidance between the two fractions was achieved. These results demonstrated that treatment precision could be improved for cancer patients with audio-visual BFB, and a strong correlation between diaphragm motion and abdominal wall motion was obtained. The use of audio-visual BFB improved the regularity of both internal and external motions, allowing confident use of the audio-visual BFB method by tracking of the external abdominal wall motion to synchrotron-based heavy-ion radiotherapy.

New physical approaches to treat cancer stem cells: a review.

Cancer stem cells (CSCs) have been identified as the main center of tumor therapeutic resistance. They are highly resistant against current cancer therapy approaches particularly radiation therapy (RT). Recently, a wide spectrum of physical methods has been proposed to treat CSCs, including high energetic particles, hyperthermia (HT), nanoparticles (NPs) and combination of these approaches. In this review article, the importance and benefits of the physical CSCs therapy methods such as nanomaterial-based heat treatments and particle therapy will be highlighted.

Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy.

The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high-risk or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow-up time was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n = 16), two (n = 74) or one of these risk factors (n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (P <0.001). CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT.

Dosimetric verification in water of a Monte Carlo treatment planning tool for proton, helium, carbon and oxygen ion beams at the Heidelberg Ion Beam Therapy Center.

The introduction of 'new' ion species in particle therapy needs to be supported by a thorough assessment of their dosimetric properties and by treatment planning comparisons with clinically used proton and carbon ion beams. In addition to the latter two ions, helium and oxygen ion beams are foreseen at the Heidelberg Ion Beam Therapy Center (HIT) as potential assets for improving clinical outcomes in the near future. We present in this study a dosimetric validation of a FLUKA-based Monte Carlo treatment planning tool (MCTP) for protons, helium, carbon and oxygen ions for spread-out Bragg peaks in water. The comparisons between the ions show the dosimetric advantages of helium and heavier ion beams in terms of their distal and lateral fall-offs with respect to protons, reducing the lateral size of the region receiving 50% of the planned dose up to 12 mm. However, carbon and oxygen ions showed significant doses beyond the target due to the higher fragmentation tail compared to lighter ions (p and He), up to 25%. The Monte Carlo predictions were found to be in excellent geometrical agreement with the measurements, with deviations below 1 mm for all parameters investigated such as target and lateral size as well as distal fall-offs. Measured and simulated absolute dose values agreed within about 2.5% on the overall dose distributions. The MCTP tool, which supports the usage of multiple state-of-the-art relative biological effectiveness models, will provide a solid engine for treatment planning comparisons at HIT.

Atrioventricular node ablation in Langendorff-perfused porcine hearts using carbon ion particle therapy: methods and an in vivo feasibility investigation for catheter-free ablation of cardiac arrhythmias.

BACKGROUND: Particle therapy, with heavy ions such as carbon-12 ((12)C), delivered to arrhythmogenic locations of the heart could be a promising new means for catheter-free ablation. As a first investigation, we tested the feasibility of in vivo atrioventricular node ablation, in Langendorff-perfused porcine hearts, using a scanned 12C beam. METHODS AND RESULTS: Intact hearts were explanted from 4 (30-40 kg) pigs and were perfused in a Langendorff organ bath. Computed tomographic scans (1 mm voxel and slice spacing) were acquired and (12)C ion beam treatment planning (optimal accelerator energies, beam positions, and particle numbers) for atrioventricular node ablation was conducted. Orthogonal x-rays with matching of 4 implanted clips were used for positioning. Ten Gray treatment plans were repeatedly administered, using pencil beam scanning. After delivery, positron emission tomography-computed tomographic scans for detection of ß(+) ((11)C) activity were obtained. A (12)C beam with a full width at half maximum of 10 mm was delivered to the atrioventricular node. Delivery of 130 Gy caused disturbance of atrioventricular conduction with transition into complete heart block after 160 Gy. Positron emission computed tomography demonstrated dose delivery into the intended area. Application did not induce arrhythmias. Macroscopic inspection did not reveal damage to myocardium. Immunostaining revealed strong γH2AX signals in the target region, whereas no γH2AX signals were detected in the unirradiated control heart. CONCLUSIONS: This is the first report of the application of a (12)C beam for ablation of cardiac tissue to treat arrhythmias. Catheter-free ablation using 12C beams is feasible and merits exploration in intact animal studies as an energy source for arrhythmia elimination.

Respiratory motion management using audio-visual biofeedback for respiratory-gated radiotherapy of synchrotron-based pulsed heavy-ion beam delivery.

PURPOSE: To efficiently deliver respiratory-gated radiation during synchrotron-based pulsed heavy-ion radiotherapy, a novel respiratory guidance method combining a personalized audio-visual biofeedback (BFB) system, breath hold (BH), and synchrotron-based gating was designed to help patients synchronize their respiratory patterns with synchrotron pulses and to overcome typical limitations such as low efficiency, residual motion, and discomfort. METHODS: In-house software was developed to acquire body surface marker positions and display BFB, gating signals, and real-time beam profiles on a LED screen. Patients were prompted to perform short BHs or short deep breath holds (SDBH) with the aid of BFB following a personalized standard BH/SDBH (stBH/stSDBH) guiding curve or their own representative BH/SDBH (reBH/reSDBH) guiding curve. A practical simulation was performed for a group of 15 volunteers to evaluate the feasibility and effectiveness of this method. Effective dose rates (EDRs), mean absolute errors between the guiding curves and the measured curves, and mean absolute deviations of the measured curves were obtained within 10%-50% duty cycles (DCs) that were synchronized with the synchrotron's flat-top phase. RESULTS: All maneuvers for an individual volunteer took approximately half an hour, and no one experienced discomfort during the maneuvers. Using the respiratory guidance methods, the magnitude of residual motion was almost ten times less than during nongated irradiation, and increases in the average effective dose rate by factors of 2.39-4.65, 2.39-4.59, 1.73-3.50, and 1.73-3.55 for the stBH, reBH, stSDBH, and reSDBH guiding maneuvers, respectively, were observed in contrast with conventional free breathing-based gated irradiation, depending on the respiratory-gated duty cycle settings. CONCLUSIONS: The proposed respiratory guidance method with personalized BFB was confirmed to be feasible in a group of volunteers. Increased effective dose rate and improved overall treatment precision were observed compared to conventional free breathing-based, respiratory-gated irradiation. Because breathing guidance curves could be established based on the respective average respiratory period and amplitude for each patient, it may be easier for patients to cooperate using this technique.

Experimental verification of ion range calculation in a treatment planning system using a flat-panel detector.

Heavy ion-beam therapy is a highly precise radiation therapy exploiting the characteristic interaction of ions with matter. The steep dose gradient of the Bragg curve allows the irradiation of targets with high-dose and a narrow dose penumbra around the target, in contrast to photon irradiation. This, however, makes heavy ion-beam therapy very sensitive to minor changes in the range calculation of the treatment planning system, as it has a direct influence on the outcome of the treatment. Our previous study has shown that ion radiography with an amorphous silicon flat-panel detector allows the measurement of the water equivalent thickness (WET) of an imaging object with good accuracy and high spatial resolution. In this study, the developed imaging technique is used to measure the WET distribution of a patient-like phantom, and these results are compared to the WET calculation of the treatment planning system. To do so, a measured two-dimensional map of the WET of an anthropomorphic phantom was compared to WET distributions based on x-ray computed tomography images as used in the treatment planning system. It was found that the WET maps agree well in the overall shape and two-dimensional distribution of WET values. Quantitatively, the ratio of the two-dimensional WET maps shows a mean of 1.004 with a standard deviation of 0.022. Differences were found to be concentrated at high WET gradients. This could be explained by the Bragg-peak degradation, which is measured in detail by ion radiography with the flat-panel detector, but is not taken into account in the treatment planning system. Excluding pixels exhibiting significant Bragg-peak degradation, the mean value of the ratio was found to be 1.000 with a standard deviation of 0.012. Employment of the amorphous silicon flat-panel detector for WET measurements allows us to detect uncertainties of the WET determination in the treatment planning process. This makes the investigated technique a very helpful tool to study the WET determination of critical and complex phantom cases.

[Irradiation with carbon ions for locally recurrent rectal cancer].

A female patient in her 70s underwent an abdominoperineal resection and bilateral lymph node dissection for advanced lower rectal cancer. The patient did not receive neoadjuvant therapy. In the Japanese classification of colorectal carcinoma (8th Edition), the tumor was a moderately differentiated type 2 adenocarcinoma, and was 4.5 cm in size. Histologically, the tumor was considered to be Stage IIIb (T3N0M0). She received no adjuvant chemotherapy. After 39 months, pelvic computed tomography (CT ) revealed a 29 mm tumor in the right pelvic wall. The patient declined surgery for recurrence so radiotherapy was planned. First, chemotherapy with mFOLFOX6 was administered for 4 courses to reduce tumor size. Consequently, irradiation with carbon ions was given to the site of recurrence at a total dose of 74 GyE in 37 fractions. There were no severe complications. Carcinoembryonic antigen (CEA) level decreased to the lower limit of the normal range from a maximum of 4.9, and no progression of the recurrent tumor was detected on CT for approximately 4 years. Systemic chemotherapy followed by irradiation with carbon ions may be effective for recurrent rectal cancer.

[A case report of hepatectomy for liver metastasis of colon cancer after heavy particle radiotherapy].

A 51-year-old female patient was admitted to our hospital with a diagnosis of sigmoid colon cancer, and a sigmoidectomy and D3 lymphadenectomy was performed. The tumor was a moderately differentiated tubular adenocarcinoma (pT3N0M0, pStage II). No adjuvant therapy was administered. An abdominal computed tomography (CT) performed 11 months after the sigmoidectomy revealed a hepatic metastasis. The patient chose to undergo carbon ion radiotherapy (53.0 GyE/1 Fr). However, a second CT performed 10 months later indicated regrowth of the hepatic metastasis. A partial liver resection was performed, and severe deformity was observed in the irradiated region of the liver. The borderline between the tumor and surrounding tissue was not clearly discriminated. Histopathological examinations indicated increased numbers of fibrous cells in the irradiated region. To perform hepatic resection safely for liver metastasis of colorectal cancer following heavy particle radiotherapy, it is necessary to accurately determine the resection line before and during surgery. When feasible, resection of the whole irradiated area should be considered.

Experimental study of nuclear fragmentation of 200 and 400 MeV/u (12)C ions in water for applications in particle therapy.

Carbon ion beams in the energy range of about 100-450 MeV/u offer excellent conditions for tumour therapy, in particular for the treatment of deep-seated radio-resistant tumours. Their depth-dose distribution is characterized by a low dose in the entrance channel, small lateral beam spread and an elevated biological effectiveness in the Bragg peak region. In comparison to protons the radiation field of heavier ions stopping in tissue is however more complex due to nuclear fragmentation reactions occurring along their stopping path. This results in an attenuation of the primary beam flux and a build-up of lower-Z fragments with longer ranges causing the characteristic dose tail beyond the Bragg peak. In the present work the characteristics of secondary charged particles at various depths of water were investigated experimentally using (12)C ion beams of 200 and 400 MeV/u delivered by the heavy-ion synchrotron SIS-18 at GSI Darmstadt. The nuclear charge Zf of secondary fragments was identified by combining energy loss and time-of-flight (TOF) measurements. Energy spectra and yields were recorded at lab angles of 0° - 10° and at seven different water depths corresponding to the entrance channel, the Bragg peak region and the tail of the Bragg curve.

Subcellular spatial correlation of particle traversal and biological response in clinical ion beams.

PURPOSE: To report on the spatial correlation of physical track information (fluorescent nuclear track detectors, FNTDs) and cellular DNA damage response by using a novel hybrid detector (Cell-Fit-HD). METHODS AND MATERIALS: The FNTDs were coated with a monolayer of human non-small cell lung carcinoma (A549) cells and irradiated with carbon ions (270.55 MeV u(-1), rising flank of the Bragg peak). Phosphorylated histone variant H2AX accumulating at the irradiation-induced double-strand break site was labeled (RIF). The position and direction of ion tracks in the FNTD were registered with the location of the RIF sequence as an ion track surrogate in the cell layer. RESULTS: All RIF sequences could be related to their corresponding ion tracks, with mean deviations of 1.09 µm and -1.72 µm in position and of 2.38° in slope. The mean perpendicular between ion track and RIF sequence was 1.58 µm. The mean spacing of neighboring RIFs exhibited a regular rather than random spacing. CONCLUSIONS: Cell-Fit-HD allows for unambiguous spatial correlation studies of cell damage with respect to the intracellular ion traversal under therapeutic beam conditions.

Ion track reconstruction in 3D using alumina-based fluorescent nuclear track detectors.

Fluorescent nuclear track detectors (FNTDs) based on Al2O3: C, Mg single crystal combined with confocal microscopy provide 3D information on ion tracks with a resolution only limited by light diffraction. FNTDs are also ideal substrates to be coated with cells to engineer cell-fluorescent ion track hybrid detectors (Cell-Fit-HD). This radiobiological tool enables a novel platform linking cell responses to physical dose deposition on a sub-cellular level in proton and heavy ion therapies. To achieve spatial correlation between single ion hits in the cell coating and its biological response the ion traversals have to be reconstructed in 3D using the depth information gained by the FNTD read-out. FNTDs were coated with a confluent human lung adenocarcinoma epithelial (A549) cell layer. Carbon ion irradiation of the hybrid detector was performed perpendicular and angular to the detector surface. In situ imaging of the fluorescently labeled cell layer and the FNTD was performed in a sequential read-out. Making use of the trajectory information provided by the FNTD the accuracy of 3D track reconstruction of single particles traversing the hybrid detector was studied. The accuracy is strongly influenced by the irradiation angle and therefore by complexity of the FNTD signal. Perpendicular irradiation results in highest accuracy with error of smaller than 0.10°. The ability of FNTD technology to provide accurate 3D ion track reconstruction makes it a powerful tool for radiobiological investigations in clinical ion beams, either being used as a substrate to be coated with living tissue or being implanted in vivo.

Engineering cell-fluorescent ion track hybrid detectors.

BACKGROUND: The lack of sensitive biocompatible particle track detectors has so far limited parallel detection of physical energy deposition and biological response. Fluorescent nuclear track detectors (FNTDs) based on Al2O3:C,Mg single crystals combined with confocal laser scanning microscopy (CLSM) provide 3D information on ion tracks with a resolution limited by light diffraction. Here we report the development of next generation cell-fluorescent ion track hybrid detectors (Cell-Fit-HD). METHODS: The biocompatibility of FNTDs was tested using six different cell lines, i.e. human non-small cell lung carcinoma (A549), glioblastoma (U87), androgen independent prostate cancer (PC3), epidermoid cancer (A431) and murine (VmDk) glioma SMA-560. To evaluate cell adherence, viability and conformal coverage of the crystals different seeding densities and alternative coating with extracellular matrix (fibronectin) was tested. Carbon irradiation was performed in Bragg peak (initial 270.55 MeV u⁻¹). A series of cell compartment specific fluorescence stains including nuclear (HOECHST), membrane (Glut-1), cytoplasm (Calcein AM, CM-DiI) were tested on Cell-Fit-HDs and a single CLSM was employed to co-detect the physical (crystal) as well as the biological (cell layer) information. RESULTS: The FNTD provides a biocompatible surface. Among the cells tested, A549 cells formed the most uniform, viable, tightly packed epithelial like monolayer. The ion track information was not compromised in Cell-Fit-HD as compared to the FNTD alone. Neither cell coating and culturing, nor additional staining procedures affected the properties of the FNTD surface to detect ion tracks. Standard immunofluorescence and live staining procedures could be employed to co-register cell biology and ion track information. CONCLUSIONS: The Cell-Fit-Hybrid Detector system is a promising platform for a multitude of studies linking biological response to energy deposition at high level of optical microscopy resolution.

Calculation of energy-deposition distributions and microdosimetric estimation of the biological effect of a 9C beam.

Among the alternative beams being recently considered for external cancer radiotherapy, (9)C has received some attention because it is expected that its biological effectiveness could be boosted by the beta-delayed emission of two alpha particles and a proton that takes place at the ion-stopping site. Experiments have been performed to characterise this exotic beam physically and models have been developed to estimate quantitatively its biological effect. Here, the particle and heavy-ion transport code system ( PHITS ) is used to calculate energy-deposition and linear energy transfer distributions for a (9)C beam in water and the results are compared with published data. Although PHITS fails to reproduce some of the features of the distributions, it suggests that the decay of (9)C contributes negligibly to the energy-deposition distributions, thus contradicting the previous interpretation of the measured data. We have also performed a microdosimetric calculation to estimate the biological effect of the decay, which was found to be negligible; previous microdosimetric Monte-Carlo calculations were found to be incorrect. An analytical argument, of geometrical nature, confirms this conclusion and gives a theoretical upper bound on the additional biological effectiveness of the decay. However, no explanation can be offered at present for the observed difference in the biological effectiveness between (9)C and (12)C; the reproducibility of this surprising result will be verified in coming experiments.

Experimental and theoretical study of the neutron dose produced by carbon ion therapy beams.

High-energy (12)C ions offer favourable conditions for the treatment of deep-seated local tumours. Several facilities for the heavy ion therapy are planned or under construction, for example the new clinical ion-therapy unit HIT at the Radiological University Clinics in Heidelberg. In order to improve existing treatment planning models, it is essential to evaluate the secondary fragment production and to include these contributions to the therapy dose with higher accuracy. Secondary neutrons are most abundantly produced in the reactions between (12)C beams and tissues. The dose contribution to tissues by a neutron is fairly small compared with the projectile and the other charged fragments due to no ionisation and the small reaction cross-sections; however, it distributes in a considerably wider region beyond the bragg-peak because of the strong penetrability. Systematic data on energy spectra and doses of secondary neutrons produced by (12)C beams using water targets of different thicknesses for various detection angles have therefore been measured in this study at GSI Darmstadt.

The potential application of beta-delayed particle decay beam 9C in cancer therapy.

A radioactive ion beam like 9C serves as a double radiation source and may be useful in cancer treatment, where the essential irradiation comes from the external beam itself and the extra one is due to the low-energy particles emitted internally during the decay of 9C. Based on the microdosimetric specific energy spectrum in cell nuclei, a model to evaluate the biological effect induced by the internally emitted particles from a beta-delayed particle decay beam has been developed. In this paper, using this model the additional contributions to the cell-killing effect due to the emitted particles from stopping 9C ions were incorporated in the design of spread-out Bragg peaks (SOBP) for radioactive 9C beams. For this purpose, a simulated annealing algorithm was employed to optimize the superposing weighting fractions of all monoenergetic beams so that a uniform cell survival level could be realized across the SOBP within an acceptable deviation of 5%. SOBPs with different widths and at different cell survival levels were designed for both therapeutic 9C and 12C beams for comparison. The potential use of the 9C beam in radiotherapy compared to the 12C beam, which is commonly adopted in the practices of current heavy-ion therapy, is shown systematically in terms of the distributions of biological effective dose and cell survival along the beam penetration.