A Computational Study on Temperature Variations in MRgFUS Treatments Using PRF Thermometry Techniques and Optical Probes.

Structural and metabolic imaging are fundamental for diagnosis, treatment and follow-up in oncology. Beyond the well-established diagnostic imaging applications, ultrasounds are currently emerging in the clinical practice as a noninvasive technology for therapy. Indeed, the sound waves can be used to increase the temperature inside the target solid tumors, leading to apoptosis or necrosis of neoplastic tissues. The Magnetic resonance-guided focused ultrasound surgery (MRgFUS) technology represents a valid application of this ultrasound property, mainly used in oncology and neurology. In this paper; patient safety during MRgFUS treatments was investigated by a series of experiments in a tissue-mimicking phantom and performing ex vivo skin samples, to promptly identify unwanted temperature rises. The acquired MR images, used to evaluate the temperature in the treated areas, were analyzed to compare classical proton resonance frequency (PRF) shift techniques and referenceless thermometry methods to accurately assess the temperature variations. We exploited radial basis function (RBF) neural networks for referenceless thermometry and compared the results against interferometric optical fiber measurements. The experimental measurements were obtained using a set of interferometric optical fibers aimed at quantifying temperature variations directly in the sonication areas. The temperature increases during the treatment were not accurately detected by MRI-based referenceless thermometry methods, and more sensitive measurement systems, such as optical fibers, would be required. In-depth studies about these aspects are needed to monitor temperature and improve safety during MRgFUS treatments.

Improved Asymptotic Expansions in High- and Low-Dose Ranges for Generalized Multi-Hit Model of Radiation-Induced Cell Survival.

By considering an upper bound on the number of radiation-induced potential lethal damages that can be repaired in a cell, we have proposed the generalized multi-hit (GMH) model with a closed-form solution, which can better fit various radiation-induced cell survival curves. Recent analysis shows that the asymptotic expansions that we gave before can be used to approximate the generalized single-hit single-target (GSHST) model rather than the GMH model. To illustrate the asymptotic trends of radiation-induced cell survival curves, in this study, we improve the asymptotic expansions of the GMH model in low- and high-dose ranges based on the limit formula of the incomplete gamma function in the corresponding dose ranges. When the upper limit of the number of radiation-induced potential lethal damages is one, the improved expansions of the GMH model can be reduced to the previous expansions of the GSHST model, and the improved asymptotic expansions of the GMH model also indicate that the GMH model has the generalized linear-quadratic-linear (LQL) feature. The numerical simulations indicate that the improved asymptotic expansions in high- and low-dose ranges agree well with the non-linear fitting of the GMH model in six kinds of cell lines under the corresponding dose ranges. In addition, we analyze the relative errors of the improved expansions of the GMH model in high- and low-dose ranges to demonstrate the accuracy and effectiveness of the improved expansions. Based on the error analysis, we further give the reasonable ranges of radiation dose applicable to the improved asymptotic expansions of the GMH model.

High-Intensity Focused Ultrasound- and Radiation Therapy-Induced Immuno-Modulation: Comparison and Potential Opportunities.

In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU-thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio-sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno-modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues.

Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma.

BACKGROUND: A new transcranial focused ultrasound device has been developed that can induce hyperthermia in a large tissue volume. The purpose of this work is to investigate theoretically how glioblastoma multiforme (GBM) can be effectively treated by combining the fast hyperthermia generated by this focused ultrasound device with external beam radiotherapy. METHODS/DESIGN: To investigate the effect of tumor growth, we have developed a mathematical description of GBM proliferation and diffusion in the context of reaction-diffusion theory. In addition, we have formulated equations describing the impact of radiotherapy and heat on GBM in the reaction-diffusion equation, including tumor regrowth by stem cells. This formulation has been used to predict the effectiveness of the combination treatment for a realistic focused ultrasound heating scenario. Our results show that patient survival could be significantly improved by this combined treatment modality. DISCUSSION: High priority should be given to experiments to validate the therapeutic benefit predicted by our model.

Modelling the radiotherapy effect in the reaction-diffusion equation.

PURPOSE: In recent years, the reaction-diffusion (Fisher-Kolmogorov) equation has received much attention from the oncology research community due to its ability to describe the infiltrating nature of glioblastoma multiforme and its extraordinary resistance to any type of therapy. However, in a number of previous papers in the literature on applications of this equation, the term (R) expressing the 'External Radiotherapy effect' was incorrectly derived. In this note we derive an analytical expression for this term in the correct form to be included in the reaction-diffusion equation. METHODS: The R term has been derived starting from the Linear-Quadratic theory of cell killing by ionizing radiation. The correct definition of R was adopted and the basic principles of differential calculus applied. RESULTS: The compatibility of the R term derived here with the reaction-diffusion equation was demonstrated. Referring to a typical glioblastoma tumour, we have compared the results obtained using our expression for the R term with the 'incorrect' expression proposed by other authors.

A new definition of biological effective dose: The dose distribution effects.

A new biological effective dose (BED) is proposed in this note. This new BED definition takes into account the fact that dose distribution is non-uniform for tumors in patients' treatments. This new BED can be calculated from the dose distribution within a tumor, making it practical and useful for clinical applications.

High-intensity focused ultrasound plus concomitant radiotherapy: a new weapon in oncology?

The potential impact of high-intensity focused ultrasound (HIFU) to general medicine and oncology seems very high. However, while in the research area, the development of this technique is very rapid and unchallenged. The direct application of HIFU to human tumour therapy is hampered by various technical difficulties, which may confine its role to a marginal device in the surgery armamentarium. To deploy the full potential of focused ultrasound in oncology, it seems necessary to review the basic relationship between HIFU and external beam radiotherapy. This is the aim of the present work.

Dose distribution changes with shielding disc misalignments and wrong orientations in breast IOERT: a Monte Carlo - GEANT4 and experimental study.

One of the most relevant risks in breast intraoperative electron radiotherapy (IOERT) is the incorrect positioning of the shielding disc. If such a setup error occurs, the treatment zone could receive a nonuniform dose delivery, and a considerable part of the electron beam could hit - and irradiate - the patient's healthy tissue. However misalignment and tilt angle of the shielding disc can be evaluated, but it is not possible to measure the corresponding in vivo dose distribution. This led us to develop a simulation using the Geant4 Monte Carlo toolkit to study the effects of disc configuration on dose distribution. Some parameters were investigated: the shielding factor (SF), the radiation back scattering factor (BSF), the volume-dose histogram in the treatment zone, and the maximum leakage dose (MLD) in normal tissue. A lateral shift of the disc (in the plane perpendicular to the beam axis) causes a decrease in SF (from 4% for a misalignment of 5 mm to 40% for a misalignment of 40 mm), but no relevant dose variations were found for a tilt angle until 10°. In the same uncorrected disc positions, the BSF shows no significant change. MLD rises to 3.45 Gy for a 14 mm misalignment and 4.60 Gy for 30° tilt angle when the prescribed dose is 21 Gy. The simulation results are compared with the experimental ones, and allow an a posteriori estimation of the dose distribution in the breast target and underlying healthy tissue. This information could help the surgical team choose a more correct clinical setup, and assist in quantifying the degree of success or failure of an IOERT breast treatment.

Can magnetic resonance image-guided focused ultrasound surgery replace local oncology treatments? A review.

Magnetic resonance image-guided focused ultrasound surgery (MRgFUS) is an innovative technology in the new panorama of treatment using ultrasound. It combines two well-known and distinct methodologies: high-intensity focused ultrasound (HIFU) and a magnetic resonance imaging system (MRI). This review on MRgFUS is focused on the technical aspects and the current clinical applications in oncology. More precisely, the advantages/disadvantages of MRgFUS compared to other local approaches such as surgery and radiotherapy are discussed in detail.

Comparison of two different types of LiF:Mg,Cu,P thermoluminescent dosimeters for detection of beta rays (beta-TLDs) from 90Sr/90Y, 85Kr and 147Pm sources.

Targeted radionuclide therapies in nuclear medicine departments increasingly depend on using unsealed beta radiation sources in the labeling of peptides and antibodies. Monitoring doses received by the fingers and hands during these procedures is best accomplished with TLD dosimeters that can be located at the fingertips. The present study examines the response of two TLD dosimeters (MCP-Ns and GR200A) to 90Sr/90Y, 85Kr, and 147Pm. The dosimeters were supplied by two different services, and all irradiations were performed at the PTB Institute in Germany. Each dosimetry service evaluated the dosimeters without knowledge that they had been purposefully irradiated. The accuracy and precision of the dosimeters were evaluated as a function of delivered dose, energy of beta particles and angular incidence. The results are compared to performance measures recommended by the IEC. Both dosimeter types displayed significant energy dependence. Angular dependence was moderate. Accuracy and precision as a function of dose (linearity) differed between the two systems, with the MCP-Ns being noticeably better than the GR200A. The superior precision makes the MCP-Ns much more useful for extremity dose measurements. The differences between these two dosimeter systems reinforce the need to evaluate a dosimeter carefully before using it in the daily work routine.

Contrast detail phantom comparison on a commercially available unit. Digital breast tomosynthesis (DBT) versus full-field digital mammography (FFDM).

The performance of a commercial digital mammographic system working in 2D planar versus tomosynthesis mode was evaluated in terms of the image signal difference to noise ratio (SDNR). A contrast detail phantom was obtained embedding 1 cm Plexiglas, including 49 holes of different diameter and depth, between two layers containing a breast-simulating material. The phantom was exposed with the details plane perpendicular to the X-ray beam using the manufacturer's standard clinical breast acquisition parameters. SDNR in the digital breast tomosynthesis (DBT) images was higher than that of the full-field digital mammography (FFDM) for 38 out of 49 details in complex background conditions. These differences (p < 0.05) are statistically significant for 19 details out of 38. The relative SDNR results for DBT and FFDM images showed a dependence on the diameter of the details considered. This paper proposes an initial framework for a global image quality evaluation for commercial systems that can operate with different image acquisition modality using the same detector.

Physical and psychophysical characterization of a novel clinical system for digital mammography.

PURPOSE: In recent years, many approaches have been investigated on the development of full-field digital mammography detectors and implemented in practical clinical systems. Some of the most promising techniques are based on flat panel detectors, which, depending on the mechanism involved in the x-ray detection, can be grouped into direct and indirect flat panels. Direct detectors display a better spatial resolution due to the direct conversion of x rays into electron-hole pairs, which do not need an intermediate production of visible light. In these detectors the readout is usually achieved through arrays of thin film transistors (TFTs). However, TFT readout tends to display noise characteristics worse than those from indirect detectors. To address this problem, a novel clinical system for digital mammography has been recently marketed based on direct-conversion detector and optical readout. This unit, named AMULET and manufactured by FUJIFILM, is based on a dual layer of amorphous selenium that acts both as a converter of x rays (first layer) and as an optical switch for the readout of signals (second layer) powered by a line light source. The optical readout is expected to improve the noise characteristics of the detector. The aim is to obtain images with high resolution and low noise, thanks to the combination of optical switching technology and direct conversion with amorphous selenium. In this article, the authors present a characterization of an AMULET system. METHODS: The characterization was achieved in terms of physical figures as modulation transfer function (MTF), noise power spectra (NPS), detective quantum efficiency (DQE), and contrast-detail analysis. The clinical unit was tested by exposing it to two different beams: 28 kV Mo/Mo (namely, RQA-M2) and 28 kV W/Rh (namely, W/Rh). RESULTS: MTF values of the system are slightly worse than those recorded from other direct-conversion flat panels but still within the range of those from indirect flat panels: The MTF values of the AMULET system are about 45% and 15% at 5 and 8 lp/mm, respectively. On the other hand, however, AMULET NNPS results are consistently better than those from direct-conversion flat panels (up to two to three times lower) and flat panels based on scintillation phosphors. DQE results lie around 70% when RQA-M2 beams are used and approaches 80% in the case of W/Rh beams. Contrast-detail analysis, when performed by human observers on the AMULET system, results in values better than those published for other full-field digital mammography systems. CONCLUSIONS: The novel clinical unit based on direct-conversion detector and optical reading presents great results in terms of both physical and psychophysical characterizations. The good spatial resolution, combined with excellent noise properties, allows the achievement of very good DQE, better than those published for clinical FFDM systems. The psychophysical analysis confirms the excellent behavior of the AMULET unit.

4D-PET data sorting into different number of phases: a NEMA IQ phantom study.

This study aims at evaluating the dependence of 4D-PET data sorting on the number of phases in which the respiratory cycle can be divided. The issue is to find the best compromise to reduce the conflicting effects induced by increasing the number of phases: lesion motion on each set of images decreases, but on the other hand image noise increases. The IQ NEMA 2001 IEC body phantom was used to simulate the movement of neoplastic lesions in the thorax and abdomen, investigating the effect of target size (10-37 mm), lesion to background activity concentrations ratio (4-to-1 and 8-to-1), total acquisition time (3, 6, 12, 20 min) and number of phase partition (1, 2, 4, 6, 8, 10, 13). The phantom was moved in a cranial-caudal direction with an excursion of 25 mm and with a period of 4.0 s. Five parameters associated to lesion volume and activity concentration were considered to assess the capability of the 4D-PET technique to "freeze" the phantom motion. The results for all the parameters showed the capability of the 4D-PET acquisition technique to "freeze" the lesion motion. The division into 6 phases was found to be the best compromise between temporal resolution and image noise for the phase where the "lesions" move faster, whereas the partition into 4 phases could be used if a stable breathing phase is considered.

Radiation protection in 90Y-labelled DOTA-D-Phe1-Tyr3-octreotide preparations.

OBJECTIVE: Beta-emitting radionuclides are being increasingly used in targeted radionuclide therapy in nuclear medicine. In particular, the pure high-energy beta-emitter 90Y (Emax=2.27 MeV) has a physical half-life compatible with the pharmacokinetics of peptides. The use of this isotope implies an increase in the radiation dose received by the nuclear medicine staff. The aim of this study is thus the evaluation of the personal beta-dosimetry data related to therapeutic 90Y-labelled DOTA-D-Phe1-Tyr3-octreotide preparation and administration in a nuclear medicine department. METHODS: Personal dose measurements were carried out with a series of thin active layer ultrasensitive MCP-Ns (LiF: Mg, Cu, P) dosimeters fixed at the operator's fingertips and by means of some direct reading dosimeters; other individual protection devices, such as shielded aprons and anti-X gloves, were also used. RESULTS: The 95th percentile of the chemist's skin equivalent dose distribution was 1.759 mSv/GBq by using 0.10-mm anti-X gloves and 0.265 mSv/GBq by using 0.20-mm anti-X gloves. The 95th percentile of the physician's skin equivalent dose distribution was 1.198 mSv/GBq by using 0.10-mm anti-X gloves. The use of an anti-X apron during administration permits saving absorbed doses by a factor over 97% for both Hp(10) and Hp(0.07). CONCLUSION: Because of the physical properties of beta-emitters, an increased number of therapeutic sessions is to be expected. The dose values measured till now, resulting from a high radioprotection level modus operandi, have always respected the threshold limits reported by the European Directive EURATOM 96/29 05/13/1996 for exposed workers, even in addition to other clinical practices in the department.