Enhancing tumor's skin photothermal therapy using Gold nanoparticles : a Monte Carlo simulation.

The aim of this study is to investigate how the introduction of Gold nanoparticles GNPs into a skin tumor affects the ability to absorb laser light during multicolor laser exposure. The Monte Carlo Geant4 technique was used to construct a cubic geometry simulating human skin, and a 5 mm tumor spheroid was implanted at an adjustable depth x. Our findings show that injecting a very low concentration of 0.01% GNPs into a tumor located 1 cm below the skin's surface causes significant laser absorption of up to 25%, particularly in the 900 nm to 1200 nm range, resulting in a temperature increase of approximately 20%. It is an effective way to raise a tumor's temperature and cause cell death while preserving healthy cells. The addition of GNPs to a tumor during polychromatic laser exposure with a wavelength ranging from 900 nm to 1200 nm increases laser absorption and thus temperature while preserving areas without GNPs.

Spatiotemporal optimisation of prostate intensity modulated proton therapy (IMPT) treatments.

Objective.In intensity modulated particle therapy (IMPT), the adoption of spatially and temporally heterogeneous dose distributions allows to decouple the fractionation scheme from the patient anatomy, so that an hypofractionated schedule can be selectively created inside the tumour, while simultaneously exploiting the fractionation effect in the healthy tissues. In this paper, the authors show the reproducibility of the method on a set of prostate patients, quantifying the dependencies of the achievable benefit with respect to conventional and hypofractionated schemes and the sensitivity of the method to setup errors and range uncertainty.Approach.On a cohort of 9 patients, non-uniform IMPT plans were optimised and compared to conventional and hypofractionated schedules. For each patient, the comparison of the three strategies has been based on the output of the cost function used to optimise the treatments. The analysis has been repeated considering differentα/ßratios for the tumour, namely 1.5, 3 and 4.5 Gy. For a single patient, setup errors and beam range uncertainty have been analysed: the plans, for each optimisation strategy, have been iteratively forward planned 500 times with randomly varying the patient position in each fraction, and 200 times for systematic range shift.Main results.An average 10% benefit has been shown for the lowestα/ßratio considered for the tumour, where the non-uniform schedule generally converges to hypofractionation; the benefit decreases to 5%-7% for higherα/ßratios, for which the non-uniform schedule always showed better outcomes with respect to the other fractionation schedules. An increased sensitivity to uncertainty, especially for setup errors, has been shown, which can be associated to the spatial non-uniformity of the dose distributions peculiar of the spatiotemporal plans.Significance.This work represents the first investigation of spatiotemporal fractionation for prostate cancer and the beginning of further investigations before clinical implementation can be considered.

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.

FLUKA simulation of target fragmentation in proton therapy.

In proton therapy, secondary fragments are created in nuclear interactions of the beam with the target nuclei. The secondary fragments have low kinetic energies and high atomic numbers as compared to primary protons. Fragments have a high LET and deposit all their energy close to the generation point. For their characteristics, secondary fragments can alter the dose distribution and lead to an increase of RBE for the same delivered physical dose. Moreover, the radiobiological impact of target fragmentation is significant mostly in the region before the Bragg peak, where generally healthy tissues are present, and immediately after Bragg peak. Considering the high biological impact of those particles, especially in the case of healthy tissues or organs at risk, the inclusion of target fragmentation processes in the dose calculation of a treatment planning system can be relevant to improve the treatment accuracy and for this reason it is one of the major tasks of the MoVe IT project. In this study, Monte Carlo simulations were employed to fully characterize the mixed radiation field generated by target fragmentation in proton therapy. The dose averaged LET has been evaluated in case of a Spread Out Bragg Peak (SOBP). Starting from LET distribution, RBE has been evaluated with two different phenomenological models. In order to characterize the mixed radiation field, the production cross section has been evaluated by means of the FLUKA code. The future development of present work is to generate a MC database of fragments fluence to be included in TPS.

RIDOS: A new system for online computation of the delivered dose distributions in scanning ion beam therapy.

PURPOSE: To describe a new system for scanned ion beam therapy, named RIDOS (Real-time Ion DOse planning and delivery System), which performs real time delivered dose verification integrating the information from a clinical beam monitoring system with a Graphic Processing Unit (GPU) based dose calculation in patient Computed Tomography. METHODS: A benchmarked dose computation algorithm for scanned ion beams has been parallelized and adapted to run on a GPU architecture. A workstation equipped with a NVIDIA GPU has been interfaced through a National Instruments PXI-crate with the dose delivery system of the Italian National Center of Oncological Hadrontherapy (CNAO) to receive in real-time the measured beam parameters. Data from a patient monitoring system are also collected to associate the respiratory phases with each spot during the delivery of the dose. Using both measured and planned spot properties, RIDOS evaluates during the few seconds of inter-spill time the cumulative delivered and prescribed dose distributions and compares them through a fast γ-index algorithm. RESULTS: The accuracy of the GPU-based algorithms was assessed against the CPU-based ones and the differences were found below 1‰. The cumulative planned and delivered doses are computed at the end of each spill in about 300 ms, while the dose comparison takes approximatively 400 ms. The whole operation provides the results before the next spill starts. CONCLUSIONS: RIDOS system is able to provide a fast computation of the delivered dose in the inter-spill time of the CNAO facility and allows to monitor online the dose deposition accuracy all along the treatment.

Radiobiological quantities in proton-therapy: Estimation and validation using Geant4-based Monte Carlo simulations.

PURPOSE: The Geant4 Monte Carlo simulation toolkit was used to reproduce radiobiological parameters measured by irradiating three different cancerous cell lines with monochromatic and clinical proton beams. METHODS: The experimental set-up adopted for irradiations was fully simulated with a dedicated open-source Geant4 application. Cells survival fractions was calculated coupling the Geant4 simulations with two analytical radiobiological models: one based on the LEM (Local Effect Model) approach and the other on a semi-empirical parameterisation. Results was evaluated and compared with experimental data. RESULTS AND CONCLUSIONS: The results demonstrated the Geant4 ability to reproduce radiobiological quantities for different cell lines.

'Survival': a simulation toolkit introducing a modular approach for radiobiological evaluations in ion beam therapy.

One major rationale for the application of heavy ion beams in tumour therapy is their increased relative biological effectiveness (RBE). The complex dependencies of the RBE on dose, biological endpoint, position in the field etc require the use of biophysical models in treatment planning and clinical analysis. This study aims to introduce a new software, named 'Survival', to facilitate the radiobiological computations needed in ion therapy. The simulation toolkit was written in C++ and it was developed with a modular architecture in order to easily incorporate different radiobiological models. The following models were successfully implemented: the local effect model (LEM, version I, II and III) and variants of the microdosimetric-kinetic model (MKM). Different numerical evaluation approaches were also implemented: Monte Carlo (MC) numerical methods and a set of faster analytical approximations. Among the possible applications, the toolkit was used to reproduce the RBE versus LET for different ions (proton, He, C, O, Ne) and different cell lines (CHO, HSG). Intercomparison between different models (LEM and MKM) and computational approaches (MC and fast approximations) were performed. The developed software could represent an important tool for the evaluation of the biological effectiveness of charged particles in ion beam therapy, in particular when coupled with treatment simulations. Its modular architecture facilitates benchmarking and inter-comparison between different models and evaluation approaches. The code is open source (GPL2 license) and available at https://github.com/batuff/Survival.

Tumour control in ion beam radiotherapy with different ions in the presence of hypoxia: an oxygen enhancement ratio model based on the microdosimetric kinetic model.

Few attempts have been made to include the oxygen enhancement ratio (OER) in treatment planning for ion beam therapy, and systematic studies to evaluate the impact of hypoxia in treatment with the beam of different ion species are sorely needed. The radiobiological models used to quantify the OER in such studies are mainly based on the dose-averaged LET estimates, and do not explicitly distinguish between the ion species and fractionation schemes. In this study, a new type of OER modelling, based on the microdosimetric kinetic model, taking into account the specificity of the different ions, LET spectra, tissues and fractionation schemes, has been developed. The model has been benchmarked with published in vitro data, HSG, V79 and CHO cells in aerobic and hypoxic conditions, for different ion irradiation. The model has been included in the simulation of treatments for a clinical case (brain tumour) using proton, lithium, helium, carbon and oxygen ion beams. A study of the tumour control probability (TCP) as a function of oxygen partial pressure, dose per fraction and primary ion type has been performed. The modelled OER depends on both the LET and ion type, also showing a decrease for an increased dose per fraction with a slope that depends on the LET and ion type, in good agreement with the experimental data. In the investigated clinical case, a significant increase in TCP has been found upon increasing the ion charge. Higher OER variations as a function of dose per fraction have also been found for low-LET ions (up to 15% varying from 2 to 8 Gy(RBE) for protons). This model could be exploited in the identification of treatment condition optimality in the presence of hypoxia, including fractionation and primary particle selection.

Quality assurance of carbon ion and proton beams: A feasibility study for using the 2D MatriXX detector.

PURPOSE: The quality assurance (QA) procedures in particle therapy centers with active beam scanning make extensive use of films, which do not provide immediate results. The purpose of this work is to verify whether the 2D MatriXX detector by IBA Dosimetry has enough sensitivity to replace films in some of the measurements. METHODS: MatriXX is a commercial detector composed of 32×32 parallel plate ionization chambers designed for pre-treatment dose verification in conventional radiation therapy. The detector and GAFCHROMIC® films were exposed simultaneously to a 131.44MeV proton and a 221.45MeV/u carbon-ion therapeutic beam at the CNAO therapy center of Pavia - Italy, and the results were analyzed and compared. RESULTS: The sensitivity MatriXX on the beam position, beam width and field flatness was investigated. For the first two quantities, a method for correcting systematic uncertainties, dependent on the beam size, was developed allowing to achieve a position resolution equal to 230µm for carbon ions and less than 100µm for protons. The beam size and the field flatness measured using MatriXX were compared with the same quantities measured with the irradiated film, showing a good agreement. CONCLUSIONS: The results indicate that a 2D detector such as MatriXX can be used to measure several parameters of a scanned ion beam quickly and precisely and suggest that the QA would benefit from a new protocol where the MatriXX detector is added to the existing systems.

Novel approach of treating Gorham-Stout disease in the humerus--Case report and review of literature.

Gorham-Stout disease or the so-called vanishing bone syndrome is a rare disorder characterized by intra-osseous proliferation of vascular channels resulting in destruction and resorption of the osseous matrix. The exact pathology of this disease showed no evidence of malignant, neuropathic, or infectious components involved in the causation of this disorder except for the culprit of lympho-vascular malformations in the bone. The mechanism of bone resorption is yet to be clarified. The clinical presentation of Gorham's disease varies according to the organ of involvement. Patients diagnosed with Gorham's disease in the bone may initially present with insidious onset of dull aching pain, progressive weakness, or pathologic fractures as the initial presentation. Gorham's disease is progressive in most patients; yet it can be self-limiting in a few reported cases. The axes of treating this disease as reported in the literature include the use of medical treatment, surgical intervention, radiotherapy and/or the combination of any them. However, there is no consensus about the most effective approach for treating this rare disease. The challenge in this disease lies in both: how to diagnose and how to treat. Our novel approach combined surgical intervention, medication and radiotherapy as a treatment of Graham-Stout disease in the humerus, and showed no progression of the disease our case.

A novel algorithm for the calculation of physical and biological irradiation quantities in scanned ion beam therapy: the beamlet superposition approach.

The calculation algorithm of a modern treatment planning system for ion-beam radiotherapy should ideally be able to deal with different ion species (e.g. protons and carbon ions), to provide relative biological effectiveness (RBE) evaluations and to describe different beam lines. In this work we propose a new approach for ion irradiation outcomes computations, the beamlet superposition (BS) model, which satisfies these requirements. This model applies and extends the concepts of previous fluence-weighted pencil-beam algorithms to quantities of radiobiological interest other than dose, i.e. RBE- and LET-related quantities. It describes an ion beam through a beam-line specific, weighted superposition of universal beamlets. The universal physical and radiobiological irradiation effect of the beamlets on a representative set of water-like tissues is evaluated once, coupling the per-track information derived from FLUKA Monte Carlo simulations with the radiobiological effectiveness provided by the microdosimetric kinetic model and the local effect model. Thanks to an extension of the superposition concept, the beamlet irradiation action superposition is applicable for the evaluation of dose, RBE and LET distributions. The weight function for the beamlets superposition is derived from the beam phase space density at the patient entrance. A general beam model commissioning procedure is proposed, which has successfully been tested on the CNAO beam line. The BS model provides the evaluation of different irradiation quantities for different ions, the adaptability permitted by weight functions and the evaluation speed of analitical approaches. Benchmarking plans in simple geometries and clinical plans are shown to demonstrate the model capabilities.

Direct evaluation of radiobiological parameters from clinical data in the case of ion beam therapy: an alternative approach to the relative biological effectiveness.

The relative biological effectiveness (RBE) concept is commonly used in treatment planning for ion beam therapy. Whether models based on in vitro/in vivo RBE data can be used to predict human response to treatments is an open issue. In this work an alternative method, based on an effective radiobiological parameterization directly derived from clinical data, is presented. The method has been applied to the analysis of prostate cancer trials with protons and carbon ions.Prostate cancer trials with proton and carbon ion beams reporting 5 year-local control (LC5) and grade 2 (G2) or higher genitourinary toxicity rates (TOX) were selected from literature to test the method. Treatment simulations were performed on a representative subset of patients to produce dose and linear energy transfer distribution, which were used as explicative physical variables for the radiobiological modelling. Two models were taken into consideration: the microdosimetric kinetic model (MKM) and a linear model (LM). The radiobiological parameters of the LM and MKM were obtained by coupling them with the tumor control probability and normal tissue complication probability models to fit the LC5 and TOX data through likelihood maximization. The model ranking was based on the Akaike information criterion.Results showed large confidence intervals due to the limited variety of available treatment schedules. RBE values, such as RBE = 1.1 for protons in the treated volume, were derived as a by-product of the method, showing a consistency with current approaches. Carbon ion RBE values were also derived, showing lower values than those assumed for the original treatment planning in the target region, whereas higher values were found in the bladder. Most importantly, this work shows the possibility to infer the radiobiological parametrization for proton and carbon ion treatment directly from clinical data.

PCR based differentiation between Streptococcus dysgalactiae subsp. equisimilis strains isolated from humans and horses.

Streptococcus dysgalactiae subsp. equisimilis (SDSE) can be severely pathogenic in humans and is increasingly isolated from horses with respiratory, reproductive or other diseases, although it is often considered a commensal bacterium. Here a PCR protocol is described for identifying SDSE recovered from humans. A multiplex PCR targeting the 16S rRNA and the streptokinase precursor gene has been optimized for differentiating between SDSE strains isolated from humans and those isolated from horses. Previously, the sequence of the streptokinase precursor gene of SDSE recovered from horses has been found in two human cases of pneumonia in Japan. Although further evaluation is required, the findings of this study suggest that SDSE strains are host-specific and this multiplex PCR protocol can be useful in further epidemiological studies and for investigating the zoonotic potential of SDSE.

Analysis of the reliability of the local effect model for the use in carbon ion treatment planning systems.

In radiotherapy with carbon ions, biological effects of treatments have to be predicted. For this purpose, one of the most used models is the local effect model (LEM) developed at the Gesellschaft für Schwerionenforschung (GSI), Germany. At the Istituto Nazionale di Fisica Nucleare, Italy, the reliability of the last published version of LEM (LEM III) in reproducing radiobiological data has been checked under both monoenergetic and spread-out Bragg peak (SOBP) carbon-ion irradiation. The reproduction of the monoenergetic measurements with the LEM was rather successful for some cell lines, while it failed for the less-radioresistant ones. The SOBP experimental trend was predicted by the LEM, but a large shift between model curves and measured points was observed.

Online beam monitoring in the treatment of ocular pathologies at the INFN Laboratori Nazionali del Sud-Catania.

A detector (MOPI) has been developed for the online monitoring of the beam at the Centro di AdroTerapia e Applicazioni Nucleari Avanzate (CATANA), where shallow tumours of the ocular region are treated with 62 MeV protons. At CATANA the beam is passively spread to match the tumour shape. The uniformity of the delivered dose depends on beam geometrical quantities which are checked before each treatment. However, beam instabilities might develop during the irradiation affecting the dose distribution. This paper reports on the use of the MOPI detector to measure the stability of the beam profile during the irradiation in the clinical practice. The results obtained in the treatment of 54 patients are also presented.

Octatropine methyl bromide and diazepam combination (Valpinax) in patients with irritable bowel syndrome: a multicentre, randomized, placebo-controlled trial.

OBJECTIVE: To investigate the efficacy and tolerability of octatropine methyl bromide plus diazepam (Valpinax) in patients with irritable bowel syndrome (IBS). MATERIALS AND METHODS: We conducted a randomized, double-blind, multicentre study in 186 patients aged 18-65 years with IBS diagnosed according to Rome II criteria. Following a 2-week washout period, patients received octatropine plus diazepam 40 mg/2.5 mg twice daily or placebo for 6 weeks. The primary efficacy endpoint was response to a weekly question: "did you have satisfactory relief of your abdominal pain and discomfort during the last week?" Other endpoints included abdominal swelling, abdominal pain and discomfort, symptom severity, and the number of bowel movements. A prespecified subgroup analysis was conducted in patients with an abdominal pain and discomfort score > or = 3. RESULTS: The primary efficacy endpoint showed a tendency towards a statistically significant benefit for octatropine plus diazepam over placebo among patients with a baseline abdominal pain and discomfort score of > or = 3 (3 vs. 0 patients; p = 0.059). Octatropine plus diazepam demonstrated significant improvements from baseline in all parameters assessed, but not compared with placebo. Adverse events were reported in 15.1% of patients receiving octatropine plus diazepam. CONCLUSIONS: Patients with IBS and an abdominal pain and discomfort score of > or = 3, who may be considered in the active phase of the disease, may derive some benefits from octatropine plus diazepam. This study highlights that Rome II criteria should be considered with particular care in the design of a clinical trial, since it does not consider disease activity level on admission.

Heuristic optimization of the scanning path of particle therapy beams.

Quasidiscrete scanning is a delivery strategy for proton and ion beam therapy in which the beam is turned off when a slice is finished and a new energy must be set but not during the scanning between consecutive spots. Different scanning paths lead to different dose distributions due to the contribution of the unintended transit dose between spots. In this work an algorithm to optimize the scanning path for quasidiscrete scanned beams is presented. The classical simulated annealing algorithm is used. It is a heuristic algorithm frequently used in combinatorial optimization problems, which allows us to obtain nearly optimal solutions in acceptable running times. A study focused on the best choice of operational parameters on which the algorithm performance depends is presented. The convergence properties of the algorithm have been further improved by using the next-neighbor algorithm to generate the starting paths. Scanning paths for two clinical treatments have been optimized. The optimized paths are found to be shorter than the back-and-forth, top-to-bottom (zigzag) paths generally provided by the treatment planning systems. The gamma method has been applied to quantify the improvement achieved on the dose distribution. Results show a reduction of the transit dose when the optimized paths are used. The benefit is clear especially when the fluence per spot is low, as in the case of repainting. The minimization of the transit dose can potentially allow the use of higher beam intensities, thus decreasing the treatment time. The algorithm implemented for this work can optimize efficiently the scanning path of quasidiscrete scanned particle beams. Optimized scanning paths decrease the transit dose and lead to better dose distributions.

Immune-mediated liver dysfunction after antiviral treatment in liver transplanted patients with hepatitis C: allo or autoimmune de novo hepatitis?

BACKGROUND: The recurrence of hepatitis C after liver transplantation is extremely frequent. Antiviral therapy combining pegylated-interferon with ribavirin is therefore increasingly used in these patients. It has been recently reported, however, that during antiviral treatment a hepatic immune-mediated liver dysfunction, similar to "de novo" autoimmune hepatitis, may develop in a few transplanted patients. PATIENTS AND METHODS: Three patients, treated with pegylated-interferon alpha-2a and ribavirin for recurrent hepatitis C after liver transplantation, developed an aggressive hepatitis with clinical, biochemical, and histological features similar to those of autoimmune hepatitis. RESULTS: In all three patients, a liver enzymes increase was evident after hepatitis C virus-RNA had become undetectable. Diagnosis of "de novo" autoimmune hepatitis was proposed, based on the presence of high-titre circulating autoantibodies and liver histology features. Following the introduction of a steroid therapy, clinical and biochemical parameters progressively improved. Hepatitis C virus infection, however, relapsed after a few months in all the patients. CONCLUSIONS: Following liver transplantation, antiviral therapy with pegylated-interferon alpha-2a and ribavirin for recurrent hepatitis C may be associated, in a few patients, with severe immune-mediated graft dysfunction similar to autoimmune hepatitis.

Mode-coupling behavior of a Lennard-Jones binary mixture upon increasing confinement.

Molecular dynamics simulations are performed on a Lennard Jones binary mixture confined in off lattice matrices of soft spheres with increasing radius. We focus on dynamics upon supercooling and in particular on testing the mode coupling theory properties of the confined mixture. Parameters of mode coupling theory in going from bulk to weak confinement, and from weak to strong confinement are extracted from simulations and analyzed. We focus on the study of the behavior of the single particle density correlators. We find that the mode coupling theory retains its validity also in the case of strong confinement, with a reduction of range of validity. The role of hopping is discussed in relation with the differences between the results obtained from the diffusion coefficients and the mode coupling theory predictions.

A treatment planning code for inverse planning and 3D optimization in hadrontherapy.

The therapeutic use of protons and ions, especially carbon ions, is a new technique and a challenge to conform the dose to the target due to the energy deposition characteristics of hadron beams. An appropriate treatment planning system (TPS) is strictly necessary to take full advantage. We developed a TPS software, ANCOD++, for the evaluation of the optimal conformal dose. ANCOD++ is an analytical code using the voxel-scan technique as an active method to deliver the dose to the patient, and provides treatment plans with both proton and carbon ion beams. The iterative algorithm, coded in C++ and running on Unix/Linux platform, allows the determination of the best fluences of the individual beams to obtain an optimal physical dose distribution, delivering a maximum dose to the target volume and a minimum dose to critical structures. The TPS is supported by Monte Carlo simulations with the package GEANT3 to provide the necessary physical lookup tables and verify the optimized treatment plans. Dose verifications done by means of full Monte Carlo simulations show an overall good agreement with the treatment planning calculations. We stress the fact that the purpose of this work is the verification of the physical dose and a next work will be dedicated to the radiobiological evaluation of the equivalent biological dose.