Validation of a dose deposited by low-energy photons using GATE/GEANT4.

The GATE Monte Carlo simulation platform based on the Geant4 toolkit has now become a diffused tool for simulating PET and SPECT imaging devices. In this paper, we explore its relevance for dosimetry of low-energy 125I photon brachytherapy sources used to treat prostate cancers. To that end, three 125-iodine sources widely used in prostate cancer brachytherapy treatment have been modelled. GATE simulations reproducing dosimetric reference observables such as radial dose function g(r), anisotropy function F(r, theta) and dose-rate constant (Lambda) were performed in liquid water. The calculations were splitted on the EGEE grid infrastructure to reduce the computing time of the simulations. The results were compared to other relevant Monte Carlo results and to measurements published and fixed as recommended values by the AAPM Task Group 43. GATE results agree with consensus values published by AAPM Task Group 43 with an accuracy better than 2%, demonstrating that GATE is a relevant tool for the study of the dose induced by low-energy photons.

Grid-added value to address malaria.

Through this paper, we call for a distributed, Internet-based collaboration to address one of the worst plagues of our present world, malaria. The spirit is a nonproprietary peer-production of information-embedding goods. And we propose to use the grid technology to enable such a worldwide "open-source" like collaboration. The first step toward this vision has been achieved during the summer 2005 on the enabling grids for E-scienceE (EGEE) grid infrastructure where 42 million ligands were docked for a total amount of 80 CPU years in 6 weeks in the quest for new drugs. The impact of this first deployment has significantly raised the interest of the research community so that several laboratories all around the world expressed interest to propose targets for a second large-scale deployment against malaria.

HOPE, an open platform for medical data management on the grid.

The paper describes a platform developed for the secure management and analysis of medical data and images in a grid environment. Designed for telemedicine and built upon the EGEE gLite middleware and particularly the metadata catalogue AMGA as well as the GridSphere web portal, the platform provides to healthcare professionals the capacity to upload and query medical information stored over distributed servers. A job submission environment is also available for data analysis. Security features include authentication and authorization by grid certificates, anonymization of medical data and image encryption. The platform is currently deployed on several sites in Europe and Asia and is being customized for applications in the field of telemedicine and medical physics.

The SHARE road map: Healthgrids for biomedical research and healthcare.

The HealthGrid White Paper was published at the third annual conference in Oxford in 2005. Starting from the conclusions of the White Paper, the EU funded SHARE project (http://www.eu-share.org) has aimed at identifying the most important steps and significant milestones towards wide deployment and adoption of healthgrids in Europe. The project has defined a strategy to address the issues identified in the action plan for European e-Health (COM(2004).356) and has devised a roadmap for the major technological and ethical and legal developments and social and economic investments needed for successful take up of healthgrids in the next 10 years. A "beta" version of the road map underwent full review by a panel of 25 prominent European experts at a workshop in December 2007. The present document is an executive policy summary of the final draft road map. It has sought to reconcile likely conflicts between technological developments and regulatory frameworks by bringing together the project's technical road map and conceptual map of ethical and legal issues and socio-economic prospects. A key tool in this process was a collection of case studies of healthgrid applications.

Replication and update of molecular biology databases.

Update of molecular biology databases is a growing burden on the biomedical research community. As the grid allows to share and replicate data, we propose a service to automatically update the molecular biology databases from a single changing reference using Web services. In this paper we report the components, the architecture, and the deployment of the update service on the french RUGBI grid infrastructure. RUGBI is a computing grid infrastructure based on existing middleware and technologies for the community of scientists in bioinformatics.

Fully 3D Monte Carlo reconstruction in SPECT: a feasibility study.

In single photon emission computed tomography (SPECT) with parallel hole collimation, image reconstruction is usually performed as a set of bidimensional (2D) analytical or iterative reconstructions. This approach ignores the tridimensional (3D) nature of scatter and detector response function that affects the detected signal. To deal with the 3D nature of the image formation process, iterative reconstruction can be used by considering a 3D projector modelling the 3D spread of photons. In this paper, we investigate the value of using accurate Monte Carlo simulations to determine the 3D projector used in a fully 3D Monte Carlo (F3DMC) reconstruction approach. Given the 3D projector modelling all physical effects affecting the imaging process, the reconstruction problem is solved using the maximum likelihood expectation maximization (MLEM) algorithm. To validate the concept, three data sets were simulated and F3DMC was compared with two other 3D reconstruction strategies using analytical corrections for attenuation, scatter and camera point spread function. Results suggest that F3DMC improves spatial resolution, relative and absolute quantitation and signal-to-noise ratio. The practical feasibility of the approach on real data sets is discussed.

Partitioning medical image databases for content-based queries on a Grid.

OBJECTIVES: In this paper we study the impact of executing a medical image database query application on the grid. For lowering the total computation time, the image database is partitioned into subsets to be processed on different grid nodes. METHODS: A theoretical model of the application complexity and estimates of the grid execution overhead are used to efficiently partition the database. RESULTS: We show results demonstrating that smart partitioning of the database can lead to significant improvements in terms of total computation time. CONCLUSIONS: Grids are promising for content-based image retrieval in medical databases.

Empowering humanitarian medical development using grid technology.

BACKGROUND: The training of local clinicians is the best way to raise the standard of medical knowledge in developing countries. This requires transferring skills, techniques and resources. OBJECTIVES: Grid technology opens new perspectives for preparation and follow-up of medical missions in developing countries as well as support to local medical centers in terms of teleconsulting, telediagnosis and patient follow-up. Indeed, grids allow to hide the complexity of handling distributed data in such a way that physicians will be able to access patient data while ignoring where these data are stored. METHODS: To meet requirements of a development project of the French NPO Chain of Hope in China, we propose to deploy a grid-based federation of databases. FIRST RESULTS AND CONCLUSIONS: A first protocol was established for describing the patients' pathologies and their pre- and post-surgery states through a web interface in a language-independent way. This protocol was evaluated by French and Chinese clinicians during medical missions in the fall of 2003. The first sets of medical patients recorded in the databases will be used to evaluate grid implementation of services.

First determination of generalized polarizabilities of the proton by a virtual compton scattering experiment

Absolute differential cross sections for the reaction ep-->epgamma have been measured at a four-momentum transfer with virtuality Q2 = 0.33 GeV2 and polarization epsilon = 0.62 in the range 33.6 to 111.5 MeV/c for the momentum of the outgoing photon in the photon-proton center of mass frame. The experiment has been performed with the high-resolution spectrometers at the Mainz Microtron MAMI. From the photon angular distributions, two structure functions which are a linear combination of the generalized polarizabilities have been determined for the first time.

Quantification of hepatitis C virus RNA in serum by branched DNA-based signal amplification assays.

The objective of the study was to compare the clinical sensitivity and specificity of versions 1.0 and 2.0 of the branched DNA (bDNA)-based hepatitis C virus (HCV) RNA quantification assay, and also to compare the values yielded by the two versions according to the HCV genotype. Serum samples from 268 patients tested routinely by a non-quantitative HCV RNA PCR assay (group A) were tested with version 2.0 of the bDNA assay. Samples from 342 HCV PCR-positive patients with chronic hepatitis C eligible for interferon treatment (group B) were tested with both version 1.0 and version 2.0 of the bDNA assay. Version 2.0 had a clinical sensitivity of 92% (95% confidence interval (CI): 87-97%) in group A and 89% (86-92%) in group B. In group B, the gain in sensitivity with bDNA 2.0 was 16% relative to bDNA 1.0 (P < 0.001). The log values of the two assays correlated with samples positive by both assays (r = 0.83, P < 0.0001), but the distribution of values was larger in samples containing HCV genotypes 2 and 3. The mean ratio of assay 2.0/assay 1.0 values was 1.69 +/- 1.44 (range: 0.33-13.43). The mean ratio was close to 1 with samples containing genotype 1 or 4, but ranged from 0.33 to more than 5. The mean ratio was close to 3 with samples containing genotype 2 or 3, and ranged from 0.5 to more than 13. HCV RNA levels were significantly lower in samples containing genotype 4 than in those containing other genotypes. Sera from 200 anti-HCV-negative, HCV RNA PCR-negative blood donors (group C), and from 164 anti-HCV-negative patients with symptoms of chronic liver disease (group D) were used to assess the clinical specificity of bDNA 2.0. In addition, samples with an HCV RNA titer between 0.2 (assay cutoff) and 0.5 MEq/ml from a group of 546 patients tested routinely for HCV RNA load by bDNA 2.0 (group E) were retested by bDNA 2.0 and by qualitative PCR. The specificity of bDNA 2.0 was 100% (98-100%) in group C and 99% (97-100%) in group D. Among the 41 samples from group E, 38 were positive by bDNA 2.0 retesting (36 were PCR-positive) and three were negative by bDNA 2.0 retesting (all were PCR-positive). It is concluded that version 2.0 of the bDNA assay is markedly more sensitive than version 1.0 and has a good specificity. In contrast with version 1.0, version 2.0 is not influenced by the HCV genotype. The relationship between values obtained with assays 1.0 and 2.0 on clinical specimens is not linear, indicating that HCV RNA titers cannot reliably be calculated from the results of version 1.0.

Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic hepatitis C.

OBJECTIVES: (i) To characterize serum cytokine levels of tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL 6), IL 8 and IL 12 in non-cirrhotic patients with chronic hepatitis C, (ii) to correlate the levels of these cytokines with the degree of the disease at the basal level, (iii) to correlate these levels with the response to therapy, (iv) to compare profiles of cytokines in monotherapy (MT) versus combination therapy (CT), and (v) to compare the immunomodulatory effects of MT versus CT. DESIGN AND METHODS: 47 patients were enrolled in the study. The controls were 120 volunteers (recruited from students and staff) that did not present HCV RNA positive and were not known to suffer any other metabolic disease. Thirty patients formed the other group of controls, with alcoholic liver disease (ALD). Serum cytokine levels were assessed using enzyme-linked immunosorbent assay (ELISA). RESULTS: The sustained responders (SRs) have basal values much lower than relapsed responders (RRs) and non-responders (NRs) regardless of the therapy. CONCLUSIONS: Cytokines can be used as non-invasive markers for sustained response and as monitors for the outcome of therapy.

Predictors of event-free survival after percutaneous mitral commissurotomy.

OBJECTIVE: To assess the long term functional result after percutaneous mitral commissurotomy and identify the predictors of event-free survival following 10 years of experience. DESIGN: Analysis of clinical, echocardiographic, and haemodynamic variables at baseline and after the procedure by univariate and multivariate analyses (Cox model). SETTING: University hospital. PATIENTS: 532 consecutive patients receiving percutaneous mitral commissurotomy in the same institution. RESULTS: The mean (SD) follow up was 3.8 (4.0) years. Survival at 3, 5, and 7.5 years was 94%, 91%, and 83%, respectively; event-free survival was 84%, 74%, and 52%. Mitral valve anatomy was identified as the strongest independent predictor of event-free survival. Age, cardiothoracic ratio, mean pulmonary artery pressure, and mean echocardiographic mitral gradient after commissurotomy were also found to be independent predictors of long term functional results. Event-free survival was 92%, 84%, and 70% at 3, 5, and 7.5 years in patients with favourable anatomy (echo score = 1), 86%, 73%, and 34% in patients with intermediate anatomy (echo score = 2), and 45%, 25%, and 16% in patients with unfavourable anatomy (echo score = 3). In patients aged < or = 65 years, the event-free survival rate was 80%, 70%, and 45% at 3, 5, and 7.5 years v 52%, 38%, and 17% in patients aged > 65 years. CONCLUSIONS: The anatomical form of the mitral valve and the patient's age were the most powerful predictors of event-free survival. Patients with intermediate or unfavourable anatomy and those aged > 65 years have low 5 and 7.5 year event-free survival rates. This must be taken into account when discussing the indications for percutaneous mitral commissurotomy; immediate mitral valve replacement is a reasonable alternative to balloon mitral commissurotomy in patients with higher risk of functional deterioration after the procedure.

Validation of the GATE Monte Carlo simulation platform for modelling a CsI(Tl) scintillation camera dedicated to small-animal imaging.

Monte Carlo simulations are increasingly used in scintigraphic imaging to model imaging systems and to develop and assess tomographic reconstruction algorithms and correction methods for improved image quantitation. GATE (GEANT4 application for tomographic emission) is a new Monte Carlo simulation platform based on GEANT4 dedicated to nuclear imaging applications. This paper describes the GATE simulation of a prototype of scintillation camera dedicated to small-animal imaging and consisting of a CsI(Tl) crystal array coupled to a position-sensitive photomultiplier tube. The relevance of GATE to model the camera prototype was assessed by comparing simulated 99mTc point spread functions, energy spectra, sensitivities, scatter fractions and image of a capillary phantom with the corresponding experimental measurements. Results showed an excellent agreement between simulated and experimental data: experimental spatial resolutions were predicted with an error less than 100 microns. The difference between experimental and simulated system sensitivities for different source-to-collimator distances was within 2%. Simulated and experimental scatter fractions in a [98-182 keV] energy window differed by less than 2% for sources located in water. Simulated and experimental energy spectra agreed very well between 40 and 180 keV. These results demonstrate the ability and flexibility of GATE for simulating original detector designs. The main weakness of GATE concerns the long computation time it requires: this issue is currently under investigation by the GEANT4 and the GATE collaborations.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

DataGrid, prototype of a biomedical grid.

BACKGROUND: The availability of large amounts of data in heterogeneous formats and the rapid progress in fields such as computer based drug design, medical imaging and medical simulations have lead to a growing demand for large computational power and easy accessibility to heterogeneous data sources. OBJECTIVES: The goal is to address these needs by deploying computing grids. Grids provide both large scale and distributed storage facilities and an increased computing power. Moreover, Grids are a promising tool to foster the synergy between bioinformatics and computerised medical imaging. METHODS: A first biomedical grid is being deployed within the framework of the DataGrid IST project (http://www.edg.org). The goal of the project is to provide a novel environment to support globally distributed scientific exploration involving up to multi-Perabyte datasets. RESULTS AND CONCLUSIONS: The first biomedical applications deployed inside the project demonstrate the relevance of the grid paradigm for genomics and medical image processing. They also highlight the specific requirements of the biomedical community.

Host-related carcinoembryonic antigen cell adhesion molecule 1 promotes metastasis of colorectal cancer.

Liver metastasis is the predominant cause of colorectal cancer (CRC)-related mortality in developed countries. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell adhesion molecule with reduced expression in early phases of CRC development and thus functions as a tumor growth inhibitor. However, CEACAM1 is upregulated in metastatic colon cancer, suggesting a bimodal role in CRC progression. To investigate the role of this protein in the host metastatic environment, Ceacam1(-/-) mice were injected intrasplenically with metastatic MC38 mouse CRC cells. A significant reduction in metastatic burden was observed in Ceacam1(-/-) compared with wild-type (WT) livers. Intravital microscopy showed decreased early survival of MC38 cells in Ceacam1(-/-) endothelial environment. Metastatic cell proliferation within the Ceacam1(-/-) livers was also diminished. Bone marrow-derived cell recruitment, attenuation of immune infiltrates and diminished CCL2, CCL3 and CCL5 chemokine production participated in the reduced Ceacam1(-/-) metastatic phenotype. Transplantations of WT bone marrow (BM) into Ceacam1(-/-) mice fully rescued metastatic development, whereas Ceacam1(-/-) BM transfer into WT mice showed reduced metastatic burden. Chimeric immune cell profiling revealed diminished recruitment of CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) to Ceacam1(-/-) metastatic livers and adoptive transfer of MDSCs confirmed the involvement of these immune cells in reduction of liver metastasis. CEACAM1 may represent a novel metastatic CRC target for treatment.

Comparison of GATE/GEANT4 with EGSnrc and MCNP for electron dose calculations at energies between 15 keV and 20 MeV.

The GATE Monte Carlo simulation platform based on the GEANT4 toolkit has come into widespread use for simulating positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging devices. Here, we explore its use for calculating electron dose distributions in water. Mono-energetic electron dose point kernels and pencil beam kernels in water are calculated for different energies between 15 keV and 20 MeV by means of GATE 6.0, which makes use of the GEANT4 version 9.2 Standard Electromagnetic Physics Package. The results are compared to the well-validated codes EGSnrc and MCNP4C. It is shown that recent improvements made to the GEANT4/GATE software result in significantly better agreement with the other codes. We furthermore illustrate several issues of general interest to GATE and GEANT4 users who wish to perform accurate simulations involving electrons. Provided that the electron step size is sufficiently restricted, GATE 6.0 and EGSnrc dose point kernels are shown to agree to within less than 3% of the maximum dose between 50 keV and 4 MeV, while pencil beam kernels are found to agree to within less than 4% of the maximum dose between 15 keV and 20 MeV.