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One of the most significant challenges in information system design is the constant and increasing need to establish interoperability between heterogeneous software systems at increasing scale. The automated translation of data between the data models and languages used by information ecosystems built around official or de facto standards is best addressed using model-driven engineering techniques, but requires handling both data and multiple levels of metadata within a single model. Standard modelling approaches are generally not built for this, compromising modelling outcomes. We establish the SLICER conceptual framework built on multilevel modelling principles and the differentiation of basic semantic relations (such as specialisation, instantiation, specification and categorisation) that dynamically structure the model. Moreover, it provides a natural propagation of constraints over multiple levels of instantiation. The presented framework is novel in its flexibility towards identifying the multilevel structure, the differentiation of relations often combined in other frameworks, and a natural propagation of constraints over multiple levels of instantiation. Refereed/Peer-reviewed

Magnetic nanoparticles are increasingly used for clinical applications such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia. A novel method of interstitial heating of tumours following direct injection of magnetic nanoparticles has been evaluated in humans in recent clinical trials. In prostate cancer this approach has been investigated in two separate phase I studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of an alternating magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography was validated. Limiting factors of the new approach at present are patient discomfort at high magnetic field strengths and irregular intratumoural heat distribution. Until these limitations are overcome and thermoablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localised prostate cancer.

In order to increase the specific power absorption (SAR) in deep seated tumors, the idea was born to use AC magnetic fields in combination with magnetic particles instead of conventional E-field dominant systems. It was found, that nanoscaled particles were superior to micron-sized, multi-domain particles in terms of SAR due to different mechanisms how the field energy is converted into heat. Crucial parameters were identified for the human application of the method, such as the AC magnetic field amplitude and frequency, the nanoparticle composition and size distribution. Based on these physical and chemical relationships, a new thermotherapy method has been developed to heat up deep regional tumors using aqueous dispersions of iron oxide nanoparticles (magnetic fluids). Several clinical studies were initiated using this new heating technology. The results of the most advanced efficacy study for recurrent glioblastoma multiforme patients in combination with conventional radiation therapy are expected at the end of this year, 16 years after publication of this fundamental paper.

The potential of colloidal subdomain ferrite particle suspensions (SDP) ('magnetic fluids'), exposed to an alternating magnetic field, is evaluated for hyperthermia. Power absorption measurements of different magnetic fluids are presented in comparison to multidomain ferrite particles (MDP). Variations with frequency as well as magnetic field strength have been investigated. The experimental results clearly indicate a definite superiority of even non-optimized magnetic fluids over MDP ferrites regarding their specific absorption rate (SAR). Based on the work of Shliomis et al. (1990) and Hanson (1991), a solid-state physical model is applied to explain the specific properties of magnetic fluids with respect to a possible use in hyperthermia. The experimentally determined SAR data on magnetic fluids are used to estimate the heating capabilities of a magnetic induction heating technique assuming typical human dimensions and tissue parameters. It is considered that for a moderate concentration of 5 mg ferrite per gram tumour (i.e. 0.5% w/w) and clinically acceptable magnetic fields, intratumoral power absorption is comparable to RF heating with local applicators and superior to regional RF heating (by comparison with clinical SAR measurements from regional and local hyperthermia treatments). Owing to the high particle density per volume, inductive heating by magnetic fluids can improve temperature distributions in critical regions. Furthermore, localized application of magnetic fluids in a tumour might be easier and less traumatic than interstitial implantation techniques.

Magnetic fluids are increasingly used for clinical applications such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia. The latter technique that has been developed as a cancer treatment for several decades comprises the injection of magnetic nanoparticles into tumors and their subsequent heating in an alternating magnetic field. Depending on the applied temperature and the duration of heating this treatment either results in direct tumor cell killing or makes the cells more susceptible to concomitant radio- or chemotherapy. Numerous groups are working in this field worldwide, but only one approach has been tested in clinical trials so far. Here, we summarize the clinical data gained in these studies on magnetic fluid induced hyperthermia.

The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique.Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transrectal ultrasound)--guided implantation with X-fluoroscopy (group B) and intra-operative infiltration under visual control (group C). In group A and B the distribution of the nanoparticles can be planned prior to implantation on the basis of three-dimensional image datasets. The specific absorption rates (SAR in W/kg) can be derived from the particle distribution imaged via CT together with the actual H-field strength (in kA/m). The temperature distribution in the tumour region is calculated using the bioheat-transfer equation assessing a mean perfusion value, which is determined by matching calculated temperatures to direct (invasive or endoluminal) temperature measurements in reference points in or near the target region.Instillation of the magnetic fluid and the thermotherapy treatments were tolerated without or with only moderate side effects, respectively. Using tolerable H-field-strengths of 3.0-6.0 kA/m in the pelvis, up to 7.5 kA/m in the thoracic and neck region and10.0 kA/m for the head, we achieved SAR of 60-380 W/kg in the target leading to a 40 degrees C heat-coverage of 86%. However, the coverage withor =42 degrees C is unsatisfactory at present (30% of the target volume in group A and only 0.2% in group B).Further improvement of the temperature distribution is required by refining the implantation techniques or simply by increasing the amount of nanofluid or elevation of the magnetic field strength. From the actual nanoparticle distribution and derived temperatures we can extrapolate, that already a moderate increase of the H-field by only 2 kA/m would significantly improve the 42 degrees C coverage towards 100% (98%). This illustrates the great potential of the nanofluid-based heating technology.

The purpose of the present study was to examine whether single human carcinoma cells labeled with iron oxide nanoparticles could be detected by magnetic resonance (MR) imaging on a clinical 3-T scanner using a surface coil only. WiDr human colon carcinoma cells were loaded with two kinds of iron oxide nanoparticles differing by coating and size: aminosilan-coated (MagForce) and carboxy-dextran-coated particles (Resovist). The latter were preferred by the colon carcinoma cell line used here and taken up much faster (12 h) than the smaller carboxydextran-coated Resovist (48 h). Labeled single carcinoma cells, distributed in an agarose gel in a monodisperse layer as controlled by light microscopy, became detectable as punctuate signal extinctions when using a small circularly polarized surface coil in conjunction with a T2*-weighted GE sequence at 3 T. The threshold for the detectability of labeled colon carcinoma cells ranged at a load of 4 –5 g iron/10 6 cells. Obviating the need for special hardware additions, this study opens a new lane for single-cell tracking on clinical 3-T MR scanners amenable to patient studies. Magn Reson Med 53:1187–1192, 2005. © 2005 Wiley-Liss, Inc.

Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.

Magnetic fractionation was applied to a common magnetic fluid based on superparamagnetic iron-oxide nano-particles with core radius of 5nm. The fractions collected were investigated with respect to particle-sizes and the influence of fractionation on the specific absorption rate, in order to optimize magnetic fluids for the application in hyperthermia.

In vitro, tumor-selective Hsp70 plasma membrane localization correlates with increased sensitivity to lysis mediated by a subpopulation of human natural killer (NK) cells that adhere to plastic following cytokine stimulation. In the present study, we analyzed the capacity of adoptively transferred human NK cells in SCID/beige mice for local tumor control and prevention of metastatic dissemination of Hsp70-expressing CX(+) and non-expressing CX(-) tumors following orthotopic (o.t.) injection. Both tumor sublines were derived by cell sorting of the original cell line, CX2, and thus exhibit an identical MHC and adhesion molecule expression pattern but differ with respect to Hsp70 plasma membrane expression. Viability of adherent, human NK cells in SCID/beige mice up to 18 days and the capacity to migrate have been demonstrated. Growth of Hsp70-expressing and non-expressing CX(+) and CX(-) tumor cells was completely suppressed when 10 x 10(6) NK cells were injected into the i.p. cavity on day 4 after inoculation of 2.5 x 10(6) tumor cells. Although a single injection of 5 or 2.5 x 10(6) NK cells was not sufficient to suppress tumor growth completely in all mice, the reduction in size of CX(+) tumors was significantly greater than that of CX(-) tumors. To mimic the clinical situation, ex vivo stimulated NK cells were injected i.v. on day 4 after o.t. injection of tumor cells. Under these conditions, growth of Hsp70-expressing primary tumors and metastases was suppressed. If CX(-) tumor cells were injected, 3 of 9 mice developed Hsp70-negative primary tumors. However, none of these mice developed distant metastases. In summary, our data indicate that Hsp70 acts as a recognition structure for adherent NK cells in a SCID/beige mouse model.

Magnetic fluids (MF) have a potential for hyperthermia due to their good power absorption capabilities. Recent in vitro experiments with the so-called 'Magnetic Fluid Hyperthermia (MFH)' have shown that human tumours cells are homogeneously inactivated after AC magnetic field excitation of extracellular MF. The aim of the present study was the evaluation of a high dose MFH on intramuscularly implanted mammary carcinoma of the mouse. The tumours originated from initial in vivo passages of a spontaneous parent tumour. Because of larger variations of tumour growth in this rather primary model, logistic regression of non-averaged volumes was performed for each treatment modality. All growing tumours were randomized 30 days after transplantation (day of treatment) with an overall size distribution between 120-400 mm3. An intratumoural steady state temperature of 47 +/- 1.0 degrees C was maintained for 30 minutes with whole-body AC magnetic fields of 6-12.5 kA/m at 520 kHz. The magnetic fluid was #P6, which is a high biocompatible dextran magnetite. #P6 was given intratumourally (1.5 x 10(-2) mg ferrite/mm3) 20-30 minutes before excitation and was combined with magnetic targeting (50 mT), which yielded a 2.5-fold enhancement of the intratumoural iron concentration. Histological examinations of tumour tissue after intralesional ferrofluid administration alone indicated deep infiltration of the fluid into the carcinoma tissue, but no evidence of tissue damage as compared with untreated controls. In contrast, widespread tumour necrosis was observed after MFH. After application of either dextran or ferrofluid alone (no difference, p = 0.665), tumour growth was slightly delayed in comparison with untreated controls (p0.001). In contrast to the good fit of the controls (R = 0.92-0.87), tumour growth after MFH was much more heterogeneous; some tumours showed no evidence for regrowth at 50 days whereas others had grown quite readily. This most probably reflected the critical problem of homogeneity of the intratumoural MF distribution, which was also confirmed qualitatively by Magnetic Resonance Imaging (MRI), heterogeneous pigmentation of MFH treated tumours, and up to 1 degree C differences between temperature probes in the same tumour during AC magnetic field application. However, a quantitative comparison between intratumoural MF-heterogeneity and tumour response could not be performed in this study. Despite these current limitations, the regression analysis of the MFH data yielded a smaller tumour volume of about 1000 mm3 at 50 days growth time in contrast to all three controls. In conclusion, encouraging results have been obtained, which show, that one single high dose MFH is already able to induce local tumour control in many cases within 30 days after treatment. To overcome the uncertainties of intratumoural MF heterogeneity, advanced intralesional application methods are currently under development.

The purpose of the present study was to examine whether single human carcinoma cells labeled with iron oxide nanoparticles could be detected by magnetic resonance (MR) imaging on a clinical 3-T scanner using a surface coil only. WiDr human colon carcinoma cells were loaded with two kinds of iron oxide nanoparticles differing by coating and size: aminosilan-coated (MagForce) and carboxy-dextran-coated particles (Resovist). The latter were preferred by the colon carcinoma cell line used here and taken up much faster (12 h) than the smaller carboxydextran-coated Resovist (48 h). Labeled single carcinoma cells, distributed in an agarose gel in a monodisperse layer as controlled by light microscopy, became detectable as punctuate signal extinctions when using a small circularly polarized surface coil in conjunction with a T(2)*-weighted GE sequence at 3 T. The threshold for the detectability of labeled colon carcinoma cells ranged at a load of 4-5 mug iron/10(6) cells. Obviating the need for special hardware additions, this study opens a new lane for single-cell tracking on clinical 3-T MR scanners amenable to patient studies.

In order to compare the intrinsic thermal sensitivity of different malignant cell lines the multi-target, single-hit model has been widely accepted. It is even applied in clinical hyperthermia by the so-called thermal isoeffect dose (TID) concept originated from this model. The second model which is preferentially used to describe radiation survival curves is the linear-quadratic (LQ) model which can be also applied to thermal response. Interestingly, no breaking point and different activation energies are obtained with this model. In the present paper we demonstrate this discrepancy with the two human colonic adenocarcinoma cell lines WiDr and SW620. Our results further validate the already earlier published persuasion, that neither the multi-target, single-hit model, nor the LQ model are adequate to describe hyperthermic survival. Since both models give completely different results, further data aquisition of isoeffect factors, breaking points and activation enthalpies based on the multi-target, single-hit model only, is unprofitable until advanced models of thermal inactivation have been developed.