Frank Hübner

Detection of hepatocellular carcinoma in transgenic mice by Gd-DTPA- and rhodamine 123-conjugated human serum albumin nanoparticles in T1 magnetic resonance imaging

Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd-Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI, which currently provides the most sensitive detection of HCC in patients. Immunohistochemical analyses revealed that the Gd-Rho-HSA-NPs were localized to macrophages, which were - similar to HCC in patients - fewer in number in HCC as compared to the liver tissue, which is in agreement with the negative contrasting of HCC in Gd-Rho-HSA-NP-enhanced MRI. Poloxamine-coated NPs showed lower accumulation in the tumor macrophages and caused a longer lasting enhancement of the MRI signal. These data indicate that Gd-Rho-HSA-NPs enable sensitive detection of HCC by T1-weighted MRI in mice with endogenous HCC through their uptake by macrophages. Poloxamine coating of the NPs delayed the tumor localization of the NPs.

A liver-mimicking MRI phantom for thermal ablation experiments

PURPOSE To develop a liver-mimicking MRI gel phantom for use in the development of temperature mapping and coagulation progress visualization tools needed for the thermal tumor ablation methods, including laser-induced interstitial thermotherapy (LITT) and radiofrequency ablation (RFA). METHODS A base solution with an acrylamide concentration of 30 vol. % was prepared. Different components were added to the solution; among them are bovine hemoglobin and MR signal-enhancing contrast agents (Magnevist as T1 and Lumirem as T2 contrast agent) for adjustment of the optical absorption and MR relaxation times, respectively. The absorption was measured in samples with various hemoglobin concentrations (0%-7.5%) at different temperatures (25-80 degrees C) using the near-infrared spectroscopy, measuring the transmitted radiation through the sample. The relaxation times were measured in samples with various concentrations of T1 (0.025%-0.325%) and T2 (0.4%-1.6%) contrast agents at different temperatures (25-75 degrees C), through the MRI technique, acquiring images with specific sequences. The concentrations of the hemoglobin and contrast agents of the gel were adjusted so that its absorption coefficient and relaxation times are equivalent to those of liver. To this end, the absorption and relaxation times of the gel samples were compared to reference values, measured in an ex vivo porcine liver at different temperatures through the same methods used for the gel. For validation of the constructed phantom, the absorption and relaxation times were measured in samples containing the determined amounts of the hemoglobin and contrast agents and compared with the corresponding liver values. To qualitatively test the heat resistance of the phantom, it was heated with the LITT method up to approximately 120 degrees C and then was cut to find out if it has been melted. RESULTS In contrast to liver, where the absorption change with temperature showed a sigmoidal form with a jump at T approximately equal 45 degrees C, the absorption of the gel varied slightly over the whole temperature range. However, the gel absorption presented a linear increase from approximately 1.8 to approximately 2.2 mm(-1) with the rising hemoglobin concentration. The gel relaxation times showed a linear decrease with the rising concentrations of the respective contrast agents. Conversely, with the rising temperature, both T1 and T2 increased linearly and showed almost the same trends as in liver. The concentrations of hemoglobin and T1 and T2 contrast agents were determined as 3.92 +/- 0.42 vol. %, 0.098 +/- 0.023 vol. %, and 2.980 +/- 0.067 vol. %, respectively. The measured ex vivo liver T1 value increased from approximately 300 to approximately 530 ms and T2 value from approximately 45 to approximately 52 ms over the temperature range. The phantom validation experiments resulted in absorption coefficients of 2.0-2.1 mm(-1) with variations of 1.5%-2.95% compared to liver below 50 degrees C, T1 of 246.6-597.2 ms and T2 of 40.8-67.1 ms over the temperature range of 25-75 degrees C. Using the Bland-Altman analysis, a difference mean of -6.1/1.9 ms was obtained for T1/T2 between the relaxation times of the phantom and liver. After heating the phantom with LITT, no evidence of melting was observed. CONCLUSIONS The constructed phantom is heat-resistant and MR-compatible and can be used as an alternative to liver tissue in the MR-guided thermal ablation experiments with laser to develop clinical tools for real-time monitoring and controlling the thermal ablation progress in liver.

1.5-T magnetic resonance-guided transgluteal biopsies of the prostate in patients with clinically suspected prostate cancer: technique and feasibility.

ObjectivesThe aim of this study was to examine the feasibility and safety of magnetic resonance–guided prostate biopsy (MRGBx) with a transgluteal approach in patients with cancer suspicious prostatic lesions. Materials and MethodsThis study was approved by the ethical committee. A total of 25 men with clinically suspected prostate cancer with increased prostate-specific antigen levels and at least 1 previous negative transrectal ultrasound–guided prostatic biopsy (TRUSBx) underwent diagnostic magnetic resonance (MR) imaging of the prostate. Cancer suspicious regions (CSR) were identified, and MRGBx with a transgluteal approach in a large closed-bore 1.5-T MR system was manually performed in coaxial technique, using transversal fat-suppressed T2-weighted true fast imaging with steady-state free precession sequences. Success rate, biopsy findings, side effects, procedure time, number of acquisitions for the repositioning of the needle guide, and length of the biopsy channel were documented. Follow-up was performed 24 months after the procedure. ResultsIn diagnostic MR imaging of the prostate, a total of 40 CSRs were detected in 25 patients. All MRGBx procedures were technically successful and all CSRs were biopsied. The mean number of core biopsies per CSR was 3.3 ± 1.5 (range, 1–7). Histopathological analysis revealed adenocarcinoma in 35% (14/40), acute or chronic prostatitis in 30% (12/40), adenofibromyomatous changes in 22.5% (9/40), and no identifiable pathology in 17.5% (7/40) of CSRs, with a pathological overlap for chronic prostatitis and adenofibromyomatous changes in 1 patient with biopsies in 2 CSRs. No missed prostate cancer after MR-guided biopsy in clinical follow-up was detected. Mean procedure time was 31 ± 7 minutes (range, 21–46 minutes). Side effects were hematuria (n = 7), hematospermia (n = 3), combined hematuria/hematospermia (n = 2), and infection (n=1). ConclusionMagnetic resonance–guided prostate biopsy of the prostate gland with a transgluteal approach is feasible, safe, and a promising technique for histological clarification of cancer suspicious lesions in patients with increased prostate-specific antigen levels after negative TRUSBx. Magnetic resonance–guided prostate biopsy offers a reasonable alternative to repeated TRUSBx for histological clarification of prostate cancer.

Detection of a fatty liver after binge drinking: correlation of MR-spectroscopy, DECT, biochemistry and histology in a rat model.

RATIONALE AND OBJECTIVES The purpose of this study was to evaluate the possibility of detecting a fatty liver after binge drinking in an animal model using (1)H magnetic resonance spectroscopy ((1)H-MRS), dual-energy computed tomography (DECT), biochemistry, and the gold standard of histology. MATERIALS AND METHODS In 20 inbred female Lewis rats, an alcoholic fatty liver was induced; 20 rats served as controls. To simulate binge drinking, each rat was given a dose of 9.3 g/kg body weight 50% ethanol twice, with 24 hours between applications. Forty-eight hours after the first injection, DECT and (1)H-MRS were performed. Fat content as well as triglycerides were also determined histologically and biochemically, respectively. To assess specific liver enzymes, blood was drawn from the orbital venous plexus. RESULTS In all 20 animals in the experimental group, fatty livers were detected using (1)H-MRS, DECT, and biochemical and histologic analysis. The spectroscopic fat/water ratio and the biochemical determination were highly correlated (r = 0.892, P < .05). A significant correlation was found between (1)H-MRS and histologic analysis (r = 0.941, P < .001). Also, a positive linear correlation was found between the dual-energy computed tomographic density of ΔHU and the biochemical (r = 0.751, P < .05) and histologic (r = 0.786, P < .001) analyses. CONCLUSIONS Quantification of hepatic fat content on (1)H-MRS showed high correlation with histologic and biochemical steatosis determination. In comparison to DECT, it is more suitable to reflect the severity of acute fatty liver.

Planar Microwave Sensor for Theranostic Therapy of Organic Tissue Based on Oval Split Ring Resonators

Microwave sensors in medical environments play a significant role due to the contact-less and non-invasive sensing mechanism to determine dielectric properties of tissue. In this work, a theranostic sensor based on Split Ring Resonators (SRRs) is presented that provides two operation modes to detect and treat tumor cells, exemplary in the liver. For the detection mode, resonance frequency changes due to abnormalities are evaluated, and in the treatment mode, microwave ablation is performed. The planar sensor structure can be integrated into a needle like a surgery tool that evokes challenges concerning size limitations and biocompatibility. To meet the size requirements and provide a reasonable operating frequency, properties of oval shaped SRRs are investigated. By elongating the radius of the SRR in one direction, the resonance frequency can be decreased significantly compared to circular SRR by a factor of two below 12 GHz. In order to validate the detection and treatment characteristics of the sensor, full wave simulations and measurements are examined. Clear resonance shifts are detected for loading the sensor structures with phantoms mimicking healthy and malignant tissue. For treatment mode evaluation, ex vivo beef liver tissue was ablated leading to a lesion zone 1.2 cm × 1 cm × 0.3 cm with a three minute exposure of maximum 2.1 W.

Validation of a mathematical model for laser-induced thermotherapy in liver tissue

The purpose of the study was to develop a simulation approach for laser-induced thermotherapy (LITT) that is based on mathematical models for radiation transport, heat transport, and tissue damage. The LITT ablation was applied to ex vivo pig liver tissue. Experiments were repeated with different laser powers, i.e., 22–34 W, and flow rates of the cooling water in the applicator system, i.e., 47–92 ml/min. During the procedure, the temperature was measured in the liver sample at different distances to the applicator as well as in the cooling circuit using a fiber optic thermometer. For validation, the simulation results were compared with the results of the laser ablation experiments in the ex vivo pig liver samples. The simulated and measured temperature curves presented a relatively good agreement. The Bland-Altman plot showed an average of temperature differences of –0.13 ∘C and 95%-limits-of-agreement of ±7.11 ∘C. The standard deviation amounted to ±3.63 ∘C. The accuracy of the developed simulation is comparable with the accuracy of the MR thermometry reported in other clinical studies. The simulation showed a significant potential for the application in treatment planning.

Human skeletal muscle behavior in vivo: Finite element implementation, experiment, and passive mechanical characterization.

In this study, useful methods for active human skeletal muscle material parameter determination are provided. First, a straightforward approach to the implementation of a transversely isotropic hyperelastic continuum mechanical material model in an invariant formulation is presented. This procedure is found to be feasible even if the strain energy is formulated in terms of invariants other than those predetermined by the softwares requirements. Next, an appropriate experimental setup for the observation of activation-dependent material behavior, corresponding data acquisition, and evaluation is given. Geometry reconstruction based on magnetic resonance imaging of different deformation states is used to generate realistic, subject-specific finite element models of the upper arm. Using the deterministic SIMPLEX optimization strategy, a convenient quasi-static passive-elastic material characterization is pursued; the results of this approach used to characterize the behavior of human biceps in vivo indicate the feasibility of the illustrated methods to identify active material parameters comprising multiple loading modes. A comparison of a contact simulation incorporating the optimized parameters to a reconstructed deformed geometry of an indented upper arm shows the validity of the obtained results regarding deformation scenarios perpendicular to the effective direction of the nonactivated biceps. However, for a valid, activatable, general-purpose material characterization, the material model needs some modifications as well as a multicriteria optimization of the force-displacement data for different loading modes.

Comparison of X-ray-Mammography and Planar UWB Microwave Imaging of the Breast: First Results from a Patient Study

Hemispherical and cylindrical antenna arrays are widely used in radar-based and tomography-based microwave breast imaging systems. Based on the dielectric contrast between healthy and malignant tissue, a three-dimensional image could be formed to locate the tumor. However, conventional X-ray mammography as the golden standard in breast cancer screening produces two-dimensional breast images so that a comparison between the 3D microwave image and the 2D mammogram could be difficult. In this paper, we present the design and realisation of a UWB breast imaging prototype for the frequency band from 1 to 9 GHz. We present a refined system design in light of the clinical usage by means of a planar scanning and compare microwave images with those obtained by X-ray mammography. Microwave transmission measurements were processed to create a two-dimensional image of the breast that can be compared directly with a two-dimensional mammogram. Preliminary results from a patient study are presented and discussed showing the ability of the proposed system to locate the tumor.

A thermometry software tool for monitoring laser-induced interstitial thermotherapy

The purpose of this study was to develop a thermometry software tool for temperature monitoring during laser-induced interstitial thermotherapy (LITT). C++ programming language and several libraries including DICOM Toolkit, Grassroots DICOM library, Insight Segmentation and Registration Toolkit, Visualization Toolkit and Quasar Toolkit were used. The softwares graphical user interface creates windows displaying the temperature map and the coagulation extent in the tissue, determined by the magnetic resonance imaging (MRI) thermometry with the echo planar imaging sequence and a numerical simulation based on the radiation and heat transfer in biological tissues, respectively. The software was evaluated applying the MRI-guided LITT to ex vivo pig liver and simultaneously measuring the temperature through a fiber-optic thermometer as reference. Using the software, the temperature distribution determined by the MRI method was compared with the coagulation extent simulation. An agreement was shown between the MRI temperature map and the simulated coagulation extent. Furthermore, the MRI-based and simulated temperatures agreed with the measured one - a correlation coefficient of 0.9993 and 0.9996 was obtained, respectively. The precision of the MRI temperature amounted to 2.4°C. In conclusion, the software tool developed in the present study can be applied for monitoring and controlling the LITT procedure in ex vivo tissues.

A cylindrical shaped theranostic applicator for percutaneous microwave ablation

The design of a minimally invasive surgery tool for the detection and treatment of cancerous tissue is presented. The planar structure is based on spiral resonators, with an operating frequency range from 4 GHz to 6 GHz, excited by a conventional coplanar waveguide to, firstly, extract resonance shifts to gain information about permittivity changes in the surrounded tissue. As second feature, tumorous cells can be eradicated by performing thermal ablation. The focus of this work lies in the integration of the structure in a needle-like tool with a diameter of 2.1 mm for percutaneous interventions by using a flexible substrate that is rolled into the desired shape. Full wave simulations of the planar and cylindrical structures are presented. Furthermore, initial measurements are performed to evaluate the detection and treatment mode characteristics. A dimension of the ablation zone of 2.9 cm3 is achieved with an input power of 20 W for 4min exposure.