US-guided high-intensity focused ultrasound (HIFU) of abdominal tumors: outcome, early ablation-related laboratory changes and inflammatory reaction. A single-center experience from Germany.

INTRODUCTION: High-intensity focused ultrasound (HIFU) is an innovative noninvasive procedure for local ablation of different benign and malignant tumors. Preliminary data of animal studies suggest an ablation-associated immune response after HIFU that is induced by cell necrosis and release of intracellular components. The aim of this study is to evaluate if a HIFU-induced early sterile inflammatory reaction is initiated after ablation of uterine fibroids (UF) and pancreatic carcinoma (PaC) which might contribute to the therapeutic effect. MATERIAL AND METHODS: A hundred patients with PaC and 30 patients with UF underwent US-guided HIFU treatment. Serum markers of inflammation (leukocytes, CRP, IL-6) and LDH in both collectives as well as tumor markers CA 19-9, CEA and CYFRA in PaC patients were determined in sub-cohorts before and directly after HIFU (0, 2, 5 and 20 h post-ablation) as well as at 3, 6, 9 and 12 months follow-up. Peri-/post interventional imaging included contrast-enhanced MRI of both cohorts and an additional CT scan of PaC patients. RESULTS: An early post-ablation inflammatory response was observed in both groups with a significant increase of leukocytes, CRP and LDH within the first 20 h after HIFU. Interestingly, IL-6 was increased at 20 h after HIFU in PaC patients. A significant reduction of tumor volumes was observed during one year follow-up (p < .001) for both tumor entities demonstrating effective treatment outcome. CONCLUSION: Tumor ablation with HIFU induces an early sterile inflammation that might serve as a precondition for long-term tumor immunity and a sustainable therapeutic effect.

Clinical experience with shear wave elastography (SWE) for assessing healthy uterus in a transabdominal approach.

Aim of the study was to evaluate the diagnostic performance and feasibility of transabdominal ultrasound shear wave elastography (SWE) in assessing sonoelastographic features of the uterus. Twenty-seven premenopausal women were enrolled between 2021 and 2022. Transabdominal SWE measured myometrial stiffness in various uterine segments. Additionally, tissue stiffness of the quadriceps femoris muscle and autochthonous back muscle was measured. Statistical analysis employed non-parametric tests, t test, and a robust mixed linear model. Stiffness values of the uterus and the two investigated muscle types exhibited a similar spectrum: 6.38 ± 2.59 kPa (median 5.61 kPa; range 2.76-11.31 kPa) for the uterine myometrium, 7.22 ± 1.24 kPa (6.82 kPa; 5.11-9.39 kPa) for the quadriceps femoris musle, and 7.43 ± 2.73 kPa (7.41 kPa; 3.10-13.73 kPa) for the autochthonous back muscle. A tendency for significant differences in myometrial stiffness was observed concerning the type of labor mode (mean stiffness of 9.17 ± 1.35 kPa after vaginal birth vs. 3.83 ± 1.35 kPa after Caesarian section, p = 0.01). No significant differences in myometrial stiffness were observed concerning age, BMI, previous pregnancies, uterine flexion and menstrual cycle phase. Transabdominal SWE of uterine stiffness seems to be a fast and practicable method in a clinical setting. Uterine stiffness appears to be largely independent of various factors, except for the mode of delivery. However, further studies are needed to validate these results.

Crushed rephased orthogonal slice selection (CROSS) for simultaneous acquisition of two orthogonal proton resonance frequency temperature maps.

PURPOSE: To evaluate a novel imaging sequence termed crushed rephased orthogonal slice selection (CROSS) that uses the available time in long echo time (TE) gradient echo (GRE) imaging-as employed for proton resonance frequency (PRF) shift thermometry-to simultaneously acquire two orthogonal magnetic resonance imaging (MRI) temperature maps around the target region. MATERIALS AND METHODS: The CROSS sequence encodes a second orthogonal slice between excitation and data readout in long-TE imaging and applies dedicated crusher (CR) gradients to separate the signals from the two slices. Numerical simulations of the Bloch equations and phantom experiments were performed to analyze the MR signal. In phantom and in vivo experiments with two domestic pigs, the applicability of the CROSS sequence for temperature mapping of thermal therapies with focused ultrasound and laser was studied. RESULTS: A successful separation of the signals from the two slices was achieved for CR dephasing lengths approaching the in-plane resolution. In the two animal experiments, CROSS temperature mapping could be successfully demonstrated at a temporal resolution of 2-3 seconds and a temperature uncertainty of 3-4K. CONCLUSION: At the expense of a reduced signal in the overlap of the two slices, the CROSS sequence achieves an improvement of temporal resolution by 50%, without requiring further acceleration techniques such as parallel imaging, over conventional sequential GRE sequences employing the same repetition time as the CROSS sequence acquires two slices within one repetition interval.

Automatic planning of MR-guided transcranial focused ultrasound treatment for essential tremor.

Introduction: Transcranial focused ultrasound therapy (tcFUS) offers precise thermal ablation for treating Parkinson's disease and essential tremor. However, the manual fine-tuning of fiber tracking and segmentation required for accurate treatment planning is time-consuming and demands expert knowledge of complex neuroimaging tools. This raises the question of whether a fully automated pipeline is feasible or if manual intervention remains necessary. Methods: We investigate the dependence on fiber tractography algorithms, segmentation approaches, and degrees of automation, specifically for essential tremor therapy planning. For that purpose, we compare an automatic pipeline with a manual approach that requires the manual definition of the target point and is based on FMRIB software library (FSL) and other open-source tools. Results: Our findings demonstrate the high feasibility of automatic fiber tracking and the automated determination of standard treatment coordinates. Employing an automatic fiber tracking approach and deep learning (DL)-supported standard coordinate calculation, we achieve anatomically meaningful results comparable to a manually performed FSL-based pipeline. Individual cases may still exhibit variations, often stemming from differences in region of interest (ROI) segmentation. Notably, the DL-based approach outperforms registration-based methods in producing accurate segmentations. Precise ROI segmentation proves crucial, surpassing the importance of fine-tuning parameters or selecting algorithms. Correct thalamus and red nucleus segmentation play vital roles in ensuring accurate pathway computation. Conclusion: This study highlights the potential for automation in fiber tracking algorithms for tcFUS therapy, but acknowledges the ongoing need for expert verification and integration of anatomical expertise in treatment planning.

Improving magnetic resonance imaging with smart and thin metasurfaces.

Over almost five decades of development and improvement, Magnetic Resonance Imaging (MRI) has become a rich and powerful, non-invasive technique in medical imaging, yet not reaching its physical limits. Technical and physiological restrictions constrain physically feasible developments. A common solution to improve imaging speed and resolution is to use higher field strengths, which also has subtle and potentially harmful implications. However, patient safety is to be considered utterly important at all stages of research and clinical routine. Here we show that dynamic metamaterials are a promising solution to expand the potential of MRI and to overcome some limitations. A thin, smart, non-linear metamaterial is presented that enhances the imaging performance and increases the signal-to-noise ratio in 3T MRI significantly (up to eightfold), whilst the transmit field is not affected due to self-detuning and, thus, patient safety is also assured. This self-detuning works without introducing any additional overhead related to MRI-compatible electronic control components or active (de-)tuning mechanisms. The design paradigm, simulation results, on-bench characterization, and MRI experiments using homogeneous and structural phantoms are described. The suggested single-layer metasurface paves the way for conformal and patient-specific manufacturing, which was not possible before due to typically bulky and rigid metamaterial structures.

A long arm for ultrasound: a combined robotic focused ultrasound setup for magnetic resonance-guided focused ultrasound surgery.

PURPOSE: Focused ultrasound surgery (FUS) is a highly precise noninvasive procedure to ablate pathogenic tissue. FUS therapy is often combined with magnetic resonance (MR) imaging as MR imaging offers excellent target identification and allows for continuous monitoring of FUS induced temperature changes. As the dimensions of the ultrasound (US) focus are typically much smaller than the targeted volume, multiple sonications and focus repositioning are interleaved to scan the focus over the target volume. Focal scanning can be achieved electronically by using phased-array US transducers or mechanically by using dedicated mechanical actuators. In this study, the authors propose and evaluate the precision of a combined robotic FUS setup to overcome some of the limitations of the existing MRgFUS systems. Such systems are typically integrated into the patient table of the MR scanner and thus only provide an application of the US wave within a limited spatial range from below the patient. METHODS: The fully MR-compatible robotic assistance system InnoMotion (InnoMedic GmbH, Herxheim, Germany) was originally designed for MR-guided interventions with needles. It offers five pneumatically driven degrees of freedom and can be moved over a wide range within the bore of the magnet. In this work, the robotic system was combined with a fixed-focus US transducer (frequency: 1.7 MHz; focal length: 68 mm, and numerical aperture: 0.44) that was integrated into a dedicated, in-house developed treatment unit for FUS application. A series of MR-guided focal scanning procedures was performed in a polyacrylamide-egg white gel phantom to assess the positioning accuracy of the combined FUS setup. In animal experiments with a 3-month-old domestic pig, the system's potential and suitability for MRgFUS was tested. RESULTS: In phantom experiments, a total targeting precision of about 3 mm was found, which is comparable to that of the existing MRgFUS systems. Focus positioning could be performed within a few seconds. During in vivo experiments, a defined pattern of single thermal lesions and a therapeutically relevant confluent thermal lesion could be created. The creation of local tissue necrosis by coagulation was confirmed by post-FUS MR imaging and histological examinations on the treated tissue sample. During all sonications in phantom and in vivo, reliable MR imaging and online MR thermometry could be performed without compromises due to operation of the combined robotic FUS setup. CONCLUSIONS: Compared to the existing MRgFUS systems, the combined robotic FUS approach offers a wide range of spatial flexibility so that highly flexible application of the US wave would be possible, for example, to avoid risk structures within the US field. The setup might help to realize new ways of patient access in MRgFUS therapy. The setup is compatible with any closed-bore MR system and does not require an especially designed patient table.

Endoluminal ultrasound applicator with an integrated RF coil for high-resolution magnetic resonance imaging-guided high-intensity contact ultrasound thermotherapy.

High-intensity contact ultrasound (HICU) under MRI guidance may provide minimally invasive treatment of endocavitary digestive tumors in the esophagus, colon or rectum. In this study, a miniature receive-only coil was integrated into an endoscopic ultrasound applicator to offer high-resolution MRI guidance of thermotherapy. A cylindrical plastic support with an incorporated single element flat transducer (9.45 MHz, water cooling tip) was made and equipped with a rectangular RF loop coil surrounding the active element. The integrated coil provided significantly higher sensitivity than a four-element extracorporeal phased array coil, and the standard deviation of the MR thermometry (SDT) improved up to a factor of 7 at 10 mm depth in tissue. High-resolution morphological images (T1w-TFE and IR-T1w-TSE with a voxel size of 0.25 x 0.25 x 3 mm3) and accurate thermometry data (the PRFS method with a voxel size of 0.5 x 0.5 x 5 mm3, 2.2 s/image, 0.3 degree C voxel-wise SDT) were acquired in an ex vivo esophagus sample, on a clinical 1.5T scanner. The endoscopic device was actively operated under automatic temperature control, demonstrating a high level of accuracy (1.7% standard deviation, 1.1% error of mean value), which indicates that this technology may be suitable for HICU therapy of endoluminal cancer.

Delivery of substances and their target-specific topical activation.

Goal in pharmaceutical research is achievement of necessary drug concentrations in the target organ, effective treatment with safe delivery of genetic agents, while sparing normal tissue and minimizing side effects. A new "BioShuttle"-delivery system harbouring a cathepsin B cutting site, a nuclear address sequence and a functional peptide was developed and tumor cells were treated. Transport and subcellular activation were determined by confocal laser scanning microscopy permitting the conclusion: BioShuttle-conjugates prove as efficient tools for genetic interventions by selective and topical activation of therapeutic peptide precursors by enzymatic cleavage. As shown here for glioma cells and the cathepsin B cleavable site, living cells can be treated with high specificity and selectivity for diagnostic and therapeutic purposes.

Thermal properties and changes of acoustic parameters in an egg white phantom during heating and coagulation by high intensity focused ultrasound.

A polyacrylamide phantom containing egg white has been proposed previously as an adequate tissue-mimicking material for high intensity focused ultrasound (HIFU) application. In this work, we report on measurements of egg white phantom thermal conductivity and specific heat capacity. We measured changes in acoustical properties which occurred during the heating and the coagulation process. Using a thin thermocouple embedded in the phantom material, we recorded the temperature response in the focus of the ultrasound field during HIFU application and phantom coagulation. The measured values for the thermal conductivity (0.59 +/- 0.06 W/m/ degrees C) and the specific heat capacity (4270 +/- 365 J/kg/ degrees C) are similar to the values of water. The attenuation coefficient decreased in the temperature range between 26 degrees C and 50 degrees C and showed a nonlinear dependence on frequency with an exponent of 1.50 +/- 0.05 that was temperature-independent within the investigated temperature range. Below 65 degrees C, no irreversible changes in material absorption were observed. The coagulation process started at 67 degrees C and no adjacent rapid changes in temperature response were detected. In comparison with the noncoagulated phantom, the coagulated phantom material showed an enhanced absorption and a threefold higher attenuation coefficient at a frequency of 1 MHz.

[STEAM-sequence with multi-echo-readout for static magnetic resonance elastography]. / STEAM-sequenz mit Multi-Echo-Auslese für die statische Magnetresonanz-Elastographie.

In static magnetic resonance elastography, the elasticity of an object is determined by measuring the internal displacement between two compression states. To reduce signal loss during the long time delay between application of external deformation and the static compression state, a STEAM sequence with a long mixing time is used This results in long scan times. The aim of this work was the development of a STEAM sequence with a multi-echo-readout, which allows the reduction of scan time and number of necessary external deformations. This new sequence was compared to the standard STEAM sequence on an agarose gel phantom with a hard inclusion. In addition, the elasticity of thermal tissue lesions was investigated, which were induced using high-intensity focused ultrasound (HIFU). During a given measurement time, more acquisitions per image can be taken using the multi-echo-readout. As a result the signal-to-noise ratio is increased and errors in the data become clearly smaller. Drawbacks of. the new sequence are its higher signal loss due to T2-decay and its greater sensitivity against ghosting artefacts caused by k-space segmentation. During the investigation of the thermally-induced lesions, a clear contrast in elasticity between normal tissue and the treated region was observed. Taking advantage of the greater accuracy of the new STEAM sequence, it was shown, that this contrast is significantly larger than the one in conventional MR parameters.

Trimodal cancer treatment: beneficial effects of combined antiangiogenesis, radiation, and chemotherapy.

It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.

A focused ultrasound treatment system for moving targets (part I): generic system design and in-silico first-stage evaluation.

BACKGROUND: Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging. METHODS: A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives. RESULTS: With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator. CONCLUSIONS: The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.

Ablation of clinically relevant kidney tissue volumes by high-intensity focused ultrasound: Preliminary results of standardized ex-vivo investigations.

PURPOSE: To investigate strategies to achieve confluent kidney-tissue ablation by high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Our model of the perfused ex-vivo porcine kidney was used. Tissue ablation was performed with an experimental HIFU device (Storz Medical, Kreuzlingen, Switzerland). Lesion-to-lesion interaction was investigated by varying the lesion distance (5 to 2.5 mm), generator power (300, 280, and 260 W), cooling time (10, 20, and 30 seconds), and exposure time (4, 3, and 2 seconds). The lesion rows were analyzed grossly and by histologic examination (hematoxylin-eosin and nicotinamide adenine dinucleotide staining). RESULTS: It was possible to achieve complete homogeneous ablation of a clinically relevant tissue volume but only by meticulous adjustment of the exposure parameters. Minimal changes in these parameters caused changes in lesion formation with holes within the lesions and lesion-to-lesion interaction. CONCLUSIONS: Our preliminary results show that when using this new device, HIFU can ablate a large tissue volume homogeneously in perfused ex-vivo porcine tissue under standardized conditions with meticulous adjustment of exposure parameters. Further investigations in vivo are necessary to test whether large tissue volumes can be ablated completely and reliably despite the influence of physiologic tissue and organ movement.

Magnetic resonance imaging for assessment of radiofrequency lesions in kidney tissue immediately after ablation: an experimental study.

BACKGROUND AND PURPOSE: Radiofrequency ablation (RFA) is an attractive minimally invasive treatment option for small renal masses. The purpose of this study was to investigate the morphologic imaging appearance of RF lesions immediately after the ablation of kidney tissue using standard clinical MR sequences, as well as to investigate the correlation between MR and gross lesion size. MATERIALS AND METHODS: Ablations were performed 17 times in a standardized model of ex-vivo perfused porcine kidneys using a resistance-controlled RF device (250 W, 470 kHz) and a nonexpandable bipolar applicator inserted into the center of healthy renal parenchyma. The RF current was applied for 9 minutes at 20 W. Imaging was performed after ablation using standard clinical MR sequences: morphologic T(1)/T(2)- weighted images and an isotropic post-contrast T(1) high-resolution measurement (VIBE). Maximum lesion diameters were measured in three directions and were compared with the measurements of the gross lesions. Histologic (hematoxylin + eosin and nicotinamide adenine dinucleotide staining) and statistical analyses were performed. RESULTS: The gross pathologic examination showed a firm, white-yellow ablation zone sharply demarcated from the untreated tissue. The histologic examination confirmed cellular viability outside but not in the treatment zone. The RF lesions were hyperintense on T(1)-weighted images and hypointense on T(2)-weighted images. The lesion size measured in the VIBE images correlated best with the macroscopic lesion size (N = 16). CONCLUSIONS: Morphologic MR T(1) and T(2) sequences of RF lesions immediately after ablation produce reliable and consistent imaging characteristics. The post-contrast, high-resolution sequence (VIBE) enables the extent of the lesion to be determined accurately. The potential uses of this imaging strategy in clinical practise warrant further investigation on human renal-cell carcinoma.

[Sound-field modification with acoustic lenses for high-intensity focused ultrasound therapy]. / Schallfeldformung mittels akustischer Linsen bei der Therapie mit hochenergetischen fokussierten Ultraschallwellen.

High-intensity focused ultrasound (HIFU) therapy is a minimally invasive method for precise thermal tissue destruction. Most applications make use of spherical, sharply focused fixed-focus transducers. These allow only small ablation rates, thus the treatment of large tumours is a very time-consuming process. The present paper describes the design of ancillary lenses, which combined with a spherical focused ultrasound transducer can be employed to reduce treatment time. The ancillary lenses shift the phase of the focused ultrasound waves, so that instead of one ellipsoidal focus multiple foci are generated. Thus, a single sonication can achieve a larger ablated area. To estimate the therapeutic benefits of the designed lenses, the lesion development during sonication was numerically simulated. Two "optimal" lenses were made of polystyrene and acoustically analysed. Using the designed lenses the theoretical lesion rate was increased by a factor of 3.7-5. There was a good correlation between simulated and measured ultrasound pressure field. The lenses reduced the system efficiency by only 13%. Thus, ancillary lenses present a technically simple and cost-effective method to accelerate ablative ultrasound therapy.

Intracellular visualization of prostate cancer using magnetic resonance imaging.

The term "molecular imaging" can be broadly defined as the in vivo characterization and measurement of biological processes at the cellular and molecular level. Is a gene expression magnetic resonance imaging (MRI) possible? Therefore, we have developed a novel intravital and intracellular MRI contrast agent composed of a gadolinium complex, an oligonucleotide sequence [peptide nucleic acid (PNA)], and a transmembrane carrier peptide that is composed of a peptide sequence similar to that of the homeodomain of the Antennapedia protein. The goal of our study was to determine whether this contrast agent could be accumulated in tumor cells in vitro (HeLa cells) and in vivo (Dunning R3327 AT1 rat prostate adenocarcinoma) and whether the specificity of the PNA for the up-regulated c-myc mRNA in the cell's cytoplasm would have an effect on contrast agent retention in the tumor cells. Using the c-myc-specific and a c-myc-nonspecific control PNA, an increase in signal intensity in the tumor cells was observed after 10 min in vitro and in vivo (maximum was reached in HeLa cells in vitro in 60 min, in Dunning R3327 AT1 rat prostate adenocarcinoma cells in vivo in 30 min). This increase of signal intensity could be maintained in vitro in HeLa cells for only 4 h and in Dunning R3327 AT1 rat prostate adenocarcinoma cells in vivo at least for 5 h by using the c-myc mRNA-specific PNA as a "retention" agent.

CNN-Gd(3+) enables cell nucleus molecular imaging of prostate cancer cells: the last 600 nm.

Molecular imaging is defined as the characterization and measurement of biological processes at the cellular and molecular level. Molecular imaging, therefore, necessitates a sufficient amount of contrast agent within the cell. Consequently, we realized that the intracellular uptake and cell compartment specificity of the commonly used interstitial contrast agent gadolinium (Gd(3+)) with a cell-nucleus directed peptide module could be helpful. This modular molecule is characterized by a Gd(3+)-complex module that is bound to a transmembrane transport unit (TPU) of human origin and further to a nucleus-directed address module (nuclear localization sequence) resulting in a specific cell nucleus-directed nuclear localization sequence-conjugated Gd(3+)-complex (CNN-Gd(3+)-complex). By use of magnetic resonance imaging, Gd(3+) was detected within DU-145 prostate cancer cells after only 10 min. The nuclear localization was confirmed with confocal laser scanning microscopy. The resulting MRI signal enhancement only slightly decreased over the next 48 h compared with an absolute loss of signal enhancement after only 8 h when a random target sequence was used. Therefore, our method seems promising for in vivo application in molecular imaging.

Combined inhibition of TGFß and PDGF signaling attenuates radiation-induced pulmonary fibrosis.

Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor ß (TGFß) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFß receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFß inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFß-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFß pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGFß signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFß and PDGF play a key role. Here, we show that a combined inhibition of TGFß and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the TGFß-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of TGFß and PDGF signaling and the attenuation of SPP1 (Osteopontin) expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis (IPF), our study suggests that the combined application of small molecule inhibitors of TGFß and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer.

Non-invasive transcranial brain ablation with high-intensity focused ultrasound.

The idea to ablate brain tissue with high-intensity focused ultrasound (HIFU) in a highly precise and localized manner is relatively old. For HIFU tissue ablation, ultrasound (US) waves are concentrated to a focal point. Due to US absorption, the focal area will be heated and consequently thermally destroyed. The spatial accuracy of the non-invasive procedure and the sharp delineation of the induced tissue lesions have led to the term 'focused ultrasound surgery' (FUS). The major obstacle for HIFU ablation in the brain is the skull bone, which absorbs most of the US energy and disturbs the focused US field. The development of large-sized phased array US transducers and adaptive focusing techniques based on computed tomography images have allowed these difficulties to be overcome. With the combination of FUS and MR-imaging and MR-thermometry (MR-guided Focused Ultrasound Surgery, MRgFUS), real-time therapy guidance and control has been established. The safety, feasibility and effectiveness of transcranial MRgFUS were investigated in four initial clinical studies including 4 to 15 patients each. In the first study, which dealt with the treatment of inoperable recurrent glioblastoma, MR was used to monitor localized tissue heating, but no tissue ablation was possible due to technical restrictions of the treatment setup. With improved equipment, the precise induction of thermal lesions in the target area was achieved in studies on neuropathic pain and essential tremor. An instantaneous and persistent significant improvement of disease symptoms was observed in most patients. However, there were serious adverse effects in two cases, where intracranial hemorrhages appeared due to the induction of cavitation. Based on these encouraging clinical results, more extensive clinical studies have been initiated. Transcranial MRgFUS is a fast-growing field of neurological research with high clinical potential.

First Steps Toward Ultrasound-Based Motion Compensation for Imaging and Therapy: Calibration with an Optical System and 4D PET Imaging.

Target motion, particularly in the abdomen, due to respiration or patient movement is still a challenge in many diagnostic and therapeutic processes. Hence, methods to detect and compensate this motion are required. Diagnostic ultrasound (US) represents a non-invasive and dose-free alternative to fluoroscopy, providing more information about internal target motion than respiration belt or optical tracking. The goal of this project is to develop an US-based motion tracking for real-time motion correction in radiation therapy and diagnostic imaging, notably in 4D positron emission tomography (PET). In this work, a workflow is established to enable the transformation of US tracking data to the coordinates of the treatment delivery or imaging system - even if the US probe is moving due to respiration. It is shown that the US tracking signal is equally adequate for 4D PET image reconstruction as the clinically used respiration belt and provides additional opportunities in this concern. Furthermore, it is demonstrated that the US probe being within the PET field of view generally has no relevant influence on the image quality. The accuracy and precision of all the steps in the calibration workflow for US tracking-based 4D PET imaging are found to be in an acceptable range for clinical implementation. Eventually, we show in vitro that an US-based motion tracking in absolute room coordinates with a moving US transducer is feasible.