[Ultrasound motion tracking for radiation therapy]. / Ultraschallbewegungstracking für die Strahlentherapie.

BACKGROUND: In modern radiotherapy the radiation dose can be applied with an accuracy in the range of 1-2 mm provided that the exact position of the target is known. If, however, the target (the tumor) is located in the lungs or the abdomen, respiration or peristalsis can cause substantial movement of the target. METHODS: Various methods for intrafractional motion detection and compensation are currently under consideration or are already applied in clinical practice. Sonography is one promising option, which is now on the brink of clinical implementation. Ultrasound is particularly suited for this purpose due to the high soft tissue contrast, real-time capability, the absence of ionizing radiation and low acquisition costs. Ultrasound motion tracking is an image-based approach, i.e. the target volume or an adjacent structure is directly monitored and the motion is tracked automatically on the ultrasound image. Diverse algorithms are presently available that provide the real-time target coordinates from 2D as well as 3D images. Definition of a suitable sonographic window is not, however, trivial and a gold standard for positioning and mounting of the transducer has not yet been developed. Furthermore, processing of the coordinate information in the therapy unit and the dynamic adaptation of the radiation field are challenging tasks. CONCLUSION: It is not clear whether ultrasound motion tracking will become established in the clinical routine although all technical prerequisites can be considered as fulfilled, such that exciting progress in this field of research is still to be expected.

The 2014 liver ultrasound tracking benchmark.

The Challenge on Liver Ultrasound Tracking (CLUST) was held in conjunction with the MICCAI 2014 conference to enable direct comparison of tracking methods for this application. This paper reports the outcome of this challenge, including setup, methods, results and experiences. The database included 54 2D and 3D sequences of the liver of healthy volunteers and tumor patients under free breathing. Participants had to provide the tracking results of 90% of the data (test set) for pre-defined point-landmarks (healthy volunteers) or for tumor segmentations (patient data). In this paper we compare the best six methods which participated in the challenge. Quantitative evaluation was performed by the organizers with respect to manual annotations. Results of all methods showed a mean tracking error ranging between 1.4 mm and 2.1 mm for 2D points, and between 2.6 mm and 4.6 mm for 3D points. Fusing all automatic results by considering the median tracking results, improved the mean error to 1.2 mm (2D) and 2.5 mm (3D). For all methods, the performance is still not comparable to human inter-rater variability, with a mean tracking error of 0.5-0.6 mm (2D) and 1.2-1.8 mm (3D). The segmentation task was fulfilled only by one participant, resulting in a Dice coefficient ranging from 76.7% to 92.3%. The CLUST database continues to be available and the online leader-board will be updated as an ongoing challenge.

Ultrasound tracking for intra-fractional motion compensation in radiation therapy.

Modern techniques as ion beam therapy or 4D imaging require precise target position information. However, target motion particularly in the abdomen due to respiration or patient movement is still a challenge and demands methods that detect and compensate this motion. Ultrasound represents a non-invasive, dose-free and model-independent alternative to fluoroscopy, respiration belt or optical tracking of the patient surface. Thus, ultrasound based motion tracking was integrated into irradiation with actively scanned heavy ions. In a first in vitro experiment, the ultrasound tracking system was used to compensate diverse sinusoidal target motions in two dimensions. A time delay of ∼200 ms between target motion and reported position data was compensated by a prediction algorithm (artificial neural network). The irradiated films proved feasibility of the proposed method. Furthermore, a practicable and reliable calibration workflow was developed to enable the transformation of ultrasound tracking data to the coordinates of the treatment delivery or imaging system - even if the ultrasound probe moves due to respiration. A first proof of principle experiment was performed during time-resolved positron emission tomography (4DPET) to test the calibration workflow and to show the accuracy of an ultrasound based motion tracking in vitro. The results showed that optical ultrasound tracking can reach acceptable accuracies and encourage further research.

Ion beam tracking using ultrasound motion detection.

PURPOSE: The use of motion mitigation techniques such as tracking and gating in particle therapy requires real-time knowledge of tumor position with millimeter precision. The aim of this phantom-based study was to evaluate the option of diagnostic ultrasound (US) imaging (sonography) as real-time motion detection method for scanned heavy ion beam irradiation of moving targets. METHODS: For this pilot experiment, a tumor surrogate was moved inside a water bath along two-dimensional trajectories. A rubber ball was used for this purpose. This ball was moved by a robotic arm in two dimensions lateral to the heavy ion beam. Trajectories having a period of 3 s and peak to peak amplitude of 20 mm were used. Square radiation fields of[Formula: see text] were irradiated on radiosensitive films with a 200 MeV/u beam of calcium ions having a FWHM of 6 mm. Pencil beam scanning and beam tracking were employed. The films were attached on the robotic arm and thus moved with the rubber ball. The position of the rubber ball was continuously measured by a US tracking system (Mediri GmbH, Heidelberg) and sent to the GSI therapy control system (TCS). This position was used as tracking vector. Position reconstruction from the US tracking system and data communication introduced a delay leading to a position error of several millimeters. An artificial neural network (ANN) was implemented in the TCS to predict motion from US measurements and thus to compensate for the delay. RESULTS: Using ANN delay compensation and large motion amplitudes, the authors could produce irradiation patterns with a few percent inhomogeneity and about 1 mm geometrical conformity. CONCLUSIONS: This pilot experiment suggests that diagnostic US should be further investigated as dose-free, high frame-rate, and model-independent motion detection method for scanning heavy ion beam irradiation of moving targets.

Neurons but not glial cells overexpress ubiquitin in the rat brain following focused ultrasound-induced opening of the blood-brain barrier.

Focused ultrasound-induced opening of the blood-brain barrier (BBB) in the presence of ultrasound contrast agents is a promising strategy for a targeted drug delivery to the brain. The aim of our study was to identify whether brain molecular stress pathways are targeted by ultrasound treatment. Using an upper level of acoustic pressures in combination with microbubbles, which have been previously reported as reliable for BBB opening without causing tissue damage, we found that ultrasound leads to an increased ubiquitinylation of proteins in neuronal (11+/-3 ubiquitin-overexpressing cells per optical field) but not glial cells 6 h post-insonation, increasing to 16 (+/-4) labelled cells after 24 h. No changes in the expression of Hsp70 and Hsc70 were detected over 24 h. Ultrasound treatment was followed by limited apoptosis after 24 h (32+/-6 cleaved-caspase 3-positive cells per optical field) in the insonated areas. Only neurons were identified in the apoptotic population. Although these observations may not be applicable for all acoustic parameters useful for BBB opening, they demonstrate that insonation of the rat brain with the parameters used in our experiments is a useful tool for BBB opening and induces specific cellular stress response restricted to neuronal cells.

[Ultrasound contrast agents. Pharmaceutical drug safety and bioeffects]. / Ultraschallkontrastmittel. Arzneimittelsicherheit und Bioeffekte.

In this overview safety aspects of ultrasound contrast agents (USCA) are described and discussed. In general USCA are very safe drugs. However, allergic adverse reactions can rarely occur, particularly due to the colloidal structure of USCA. In addition, the use of USCA could reduce the threshold for acoustically induced bioeffects and has the potential to increase these effects. In in vitro studies and animal trials USCA caused petechial hemorrhages, vascular damage, and the formation of free radicals. Even DNA damage with single strand breaks could be demonstrated. In human studies and clinical practice none of these bioeffects could be observed. In contrast-enhanced echocardiography a higher rate of premature ventricular contractions has been reported when imaging was triggered at the end systole. Compared with other contrast agents contrast-enhanced ultrasound showed no nephrotoxic effects and could prove to be an alternative diagnostic method for patients with renal failure.

Generation, application and quantification of clamp-BioShuttle carriers for plasmid delivery into nuclei of prostate cancer cells.

This paper presents the BioShuttle platform as a delivery vehicle for transfer of contrast agents and genetic material into target cells, which can be followed by activation of the BioShuttle inside the target cell. Here, we present a transporter system and summarize the findings on transporter use in vivo and in vitro. The results here are limited to examples where cargoes (drugs, genetically active materials or contrast agents) are covalently associated with the transporter module. A further example, in which the cargo is non-covalently attached to the BioShuttle, is also discussed. Finally, attempts have been made to solve some of the issues surrounding the efficiency of transfer of therapeutic or diagnostic agents and their later activity in the cell.

[Focused ultrasound surgery. Basics, current status, and new trends]. / Fokussierte Ultraschallchirurgie. Grundlagen, aktueller Stand und neueste Trends.

There is an increasing interest in high intensity focused ultrasound (HIFU) for thermo ablative tumor therapy. The attractiveness of this method is based on its ability to destroy tumor tissue non invasively while sparing surrounding tissue from outside the body. HIFU induced tissue necroses are sharply circumscribed. Therefore this method was termed focused ultrasound surgery (FUS). The therapeutic potential of FUS is under investigation in several clinical studies. Main objects of these studies are prostate carcinomas, breast kidney and liver tumors. The next innovative step will be the non invasive FUS treatment of brain through the intact skull. Combining FUS with magnetic resonance imaging (MRI) or diagnostic ultrasound allows accurate and online therapy guiding and monitoring. This article gives an overview of the basics, the latest developments and actual clinical studies in the field of focused ultrasound surgery.

Successful surgery using recombinant factor VIIa for recurrent, idiopathic nonulcer duodenal bleeding in a patient with Glanzmann's thrombasthenia.

A 68-year-old man with Glanzmann's thrombasthenia suffered from recurrent cryptogenic bleeding originating in the upper duodenal flexure. Extensive endoscopic procedures and medical treatments were unsuccessful and proximal duodenectomy was proposed. In preceding years platelet transfusions had often had a suboptimal result and were complicated by allergic reactions. Surgery was carried out while he was being treated with recombinant Factor VIIa. Neither major blood loss nor other complications occurred. Histological examination of the bleeding site failed to show abnormalities and the nature of this patient's bleeding problem remained unexplained. Glanzmann's thrombasthenia is a rare autosomal recessive disorder of platelet aggregation characterized by a lifelong bleeding tendency due to abnormalities of the glycoprotein IIb-IIIa membrane complex. Common clinical manifestations include purpuric type bleeding, epistaxis, menorrhagia and gingival bleeding. Spontaneous bleeding is uncommon but posttraumatic and postoperative hemorrhage may be particularly serious. There is no specific treatment. Prophylactic and therapeutic platelet transfusions are the cornerstone of supportive treatment. In many patients the efficacy of this approach is diminished by allo-anti-platelet antibodies. We report on a patient with Glanzmann's disease with recurrent nonulcer duodenal bleeding refractory to conservative medical treatment. Despite documented suboptimal effectiveness of platelet transfusions, he underwent successful surgery with administration of recombinant factor VIIa (rFVIIa).

A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery.

An ideal vision of modern medicine includes tumor surgery with the human body remaining completely intact. A noninvasive therapy could avoid infections and scar formation; it would require less anesthesia, reduce recovery time, and possibly also reduce costs. This study investigated whether human breast cancer can be effectively treated with a novel combination of image guidance and energy delivery, noninvasive magnetic resonance imaging (MRI)-guided focused ultrasound (FUS). We have developed a FUS therapy unit guided by MRI for the treatment of human breast tumors in a clinical 1.5 T MR scanner. With interactive target segmentation on MRI, defined volumes could be noninvasively treated in a single session with on-line MR temperature control. The ultrasound waves were focused through the intact skin and resulted in the localized thermal tissue ablation at a maximum temperature of 70 degrees C. The therapy principle was first demonstrated in sheep breast in vivo and was then applied in a patient with core biopsy-proven invasive breast cancer 5 days before breast-conserving surgery. MRI proved suitable to delineate the breast cancer, served as stereotactic treatment planning platform, and delineated the FUS-related tissue changes such as interruption of tumor blood flow. Furthermore, MRI localized the hot spot in the tumor and measured temperature elevation during the treatment. This allowed us to monitor the efficacy and safety of FUS therapy. Immunohistochemistry of the resected specimen demonstrated that FUS homogeneously induced lethal and sublethal tumor damage with consecutive up-regulation of p53 and loss of proliferative activity. This effect was realized without anesthesia and damage to the surrounding healthy tissue or systemic effects. Overall, our results show that noninvasive MRI-guided therapy of breast cancer is feasible and effective. Thus, MRI-guided FUS may represent a new strategy for the neoadjuvant, adjuvant, or palliative treatment in selected breast cancer patients and in patients with other soft-tissue tumors.

Outpatient management of low-velocity gunshot-induced fractures.

This prospective study evaluated the efficacy of an outpatient management protocol for patients with a gunshot-induced fracture with a stable, nonoperative configuration. Forty-one patients (44 fractures) with a grade I or II open, nonoperative fracture secondary to a low-velocity missile comprised the study population. Patients were treated by a standard protocol, which included 1 g of cefazolin administered in the emergency room and a 7-day course of oral cephalexin. Follow-up visits were performed until complete wound and fracture healing were achieved. Thirty-two (78%) of 41 patients underwent full follow-up. Average follow-up was 5.2 months. One (2.8%) fracture (distal fibula) developed a superficial infection, which responded to an additional week of oral antibiotics, and no patient developed a deep infection. There was 1 delayed union and 2 patients with painful retained shrapnel. These results demonstrate that patients with stable, low-velocity, gunshot-induced fractures can be managed effectively and safely on an outpatient basis using this protocol.

[Cavitations in biological tissues]. / Kavitation in biologischem Gewebe.

AIM: An important reason for the high popularity of diagnostic ultrasound is its lack of hazardous side effects. However, as described below, the probability of inducing undesirable thermal and mechanical effects in tissue increases with a rise in the output of diagnostic ultrasound machines. METHODS AND RESULTS: The use of increasing negative peak pressures of the applied ultrasound pulse enhances the risk of inducing cavitation inside the body. The potential damage of cavitation results from the dynamic, e. g. wild pulsation, and a collapse of bubbles in the respective sound field. The collapse, especially, releases a high amount of energy, related to secondary effects like shock waves, jet formation and the formation of free radicals. To estimate the likelihood of cavitation and ensuing mechanical biological effects the so-called mechanical index was defined. Nowadays, the mechanical index is displayed in real-time on modern diagnostic ultrasound machines. Echo-contrast agents play an increasing role in sonography. These stabilised gas particles increase the likelihood of cavitation formation and the occurrence of other biological side effects. The potential for mechanically induced side effects of diagnostic ultrasound was tested in many animal studies. As for the use of ultrasound for diagnostic purposes, adverse side effects, like haemorrhage or rupture of capillaries, were only observed in the presence of tissue-gas interfaces - as found in the lung or the intestine - or with high concentrations of contrast media. CONCLUSION: Even though no adverse effects of diagnostic ultrasound have been reported in humans, potentially damaging effect of advanced ultrasound techniques cannot be denied. Various ultrasound organizations, e.g. WFUMB, have therefore formulated recommendations for the safe use of diagnostic ultrasound.

MR monitoring of focused ultrasound surgery in a breast tissue model in vivo.

The objective of this study was to investigate MRI methods for monitoring focused ultrasound surgery (FUS) of breast tumors. To this end, the mammary glands of sheep were used as tissue model. The tissue was treated in vivo with numerous single sonications which covered extended target volumes by employing a scanning technique. The ultrasound focus position was controlled by online temperature mapping based on the temperature dependence of the relaxation time T(1). This approach proved to be reliable and offers thus an alternative to proton resonance frequency methods, whose application is hampered in fatty tissues. FUS-induced tissue changes were visible on T(2)- as well as on pre- and post-contrast T(1)-weighted images. According to our initial experience, noninvasive MRI-guided FUS of breast tumors is feasible.

[Magnetic resonance-guided therapy with focused ultrasound. Non-invasive surgery of breast carcinoma?]. / Kernspingesteuerte Therapie mit fokussiertem Ultraschall. Nichtinvasive Chirurgie des Mammakarzinoms?

Magnetic resonance guided focused ultrasound surgery (MRgFUS) has the potential to become an important therapy modality in the adjuvant, neoadjuvant or palliative cancer treatment. All ultrasound accessible regions are possible target areas, especially breast tumors. Ultrasound propagation is well predictable. The ultrasound energy can be focused to a defined spot through the intact skin, and temperatures of 60 degrees C to 85 degrees C can be induced locally for a few seconds that instantaneously necrose biological tissues, while sparing surrounding healthy tissue. In addition, MRI is sensitive to temperature allowing for online monitoring of the temperature focus. In this work we demonstrate our Heidelberg experiments from basic research and animal studies towards the clinical realization of MRgFUS in breast cancer patients. The most important of these experiments involved sheep as an appropriate model for the human breast. A new therapy setup is designated to treat human breast patients in a clinical 1.5 T MRI scanner. While the therapies have been successful so far without any side effects, the future clinical role of noninvasive MRgFUS has to be defined by clinical studies.

Control of cavitation activity by different shockwave pulsing regimes.

The aim of the study was to control the number of inertial cavitation bubbles in the focal area of an electromagnetic lithotripter in water independently of peak intensity, averaged intensity or pressure waveform. To achieve this, the shockwave pulses were applied in double pulse sequences, which were administered at a fixed pulse repetition frequency (PRF) of 0.33 Hz. The two pulses of a double pulse were separated by a variable short pulse separation time (PST) ranging from 200 micros to 1500 ms. The number and size of the cavitation bubbles were monitored by scattered laser light and stroboscopic photographs. We found that the number of inertial cavitation bubbles as a measure of cavitation dose was substantially influenced by variation of the PST, while the pressure pulse waveform, averaged acoustic intensity and bubble size were kept constant. The second pulse of each double pulse generated more cavitation bubbles than the first. At 14 kV capacitor voltage, the total number of cavitation bubbles generated by the double pulses increased with shorter PST down to approximately 400 micros, the cavitation lifespan. The results can be explained by cavitation nuclei generated by the violently imploding inertial cavitation bubbles. This method of pulse administration and cavitation monitoring could be useful to establish a cavitation dose-effect relationship independently of other acoustic parameters.

Sonochemically induced radicals generated by pulsed high-energy ultrasound in vitro and in vivo.

The aim of this study was to evaluate the role of radicals as a mechanism of tissue damage induced by pulsed high-energy ultrasound. Transient cavitation has proved to be an important mechanism for the generation of reactive radical species during pulsed high-energy ultrasound applications. The amount of radicals studied in in vitro experiments using a chemical dosimeter based on iodine release is proportional to the number of pulses. Sonications of the R3327-AT1 subline of the Dunning prostate rat tumor transplanted in the thigh of Copenhagen rats were performed applying 500 and 2000 pulses at a pulse repetition frequency of 1 Hz. Tumor growth after treatment was compared with sham-treated controls. We were able to assess a significant growth delay, but could not find a significant difference between the two groups treated. In conclusion, radical formation does not seem to be the major mechanism for tissue necrosis induced by pulsed high-energy ultrasound.

Quantitative MR temperature monitoring of high-intensity focused ultrasound therapy.

A new quantitative method has been developed for real-time mapping of temperature changes induced by high intensity focused ultrasound (HIFU). It is based on the temperature dependence of the T1 relaxation time and the equilibrium magnetization. To calibrate the temperature measurement, the functional relationship between T1 and temperature was examined in different samples of porcine muscle and fatty tissue. The method was validated by a comparison of calculated temperature maps with fiber-optic measurements in heated muscle tissue. The experiment showed that the accuracy of the MR method for temperature measurements is better than 1 degree C. Since the acquisition time of the employed MR sequence takes only 3 s per slice and the calculation of the temperature map can be performed within seconds, the imaging technique works nearly in real-time. The temperature measurement could be realized during HIFU showing no disturbances by ultrasound sonication. In comparison to other MR approaches, the advantages of the introduced method lie in a sufficient accuracy and time resolution combined with a reasonable robustness against motion as well as the feasibility for temperature monitoring in fatty tissues.

A comparison of shock wave and sinusoidal-focused ultrasound-induced localized transfection of HeLa cells.

Both shock waves and sinusoidal continuous wave ultrasound can mediate DNA transfer into cells. The relative transfection efficiencies of different ultrasound modalities are unclear. The purpose of this paper is to compare the transfection efficiency of lithotripter shock waves and focused sinusoidal ultrasound in vitro. HeLa cells were transfected with beta-galactosidase and luciferase plasmid DNA reporter. Shock waves were generated by an electromagnetic sound source. Sixty to 360 pulses at 1 Hz pulse frequency were administered at 13, 16 or 19 kV capacitor voltage. Sinusoidal focused ultrasound was generated by a single focus piezoceramic air-backed disk transducer at a carrier frequency of 1.18 MHz operated in a pulsed mode. Compared to cells mixed with DNA only, shock waves induced up to eightfold more transfected cells at a cell viability of 5%, while sinusoidal-focused ultrasound induced up to 80-fold more transfected cells at a cell viability of 45%. The corresponding transfection efficiencies of the HeLa cells were 0.08% for shock waves and 3% for focused ultrasound. These results may contribute to the selection of the ultrasound modality as a localized, noninvasive and safe tool to mediate gene transfer.