[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.

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.

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.

Theophylline as a bronchodilator in COPD and its combination with inhaled beta-adrenergic drugs.

The bronchodilating action of theophylline in COPD has been examined, with emphasis on its combined use with inhaled beta 2 agonists. The suggestion is made that failure to recognize the nonlinearity of the dose-response curves for bronchodilators has resulted in underestimating their combined action. Recent studies suggest that systemic theophylline has somewhat different actions on the airways in COPD than inhaled beta agonists, and that more bronchodilation may be possible when the two are used together than large doses of either one. By analogy, with asthma the suggestion is also made that the addition of theophylline is also likely to provide a more constant bronchodilation, reducing peak-trough variations in flow. The most complete clinical comparison to date suggests that, in currently sanctioned doses, a regimen containing both theophylline and an inhaled beta 2 agonist provides significantly greater bronchodilation than either drug alone, with fewer patient withdrawals. Further carefully designed studies are needed to resolve this issue, and particularly, to identify those patients who will derive the greatest benefit from a combined regimen.

Comparative bronchodilator responses to atropine and terbutaline in asthma and chronic bronchitis.

We have compared bronchodilator responses to atropine and terbutaline in 39 chronic bronchitics and 16 stable asthmatics. Fasting subjects were given either 1.05 mg atropine of 5.0 mg terbutaline orally. Pulmonary function was assessed using the peak responses, namely: three 60-minute intervals for terbutaline and three 30-minute intervals for atropine. A subgroup of five reactive bronchitis patients was given a placebo with no response. Areas under the percent response-time interval curve were compared. Both patient groups responded to the same degree to atropine and terbutaline with respect to reduction of airway resistance. However, the FEV1 and V50 responses to terbutaline were markedly enhanced compared to atropine in the asthmatics while equal to the atropine response in the bronchitis patients. Thus, atropine appears to exert its effect upon both large and small airways in bronchitis, but predominantly on large airways in asthma. The results are consistent with a state of enhanced vagal tone in small airways in bronchitis compared to asthma, but other explanations are conceivable.

Puncture injuries due to needles removed from intravenous lines: should the source patient routinely be tested for bloodborne infections?

OBJECTIVE: To better assess the risk of exposure to bloodborne pathogens following puncture injuries due to needles removed from intravenous (IV) lines. SETTING: Tertiary care community medical center. PATIENTS: A convenience sample of hospitalized patients requiring IV piggy-back medications. METHODS: Examination of 501 IV ports of peripheral lines, heparin-locks, and central venous lines for visible blood and testing the residual fluid in the needles removed from these ports for the presence of occult blood by using guaiac-impregnated paper. RESULTS: The proximal ports of central venous lines and heparin-locks were statistically more likely to contain visible blood than proximal and distal ports of peripheral lines (17% and 20% versus 1% and 3% respectively, P < 0.05). Similarly, needles removed from proximal ports of central venous lines and heparin-locks were statistically more likely to contain occult blood than those from peripheral lines (11% and 14% versus 2%, respectively, P < 0.05). Only two needles removed from IV lines without visible blood contained occult blood: one from the proximal port of a central line and another from a heparin-lock. None of the needles from peripheral lines without visible blood contained occult blood. Estimation of the risk of transmission of hepatitis B and C and human immunodeficiency virus (HIV) following injury by needles from various IV lines revealed that injury due to needles removed from peripheral IV lines and distal ports of central lines without visible blood was associated with "near zero" risk of transmission of these bloodborne infections at our medical center. CONCLUSIONS: Routine serological testing of source patients involving injury due to needles removed from peripheral IV lines and distal ports of central lines without visible blood is not necessary at our medical center. Conversely, due to the relatively high rate of occult blood in the needles removed from proximal ports of central venous lines and heparin-locks, puncture injuries due to these needles are considered significant and managed accordingly.

Clostridium difficile contamination of blood pressure cuffs: a call for a closer look at gloving practices in the era of universal precautions.

We report an outbreak of Clostridium difficile-associated diarrhea at our medical center following adoption of Universal Precautions. Environmental cultures revealed unexpected contamination of blood pressure cuffs at a rate similar to that for bedside commodes (10% and 11.5%, respectively). An observational survey revealed that healthcare workers in the patient care areas not infrequently failed to remove their potentially stool-contaminated gloves prior to touching clean surfaces, which might have contributed to contamination of blood pressure cuffs.

Loss of antimicrobial susceptibility in aerobic gram-negative bacilli repeatedly isolated from patients in intensive-care units.

OBJECTIVE: To study the loss of antimicrobial susceptibility in repeat (same patient, same bacterial species, and same site) aerobic gram-negative bacilli (AGNB) isolated from individual patients during their stay in the intensive-care unit (ICU). SETTING: A 792-bed, tertiary-care community hospital with a total of 107 adult, pediatric, and neonatal ICU beds. METHOD: An observational prospective study performed November 1992 through mid-July 1993. RESULTS: Of 594 consecutive AGNB from 287 ICU patients, 117 isolates (20%) from 55 patients (19%) were repeat isolates, with the majority obtained from respiratory secretions (83%). Pseudomonas aeruginosa and Enterobacter species accounted for 61% of the isolates. Forty-two (36%) of the repeat isolates from 24 patients (44%) had > or = 4-fold increase in minimum inhibitory concentration to at least one antibiotic and no longer were considered fully susceptible based on National Committee on Clinical Laboratory Standards criteria. Loss of antimicrobial susceptibility often developed within several (median 8) days and was associated only infrequently with simultaneous transition from colonization to infection in the individual patient. Use of certain beta-lactam antibiotics was associated with increasing resistance to several other antibiotics in the same class. Concurrent use of beta-lactams and aminoglycosides did not prevent loss of antimicrobial susceptibility to the former in repeat isolates. CONCLUSION: We conclude that loss of antimicrobial susceptibility in repeat AGNB isolated from ICU patients is common, usually is not associated with transition from colonization to infection, and often is associated with prior use of antibiotics. Minimizing antibiotic use in ICU patients should help reduce the risk of antimicrobial resistance in repeat AGNB isolates.

In vivo functional antagonism between isoproterenol and bronchoconstrictants in the dog.

The functional antagonism between isoproterenol and methacholine, histamine and serotonin, as described in vitro in respiratory smooth muscle was explored in vivo in a canine model. Infusions of isoproterenol were administered during brief peaks of bronchospasm produced by aerosolized methacholine and histamine, or during sustained bronchospasm produced by infused serotonin. In eight mongrel dogs anesthetized with pentobarbital sodium, the mean protection by infused isoproterenol against methacholine challenge decreased from 60.6 to 29.1% as the mean lung resistance (RL) was increased from 78 to 232% over base line by a fourfold increase in methacholine (P less than 0.002). In six dogs, the mean protection by isoproterenol against histamine decreased from 55.5 to 26.9% as the opposing RL increased from 80 to 182% over base line with a fourfold increase in histamine (P less than 0.02). However, with serotonin infusions there was only a small 18% mean decrease in protection (P = 0.05), associated with a correspondingly small 37% mean increase in dose of serotonin despite a 269% mean increase in resistance (P = 0.02). In all cases, the loss of protection correlated more closely with the dose of constrictant than the resistance increase over base line. These findings demonstrate in vivo functional antagonism between isoproterenol and the dose of bronchoconstrictant but not necessarily resistance increase per se.

Theophylline use in asthma. Some current issues.

This article summarizes the current use of theophylline and lays a simple pharmacokinetic background for understanding its safe use. Dosing practices that will minimize side effects and toxicity are stressed, along with their management if they do occur. Finally, some currently debated issues over optimal theophylline use are addressed.

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.

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.

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.

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.

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.

Quality assurance tools for therapeutic ultrasound.

Compared to diagnostic ultrasound, special phantoms and measurement techniques for therapeutic ultrasound are still far from standardization. In the following article, the development of quality assurance (QA) tools for two therapy methods are described: Extracorporeal shockwave lithotripsy (ESWL) and high intensity focused ultrasound (HiFU). The three consequent parts are QA tools in research and development, QA in clinical environment and standardization. For part one the computerized scanning with hydrophones, the use of Schlieren optics and sound force balances are state of the art. For clinical use the test procedures have to be simple so that routine checking of the equipment becomes convenient.

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.

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.