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.

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.

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.

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.

[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.

Effect of disease states on theophylline elimination.

Host factors play an important role in the dosing requirements of theophylline. Theophylline metabolism and clearance depend principally on liver cell function rather than on hepatic flow. The effects of acute hypoxemia require more study; however, patients with chronic obstructive pulmonary disease who have chronic hypoxemia appear to have some impairment of clearance. Clearance is variably and sometimes drastically reduced in patients with liver disease and heart failure, and is reduced by some viral infections. It is not impaired by renal failure. Current split-virus vaccine mixtures do not appear to affect clearance. Clearance is increased in patients with cystic fibrosis and hyperthyroidism. The depressed clearance seen in the severely ill patients who require intensive care improves with improvement in the patient's condition, but the individual factors involved have not been identified. An area requiring more study is the effect of pH on the apparent distribution volume for theophylline. In the presence of liver disease, heart failure, or serious illness, caution must be applied in theophylline dosing, with frequent monitoring of serum levels. Stable patients also warrant an initially conservative dose until serum levels are obtained to guide further dose adjustments.

Growth Inhibition of Mycobacterium tuberculosis After Single-Pulsed Exposures to Streptomycin, Ethambutol, and Rifampin.

It was reported earlier that the degree of growth inhibition of tubercle bacilli after single-pulsed isoniazid exposures is a function of the time-concentration product (TCP) of exposure rather than of either time or concentration alone (TCP = hr exposure x mug of drug/ml). In the present investigation, these time and concentration studies have been extended to streptomycin (SM), ethambutol (EMB), and rifampin (RMP). Mycobacterium tuberculosis H37Ra was grown in Sautons liquid medium at 37 C with aeration. Rapidly growing cells were harvested and resuspended at 0.5 to 0.6 mg (dry wt)/ml in fresh medium; incubation was continued in the presence of various concentrations of the appropriate drug. At time intervals, samples were diluted 1:200 into drug-free medium for turbidimetric growth assay. Minimal inhibitory concentrations of EMB, SM, and RMP were approximately 0.2, 0.02, and 0.002 mug/ml, respectively. When cells were pulsed with 0.0125 to 0.0625 mug of RMP per ml at time intervals of up to 9.5 hr, the degree of subsequent growth inhibition appeared to be a function of TCP. A similar relationship was observed when SM was tested over a range of 0.125 to 1.0 mug/ml and various time intervals of up to 8 hr. In contrast, inhibition of tubercle bacilli after EMB exposures was dependent primarily on exposure time and was affected only slightly by concentration. At any particular exposure time between 3 and 16 hr, 1.25 to 7.5 mug of EMB per ml produced similar levels of inhibition, but marked inhibition did not occur unless the exposure time exceeded 10 hr. Relationships of these latter findings to the mode of action of EMB and the potential clinical significance of the RMP, SM, and EMB data are discussed.