Marker-less online MR-guided stereotactic body radiotherapy of liver metastases at a 1.5 T MR-Linac - Feasibility, workflow data and patient acceptance.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is an established ablative treatment for liver tumors with excellent local control rates. Magnetic resonance imaging guided radiotherapy (MRgRT) provides superior soft tissue contrast and may therefore facilitate a marker-less liver SBRT workflow. The goal of the present study was to investigate feasibility, workflow parameters, toxicity and patient acceptance of MRgSBRT on a 1.5 T MR-Linac. METHODS: Ten consecutive patients with liver metastases treated on a 1.5 T MR-Linac were included in this prospective trial. Tumor delineation was performed on four-dimensional computed tomography scans and both exhale triggered and free-breathing T2 MRI scans from the MR-Linac. An internal target volume based approach was applied. Organ at risk constraints were based on the UKSABR guidelines (Version 6.1). Patient acceptance regarding device specific aspects was assessed and toxicity was scored according to the common toxicity criteria of adverse events, version 5. RESULTS: Nine of ten tumors were clearly visible on the 1.5 T MR-Linac. No patient had fiducial markers placed for treatment. All patients were treated with three or five fractions. Median dose to 98% of the gross tumor volume was 38.5 Gy. The median time from "patient identity check" until "beam-off" was 31 min. Median beam on time was 9.6 min. Online MRgRT was well accepted in general and no treatment had to be interrupted on patient request. No event of symptomatic radiation induced liver disease was observed after a median follow-up of ten month (range 3-17 months). CONCLUSION: Our early experience suggests that online 1.5 T MRgSBRT of liver metastases represents a promising new non-invasive marker-free treatment modality based on high image quality, clinically reasonable in-room times and high patient acceptance. Further studies are necessary to assess clinical outcome, to validate advanced motion management and to explore the benefit of online response adaptive liver SBRT.

Combined epidural analgesia and general anesthesia induce ischemia distal to a severe coronary artery stenosis in swine.

Epidural analgesia combined with general anesthesia may improve cardiac function and reduce the work of the heart by decreasing the rate pressure product. However, the effect of this combined technique has not been studied in the presence of severe coronary artery stenosis. Therefore, we investigated epidural analgesia combined with general anesthesia in a swine model with a tight coronary artery stenosis. The coronary stenosis placed around the proximal left anterior descending coronary artery (LAD) allowed normal blood flow at rest but only minimum hyperemia in response to the coronary dilator, adenosine. To accomplish an extensive sympathetic block, we injected enough bupivacaine 0.5% into the lumbar epidural space to reach at least the level of the first thoracic vertebra (T1). Epidural catheter position was verified by fluoroscopy. Hemodynamic changes, LAD myocardial blood flow, and regional myocardial wall thickening were measured. Fifteen minutes after the injection of bupivacaine, systolic and diastolic blood pressure decreased 24.1% and 26%, respectively, cardiac output decreased 25.6%, and mean coronary blood flow decreased 42%, compared to the saline control. Myocardial wall thickening in the LAD bed decreased 31%, although it remained unchanged in the normal myocardium. Epidural bupivacaine added to general anesthesia resulted in moderate hypotension. Distal to the coronary stenosis was a moderate decrease in regional myocardial function and a severe reduction in blood flow.

Expression of a chimaeric granule-bound starch synthase-GUS gene in transgenic potato plants.

Granule-bound starch synthase is the key enzyme in amylose synthesis. The regulation of this gene was investigated using a chimaeric gene consisting of a 0.8 kb 5' upstream sequence of the granule-bound starch synthase gene from potato and the beta-glucuronidase gene which was introduced into potato using an Agrobacterium tumefaciens binary vector system. The chimaeric gene was highly expressed in stolons and tubers, whereas the expression in leaves, stems or roots from greenhouse-grown plants was relatively low. However, leaves from in vitro grown plantlets exhibited an elevated GUS expression. The expression of the chimaeric gene was inducible in leaves by growth on relatively high concentrations of sucrose, fructose and glucose and was about 30- to 50-fold higher than in leaves from greenhouse-grown plants. The granule-bound starch synthase gene is expressed organ-specifically since stolons and tubers showed GUS activities 125- to 3350-fold higher than in leaves. The activities in these two organs are 3- to 25-fold higher than the expression of the CaMV-GUS gene. Histochemical analysis of different tissues showed that only certain regions of leaves and roots express high GUS activities. Stolons and tubers show high expression.

Hypokalemia in rats produces resistance to dysrhythmias under halothane anesthesia.

The arrhythmogenic threshold was investigated during acute and chronic hypokalemia under halothane anesthesia with an epinephrine challenge in the rat model. It was hypothesized that in the setting of severe hypokalemia, general anesthesia would be arrhythmogenic and would be exaggerated with increased levels of catecholamines. Rats were divided into four groups as follows: normokalemic control (group I, n = 10), acute hypokalemia with furosemide (group II, n = 16), acute hypokalemia with hyperventilation (group III, n = 18), and chronic hypokalemia induced by a low potassium (K+) diet (group IV, n = 22). There were no significant differences (P less than .05) in baseline K+ and arterial blood gases among the four groups. There was a significant difference between groups I and II and groups I and IV (P less than 0.05) in serum K+ values after the low K+ diet, but no differences were observed between groups II and IV or groups I and III in serum K+ levels. There was no significant difference in myocardial tissue K+ among the four groups. There was a significant difference in the arrhythmic dose of epinephrine among the four groups (P less than 0.05). Acute hypokalemia was more prone to dysrhythmias than chronic hypokalemia. However, compared with control, acute and chronic hypokalemia groups were resistant to dysrhythmias is probably based on compensatory mechanisms. The heart seems more resistant to K+ changes than skeletal muscle. This resistance is associated with compensation by the cardiac muscle sodium pump in the face of K+ depletion. Hypokalemia per se did not increase the incidence of dysrhythmias under halothane anesthesia in rats.

The effect of arterial pressure alterations during halothane anesthesia on residual flow and infarct size with transient regional ischemia of the dog.

The present study was designed to determine if infarct size under halothane anesthesia could be reduced by increasing the pressure gradient across the collateral vascular bed, thereby increasing flow within the occluded vascular bed. Forty-nine mongrel dogs were anesthetized with halothane under identical physiologic conditions with the exception of systemic arterial blood pressure. The control group of 18 animals anesthetized with halothane was compared to two experimental groups. In one group of 15 dogs, the mean systemic pressure was raised 25% above control with phenylephrine (BP25). In the second group of 15 dogs, systemic pressure was raised 50% above control (BP50). Adjacent marginal branches of the left circumflex coronary artery were ligated for 90 minutes followed by 90 minutes of reflow. The area of the occluded vascular bed was similar in all groups, but the area of infarction as a percentage of the occluded vascular bed was reduced from 47.7 +/- 4.7% to 25.4 +/- 4.3% in the BP25 group (P < or = .05 v control) and to 33.1 +/- 5.0% in the BP50 group. Flow measurements using microspheres showed a larger zone of ischemic tissue receiving adequate residual flow in the BP25 and BP50 groups compared to the control. It is concluded that infarct size during halothane anesthesia in the dog can be reduced by increasing systemic blood pressure with phenylephrine.

Cardiovascular effects and placental passage of dantrolene in the maternal-fetal sheep model.

Using the chronic maternal-fetal sheep preparation, nine pregnant ewes were studied to determine the effects of intravenous dantrolene sodium on maternal and fetal physiology, with particular reference to its placental passage, and its effects on uterine blood flow and uterine tone. Two doses of dantrolene sodium were studied: 1.2 mg/kg and 2.4 mg/kg. After 2.4 mg/kg, maternal cardiac output increased 29% (P less than 0.05) after 1 min and returned to normal after 30 min. Maternal mean arterial pressure increased 13% after 1 min and remained significantly elevated (P less than 0.01) for 3 h. No significant changes (P greater than 0.05) were observed in maternal heart rate, uterine artery blood flow, or central venous pressure. Maternal arterial pH declined from 7.42 to 7.39 (P less than 0.01) after 1 min and returned to baseline values after 10 min. Fetal heart rate decreased 24% (P less than 0.01) after 3 min and returned to normal after 10 min; the mean fetal arterial pressure remained unchanged (P greater than 0.05). Fetal arterial pH declined from 7.29 to 7.27 (P less than 0.05) after 1 min and remained significantly decreased for 120 min. Similar changes of lesser magnitude and shorter duration were seen following the 1.2 mg/kg dose. Maternal levels of dantrolene were less than 3 micrograms/ml. Although an equilibrium between maternal and fetal plasma dantrolene concentrations was apparent at 5 min, the fetal levels of dantrolene were approximately 10% of the mother's. The results indicate that the administration of intravenous dantrolene at 1.2 mg/kg or 2.4 mg/kg has no clinically significant adverse effect on mother or fetus in the sheep model.

Fentanyl, Na-pentobarbital and halothane influence myocardial infarct size.

We investigated the effects of three anesthetics on the size of myocardial infarction and on blood flow distribution within the myocardial wall. Myocardial infarcts were induced in 34 dogs by ligating a coronary artery for 90 minutes, and permitting reflow for 90 minutes. The anesthetics used were fentanyl, Na-pentobarbital, and halothane. Under halothane the mean blood pressure (BP) during coronary artery ligation was 113 +/- 2/82 +/- 2 mm Hg and the heart rate (HR) was 135 +/- 2/min. Under fentanyl, the BP was 143 +/- 3/91 +/- 2 mm Hg and HR 99 +/- 3/min. Under Na-pentobarbital, BP was 141 +/- 2/104 +/- 2 mm Hg and HR 146 +/- 2/min. A higher mean BP combined with a slower HR, as seen under fentanyl, was associated with the smallest infarct (24 +/- 8%). Low BP and higher HR, as seen under halothane, was associated with the largest infarct (51 +/- 5%). Na-pentobarbital, with a higher BP but also a faster HR, resulted in an infarct size of 32 +/- 5%. We conclude that a higher mean BP combined with a slower HR might favor the preservation of a larger mass of vulnerable myocardial tissue in a totally occluded coronary artery.

The maternal and fetal cardiovascular effects of epidural fentanyl in the sheep model.

Since the demonstration of opiate receptors in the spinal cord in the mid-1970s, investigators have been looking for the most effective epidural narcotic. With the use of the chronically catheterized maternal sheep model, we injected two different doses of preservative-free fentanyl (50 and 100 micrograms) into the epidural space. No statistically significant changes were observed, either in maternal or fetal arterial pressure and acid-base status or in maternal central venous pressure, systemic and pulmonary vascular resistance, cardiac output, and intrauterine pressure (p greater than 0.05). With a dose of 50 micrograms of fentanyl, maternal levels of fentanyl peaked at 60 minutes (50 pg/ml) and the fetal levels of fentanyl peaked at 45 minutes (20 pg/ml). With the 100 micrograms dose of fentanyl, maternal levels of fentanyl peaked at 45 minutes (230 pg/ml) and the fetal levels peaked at 15 minutes (110 pg/ml). We conclude that the injection of 50 and 100 micrograms of fentanyl into the maternal epidural space has no adverse effects on mother or fetus in the sheep model.