Synergetic bitherapy in mice with xenografts of human prostate cancer using a methional mimic (METLICO) and an aldehyde dehydrogenase 3 inhibitor (MATE): systemic intraperitoneal (IP) and targeted intra-tumoral (IT) administration.

An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.

Brachytherapy: state of the art and possible improvements.

Cancer often remains an incurable disease, despite significant progresses in diagnosis and treatment that have been made. Specifically, the use of nuclear medicine in oncology is greatly contributing to both imaging and therapy aspects. Targeted therapies are a major field of interest since it increases efficiency and reduces side effects. Brachytherapy is among the most valuable of recent developments for treating localized tumours resulting in improvements in improved quality of life. This is primarily because it irradiates cancerous cells most exclusively while barely effecting healthy tissue. The use of radiochemicals implies specific management for production, transport and handling that have limited the development of this technique. This review article describes brachytherapy and their latest developments. Furthermore, alternative activation methods for the production of radioisotopes and a novel delivery system for targeted multi-therapy by using PLA-ferrite nanospheres are described.

Experimental study on a large animal model of a new thermoablation technique.

BACKGROUND: A novel technique of thermoablation, using a microtube to deliver pulses of hot water vapour, was tested on a large animal model in order to evaluate its efficacy and potential adverse effects. MATERIALS AND METHODS: The medical device consisted of a microtube extension connected to a hydropneumatic pump. Pulses of pure water were injected though the microtube where they were heated and delivered as vapour into the target zone. The method was tested on the liver of 12 healthy pigs, either during open surgery or percutaneously under ultrasounds. RESULTS: The technique was efficient and well-tolerated by the animals. Large volumes of necrotic tissue were created in a significantly short time compared to concurrent thermoablative techniques. CONCLUSION: Anticipating human application, this experimental study demonstrated a safe and efficient innovative thermoablation technique. The first human applications have been successfully performed and will be reported soon.

A new method of thermoablation with hot water vapour for localized tumours.

BACKGROUND: A new method of thermoablation with hot water vapour based on a new type of microtube was developed. This approach allows tumours, with volume and anatomical positions not accessible to other techniques (cryoablation, radiofrequency ablation, laser ablation) to be treated. MATERIALS AND METHODS: The method was tested on a human colon carcinoma grafted subcutaneously in Swiss nude mice and the experiment monitored under magnetic resonance imaging. RESULTS: It was found that 2.52 cal s(-1) per cm3 of tumour were necessary to reduce tumour size. The microtube is built to withstand a large range of temperatures and pressures and is biocompatible. CONCLUSION: A specific feature of this technique is that, besides hot vapour, several types of drugs can be delivered through the same microtube depending of the location, type or size of the tumour. These properties make it a unique device for multi-therapeutic treatments.

Human tibia bone marrow blood perfusion by non-invasive near infrared spectroscopy: a new tool for studies on microgravity.

Human tibia bone marrow (BM) and tibialis anterior muscle (TA) perfusion index (PI) was assessed non-invasively by near infrared spectroscopy. A decrease in the postis-chaemic reperfusion capability of the human tibia BM and TA muscle was observed for increasing age i.e., PI increases linearly as a function of age, starting from 30 years, both for BM (0.062 %/year, from -4.185 to -0.967 %/s) and TA muscle (0.046 %/year, from -5.760 to -3.883 %/s). The results define a "normal" baseline and demonstrate the sensitivity of the method to PI changes. The present technique should allow one to investigate physio-pathological effects induced by microgravity on tibia BM blood perfusion.

Age dependence of human gastrocnemius Mg2+: fitting 31P-NMR spectra using quantum mechanics-based prior knowledge.

The age dependence of human gastrocnemius Mg2+ concentration is demonstrated. To quantitate Mg2+ concentration, an original and accurate fitting algorithm using quantum mechanics-based prior knowledge is detailed. In a group of 28 volunteers (14 females) in the age range 5-80 years, pH, PCr/ATP and Pi/ATP values in the gastrocnemius were 7.02 +/- 0.02 pH, 4.16 +/- 0.33 and 0.13 +/- 0.02, respectively and independent of age and sex. By contrast, intracellular Mg2+ concentration (mM) decreased linearly (p < 0.05) with age (Mg2+ = 0.7803 +/- 0.0247-0.0027 +/- 0.0005 * age). No difference was found between sexes. From these results, it follows that care must be taken when comparing muscle Mg2+ data from subjects of different age. The hypothesis can be put forward that during aging insufficient intake and/or increased depletion of Mg2+ (e.g., intestinal hypoabsorption or urinary leakage) may affect the musculoskeletal system.

Open magnetic resonance imaging using titanium-zirconium needles: improved accuracy for interstitial brachytherapy implants?

PURPOSE: To evaluate the benefit of using an open magnetic resonance (MR) machine and new MR-compatible needles to improve the accuracy of brachytherapy implants in pelvic tumors. METHODS AND MATERIALS: The open MR machine, foreseen for interventional procedures, allows direct visualization of the pelvic structures that are to be implanted. For that purpose, we have developed MR- and CT-compatible titanium-zirconium (Ti-Zr) brachytherapy needles that allow implantations to be carried out under the magnetic field. In order to test the technical feasibility of this new approach, stainless steel (SS) and Ti-Zr needles were first compared in a tissue-equivalent phantom. In a second step, two patients implanted with Ti-Zr needles in the brachytherapy operating room were scanned in the open MR machine. In a third phase, four patients were implanted directly under open MR control. RESULTS: The artifacts induced by both materials were significantly different, strongly favoring the Ti-Zr needles. The implantation in both first patients confirmed the excellent quality of the pictures obtained with the needles in vivo and showed suboptimal implant geometry in both patients. In the next 4 patients, the tumor could be punctured with excellent accuracy, and the adjacent structures could be easily avoided. CONCLUSION: We conclude that open MR using MR-compatible needles is a very promising tool in brachytherapy, especially for pelvic tumors.

Temperature dependence of human gastrocnemius pH and high-energy phosphate concentration by noninvasive techniques.

It is well established that ADP is an important regulator of the oxidative phosphorylation in the mitochondria. Thus, by means of noninvasive techniques it is demonstrated that the relationship between O(2) consumption of the human gastrocnemius at rest and its temperature is likely determined by at least two factors: 1) the modulation of the rate of the chemical reactions imposed by the "physical" temperature-effect; 2) the influence of temperature-induced ADP concentration changes ( approximately 0.83 microM degrees C(-1)) on oxidative phosphorylation. ADP was assessed by applying the temperature-corrected Lohmann equilibrium equation. PCr and ATP were found to increase, with decreasing temperature (-0.54+/-0.05 and -0.17+/-mM degrees C(-1), respectively), while pH varies following the alpha-stat hypothesis (-0.016+/-0.001 pH degrees C(-1)). These findings should be of value when dealing with muscle physiology in extreme environments or clinical applications of hypothermia.

Human calf microvascular compliance measured by near-infrared spectroscopy.

The purpose of this study is to develop a new method for the measurement in humans of the compliance of the microvascular superficial venous system of the lower limb by near-infrared spectroscopy (NIRS). This method is complementary to strain-gauge plethysmography, which does not allow compliance between deep and superficial venous or between venous and arterial compartments to be distinguished. In practice, hydrostatic pressure (P) changes were induced in a calf region of interest by head-up tilt of the subject from alpha = -10 to 75 degrees. For P < or = 24 mmHg, the measured compliance [0.086 +/- 0.005 (SD) ml. l(-1). mmHg(-1)] based on NIRS data of total, deoxygenated, and oxygenated hemoglobin, reflects essentially that of the superficial venous system. For P > or = 24 mmHg, no distinction can be made between arterial and venous volumes changes. However, by following the changes in oxy- and deoxyhemoglobin in the P range -16 to 100 mmHg, it appears to be possible to assess the characteristics of the vasomotor response of the arteriolar system.

Muscle O(2) consumption by NIRS: a theoretical model.

In the past, the measurement of O(2) consumption ((2)) by the muscle could be carried out noninvasively by near-infrared spectroscopy from oxyhemoglobin and/or deoxyhemoglobin measurements only at rest or during steady isometric contractions. In the present study, a mathematical model is developed allowing calculation, together with steady-state levels of (2), of the kinetics of (2) readjustment in the muscle from the onset of ischemic but aerobic constant-load isotonic exercises. The model, which is based on the known sequence of exoergonic metabolic pathways involved in muscle energetics, allows simultaneous fitting of batched data obtained during exercises performed at different workloads. A Monte Carlo simulation has been carried out to test the quality of the model and to define the most appropriate experimental approach to obtain the best results. The use of a series of experimental protocols obtained at different levels of mechanical power, rather than repetitions of the same load, appears to be the most suitable procedure.

Energy metabolism and interstitial fluid displacement in human gastrocnemius during short ischemic cycles.

Energy metabolism and interstitial fluid displacement were studied in the human gastrocnemius during three subsequent 5-min ischemia-reperfusion periods [ischemic preconditioning (IP)]. The muscle energy balance was assessed by combining near-infrared spectroscopy (NIRS) and 31P-nuclear magnetic resonance spectroscopy (31P-NMRS). The interstitial fluid displacement was determined by combining NIRS and 23Na-NMRS. No changes in total energy consumption or in the fractional contribution of the underlying energy sources (aerobic glycolysis, anaerobic glycolysis, and Lohmann reaction) were observed in the muscle during the tested IP protocol. Oxygen consumption in the muscle region of interest, as estimated by NIRS, was approximately 8 micromol . 100 g-1 . min-1 and did not change during IP. Phosphocreatine and ATP concentrations did not change over the whole experimental period. A slight but significant (P < 0.05) increase in intracellular pH was observed. Compared with the control, a 10% greater interstitial fluid content per muscle unit volume was observed at the end of the IP protocol. It is concluded that, at variance with cardiac muscle, repeated 5-min ischemia-reperfusion cycles do not induce metabolic changes in human gastrocnemius but alter the interstitial fluid readjustment. The techniques developed in the present study may be useful in identifying protocols suitable for skeletal muscle preconditioning and to explain the functional basis of this procedure.

Step vs. progressive exercise: the kinetics of phosphocreatine hydrolysis in human muscle.

It is well known that the VO2 readjustment rate of the whole body is faster when carrying out a given constant work load starting from a baseline of moderate exercise than from rest. However, it has not been established whether the above change is the result of faster kinetics of the oxidative machinery or, alternatively, the consequence of a reduced involvement of confounding factors such as anaerobic glycolysis or tissue O2 stores. The problem, earlier approached by chemical methods, was studied in man by 31P-NMRS assessment of the kinetics of phosphocreatine (PC) hydrolysis at the muscle level which is known to reflect the readjustment rate of the oxidative reactions. Twelve normal subjects carried out in a 90 cm bore modified Picker (1.5 T) magnet, a series of contractions by the plantar flexors reaching pre-set submaximal loads either in single steps (constant load, CL) or progressively (incremental exercise. I). If preceding exercise (I), compared to rest, influenced the rate of oxidations, the PC concentration at the target loads would be different for the two exercise modes, reflecting different energy deficits. This was not the case. Thus the present results show that the rate of readjustment of oxidations at the muscle level is not affected by priming exercise confirming previous findings and showing that theoretical models of VO2 control are experimentally applicable to man.

Dynamic phosphorus-31 spectroscopy after fructose load in experimental biliary liver cirrhosis.

RATIONALE AND OBJECTIVES: The authors investigated the usefulness of dynamic phosphorus-31 magnetic resonance (MR) spectroscopy in the assessment of hepatic function by studying the effect of a fructose load on a rat model of liver cirrhosis. METHODS: In vivo P-31 MR liver spectra of eight rats with bile duct ligature and 10 control rats were obtained every 4.6 minutes before and after intraperitoneal fructose load (10 mmol per kilogram of body weight). RESULTS: In the basal spectra of the experimental group, the phosphomonoester peak was higher than in the control group (P = .026). After the fructose load, the phosphomonoester peak increase and the inorganic phosphate peak decrease were significantly less marked in the experimental group (P = .003). There was a linear correlation between the serum level of bilirubin and the phosphomonoester increase (r = .61, P < .001). CONCLUSION: Dynamic P-31 MR spectroscopy may be useful in the assessment of hepatic function in chronic liver disease.

In vivo human gastrocnemius architecture with changing joint angle at rest and during graded isometric contraction.

1. Human gastrocnemius medialis architecture was analysed in vivo, by ultrasonography, as a function of joint angle at rest and during voluntary isometric contractions up to the maximum force (MCV). maximum force (MVC). 2. At rest, as ankle joint angle increased from 90 to 150 deg, pennation increased from 15.8 to 27.7 deg, fibre length decreased from 57.0 to 34.0 mm and the physiological cross-sectional area (PCSA) increased from 42.1 to 63.5 cm2. 3. From rest to MVC, at a fixed ankle joint angle of 110 deg, pennation angle increased from 15.5 to 33.6 deg and fibre length decreased from 50.8 to 32.9 mm, with no significant change in the distance between the aponeuroses. As a result of these changes the PCSA increased by 34.8%. 4. Measurements of pennation angle, fibre length and distance between the aponeuroses of the gastrocnemius medialis were also performed by ultrasound on a cadaver leg and found to be in good agreement with direct anatomical measurements. 5. It is concluded that human gastrocnemius medialis architecture is significantly affected both by changes of joint angle at rest and by isometric contraction intensity. The remarkable shortening observed during isometric contraction suggests that, at rest, the gastrocnemius muscle and tendon are considerably slack. The extrapolation of muscle architectural data obtained from cadavers to in vivo conditions should be made only for matching muscle lengths.

Human intramuscular temperature and heat flow transients at rest.

A general model for heat exchange, comprising the major models in the literature, was developed. Temperature changes as a function of space and time were determined in six resting humans (age 32.7 +/- 4.5 yr) during temperature transients by magnetic resonance imaging (MRI), so that the exact solution of the model was obtained. These results allowed application of the model, e.g., the analysis of transient muscle heat flow changes, which could not be assessed by previous steady-state analyses. A microthermocouple was inserted in muscle vastus lateralis 2-3 cm below the skin surface. The measured temperature was used for calibrating the pixel intensity of a temporal series of transaxial magnetic resonance images obtained with a spin echo sequence around the microthermocouple position. After muscle temperature was increased by immersion in a controlled water bath, MRI acquisition was performed while muscle temperature was decreasing. Temperature maps relative to space and time inside a homogeneous region of interest were reconstructed by neural networks, showing specific temperature patterns. Subsequently calculated heat flows (with negative sign) appeared to increase linearly as temperature decreased, until a maximum was attained at a critical temperature, below which dramatic consistent heat flow changes were found. In conclusion, MRI is indeed a powerful technique, useful to study the determinants of muscle temperature and heat flow changes in space and time.

Magnetic resonance imaging with superparamagnetic iron oxide particles to evaluate hepatic macrophage-monocytic phagocytosis after arterial devascularization in minipigs.

RATIONALE AND OBJECTIVES: We examined the effects of arterial ischemia on the phagocytic activity of the hepatic macrophage-monocytic phagocytic system (MMPS). METHODS: Six minipigs were studied before and 24 hr after complete arterial devascularization of the liver. Magnetic resonance (MR) imaging was performed at 1.5 T using superparamagnetic iron oxide (SPIO) particles (18 mumol Fe/kg body weight) as an MMPS-specific contrast agent. Hepatobiliary scintigraphy, measurements of serum liver enzymes, and histology also were obtained. RESULTS: On MR imaging, the postcontrast-to-precontrast ratios of the arterially devascularized livers were significantly higher than the corresponding baseline values (p < .01). The greatest difference (52%) between the baseline and the postoperative values was observed on gradient-echo (GE) images. Scintigraphy, laboratory analyses, and histology results indicate that the MR imaging findings were probably predominantly attributable to a reduction in phagocytic activity of the hepatic MMPS. CONCLUSION: SPIO particles have already proved useful for improving detection of liver neoplasms on MR imaging, but they also may provide a novel way of evaluating the function of the hepatic MMPS in liver diseases.

Metabolic transient studies by NMR.

The time course of phosphocreatine (PC) hydrolysis in humans was measured by 31P-NMR spectroscopy (31P-NMRS) with a time resolution of 10.8 s in the gastrocnemius muscle and a relationship between muscle O2 consumption (VO2) and [PC] was derived from a bioenergetic model. This allowed a direct estimate of the half-time of the intracellular VO2 kinetics (t1/2 VO2) of the contracting human gastrocnemius in aerobic conditions. t1/2 VO2 was found to be approximately 16 s and independent of the work load. This value corresponds to the shortest t1/2 VO2 determined at the mouth of the subject in the absence of lactate accumulation in the rest to work transient. t1/2 VO2 may now be assessed in man at low muscle temperatures. To this aim a procedure was developed allowing corrections of the 31P-NMR spectra based on the muscle temperature profiles obtained by a simultaneously acquired proton image.

Self-referencing subtractive angiography by modified stimulated echo in magnetic resonance imaging.

In magnetic resonance imaging, the modified stimulated echo sequence (MSTE) method significantly reduces the signal from stationary nuclei. This sequence was successfully applied to transverse imaging, improving the contrast of moving materials. With the results reported here, it will be shown that projective angiography using MSTE is also feasible without the usual subtraction of two separated images. Another advantage is selectivity with respect to velocity.

Modified stimulated echo sequence for elimination of signals from stationary spins in MRI.

Simple modification of the basic stimulated echo sequence (MSTE), including bipolar gradient modulation, permits one to generate relative motion phase modulations between the two STE magnetization components. It is shown how this self-referencing process can provide flow enhancement without combination of separated images.