The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle.

BACKGROUND AND AIMS: Metabolic factors initiating adipose tissue expansion and ectopic triglyceride accumulation are not completely understood. We aimed to investigate the independent role of circulating glucose, NEFA and insulin on glucose and NEFA uptake, and lipogenesis in skeletal muscle and subcutaneous adipose tissue (SCAT). METHODS AND RESULTS: Twenty-two pigs were stratified according to four protocols: 1) and 2) low NEFA + high insulin ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia), 3) high NEFA + low insulin (fasting), 4) low NEFA + low insulin (nicotinic acid). Positron emission tomography with [18F]fluoro-2-deoxyglucose and [11C]acetate, was combined with [14C]acetate and [U-13C]palmitate enrichment techniques to assess glucose and lipid metabolism. Hyperinsulinaemia increased glucose extraction, whilst hyperglycaemia enhanced glucose uptake in skeletal muscle and SCAT. In SCAT, during hyperglycaemia, elevated glucose uptake was accompanied by greater [U-13C]palmitate-TG enrichment compared to the other groups, and by a 39% increase in de novo lipogenesis (DNL) compared to baseline, consistent with a 70% increment in plasma lipogenic index. Conversely, in skeletal muscle, [U-13C]palmitate-TG enrichment was higher after prolonged fasting. CONCLUSIONS: Our data show the necessary role of hyperglycaemia-hyperinsulinaemia vs euglycaemia-hyperinsulinaemia in promoting expansion of TG stores in SCAT, by the consensual elevation in plasma NEFA and glucose uptake and DNL. In contrast, skeletal muscle NEFA uptake for TG synthesis is primarily driven by circulating NEFA levels. These results suggest that a) prolonged fasting or dietary regimens enhancing lipolysis might promote muscle steatosis, and b) the control of glucose levels, in association with adequate energy balance, might contribute to weight loss.

Archaeology. The makers of the Protoaurignacian and implications for Neandertal extinction.

The Protoaurignacian culture is pivotal to the debate about the timing of the arrival of modern humans in western Europe and the demise of Neandertals. However, which group is responsible for this culture remains uncertain. We investigated dental remains associated with the Protoaurignacian. The lower deciduous incisor from Riparo Bombrini is modern human, based on its morphology. The upper deciduous incisor from Grotta di Fumane contains ancient mitochondrial DNA of a modern human type. These teeth are the oldest human remains in an Aurignacian-related archaeological context, confirming that by 41,000 calendar years before the present, modern humans bearing Protoaurignacian culture spread into southern Europe. Because the last Neandertals date to 41,030 to 39,260 calendar years before the present, we suggest that the Protoaurignacian triggered the demise of Neandertals in this area.

Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin.

AIMS/HYPOTHESIS: Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. METHODS: Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET. RESULTS: There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.

Analysis of image sharpness reproducibility on a novel engineered micro-CT scanner with variable geometry and embedded recalibration software.

This study investigates the reproducibility of the reconstructed image sharpness, after modifications of the geometry setup, for a variable magnification micro-CT (µCT) scanner. All the measurements were performed on a novel engineered µCT scanner for in vivo imaging of small animals (Xalt), which has been recently built at the Institute of Clinical Physiology of the National Research Council (IFC-CNR, Pisa, Italy), in partnership with the University of Pisa. The Xalt scanner is equipped with an integrated software for on-line geometric recalibration, which will be used throughout the experiments. In order to evaluate the losses of image quality due to modifications of the geometry setup, we have made 22 consecutive acquisitions by changing alternatively the system geometry between two different setups (Large FoV - LF, and High Resolution - HR). For each acquisition, the tomographic images have been reconstructed before and after the on-line geometric recalibration. For each reconstruction, the image sharpness was evaluated using two different figures of merit: (i) the percentage contrast on a small bar pattern of fixed frequency (f = 5.5 lp/mm for the LF setup and f = 10 lp/mm for the HR setup) and (ii) the image entropy. We have found that, due to the small-scale mechanical uncertainty (in the order of the voxel size), a recalibration is necessary for each geometric setup after repositioning of the system's components; the resolution losses due to the lack of recalibration are worse for the HR setup (voxel size = 18.4 µm). The integrated on-line recalibration algorithm of the Xalt scanner allowed to perform the recalibration quickly, by restoring the spatial resolution of the system to the reference resolution obtained after the initial (off-line) calibration.

A micro-PET/CT approach using O-(2-[18F]fluoroethyl)-L-tyrosine in an experimental animal model of F98 glioma for BNCT.

The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron Capture Therapy (BNCT), which integrates, in the same frame, micro-CT derived anatomy and PET radiotracer distribution. Preliminary results have demonstrated that (18)F-fluoroethyl-tyrosine (FET)/PET allows the identification of the extent of cerebral lesions in F98 tumor bearing rat. Neutron autoradiography and α-spectrometry on axial tissues slices confirmed the tumor localization and extraction, after the administration of fructose-boronophenylalanine (BPA). Therefore, FET-PET approach can be used to assess the transport, the net influx, and the accumulation of FET, as an aromatic amino acid analog of BPA, in experimental animal model. Coregistered micro-CT images allowed the accurate morphological localization of the radiotracer distribution and its potential use for experimental BNCT.

Contribution of organ blood flow, intrinsic tissue clearance and glycaemia to the regulation of glucose use in obese and type 2 diabetic rats: a PET study.

BACKGROUND AND AIMS: Chronic hyperglycaemia aggravates obesity and diabetes mellitus. The use of glucose by body organs depends on several factors. We sought to investigate the role of blood flow, intrinsic tissue glucose clearance and blood glucose levels in regulating tissue glucose uptake under fasting conditions (FCs) and in response to acute hyperglycaemia (AH) in obese and type 2 diabetic rats. METHODS AND RESULTS: Thirty-six Zucker rats were studied by positron emission tomography to quantify perfusion and glucose uptake during FC and after AH in the liver, myocardium, skeletal muscle and subcutaneous adipose tissue. Progressively higher glucose uptake rates were observed from lean to obese (p < 0.05) and to diabetic rats (p < 0.05) in all tissues during both FC and AH. In FC, they were increased of 7-18 times in obese rats and 11-30 times in diabetic rats versus controls. Tissue glucose uptake was increased by over 10-fold during AH in controls; this response was severely blunted in diseased groups. AH tended to stimulate organ perfusion in control rats. Tissue glucose uptake was a function of intrinsic clearance and glycaemia (mass action) in healthy animals, but the latter component was lost in diseased animals. Differences in perfusion did not account for those in glucose uptake. CONCLUSIONS: Each organ participates actively in the regulation of its glucose uptake, which is dependent on intrinsic tissue substrate extraction and extrinsic blood glucose delivery, but not on perfusion, and it is potently stimulated by AH. Obese and diabetic rats had an elevated organ glucose uptake but a blunted response to acute glucose intake.

Positron emission tomography and [18F]BPA: a perspective application to assess tumour extraction of boron in BNCT.

Positron emission tomography (PET) has become a key imaging tool in clinical practice and biomedical research to quantify and study biochemical processes in vivo. Physiologically active compounds are tagged with positron emitters (e.g. (18)F, (11)C, (124)I) while maintaining their biological properties, and are administered intravenously in tracer amounts (10(-9)-10(-12)M quantities). The recent physical integration of PET and computed tomography (CT) in hybrid PET/CT scanners allows a combined anatomical and functional imaging: nowadays PET molecular imaging is emerging as powerful pharmacological tool in oncology, neurology and for treatment planning as guidance for radiation therapy. The in vivo pharmacokinetics of boron carrier for BNCT and the quantification of (10)B in living tissue were performed by PET in the late nineties using compartmental models based on PET data. Nowadays PET and PET/CT have been used to address the issue of pharmacokinetic, metabolism and accumulation of BPA in target tissue. The added value of the use of L-[(18)F]FBPA and PET/CT in BNCT is to provide key data on the tumour extraction of (10)B-BPA versus normal tissue and to predict the efficacy of the treatment based on a single-study patient analysis. Due to the complexity of a binary treatment like BNCT, the role of PET/CT is currently to design new criteria for patient enrolment in treatment protocols: the L-[(18)F]BPA/PET methodology could be considered as an important tool in newly designed clinical trials to better estimate the concentration ratio of BPA in the tumour as compared to neighbouring normal tissues. Based on these values for individual patients the decision could be made whether BNCT treatment could be advantageous due to a selective accumulation of BPA in an individual tumour. This approach, applicable in different tumour entities like melanoma, glioblastoma and head and neck malignancies, make this methodology as reliable prognostic and therapeutic indicator for patient undergoing BNCT.

In vitro neutron irradiation of glioma and endothelial cultured cells.

To fully develop its potential boron neutron capture therapy (BNCT) requires the combination of a suitable thermal/epithermal neutron flux together with a selective intake of (10)B-boron nuclei in the target tissue. The latter condition is the most critical to be realized as none of the boron carriers used for experimental or clinical purposes proved at the moment an optimal selectivity for cancer cells compared to normal cells. In addition to complex physical factors, the assessment of the intracellular concentration of boron represent a crucial parameter to predict the dose delivered to the cancer cells during the treatment. Nowadays the dosimetry calculation and then the prediction of the treatment effectiveness are made using Monte Carlo simulations, but some of the model assumption are still uncertain: the radiobiological dose efficacy and the probability of tumour cell survival are crucial parameters that needs a more reliable experimental approach. The aim of this work was to evaluate the differential ability of two cell lines to selectively concentrate the boron-10 administered as di-hydroxyboryl-phenylalanine (BPA)-fructose adduct, and the effect of the differential boron intake on the damage produced by the irradiation with thermal neutrons; the two cell lines were selected to be representative one of normal tissues involved in the active/passive transport of boron carriers, and one of the tumour. Recent in vitro studies demonstrated how BPA is taken by proliferating cells, however the mechanism of BPA uptake and the parameters driving the kinetics of influx and the elimination of BPA are still not clarified. In these preliminary studies we analysed the survival of F98 and human umbilical vein endothelial cells (HUVEC) cells line after irradiation, using different thermal fluencies at the same level of density population and boron concentration in the growing medium prior the irradiation. This is first study performed on endothelium model obtained by a primary human cell line (HUVEC). The perspective application of this work is to develop a model able to foresee the effects produced by different combination of boron influx with a thermal neutron fluencies, applying a standardized radiobiological methodology, and in particular to continue the investigation of the radiobiological effects on the endothelium model as the main tissue involved in the transport of boronated molecules.

Significance of both negative T waves and stress-induced normalization of the repolarization phase in infarcted patients: a positron-emission-tomography assessment of regulation of myocardial blood flow and viability of myocardium.

BACKGROUND: The clinical correlation of stress-induced normalization of previously negative T waves (NNTW) to regulation of regional myocardial blood flow (MBF) and tissue viability is still being debated. OBJECTIVE: To clarify its meaning. METHODS: We studied 25 patients, who had previously suffered anterior myocardial infarction and for whom negative T waves were recorded on baseline electrocardiographic precordial leads, by means of positron emission tomography. We obtained MBF in the infarcted myocardial regions under resting conditions for all patients, during infusion of dipyridamole (17 patients) and dobutamine (20 patients), using [13N]-ammonia as a flow tracer. RESULTS: During stress tests, 13 patients exhibited NNTW (group 1) whereas the remaining 12 presented persistent negative T waves (group 2). NNTW was observed in 18 stress studies (for 10 and eight patients during administration of dobutamine and dipyridamole, respectively) whereas persistent negative T waves occurred 19 times (for 10 patients during infusion of dobutamine and nine patients during administration of dipyridamole). A complete concordance of the modifications of the repolarization phase was observed for patients who were subjected both to dipyridamole and to dobutamine studies. Furthermore, we assessed viability of myocardium in 20 of 25 patients using [18F]-fluorodeoxyglucose. For the remaining five patients not subjected to metabolic imaging, a coronary reserve of 1.65 was considered a cut-off of viability. Resting MBF for patients in groups 1 and 2 were similar (0.53 +/- 0.20 versus 0.47 +/- 0.17 ml/min per g, respectively, NS) whereas during pharmacological stress, MBF of patients in group 1 was significantly higher than that for patients in group 2 (0.99 +/- 0.41 versus 0.56 +/- 0.26 ml/min per g, respectively, P < 0.0001). Coronary vasodilating capability, expressed as stress/resting MBF ratio, turned out to be 1.88 +/- 0.49 and 1.16 +/- 0.37 for patients in groups 1 and 2, respectively (P < 0.0001). We observed no difference in mean exercise work load (9.6 +/- 2.80 versus 8.46 +/- 2.18 min, NS) and rate- pressure product (24230 +/- 6425 versus 24207 +/- 8146 mmHg beats/ min, NS) at peak for the two categories of patients. All 13 patients in group 1 (100%) had viable myocardium in the anterior infarcted areas whereas only one of 12 patients in group 2 did (9%, P< 0.0001 versus group 1). Finally, a subanalysis for the specific pharmacological agent used was performed and it gave similar results. CONCLUSION: Regardless of the specific stress test able to elicit the electrocardiographic sign, infarcted dysfunctional areas with stress-induced NNTW were demonstrated to have a higher coronary vasodilating capability and a greater probability of viability of myocardium than had persistent negative T wave regions. Therefore, detection of NNTW appears to be a cheap first-line method for the identification both of a better preserved coronary microcirculatory function and of the persistence of viability of myocardium in the infarcted areas.

Role of 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the early assessment of response to chemotherapy in metastatic breast cancer patients.

We investigated the role of 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the early evaluation of response to chemotherapy in metastatic breast cancer patients. Breast cancer patients who received an epirubicin/paclitaxel--containing regimen as first-line treatment for metastatic disease were included in this study. A PET study was performed within 1 week before the start of treatment, at day 8 after the first course, and at the end of the planned program of chemotherapy. Tumor response was determined clinically and radiographically every 2 courses of treatment. Thirteen patients with metastatic breast cancer who were referred for treatment protocols with gemcitabine/epirubicin/paclitaxel or epirubicin/paclitaxel chemotherapy regimens were included in this study. All metastatic sites were easily visualized on the baseline FDG-PET images, obtained 50 to 60 minutes after tracer injection. Nine patients who completed the planned courses of chemotherapy and the FDG-PET studies were available for analysis. In the six patients who achieved a response to treatment, median glucose standard uptake value (SUV) (semiquantitative analysis) was 7.65 (range, 3.4-12.3) at baseline, 5.7 (range, 2.8-7.6) at day 8 after the first course, and 1.2 (range, 0.99-1.3) at the end of the 6 planned courses of chemotherapy. Three patients who obtained a stable disease as best response had no significant decrease in tumor glucose SUV compared to baseline levels. Qualitative visual analysis in the six responding patients showed a decrease in delineation of tumor mass from background activity soon after the first course, while the nonresponding patients had no significant modification from basal levels. Semiquantitative FDG-PET scanning of metastatic breast cancer sites showed a rapid and significant decrease in tumor glucose metabolism soon after the first course of treatment in patients who achieved a response to first-line chemotherapy. On the contrary, no significant decrease was observed in nonresponding patients.

Tumor targeting by intra-arterial infusion of 5-[123I]iodo-2'-deoxyuridine in patients with liver metastases from colorectal cancer.

UNLABELLED: We previously showed the tumor-targeting potential of the 125I-labeled thymidine analog 5-iodo-2'-deoxyuridine (IUdR) injected intratumorally in patients with high tumor-cell kinetics. In this study, we evaluated the tumor incorporation of [123I]IUdR infused intra-arterially in patients with liver metastases from colorectal cancer. METHODS: Iodine-123-IUdR (110-300 MBq, 3-8 mCi, specific activity, 150-200 Ci/mumole) was infused into the hepatic artery of 16 patients with inoperable liver metastases over 30-45 min through a permanent intra-arterial catheter. A dynamic sequence during infusion, spot images, whole-body scans and SPECT acquisitions were recorded up to 42 hr. Blood and urine samples were obtained for biodistribution and HPLC analyses. RESULTS: In the 14 patients with adequate tumor perfusion patterns, tumor uptake reached 2%-17.6% ID at the end of infusion. After a washout phase that lasted 18-20 hr, incorporated radioactivity remained steadily associated with the tumor lesions until at least 42 hr after infusion (about 1.4%-11.1% ID). HPLC analysis indicated a virtually 100% first-pass hepatic deiodination of unincorporated [123I]IUdR (about 80%-95% ID recovered in the 42-hr urine). No significant uptake was detected in the bone marrow or in other normal dividing tissues. CONCLUSION: These results encourage further studies to enable dosimetric estimates, optimization of dose regimens, and examination of the therapeutic potential of Auger-electron-emitter-labeled IUdR in cancer therapy utilizing this type of approach.

EEG, PET, SPET and MRI in intractable childhood epilepsies: possible surgical correlations.

Magnetic resonance imaging (MRI), single photon emission tomography (SPET), and positron emission tomography (PET) using [18F]fluorodeoxyglucose were used in combination with scalp and scalp-video EEGs in a group of 30 pediatric patients with drug resistant epilepsy (DRE) in order to identify patients who could benefit from neurosurgical approach. Seizures were classified according to the consensus criteria of The International League Against Epilepsy. In three patients infantile spasms (IS) were diagnosed; 13 subjects were affected by different types of generalized seizures, associated with complex partial seizures (CPS) in three. In the other 14 patients partial seizures, either simple (SPS) or complex, were present. A localized abnormality was demonstrated in one patient with IS and in three patients with generalized seizures. Of the group of 14 subjects with CPS, MRI and CT were normal in 7, but SPET or PET indicated focal hypoperfusion or hypometabolism concordant with the localization of the EEG abnormalities. In 5 of the other 7 patients anatomical and functional imaging and EEG findings were concordant for a localized abnormality. It can be concluded that functional imaging combined with scalp EEGs appears to be superior to the use of only CT and MRI for selecting children with epilepsy in whom a surgical approach can be considered, in particular when CPS resistant to therapy are present.

Initial tumor targeting, biodistribution, and pharmacokinetic evaluation of the monoclonal antibody PAM4 in patients with pancreatic cancer.

This pharmacokinetic study was performed to assess the potential usefulness of the murine monoclonal antibody (MoAb) PAM4-IgG1 as an immunotargeting agent for pancreatic cancer imaging or therapy. This MoAb reacts specifically with mucin purified from human pancreatic cancer. 131I-labeled PAM4-IgG1 was injected i.v. into five patients with suspected pancreatic cancer. Whole-body scans and spot views of the abdominal area were recorded with a computerized gamma camera, and specific regions of interest were drawn over the liver and spleen to define the kinetics of activity in these organs. Blood samples taken from 0.1-144 h after injection served to define the kinetics of plasma distribution and removal of activity from the body. Surgery confirmed pancreatic cancer in four of the five patients, whereas chronic pancreatitis was present in the fifth patient; in all four pancreatic cancer patients, immunostaining with the MoAb PAM4 demonstrated the presence of the specific antigen, with a cytoplasmic and endoluminal/secretory pattern of distribution. Nonspecific radioactivity accumulation in the liver, spleen, and bone marrow was low, linked essentially to the blood pool effect of circulating activity in these organs. The overall quality of scintigraphic maps recorded over the abdomen was quite satisfactory due to the low liver and spleen activity, with good scintigraphic demonstration of the pancreatic cancers (either primary or metastatic); the patient subsequently found to have pancreatitis failed to show PAM4 targeting. Except in one patient with widespread peritoneal metastases (in whom these tumor implants were detected scintigraphically already 24-48 hours after tracer injection), scintigraphic evidence of the tumor lesions was usually late, starting at about 72-96 h after tracer injection. The results obtained in this preliminary study indicate the potential usefulness of MoAb PAM4 for immunoscintigraphy in patients with either primary and/or recurrent pancreatic cancer while also suggesting that the use of the faster-clearing Fab fragments of this MoAb probably would result in improved immunoscintigraphic properties.

Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy.

Angina, despite angiographically normal coronary arteries, is a common symptom in patients with hypertrophic cardiomyopathy (HC). Verapamil has been shown to ameliorate silent myocardial perfusion defects documented by thallium-201 in patients with HC. The aim of this study was to investigate the effects of verapamil on absolute regional myocardial blood flow and flow reserve, measured by positron emission tomography (PET) in patients with HC. Echocardiography, exercise stress testing, and measurements of myocardial blood flow at rest and after administration of intravenous dipyridamole (0.56 mg/kg) were undertaken in 20 patients with HC at baseline study and 8 +/- 2 weeks after double-blind randomization to either slow-release verapamil 240 mg or placebo once daily. During treatment, resting myocardial blood flow in the interventricular septum was 0.81 +/- 0.23 versus 0.96 +/- 0.42 ml/min/g in the placebo and verapamil group, respectively (p = NS between groups and when compared with respective baseline study); resting myocardial blood flow in the left ventricular free wall was 0.67 +/- 0.17 versus 0.74 +/- 0.45 ml/min/g, respectively (p = NS). After dipyridamole infusion, myocardial blood flow in the interventricular septum was 1.42 +/- 0.52 versus 1.92 +/- 1.23 ml/min/g (p = NS between groups and when compared with respective baseline study); myocardial blood flow in the left ventricular free wall was 1.25 +/- 0.41 versus 1.68 +/- 1.37 ml/min/g, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergically mediated coronary vasoconstriction in patients with syndrome X.

Several studies have shown that coronary vasodilator reserve is impaired in some patients with chest pain and angiographically normal coronary arteries. In a subgroup of these patients, who additionally show ST depression on the electrocardiogram during exercise and are generally labelled as having Syndrome X, the impairment of coronary flow reserve is associated with metabolic and functional signs consistent with an increased sympathetic drive. The aim of the present investigation was to ascertain whether the impairment of coronary vasodilator reserve in patients with Syndrome X is due to adrenergically mediated vasoconstriction of coronary microcirculation. Myocardial blood flow (MBF), at baseline and following intravenous infusion of dipyridamole (0.56 mg/kg over 4 minutes), was measured by means of 13N-ammonia and dynamic positron emission tomography in 10 females (mean age 52 +/- 8 years) with a chest pain history, ST-segment depression during exercise, and angiographically normal coronaries. The first MBF study was performed while the patients were off therapy; a repeat MBF study was performed following 1 week of treatment with the alpha-1 blocker doxazosin (2 mg/day). Off therapy MBF was 1.13 +/- 0.25 ml/min/g at baseline and increased to 2.35 +/- 0.66 ml/min/g following dipyridamole. Coronary vasodilator reserve (dipyridamole/baseline MBF) was 2.18 +/- 0.56. During treatment with doxazosin, baseline MBF was not different from the control value (1.25 +/- 0.50 ml/min/g), while added dipyridamole significantly increased MBF to 3.52 +/- 1.20 ml/min/g (p < 0.01 vs. off therapy). Coronary vasodilator reserve was significantly increased (2.91 +/- 0.92, p < 0.01 vs. control value) by doxazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor targeting potential and metabolism of 5-[125I]iodo-2'-deoxyuridine injected intratumorally in patients with breast cancer.

We have previously demonstrated the high tumor targeting potential of the thymidine analogue 125IUdR in experimental animal models following direct intratumoral or locoregional (intracavitary) administration. The aim of the present work was to evaluate the metabolism and selectivity (based on differential cell proliferation kinetics) of 125IUdR incorporation in patients with breast cancer following a similar approach. 125IUdR (4-8 MBq) was injected intratumorally by ultrasound-guided percutaneous injection in 7 patients with breast cancer 24 hours before ablative surgery. Blood and urine samples were collected up to 72 hours after injection and analyzed by HPLC using a C18 reversed-phase column and methanol:water (20:80) as the mobile phase. Following resection, the radioactivity of the tumor and the surrounding tissues was measured in a gamma counter, and microautoradiography was performed on semithin tissue sections to determine the site of tracer incorporation at the cellular level. Activity in plasma peaked at 0.5 to 1 hour after 125IUdR injection (4.96 +/- 1.08% of injected dose/liter), declining thereafter with a mean T1/2 of 11.24 +/- 2.78 hours. By HPLC analysis, undegraded 125IUdR was about 15-30% of total plasma activity, with a biphasic pattern peaking at both 1-3 hours and approximately 12 hours. In addition to free 125I-, about 10% of early plasma activity was constituted by a labeled metabolite (tentatively identified as radio-iodouracil), rising to about 50-60% at later time points. About 70-90% of urinary radioactivity was 125I-, and 5-20% was undegraded 125IUdR in the first 24-hour samples, while the remainder was iodouracil. High tumor/nontumor ratios were obtained (mean 147.4 +/- 125.2, range 27-397) with average tumor/blood ratios at the time of surgery equal to 32.7 +/- 18.6 (range 5-56). An average 0.0244 +/- 0.0189% of the injected dose was present per gram of tumor (range 0.001-0.061% ID/g). Microautoradiography confirmed the high values of tumor/nontumor incorporation ratios and demonstrated the specificity of 125IUdR incorporation mostly in the tumor cell nuclei, with only occasional incorporation by normal-appearing tubular cells. These results suggest the potential of radiolabeled IUdR for tumor targeting in humans, to be used whenever a satisfactory route of locoregional administration allowing for homogeneous tracer distribution within the tumor mass is accessible and in the presence of favorable tumor cell proliferations kinetics.

Coronary reserve and exercise ECG in patients with chest pain and normal coronary angiograms.

BACKGROUND: Coronary vasodilator reserve is reduced in some patients with a history of chest pain and angiographically normal coronary arteries. ECG changes suggestive of myocardial ischemia during exercise also can be demonstrated in a subset of these patients. METHODS AND RESULTS: We have investigated the correlation between coronary vasodilator reserve, assessed with 13N-labeled ammonia and positron emission tomography, and the ECG during exercise stress in 45 patients with a history of chest pain, angiographically normal coronary arteries, and a negative ergonovine test. ST segment depression on the ECG during exercise was present in 29 of 45 patients. Mean resting left ventricular blood flow was 1.04 +/- 0.22 ml.min-1.g-1; it increased to 1.32 +/- 0.47 ml.min-1.g-1 (p less than 0.01 versus baseline value) during atrial pacing and to 2.52 +/- 0.96 ml.min-1.g-1 (p less than 0.01 versus baseline value) after dipyridamole (0.56 mg/kg i.v.). No regional flow defects could be demonstrated in any patient during pacing or after dipyridamole. Myocardial flows after dipyridamole, however, did not show a normal frequency distribution (Kolmogorov-Smirnov test), and two patient populations could be identified. Twenty-nine (67%) patients had a mean left ventricular flow of 3.02 +/- 0.33 ml.min-1.g-1 after dipyridamole (range, 2.13-5.46 ml.min-1.g-1), and 14 (33%) patients had a mean flow of 1.48 +/- 0.29 ml.min-1.g-1 (range, 1.06-2.04 ml.min-1.g-1, p less than 0.01 versus the "high-flow group"). CONCLUSIONS: Approximately one third of patients in our series showed a reduced coronary vasodilator reserve. Although 12 of 14 patients in the "low-flow group" had ST segment depression during exercise stress, 16 of 29 patients in the high-flow group also had ST segment depression during exercise stress. Therefore, despite a good sensitivity (86%) in identifying patients with a blunted increment of coronary flow, the ECG response during exercise stress appears to have a rather low specificity (45%). This suggests that factors other than reduced coronary reserve and myocardial ischemia may play a role in the genesis of the ST segment depression in these patients.