Mapping of brain tissue hematocrit in glioma and acute stroke using a dual autoradiography approach.

Hematocrit (Hct) determines the ability of blood to carry oxygen. While changes in systemic Hct are known to impact stroke or tumor control, changes in local (tissue) Hct (tHct) induced by these diseases have however received little attention. In this study, we evaluate tHct in acute stroke and in glioma models using a new approach to map tHct across the brain, a dual isotope autoradiography, based on injections of 125I-labeled albumin and 99mTc-lalbeled red blood cells in the same animal. For validation purpose, tHct was mapped in the rat brain (i) under physiological conditions, (ii) following erythropoietin injection, and (iii) following hemodilution. Then, tHct was then mapped in stroke (middle cerebral artery occlusion) and tumor models (9LGS and C6). The mean tHct values observed in healthy brains (tHct = 29 ± 1.3%), were modified as expected by erythropoietin (tHct = 36.7 ± 2.6%) and hemodilution (tHct = 24.2 ± 2.4%). Using the proposed method, we observed a local reduction, spatially heterogeneous, in tHct following acute stroke (tHct = 19.5 ± 2.5%) and in both glioma models (9LGS: tHct = 18.5 ± 2.3%, C6: tHct = 16.1 ± 1.2%). This reduction and this heterogeneity in tHct observed in stroke and glioma raises methodological issues in perfusion imaging techniques where tHct is generally overlooked and could impact therapeutic strategies.

Targeted radionuclide therapy with RAFT-RGD radiolabelled with (90)Y or (177)Lu in a mouse model of αvß3-expressing tumours.

PURPOSE: The αvß3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvß3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with ß(-) emitters in a nude mouse model of αvß3 integrin-expressing tumours. METHODS: Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvß3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvß3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvß3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. RESULTS: Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvß3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvß3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvß3-negative tumours. CONCLUSION: (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvß3-expressing tumours for internal targeted radiotherapy.

First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus (125)IUdR.

PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.

Assessment of insulin sensitivity in vivo in control and diabetic mice with a radioactive tracer of glucose transport: [125I]-6-deoxy-6-iodo-D-glucose.

BACKGROUND: Impairment of insulin-stimulated glucose transport is a characteristic of type 2 diabetes. A radioactive glucose analogue has been synthesized: [(125)I]-6-deoxy-6-iodo-D-glucose. Its biological behaviour in vitro is similar to that of 3-O-methyl-D-glucose, the reference tracer of glucose transport. The aim of the present study was to determine the ability of [(125)I]-6-deoxy-6-iodo-D-glucose to evaluate variations in glucose transport in vivo. METHODS: Biodistributions of [(125)I]-6-deoxy-6-iodo-D-glucose were performed with or without exogenous insulin (iv injection of 1.5 IU/kg) in db/+ non-diabetic control mice and in db/db type 2 diabetic mice, exhibiting a severe insulin resistance characterized by a lack of increase in glucose uptake in response to insulin. RESULTS: In db/+ mice, insulin increased [(125)I]-6-deoxy-6-iodo-D-glucose transport by 30% in most insulin-sensitive tissues (heart, diaphragm and skeletal muscle, p < 0.05) and had no effect in other organs. In db/db mice, [(125)I]-6-deoxy-6-iodo-D-glucose transport in these organs was not modified by insulin. CONCLUSION: [(125)I]-6-deoxy-6-iodo-D-glucose is able to trace in vivo an increase in glucose transport with insulin in non-diabetic mice and a defect of glucose transport in type 2 diabetic mice. It is the first time that an iodinated analogue of glucose has shown such promising results after in vivo injection. The use of this tracer to assess glucose transport in vivo in humans via nuclear imaging warrants further investigation.

Detection of chemoresistance profile of cell lines K562, KB, GLC4 and HL60 through characterisation of the hmdr1, mrp and lrp transcripts.

The current trend in innovative cancer therapy is moving towards targeting the genes of interest by means of oligonucleotides developed for therapeutic or diagnostic use. These new approaches are of particular interest in oncology, and it would therefore be extremely useful to characterise all the biological tools currently available in this field. The chemoresistance profiles of four human cancer cell lines were determined by identifying of the operating conditions needed to characterise the presence of hmdr1, mrp and lrp mRNA by gene amplification.

Prediction of cardiovascular events in clinically selected high-risk NIDDM patients. Prognostic value of exercise stress test and thallium-201 single-photon emission computed tomography.

OBJECTIVE: We evaluated the prognostic value of an exercise stress test and thallium-201 scintigraphy for the prediction of cardiac events in selected high-risk NIDDM patients. RESEARCH DESIGN AND METHODS: NIDDM patients (n = 158, 105 men, aged 63 +/- 9 years) with two or more of the following criteria were prospectively included: age > or = 65 years, active smoking, hypertension > 160/95 mmHg, hypercholesterolemia (cholesterol > 5.70 mmol/l or LDL > 3.10 mmol/l), peripheral artery disease, abnormal rest electrocardiogram, or microalbuminuria (20-200 micrograms/min). An exercise-stress scintigraphy was performed in 77 patients able to exercise, while a dipyridamole scintigraphy was performed in 80 patients unable to exercise. Follow-up was 23 +/- 17 months. Major end points were cardiac deaths or nonfatal myocardial infarction. RESULTS: The annual event rate was 7.31% (deaths: 8, myocardial infarction: 14). Independent predictors of events were as follows: an age > 60 (P = 0.02), an abnormal rest electrocardiogram (P = 0.02), microalbuminuria (P = 0.001), the inability to exercise (P = 0.009), and the presence of more than two defects on scintigraphy (P = 0.001). A cardiac death occurred in 1.3% of patients able to exercise versus 8.8% of patients unable to exercise (odds ratio = 6.8, P = 0.001). Among patients unable to exercise, large perfusion defects corresponded to an annual mortality rate of 22.3%. Conversely, the negative predictive value of a normal scintigraphy for the occurrence of death was 97%. CONCLUSIONS: Inability to exercise and large perfusion defects on thallium-201 scan are major predictors of future death and myocardial infarction in high-risk NIDDM patients.

[Evaluation of a clinical and scintigraphic management strategy for cardiac risk before abdominal aorta surgery. Apropos of 982 surgical patients]. / Evaluation d'une stratégie clinique et scintigraphique de prise en charge du risque cardiologique avant chirurgie de l'aorte abdominale. A propos de 982 patients opérés.

The incidence of major cardiac events (death, infarction) is over 5% after programmed aortic vascular surgery. The aim of this study was to evaluate a management strategy of this risk based on the clinical status and targeted indication of myocardial scintigraphy, coronary angiography and myocardial revascularisation. A first phase (1991-1993, 451 patients) confirmed the prognostic value of clinical (age, previous cardiac history, diabetes, hypertension, electrocardiogrammes) and scintigraphic features: the cardiac mortality was 1.25% in patients with a low clinical risk (70.3% of cases) and 4.5% in patients with a high clinical risk (2 factors, 29.3% of cases) (p < 0.01). In the latter group, the mortality was zero after normal myocardial scintigraphy and 7.2% after abnormal myocardial scintigraphy (p < 0.01) and 12.5% in cases with reversible defects (p < 0.01). During the second phase of the study (1994-1997, 531 patients) coronary angiography was performed in patients with a high clinical risk and abnormal scintigraphy (10.9% of cases). This led to a myocardial revascularisation in 3.6% of patients. The cardiac mortality was then the same in the low and high a priori clinical risk: 2.3 and 2.8% (NS). The use of simple clinical criteria enables surgery in the majority of candidates for aortic vascular surgery, scintigraphy being reserved for about one patient in ten with myocardial revascularisation in less than 4% of cases. The operative cardiac mortality then decreases to under 2.5%.

Can tumour marker assays be a guide in the prescription of bone scan for breast and lung cancers?

Considering the current need to improve cost-effectiveness in cancer patient management, a prospective study was undertaken in order to define the optimal combination of bone scan and tumour marker assays in breast and lung cancer strategies, as has been done in the case of prostate cancer. All patients with breast or lung cancer referred to the Nuclear Medicine Department of the Grenoble Teaching Hospital between December 1995 and April 1997 were included. A blood sample was drawn in each case for marker assay (CA15-3 or CEA and CYFRA 21-1) on the same day as the bone scan. Two hundred and seventy-five patients were included: 118 with lung cancer and 157 with breast cancer. With regard to lung cancer, no information useful for guiding bone scan prescription was obtained through CEA and CYFRA 21-1 assays. For breast cancer, the results suggest that in asymptomatic patients, a CA15-3 level of less than 25 U/ml (upper normal value chosen as the threshold) is strongly predictive of a negative bone scan; by contrast, high tumour marker levels are predictive of neoplastic bone involvement. When a doubtful bone scan is obtained in a patient with breast cancer, a normal marker level makes it highly probable that bone scan abnormalities are not related to malignancy.

Potential use of radiolabeled antisense oligonucleotides in oncology.

Antisense oligodeoxynucleotides (ODNs) have great promise for therapy. Oligomers labeled with gamma-emitting radioelements have great promise for diagnosis. These radiolabeled oligomers can be used to identify the presence of a particular messenger RNA through simple external detection of radioactivity by means of scintigraphy. This review evaluates the progress in the development of antisense oligodeoxynucleotides for non-invasive imaging of chemoresistance. As nominated by H.N. Wagner at the final session of Nuclear Medicine congress in Denver, the deoxyribonucleic acid is "the molecule of the millennium".

Assessment of myocardial viability in patients with previous myocardial infarction by using single-photon emission computed tomography with a new metabolic tracer: [123I]-16-iodo-3-methylhexadecanoic acid (MIHA). Comparison with the rest-reinjection thallium-201 technique.

OBJECTIVES: We compared the ability of rest single-photon emission computed tomography (SPECT) with [123I]-16-iodo-3-methylhexadecanoic acid (MIHA) and the thallium-201 (Tl-201) rest-reinjection technique to detect myocardial viability after infarction. BACKGROUND: After myocardial infarction, MIHA frequently shows increased uptake in the areas with exercise Tl-201 defects (mismatch), even in patients with an irreversible Tl-201 reinjection defect. Whether such increased uptake is indicative of ischemic but viable myocardium is not known. METHODS: We studied 38 patients who 1) underwent exercise SPECT Tl-201 with rest-reinjection and rest SPECT with MIHA before undergoing percutaneous transluminal coronary angioplasty (PTCA) of an infarct-related coronary artery, and 2) were found to have successful revascularization at follow-up angiography. The relation between SPECT results before PTCA and subsequent improvement in left ventricular wall motion was assessed. RESULTS: A mismatch was evident before PTCA in 51 of 76 infarct-related segments and correlated with subsequent improvement in wall motion (overall accuracy 71%), even for the 27 segments whose exercise defects remained irreversible after Tl-201 reinjection (overall accuracy 81%). The finding of a mismatch clearly enhanced the results provided by the finding of > or = 50% Tl-201 uptake as determined at redistribution (p < 0.05), but not as determined at reinjection, although there was a trend toward a better specificity for the findings of a mismatch. CONCLUSIONS: MIHA is an efficient marker of viability inside exercise-underperfused areas after infarction, even in patients with irreversible Tl-201 reinjection defects. Assessment by conventional SPECT of a mismatch between results obtained with a metabolic tracer (MIHA) and a flow tracer analyzed at exercise (Tl-201) as a marker of myocardial viability is a promising area of research.

[123I]-6-deoxy-6-iodo-D-glucose (6DIG): a potential tracer of glucose transport.

A glucose analogue labelled with iodine-123 in position 6 has been synthesized: [123I]-6-deoxy-6-iodo-D-glucose (6DIG). The aim of this study was to examine its biological behaviour in order to assess whether it could be used to evaluate glucose transport with SPECT. To establish whether 6DIG enters the cells using the glucose transporter, four biological models have been used: human erythrocytes in suspension, neonatal rat cardiomyocytes in culture, isolated perfused rat hearts, and biodistribution in mice. 6DIG competed with D-glucose to enter the cells and its entry was increased by insulin and inhibited in the presence of cytochalasin B. The biological behaviour of 6DIG was similar to that of 3-O-methyl-D-glucose. 6DIG is a tracer of glucose transport which is very promising for clinical studies.

Metabolic myocardial viability assessment with iodine 123-16-iodo-3-methylhexadecanoic acid in recent myocardial infarction: comparison with thallium-201 and fluorine-18 fluorodeoxyglucose.

The best test presently available to ascertain residual viability within an infarct-related area involves the use of fluorine-18 fluorodeoxyglucose (FDG) to detect the persistence of some cellular metabolism. Rest reinjection of thallium-201 is a less accurate alternative but is easy to perform. Iodinated fatty acids, which are used with standard gamma cameras, are proposed as markers of cellular metabolism. This study was performed to assess the value of 16-iodo-3-methylhexadecanoic acid (MIHA) as a marker of the residual cellular metabolism by comparison with FDG in patients with a recent myocardial infarction, and to evaluate its contribution compared with the 201Tl stress-redistribution-reinjection technique. Stress-redistribution-reinjection 201Tl imaging, rest MIHA imaging and glucose-loaded FDG imaging were performed in 22 patients with recent myocardial infarction. Out of the 628 myocardial segments obtained from the left ventricular analysis, 400 were hypoperfused (relative uptake <0.75 of maximum uptake on stress 201Tl imaging), 177 of which were severely hypoperfused (relative uptake <0.50). Receiver operating characteristic (ROC) curves for predicting metabolic myocardial viability with FDG were derived from the results in respect of (a) 201Tl activity during exercise, redistribution and reinjection and (b) MIHA uptake, using the two FDG thresholds most commonly considered to define metabolic viability (0.50 and 0.60). Analysis of the 400 hypoperfused segments demonstrated that 201Tl reinjection was the most accurate test in predicting the presence of myocardial viability (area under the ROI curves=0.85 and 0.86 at the 0.50 and 0.60 FDG thresholds, respectively; P<0.05 vs other tests). The global predictive values of MIHA and 201Tl reinjection were, respectively, 0.87 and 0.89 at the 0.50 FDG threshold (NS), and 0.82 and 0.87 at the 0.60 FDG threshold (NS). When only the 177 severely hypoperfused segments were considered, 201Tl reinjection remained the most accurate test (accuracy 0.84 at the 0.50 FDG threshold and 0.82 at the 0.60 FDG threshold), while the accuracy of MIHA decreased significantly (0.78 at the 0.50 FDG threshold and 0.73 at the 0.60 FDG threshold, P<0.05 vs 201Tl reinjection). In all circumstances, MIHA was less specific than 201Tl reinjection for the detection of metabolic viability. In conclusion, in patients with recent myocardial infarction, MIHA accurately detects the persistence of metabolic viability, but is not superior to 201Tl.

Additive value of thallium single-photon emission computed tomography myocardial imaging for prediction of perioperative events in clinically selected high cardiac risk patients having abdominal aortic surgery.

The present study was designed to prospectively evaluate whether reinjection thallium-201 single-photon emission computed tomography (SPECT) has a significant additive predictive value for occurrence of perioperative cardiac events in clinically selected patients at high cardiac risk undergoing abdominal aortic surgery. Of a group of 517 consecutive patients referred, 134 had > or = 2 of the following clinical or electrocardiographic cardiac risk variables: age > 70 years; history of myocardial infarction, angina, or congestive heart failure; diabetes mellitus; hypertension with severe left ventricular hypertrophy; and Q waves or ischemic ST-segment abnormalities on electrocardiogram at rest. Operation was performed after thallium SPECT study. Twelve patients (9%) had major perioperative events (cardiac death or nonfatal myocardial infarction) and 18 patients had other cardiac events (unstable angina, congestive heart failure, or severe ventricular tachyarrhythmia). Variables correlated with the occurrence of major events were history of myocardial infarction (p < 0.05) and the presence (p < 0.001) and number of segments with thallium reversible defects (p < 0.001). In multivariate analysis, history of myocardial infarction (p < 0.05) and the number of segments with reversible thallium defects (p < 0.001) were independent predictors. When all the cardiac events were taken into consideration, all the previous variables, as well as Q waves and ischemic ST abnormalities on the electrocardiogram, showed significant predictive value in both univariate and multivariate analyses. Furthermore, thallium SPECT imaging has an additive predictive value for major cardiac events over clinical and electrocardiographic risk factors. When performed on clinically selected patients at high cardiac risk undergoing abdominal aortic surgery, thallium SPECT demonstrates significant prognostic value for cardiac events over that provided by clinical variables alone.

Regional uptake of [123I]-16-iodo3-R,S-methyl hexadecanoic acid in patients with myocardial infarction. Comparison with thallium 201 uptake and wall motion.

Thirty patients with recent myocardial infarction were intravenously injected with the modified fatty acid [123I]16-iodo-3R,S-methyl hexadecanoic acid (MIHA) at peak exercise to quantify viable myocardium after infarction. The results were analysed visually and quantitatively and compared with those obtained after injection of thallium 201 at peak exercise with single-photon emission computed tomography (SPECT) imaging immediately and 4 hours later. Ventriculography was used to study regional wall motion in all patients. In the visual comparison of 201Tl- and MIHA-SPECT scintigrams, 98.8% of normal segments (N) and 96% of temporary thallium-defect segments (T) were N or T on MIHA-SPECT scintigrams (91.3% and 70.5%, respectively, in the quantitative analyses). In contrast, 47.2% of permanent thallium-defect segments (P) were N or T on the MIHA-SPECT scintigrams (20.6% in the quantitative analysis). Revascularization therapy could only be recommended on the basis of MIHA-SPECTs in 5 to 8 of the 30 patients. To confirm the superiority of MIHA over 201Tl to evaluate myocardial viability, one must compare their uptake with myocardial contractility after revascularization.

Effect of glucose on the distribution of iodine-123-IHA-16 between esterification and oxidation in canine myocardium.

To evaluate the effect of glucose perfusion on the myocardial metabolism of [123I]-16-iodo-9-hexadecenoic acid (IHA), the latter was injected intravenously into six fasting dogs perfused with a solution lacking glucose (controls) and seven fasting dogs perfused with glucose and insulin. The distribution of myocardial 123I among iodides, free IHA, and esterified IHA was measured in myocardial biopsy specimens. The increase in esterification and decrease in oxidation of IHA due to glucose were quantified using a compartmental mathematical model of myocardial IHA metabolism. Subsequently, in six control and six glucose-perfused dogs, cardiac radioactivity was measured with a scintillation camera for 1 hr following i.v. injection of IHA. Four different methods were used to analyze the myocardial time-activity curves and to calculate the distribution of IHA between oxidation and esterification. Results comparable to those provided by analysis of biopsy specimens can be obtained by considering the curve to be the sum of an exponential and a constant, or by analyzing it with a compartmental mathematical model.