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Purpose: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively.Methods: We designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab′)2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab′)2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors.Results: Radiolabeling procedure did not change F(ab′)2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab′)2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab′)2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses.Conclusions: 111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging. [ABSTRACT FROM AUTHOR]

Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab – which targets the HER2/neu receptor – and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 °C, and the radiochemical purity of each 64Cu-BFC-Fab-trastuzumab reached 97% after purification. The affinity of each 64Cu-BFC-Fab-trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of 64Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g−1 24 hours post-injection and significant differences in non-specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the prognostic significance of microvascular obstruction (MO) and persistent microvascular obstruction (PMO) as assessed by cardiac magnetic resonance (CMR) in patients with acute myocardial infarction (AMI). CMR was performed in 184 patients within the week following successfully reperfused first AMI. First-pass images were performed to evaluate extent of MO and late gadolinium-enhanced images to assess PMO and infarct size (IS). Major adverse cardiac events (MACE) were collected at 1-year follow-up. MO and PMO were found in 127 (69%) and 87 (47%) patients, respectively. By using univariate logistic regression analysis, high Global Registry of Acute Coronary Events (GRACE) risk score (odds ratio [OR] 95% confidence interval [CI]: 3.6 [1.8-7.4], p < 0.001), IS greater than 10% (OR [95% CI]: 2.7 [1.1-6.9], p = 0.036), left ventricular ejection fraction less than 40% (OR [95% CI]: 2.4 [1.1-5.2], p = 0.027), presence of MO (OR [95% CI]: 3.1 [1.3-7.3], p = 0.004) and presence of PMO (OR [95% CI]:10 [4.1-23.9], p < 0.001) were shown to be significantly associated with the outcome. By using multivariate analysis, presence of MO (OR [95% CI]: 2.5 [1.0-6.2], p = 0.045) or of PMO (OR [95% CI]: 8.7 [3.6-21.1], p < 0.001), associated with GRACE score, were predictors of MACE. Presence of microvascular obstruction and persistent microvascular obstruction is very common in AMI patients even after successful reperfusion and is associated with a dramatically higher risk of subsequent cardiovascular events, beyond established prognostic markers. Moreover, our data suggest that the prognostic impact of PMO might be superior to MO. [ABSTRACT FROM AUTHOR]

The calculation of the left ventricular ejection fraction(LVEF) is dependent upon the accurate measurement of diastolic and systolic left ventricular volumes. Although breath-hold cine magnetic resonance imaging(MRI) allows coverage of the whole cardiac cycle with an excellent time resolution, many authors rely on the visual selection of diastolic and the systolic short-axis slices in order to reduce the postprocessing time. An automatic method was developed to detect the endocardial contour on each image, allowing an automatic selection of the systolic frame. The calculated ejection fraction was compared with radionuclide ventriculography(RNV). Sixty-five patients were examined using an electrocardiogram(ECG)-gated gradient echo sequence. Among these examinations, manual and automatic processing with MRI were compared when the time of the systolic frame concorded. Good correlations have been found between the automatic MRI approach and RNV, and between manual and automatic processing on MRI alone. The results show that the automatic determination of the ejection fraction is feasible, and should constitute an important step toward a larger acceptance of MRI as a routine tool in heart disease imaging. One major benefit of using automatic postprocessing is that it may eliminate the visual choice of the systolic frame, inaccurate in more than 50% of the studied patients. [ABSTRACT FROM AUTHOR]

Background and purpose – To evaluate the functional prognostic value of proton magnetic resonance spectroscopy performed within the 5 days of an infarction of the middle cerebral artery territory, compared with previously demonstrated prognostic factors. Methods – Proton magnetic resonance spectroscopy was performed on 77 consecutive non‐comatosed patients during the acute stage of middle cerebral artery infarction. The functional status was determined for each patient via the Orgogozo score. Proton magnetic resonance spectroscopic data were acquired in the infarction and in contra‐lateral normal tissue and the results were expressed as metabolite ratios. Correlations were evaluated between the Orgogozo score at day 1 and day 30, the age, the sex, the volume of the infarction, and the metabolic ratios. Results – In a monovariate analysis, the decrease of the NAA/choline ratio was correlated with a low Orgogozo score at days 1 and 30 (P<0.05) and with a large infarction (P<0.05). A stepwise analysis showed a significant relationship between the Orgogozo score at day 30 and the Orgogozo score at day 1, the sex, the volume of infarction, and the NAA/Cho ratio within the infarction. Conclusions – Our work demonstrates that a good clinical outcome at day 30 depends on a good initial clinical score at day 1, a small volume of infarction, a small decrease of NAA/Cho, and being of the female gender. [ABSTRACT FROM AUTHOR]

Objective: The aim was to document the response of aortic rings from a rat model of heart failure to endothelium dependent and endothelium independent vasodilating agents. The effects of an exercise training schedule upon these responses was studied. Methods: Heart failure was produced in one group of female Wistar rats by coronary artery occlusion, and sham operations were performed in a matched group. The rats were allowed to recover for six weeks, following which half the rats with heart failure were started on a treadmill exercise schedule for a further six weeks. After this time the rats were killed, and rings of aorta were studied in an organ bath to measure the response to both endothelium dependent and endothelium independent vasoactive agents. Results: The presence of heart failure was confirmed in both the non-trained (NT, n=5) and trained rats (TR, n=5), but not in the sham operated animals (SH, n=6). The constrictor response to prostaglandin F2α was similar in aortic rings from all the animals. The relaxation response to the endothelium dependent vasodilator acetylcholine (10−7 and 10−1M) was impaired in the rats with heart failure compared to the sham operated animals (10% v 33% with 10−7M acetylcholine, p<0.005). The dilator response in the trained rats was not significantly greater than in the non-trained rats (TR 35% v NT 24% with 10−1M acetylcholine). There was no difference in the response to sodium nitroprusside (10−7 and 10−1M) between the three groups. Conclusions: Chronic heart failure impairs the response of aortic rings to the endothelium dependent vasodilator acetylcholine in a rat model of heart failure. The response to sodium nitroprusside, an endothelium independent relaxing agent, is not impaired by heart failure. These findings may help to explain the raised systemic vascular resistance and the failure of vasodilatation in skeletal muscle vasculature which limits exercise capacity in subjects with heart failure. [ABSTRACT FROM PUBLISHER]

Objective: To distinguish between the effects of reduced oxidative capacity and reduced metabolic efficiency on skeletal muscle bioenergetics during exercise in patients with congestive heart failure.Design and Patients: Patients were studied by 31P magnetic resonance spectroscopy during aerobic exercise and recovery, and results compared with controls.Results: In flexor digitorum superficialis muscle (26 patients) there was a 30% decrease in oxidative capacity compared with control (mean (SE) 36 (2) v 51 (4) mM/min) and also a 40% decrease in "effective muscle mass" (5 (1) v 9 (1) arbitrary units), probably at least partly the result of reduced metabolic efficiency. Both contribute to increased phosphocreatine depletion and intracellular acidosis during exercise. However, an increased concentration of ADP (an important mitochondrial regulator) during exercise permitted near-normal rates of oxidative ATP synthesis. Results were similar in gastrocnemius muscle (20 patients), with a 30% decrease in maximum oxidative capacity (29 (4) v 39 (3) mM/min) and a 65% decrease in effective muscle mass (5 (1) v 13 (2) arbitrary units). Exercise training improved maximum oxidative capacity in both muscles, and in gastrocnemius effective muscle mass also.Conclusions: Skeletal muscle exercise abnormalities in patients with congestive heart failure results more from decreased metabolic efficiency than from the abnormalities in mitochondrial oxidation. Both decreased efficiency and defective mitochondrial oxidation result in an increased activation of glycogen phosphorylase, and may be improved by exercise training. [ABSTRACT FROM AUTHOR]

Of 46 consecutive patients who underwent percutaneous transluminal coronary angioplasty (PTCA) from April 1980 to August 1982 and who had a satisfactory angiographic result six months later, one died of cancer and 41 had a detailed evaluation with exercise single-photon emission computed tomography (SPECT, 40 patients) or repeat coronary angiography (one patient), 48–78 months after the procedure. During follow-up, two patients had recurrent angina due to progression of coronary artery disease requiring a second PTCA procedure of another coronary artery; one of them later had a limited myocardial infarction in an area supplied by the vessel initially dilated. At follow-up, only one patient had definite angina. All but one patient had a negative exercise test. Myocardial perfusion during exercise in the PTCA-related area, assessed by SPECT, was normal in 90% of the patients and showed a limited defect due to reversible ischaemia in the remaining four (10%). It is concluded that patients with a less than 50% stenosis six months after PTCA show sustained improvement in their functional status and myocardial perfusion, four to six years after the procedure suggesting continued patency of the coronary artery. [ABSTRACT FROM PUBLISHER]

The study of Ga-citrate uptake and calcium transport in Ehrlich ascites tumour cells seems to indicate that their peculiar characteristic of increased permeability to extracellular calcium ion might be responsible for their Ga accumulation. Experiments performed under different conditions of extracellular calcium, temperature, and presence of ionophore and other plasma membrane modifying agents such as lanthanum appear to corroborate this hypothesis. [ABSTRACT FROM AUTHOR]

The uptake of Ga-citrate and Fe-citrate by tumor cells treated with hyperthermia or with hyperthermia plus lanthanum has been studied. The comparison of these results with ion flux determinations (K) appears to indicate that hyperthermia alone or combined with lanthanum modifies the ionic permeability of the plasma membrane. This phenomenon seems to be responsible for the increased accumulation of Ga and Fe. [ABSTRACT FROM AUTHOR]

Ferric citrate inhibited in vitro and in vivo uptake of Ga-citrate by DS sarcoma cells. In vitro, gallium micked iron and the uptake of both cations was inhibited by transferrin. In vivo, muscle and tumor tissues were the most affected by simultaneous injection of cold ferric citrate. The different behavior of tumor tissue and blood suggests different binding site characteristics in each case. [ABSTRACT FROM AUTHOR]

A patient developed weakness of the right leg and homolateral ataxia of the arm, caused by a subcortical infarct in the area supplied by the anterior cerebral artery in the left paracentral region, demonstrated by CT and MRI. Cerebral blood flow studied by technetium-labelled hexamethyl-propylene-amine oxime using single photon emission computed tomography showed decreased blood flow in the left lateral frontal cortex and in the right cerebellar hemisphere ("crossed cerebral-cerebellar diaschisis"). The homolateral ataxia of the arm may be caused by decreased function of the right cerebellar hemisphere, because of a lesion of the corticopontine-cerebellar tracts, whereas crural hemiparesis is caused by a lesion of the upper part of the corona radiata. [ABSTRACT FROM AUTHOR]

The article presents information on a case study related to the double mycotic aneurysm of the descending thoracic aorta. A 71 year old man was admitted with fever and chills. On admission his temperature was 39 degree C; physical examination was normal except for a grade I/VI aortic systolic murmur. Blood cultures and urine samples grew Staphylococcus aureus. Transoesophageal echocardiography (TOE) showed a mildly calcified aortic valve without vegetations, and diffuse atheroma of the descending aorta. Despite appropriate antibiotic treatment the patient remained febrile, and developed clinical and radiological signs of pulmonary oedema. A subsequent TOE revealed the presence of two saccular aneurysms of the descending aorta, one just beneath the isthmus and the second one just above the diaphragm. These aneurysms arose from two localised ruptures in the atheromatous intima.