Successful migration of three tracers without identification of sentinel nodes during intraoperative lymphatic mapping for non-small cell lung cancer.

Prospective comparative evaluation of patent V blue, fluorescein and (99m)TC-nanocolloids for intraoperative sentinel lymph node (SLN) mapping during surgery for non-small cell lung cancer (NSCLC). Ten patients with peripherally localised clinical stage I NSCLC underwent thoracotomy and peritumoral subpleural injection of 2 ml of patent V blue dye, 1 ml of 10% fluorescein and 1ml of (99m)Tc-nanocolloids (0.4 mCi). The migration and spatial distribution pattern of the tracers was assessed by direct visualisation (patent V blue), visualisation of fluorescence signalling by a lamp of Wood (fluorescein) and radioactivity counting with a hand held gamma-probe ((99m)Tc-nanocolloids). Lymph nodes at interlobar (ATS 11), hilar (ATS 10) and mediastinal (right ATS 2,4,7; left ATS 5,6,7) levels were systematically assessed every 10 min up to 60 min after injection, followed by lobectomy and formal lymph node dissection. Successful migration from the peritumoral area to the mediastinum was observed for all three tracers up to 60 min after injection. The interlobar lympho-fatty tissue (station ATS 11) revealed an early and preferential accumulation of all three tracers for all tumours assessed and irrespective of the tumour localisation. However, no preferential accumulation in one or two distinct lymph nodes was observed up to 60 min after injection for all three tracers assessed. Intraoperative SLN mapping revealed successful migration of the tracers from the site of peritumoral injection to the mediastinum, but in a diffuse pattern without preferential accumulation in sentinel lymph nodes.

Immunociblage des tumeurs: situation et perspectives en 2000

Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal antibodies directed against tumor associated antigens shows now important clinical developments. This is mainly due to encouraging therapeutic results which have obtained using humanized antibodies such as the anti-CD20 rituximab in follicular B lymphomas and the anti-DrbB2 herceptin in breast carcinomas. Thanks to genetic engineering it is possible to graft variable or hypervariable regions from murine antibodies to human IgG, and even to obtain fully human antibodies by using either transgenic mice containing a large part of the human repertoire of human IgG, or selection of human antibody fragments expressed by phages. Radiolabeling of antibodies played a major role to demonstrate the tumor immunotargeting specificity and remains attractive for the diagnosis by immunoscintigraphy as well as for the treatment by radioimmunotherapy of some cancers. In this review, the current results and the prospects of diagnostic and therapeutic uses of anti-tumor antibodies and their fragments will be described. Concerning diagnosis, 123-iodine or 99m-technetium labeled Fab fragments allowed very demonstrative tumor images but this technique has a limited effect upon the therapeutic attitude. Immuno-PET (positron emission tomography) could enhance the sensitivity of this imaging method. Radio-immunoguided surgery and immunophotodetection are attractive techniques still under evaluation. Concerning therapy, 131-iodine labeled anti-CD20 antibodies gave spectacular results in non-Hodgkin's B lymphomas. In solid tumors which as less radiosensitive, radioimmunotherapy could concern small tumors and need the use of two-steps targeting and/or alpha emitters radioisotopes. Some other strategies will be described such as bispecific antibodies directed against tumors and immune effector cells, some antibody fragments expressed on T cells called T-bodies or some biological studies using intrabodies. Published data and works in progress demonstrate that immunotargeting of tumors will have a growing place in the treatments of cancer patients.

Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family.

AIM: To describe a large family with autosomal dominant parkinsonism. BACKGROUND: Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. MATERIAL AND METHODS: Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2, SCA3, UCHL1, SNCA, LRRK2, PINK1, PRKN, PGRN, FMR1 premutation, and MAPT. The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. RESULTS: Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for alpha-synuclein. CONCLUSION: Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.

How to Prepare a Patient for Transarterial Radioembolization? A Practical Guide.

Transarterial radioembolization consist in delivering small particles loaded with Yttrium90, a pure beta emitter, in order to treat primary and secondary liver tumors. This treatment needs precaution since inadequate delivery of these beads can lead to severe complications. Moreover, a precise radiation dosing is crucial to achieve a good clinical success and to avoid complications such as radioembolization-induced liver disease. This review describes all the precautions and highlights clinical and technical considerations that need to be taken to avoid complications.

MÉTODOS SELETIVOS DE FLUORAÇÃO DE MOLÉCULAS ORGÂNICAS

Presently, the world depends on a wide variety of new materials based on organofluorine compounds. These compounds can be used as surfactants, high resistance polymers, liquid crystals, agrochemicals, radiopharmaceuticals for positron emission tomography, and drugs. However, the selective formation of C–F bonds remains a challenge. This study reviews our knowledge of organofluorine compounds and describes conventional and modern selective fluorination methods for obtaining these compounds. Here, we highlight the most common fluorination reagents and describe the fluorination reactions. This review is organized by the type of fluorine transfer: nucleophilic, electrophilic, and enzymatic

Imaging of Dopamine and Serotonin Transporters. Pre-clinical Studies with Radiotracers for Positron Emission Tomography

The action of the neurotransmitters dopamine (DA) and serotonin (5-HT) at synapses is terminated by their rapid reuptake into presynaptic nerve endings via plasma membrane dopamine (DAT) and serotonin (SERT) transporters. Alterations in the function of these transporters have been suggested as a feature of several neurological and neuropsychiatric diseases, such as Parkinson’s disease (PD), depression, and anxiety. A suitable clinical method for studying these transporters non-invasively in vivo is positron emission tomography (PET) utilizing radiopharmaceuticals (tracers) labelled with short-lived positron-emitting radionuclides. The aim of this study was to evaluate in rats two novel radiotracers, [¹⁸F]beta -CFT-FP and ¹⁸FFMe-McN, for imaging DAT and SERT, respectively, using in vitro, ex vivo and in vivo methods. Substituting an N-methyl in [¹⁸F]beta-CFT, a well known DAT tracer, with a ¹⁸Ffluoropropyl group significantly changed the properties of the tracer. [¹⁸F]beta- CFT showed slow kinetics and metabolism, and a high specific uptake in the striatum, whereas [¹⁸F]beta-CFT-FP showed fast kinetics and metabolism, and a moderate specific uptake in the striatum. [¹⁸F]betaCFT-FP was selective for DAT; but [¹⁸F]beta-CFT also bound to the noradrenaline transporter. [¹⁸F]beta-CFT-FP may be a suitable PET tracer for imaging the striatal DAT sites, but a tracer with a higher affinity is needed for imaging extrastriatal DAT sites. In rats, ¹⁸FFMe-McN showed high target-to-non-target ratios, specificity and selectivity for SERT, but slow kinetics. However, ¹⁸FFMe-McN reveals potential for imaging SERT, at least in pre-clinical studies. In addition, the sensitivities of [¹⁸F]beta CFT and [¹⁸ F]FDOPA (a precursor of DA) for detecting mild nigrostriatal hypofunction were compared in an animal model of PD. The uptake of [¹⁸F]FDOPA was significantly affected by compensatory effects in dopaminergic cells, whereas [¹⁸F]beta-CFT was more sensitive and therefore more suitable for PET studies of mild dopaminergic symptoms. In conclusion, both novel tracers, [¹⁸F]-CFT-FP and ¹⁸FFMe-McN, have potential, but are not optimal PET tracers for DAT and SERT imaging in rats, respectively. [¹⁸F]beta-CFT is superior to [18F]FDOPA for imaging mild nigral lesions in rat brains.

Translational models of coronary artery disease, myocardial infarction and heart failure. Development, validation and in vivo imaging studies using positron emission tomography

Coronary artery disease is an atherosclerotic disease, which leads to narrowing of coronary arteries, deteriorated myocardial blood flow and myocardial ischaemia. In acute myocardial infarction, a prolonged period of myocardial ischaemia leads to myocardial necrosis. Necrotic myocardium is replaced with scar tissue. Myocardial infarction results in various changes in cardiac structure and function over time that results in “adverse remodelling”. This remodelling may result in a progressive worsening of cardiac function and development of chronic heart failure. In this thesis, we developed and validated three different large animal models of coronary artery disease, myocardial ischaemia and infarction for translational studies. In the first study the coronary artery disease model had both induced diabetes and hypercholesterolemia. In the second study myocardial ischaemia and infarction were caused by a surgical method and in the third study by catheterisation. For model characterisation, we used non-invasive positron emission tomography (PET) methods for measurement of myocardial perfusion, oxidative metabolism and glucose utilisation. Additionally, cardiac function was measured by echocardiography and computed tomography. To study the metabolic changes that occur during atherosclerosis, a hypercholesterolemic and diabetic model was used with [18F] fluorodeoxyglucose ([18F]FDG) PET-imaging technology. Coronary occlusion models were used to evaluate metabolic and structural changes in the heart and the cardioprotective effects of levosimendan during post-infarction cardiac remodelling. Large animal models were used in testing of novel radiopharmaceuticals for myocardial perfusion imaging. In the coronary artery disease model, we observed atherosclerotic lesions that were associated with focally increased [18F]FDG uptake. In heart failure models, chronic myocardial infarction led to the worsening of systolic function, cardiac remodelling and decreased efficiency of cardiac pumping function. Levosimendan therapy reduced post-infarction myocardial infarct size and improved cardiac function. The novel 68Ga-labeled radiopharmaceuticals tested in this study were not successful for the determination of myocardial blood flow. In conclusion, diabetes and hypercholesterolemia lead to the development of early phase atherosclerotic lesions. Coronary artery occlusion produced considerable myocardial ischaemia and later infarction following myocardial remodelling. The experimental models evaluated in these studies will enable further studies concerning disease mechanisms, new radiopharmaceuticals and interventions in coronary artery disease and heart failure.

Performance assessment of the single photon emission microscope: high spatial resolution SPECT imaging of small animal organs

The single photon emission microscope (SPEM) is an instrument developed to obtain high spatial resolution single photon emission computed tomography (SPECT) images of small structures inside the mouse brain. SPEM consists of two independent imaging devices, which combine a multipinhole collimator, a high-resolution, thallium-doped cesium iodide [CsI(Tl)] columnar scintillator, a demagnifying/intensifier tube, and an electron-multiplying charge-coupling device (CCD). Collimators have 300- and 450-µm diameter pinholes on tungsten slabs, in hexagonal arrays of 19 and 7 holes. Projection data are acquired in a photon-counting strategy, where CCD frames are stored at 50 frames per second, with a radius of rotation of 35 mm and magnification factor of one. The image reconstruction software tool is based on the maximum likelihood algorithm. Our aim was to evaluate the spatial resolution and sensitivity attainable with the seven-pinhole imaging device, together with the linearity for quantification on the tomographic images, and to test the instrument in obtaining tomographic images of different mouse organs. A spatial resolution better than 500 µm and a sensitivity of 21.6 counts·s-1·MBq-1 were reached, as well as a correlation coefficient between activity and intensity better than 0.99, when imaging 99mTc sources. Images of the thyroid, heart, lungs, and bones of mice were registered using 99mTc-labeled radiopharmaceuticals in times appropriate for routine preclinical experimentation of <1 h per projection data set. Detailed experimental protocols and images of the aforementioned organs are shown. We plan to extend the instrument's field of view to fix larger animals and to combine data from both detectors to reduce the acquisition time or applied activity.

Metal complexes of cyclen and cyclam derivatives useful for medical applications: a discussion based on thermodynamic stability constants and structural data

A series of the most common chelators used in magnetic resonance imaging ( MRI) and in radiopharmaceuticals for medical diagnosis and tumour therapy, H(4)dota, H(4)teta, H(8)dotp and H(8)tetp, is examined from a chemical point of view. Differences between 12- and 14-membered tetraazamacrocyclic derivatives with methylcarboxylate and methylphosphonate pendant arms and their chelates with divalent first-series transition metal and trivalent lanthanide ions are discussed on the basis of their thermodynamic stability constants, X- ray structures and theoretical studies.

Mixed-Ligand Complexes of Technetium and Rhenium with Tridentate Benzamidines and Bidentate Benzoylthioureas

Mixed-ligand complexes of technetium(V) or rhenium(V) containing tridentate N-[(dialkylamino)(thiocarbonyl)]benzamidine (H(2)L(1)) and bidentate N,N-dialkyl-N`-benzoylthiourea (HL(2)) ligands were formed in high yields when (NBu(4))[MOCl(4)] (M = Tc or Re) or [ReOCl(3)(PPh(3))(2)] was treated with mixtures of the proligands. Other approaches for the synthesis of the products are reactions of [MOCl(L(1))] complexes with HL(2) or compounds of the-composition [ReOCl(2)(PPh(3))(L(2))] with H(2)L(1). The resulting air-stable [MO(L(1))(L(2))] complexes possess potential for the development of metal-based radiopharmaceuticals. [TcO(L(1))(L(2))] complexes are readily reduced by PPh3 with formation of [Tc(L(1))(L(2))(PPh(3))]. The resulting Tc(III) complexes undergo two almost-reversible oxidation steps corresponding to one-electron transfer processes. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Biodistribution of technetium-99m pertechnetate after Roux-en-Y gastric bypass (Capella technique) in rats

The biodistribution of sodium pertechnetate, the most used radiopharmaceutical in nuclear medicine, has not been studied in details after bariatric surgery. The objective was to investigate the effect of Roux-en-Y gastric bypass (RYGB) on biodistribution of sodium pertechnetate (Na99mTc-) in organs and tissues of rats. Methods: Twelve rats were randomly divided into two groups of 6 animals each. The RYGB group rats were submitted to the Roux-en-Y gastric bypass and the control group rats were not operated. After 15 days, all rats were injected with 0.1mL of Na99mTc- via orbital plexus with average radioactivity of 0.66 MBq. After 30 minutes, liver, stomach, thyroid, heart, lung, kidney and femur samples were harvested, weighed and percentage of radioactivity per gram (%ATI/g) of each organ was determined by gama counter Wizard Perkin-Elmer. We applied the Student t test for statistical analysis, considering p<0.05 as significant. Results: Significant reduction in mean %ATI/g was observed in the liver, stomach and femur in the RYGB group animals, compared with the control group rats (p<0.05). In other organs no significant difference in %ATI/g was observed between the two groups. Conclusion: This work contributes to the knowledge that the bariatric surgery RYGB modifies the pattern of biodistribution of Na99mTc

Biodistribution of samarium-153-EDTMP in rats treated with docetaxel

Purpose: Many patients with metastatic bone disease have to use radiopharmaceuticals associated with chemotherapy to relieve bone pain. The aim of this study was to assess the influence of docetaxel on the biodistribution of samarium-153-EDTMP in bones and other organs of rats. Methods: Wistar male rats were randomly allocated into 2 groups of 6 rats each. The DS (docetaxel/samarium) group received docetaxel (15 mg/kg) intraperitoneally in two cycles 11 days apart. The S (samarium/control) group rats were not treated with docetaxel. Nine days after chemotherapy, all the rats were injected with 0.1ml of samarium-153-EDTMP via orbital plexus (25μCi). After 2 hours, the animals were killed and samples of the brain, thyroid, lung, heart, stomach, colon, liver, kidney and both femurs were removed. The percentage radioactivity of each sample (% ATI/g) was determined in an automatic gamma-counter (Wizard-1470, Perkin-Elmer, Finland). Results: On the 9th day after the administration of the 2nd chemotherapy cycle, the rats had a significant weight loss (314.50±22.09g) compared (p<0.5) to pre-treatment weight (353.66± 22.8). The % ATI/g in the samples of rats treated with samarium-153-EDTMP had a significant reduction in the right femur, left femur, kidney, liver and lungs of animals treated with docetaxel, compared to the control rats. Conclusion: The combination of docetaxel and samarium-153-EDTMP was associated with a lower response rate in the biodistribution of the radiopharmaceutical to targeted tissues. Further investigation into the impact of docetaxel on biodistribution of samarium-153-EDTMP would complement the findings of this study

Biodistribution of the Radiopharmaceutical Technetium- 99m-Sodium Phytate in Rats After Splenectomy

Drugs and surgery can interfere with the biodistribution of radiopharmaceuticals and data about the effect of splenectomy on the metabolism of phytate-Tc-99m are scarce. This study aimed at evaluating the interference of splenectomy on phytate-Tc-99m biodistribution and liver function in rats. The SP group rats (n=6) underwent splenectomy. In group C (control) the animals were not operated on. After 15 days, all rats were injected with 0.1mL of Tc-99m-phytate via orbital plexus (0.66MBq). After 30 minutes, liver samples were harvested, weighed and the percentage of radioactivity per gram (%ATI-g) was determined by a Wizard Perkin-Elme gama counter. The ATI%-g in splenectomized rats (0.99±0.02) was significantly higher than in controls (0.4±0.02), (p=0.034). ALT, AST and HDL were significantly lower in SP rats (p= 0.001) and leukocytosis was observed in SP rats. In conclusion, splenectomy in rats changed the hepatic biodistribution of Tc-99m-phytate and liver enzimatic activity

Efeito de um extrato de chrysobalanus icaco na marcação de constituíntes sanguíneos com tecnécio-99m, na morfologia de hemácias, na topologia plasmidial e na ação do cloreto estanoso no dna plasmidial

The use of radionuclides has contributed for advances in Health Sciences, to research or to the diagnosis and/or treatment of diseases. These advances have been possible with the utilization of radiopharmaceuticals labeled with technetium-99m (99mTc). Stannous chloride (SnCl2) has the main reducing agent utilized to obtain radiopharmaceuticals labeled with technetium-99m. It has been reported that several natural or synthetic drugs are capable to alter the labeling of blood constituents with 99mTc, as well as the red blood cells morphology. The aim of this study was to evaluate possible alterations of Chrysobalanus icaco extract on the labeling of blood constituents with 99mTc, on the morphology of RBC of blood of Wistar rats, on the breakage of plasmid DNA and on the effects of stannous chloride on plasmid DNA. The results showed significant (P<0.05) alteration of the labeling of blood constituents with 99mTc, as well as, modification of the morphology and morphometry (perimeter/area ratio) of the RBC in presence of the extract. These data suggest that this abajeru extract could alter the labeling of blood constituents with 99mTc by its chelating/antioxidant action and/or effects on membrane structures. Moreover C. icaco extract altered the electrophoretic profile and decreased significantly (p<0.05) the effect of SnCl2 on plasmid DNA. The results obtained in this work could indicate a dose-dependent protective action against the SnCl2 and a genotoxic effect of C. icaco extract on plasmid DNA