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BACKGROUND: Integrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of 68Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of 68Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TOF) PET/CT scans 10, 60 and 120 min after tracer injection (200 MBq). Quantification of 68Ga activity concentration was first validated by a phantom study. To be used as input in OLINDA/EXM, time-activity curves were derived from manually drawn regions of interest over the following organs: brain, thyroid, lungs, heart, liver, spleen, stomach, kidneys, red marrow, pancreas, small intestine, colon, urinary bladder and whole body. A separate dosimetric analysis was performed for the choroid plexuses. Female dosimetry was extrapolated from male data. Effective doses (EDs) were estimated according to both ICRP60 and ICRP103 assuming 30-min and 1-h voiding cycles. RESULTS: The body regions receiving the highest dose were urinary bladder, kidneys and choroid plexuses. For a 30-min voiding cycle, the EDs were 15.7 and 16.5 µSv/MBq according to ICRP60 and ICRP103, respectively. The extrapolation to female dosimetry resulted in organ absorbed doses 17% higher than those of male patients, on average. The 1-h voiding cycle extrapolation resulted in EDs of 19.3 and 19.8 µSv/MBq according to ICRP60 and ICRP103, respectively. A comparison is made with previous mouse dosimetry and with other human studies employing different RGD-based radiopharmaceuticals. CONCLUSIONS: According to ICRP60/ICRP103 recommendations, an injection of 200 MBq 68Ga-NODAGA-RGDyK leads to an ED in man of 3.86/3.92 mSv. For future therapeutic applications, specific attention should be directed to delivered dose to kidneys and potentially also to the choroid plexuses. TRIAL REGISTRATION: Clinical trial.gov, NCT01608516.
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AIMS: Vaccination by aerosol inhalation can be used to efficiently deliver antigen against HPV to mucosal tissue, which is particularly useful in developing countries (simplicity of administration, costs, no need for cold chain). For optimal immunological response, vaccine particles should preferentially be delivered to proximal bronchial airways. We aimed at quantifying the deposition of inhaled particles in central airways and peripheral lung, and to assess administration biosafety. Participants, methods: 20 healthy volunteers (13W/7M, aged 24±4y) performed a 10-min free-breathing inhalation of (99m)Tc-stannous chloride colloid aerosol (450 MBq) in a buffer solution without vaccinal particles using an ultrasonic nebulizer (mass median aerodynamic diameter 4.2 µm) and a double mask inside a biosafety cabinet dedicated to assess environmental particle release. SPECT/CT and whole-body planar scintigraphy were acquired to determine whole-body and regional C/P distribution ratio (central-to-peripheral pulmonary deposition counts). Using a phantom, SPECT sensitivity was calibrated to obtain absolute pulmonary activity deposited by inhalation. RESULTS: All participants successfully performed the inhalation that was well tolerated (no change in pulmonary peak expiratory flow rate, p = 0.9). It was environmentally safe (no activity released in the biosafety filter.) 1.3±0.6% (range 0.4-2.6%) of the total nebulizer activity was deposited in the lungs with a C/P distribution ratio of 0.40±0.20 (range 0.15-1.14). CONCLUSION: Quantification and regional distribution of inhaled particles in an aerosolized vaccine model is possible using radioactive particles. This will allow optimizing deposition parameters and determining the particles charge for active-particles vaccination.
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Aerosoles/farmacocinética , Bronquios/diagnóstico por imagen , Bronquios/metabolismo , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/farmacocinética , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Administración por Inhalación , Adulto , Aerosoles/administración & dosificación , Femenino , Humanos , Marcaje Isotópico , Masculino , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/prevención & control , Radiofármacos/farmacocinética , Tecnecio/farmacocinética , Distribución TisularRESUMEN
PURPOSE: This study aimed to evaluate the efficacy and toxicity of radioimmunotherapy (RIT) in recurrent lymphoma after hematopoietic stem cell transplantation (HSCT). METHODS: We reviewed 9 patients, 7 with follicular lymphoma (DLBCL), 1 with mantle cell lymphoma (MCL), and 1 with diffuse large B-cell lymphoma treated with 90Y-ibritumomab tiuxetan 6 to 140 months after HSCT. Patients underwent 111In-ibritumomab scintigraphy and were treated 1 week later with standard 14.8 MBq/kg (n = 4) or 11.1 MBq/kg (n = 4) 90Y-ibritumomab. One patient who had allo-HSCT had reduced activity (70%) treatment. RESULTS: Among the 7 FL patients, we observed complete response (CR) in 2 patients and partial response (PR) in 5 patients. One patient with CR relapsed after 15 months; the other persisted 43.5 months after RIT. Of 5 patients with PR, 3 relapsed between 13 and 17 months; 1 persisted until unrelated death at 11.5 months. The fifth patient with PR received adoptive immunotherapy and improved to metabolic (FDG-PET) CR that persists 45.5 and 41 months after 90Y-ibritumomab and immunotherapy, respectively. Patients with MCL and DLBCL progressed or experienced stabilization (5 months), respectively. Six patients had grade 1 to 3 bone marrow (BM) toxicity and recovered within 3 months. Three patients having 90Y-ibritumomab 6, 14, and 24 months after HSCT experienced grade 4 BM toxicity. One of them (RIT 24 months after HSCT) recovered after 3 months, another delayed after 9 months, and the third patient only partially recovered, eventually developed myelodysplasia, and was allografted. CONCLUSIONS: Radioimmunotherapy after HSCT is an effective rescue therapy in FL. However, BM toxicity may be important; 3 of 8 patients treated with standard 90Y-ibritumomab activity experienced grade 4 BM toxicity, with incomplete recovery 3 months after RIT in 2 patients, both treated early (6 and 14 months) after HSCT.
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Anticuerpos Monoclonales/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfoma/radioterapia , Linfoma/cirugía , Radioinmunoterapia/efectos adversos , Adulto , Anciano , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Trasplante Homólogo/efectos adversosRESUMEN
PURPOSE: The biokinetics and dosimetry of (111)In-DOTA-NOC-ATE (NOCATE), a high-affinity ligand of SSTR-2 and SSTR-5, and (111)In-DTPA-octreotide (Octreoscan™, OCTREO) were compared in the same patients. METHODS: Seventeen patients (10 men, 7 women; mean age 60 years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior-posterior scans were recorded 0.5 (100 % reference scan), 4, 24 and 48 h (17 patients) and 120 h (5 patients) after injection. In 16 patients the OCTREO scan (178 ± 15 MBq) was performed 16 ± 5 days before the NOCATE scan (108 ± 14 MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5 min to 48 h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM. RESULTS: Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p < 0.001) and remained so over time. Whole-body activity showed similar α and ß half-lives, but the ß fraction of NOCATE was double that of OCTREO. Blood T (1/2)ß for NOCATE was longer (19 vs. 6 h). As a result, the effective dose of NOCATE (105 µSv/MBq) exceeded that of OCTREO (52 µSv/MBq), and the latter result was similar to the ICRP 106 value of 54 µSv/MBq. Differential activity measurement in blood cells and plasma showed an average of <5 % of NOCATE and OCTREO attached to globular blood components. CONCLUSION: NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTREO.
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Tumores Neuroendocrinos/diagnóstico por imagen , Octreótido/análogos & derivados , Compuestos Organometálicos/farmacocinética , Ácido Pentético/análogos & derivados , Radiofármacos/farmacocinética , Timoma/diagnóstico por imagen , Neoplasias del Timo/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico por imagen , Adulto , Anciano , Carcinoma Neuroendocrino , Femenino , Humanos , Masculino , Persona de Mediana Edad , Octreótido/farmacocinética , Ácido Pentético/farmacocinética , Radiometría , Cintigrafía , Distribución TisularRESUMEN
PURPOSE: Quantification of myocardial blood flow (MBF) with generator-produced (82)Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate (82)Rb-measured MBF in relation to that measured using (15)O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD). METHODS: MBF was measured at rest and during adenosine-induced hyperaemia with (82)Rb and (15)O-water PET in 33 participants (22 control subjects, aged 30 ± 13 years; 11 CAD patients without transmural infarction, aged 60 ± 13 years). A one-tissue compartment (82)Rb model with ventricular spillover correction was used. The (82)Rb flow-dependent extraction rate was derived from (15)O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson's correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin's concordance correlation ρ (c) (measuring both precision and accuracy) were used. RESULTS: Over the entire MBF range (0.66-4.7 ml/min/g), concordance was excellent for MBF (r = 0.90, [(82)Rb-(15)O-water] mean difference ± SD = 0.04 ± 0.66 ml/min/g, LoA = -1.26 to 1.33 ml/min/g, ρ(c) = 0.88) and MFR (range 1.79-5.81, r = 0.83, mean difference = 0.14 ± 0.58, LoA = -0.99 to 1.28, ρ(c) = 0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53 ± 0.74 vs. 3.62 ± 0.68 ml/min/g, p = 0.002, for (15)O-water; 2.53 ± 1.01 vs. 3.82 ± 1.21 ml/min/g, p = 0.013, for (82)Rb) and this was paralleled by a lower MFR (2.65 ± 0.62 vs. 3.79 ± 0.98, p = 0.004, for (15)O-water; 2.85 ± 0.91 vs. 3.88 ± 0.91, p = 0.012, for (82)Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p > 0.31). CONCLUSION: Quantification of MBF with (82)Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using (15)O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. (82)Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routine.
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Circulación Coronaria , Tomografía de Emisión de Positrones/métodos , Radioisótopos de Rubidio , Agua , Adulto , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Imagen de Perfusión Miocárdica , Radioisótopos de Oxígeno , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: In nuclear medicine, the activity of a radionuclide is measured with a radionuclide calibrator that often has a calibration coefficient independent of the container type and filling. METHODS: To determine the effect of the container on the accuracy of measuring the activity injected into a patient, The authors simulated a commercial radionuclide calibrator and 18 container types most typically used in clinical practice. The instrument sensitivity was computed for various container thicknesses and filling levels. Monoenergetic photons and electrons as well as seven common radionuclides were considered. RESULTS: The quality of the simulation with gamma-emitting sources was validated by an agreement with measurements better than 4% in five selected radionuclides. The results show that the measured activity can vary by more than a factor of 2 depending on the type of container. The filling level and the thickness of the container wall only have a marginal effect for radionuclides of high energy but could induce differences up to 4%. CONCLUSIONS: The authors conclude that radionuclide calibrators should be tailored to the uncertainty required by clinical applications. For most clinical cases, and at least for the low-energy gamma and x-ray emitters, measurements should be performed with calibration coefficients specific to the container type.
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Artefactos , Radioisótopos/análisis , Radioisótopos/normas , Radiometría/métodos , Radiometría/normas , Manejo de Especímenes/instrumentación , Manejo de Especímenes/normas , Calibración , Rayos gamma , Dosis de Radiación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
UNLABELLED: The purpose of our study was to update the safety and efficacy results of radioimmunotherapy in relapsed or resistant indolent or transformed non-Hodgkin lymphoma. METHODS: More than 9 y ago, we treated 12 indolent and 4 transformed, relapsed or refractory lymphoma patients with a single administration of nonmyeloablative therapy with tositumomab and (131)I-tositumomab. The 16 patients had a mean of 3.1 (range, 1-6) previous chemotherapy and antibody treatments. RESULTS: Six of 12 relapsed indolent lymphoma patients remain disease-free a mean of 9.8 y (range, 8.6-10.7 y) after radioimmunotherapy. Three of 4 transformed lymphoma patients progressed after radioimmunotherapy, and 1 patient had a partial response of 10 mo. CONCLUSION: Optimal patient benefit might be obtained in indolent lymphoma when administering radioimmunotherapy up-front in combination with chemotherapy and rituximab treatment. However, these results show that radioimmunotherapy alone achieved long-lasting remissions in 6 of 12 (50%) indolent lymphoma patients in relapse after 1 or multiple chemotherapies.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia , Radiofármacos/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Antígenos CD20/metabolismo , Antineoplásicos/efectos adversos , Médula Ósea/efectos de la radiación , Enfermedades de la Médula Ósea/etiología , Resistencia a Antineoplásicos , Inglaterra , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Interferón Tipo I/uso terapéutico , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Radiometría , Radiofármacos/efectos adversos , Proteínas Recombinantes , Inducción de Remisión , Suiza , Estados UnidosRESUMEN
BACKGROUND: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. RESULTS: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. CONCLUSIONS: Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential.
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Anticuerpos Monoclonales/farmacología , Antígenos de Superficie/inmunología , Antineoplásicos/farmacología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Línea Celular Tumoral , Activación de Complemento/efectos de los fármacos , Activación de Complemento/inmunología , Humanos , Radioisótopos de Yodo , Leucemia de Células B/fisiopatología , Linfoma/fisiopatología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones SCID , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Unión Proteica , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2'-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [(18)F]FLT in tumor xenografts. METHODS: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[(125)I]iodo-2'-deoxyuridine biodistribution measurements. In [(18)F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [(18)F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [(18)F]FDG tumor uptake. Using microPET, the dynamic distribution of [(18)F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation. RESULTS: FdUrd induced an immediate increase in tumor uptake of 5-[(125)I]iodo-2'-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [(18)F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [(18)F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [(18)F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [(18)F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis. CONCLUSION: We showed a reliable and significant uptake increase of [(18)F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [(18)F]FLT PET.
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Didesoxinucleósidos/farmacocinética , Floxuridina/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Tomografía de Emisión de Positrones/métodos , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Didesoxinucleósidos/farmacología , Citometría de Flujo , Floxuridina/farmacología , Humanos , Imagen por Resonancia Magnética , Ratones , Factores de Tiempo , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as [(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3' and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide-alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3' or N3 position with chelating systems suitable for the M(CO)(3) core (M = (99m)Tc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substrates in which thymidine is modified at the C3' position were identified. Phosphorylation of the organometallic derivatives was measured relative to thymidine. We have shown that the influence of the overall charge of the derivatives is dependent on the position of functionalization. In the case of the C3'-functionalized derivatives, neutral and anionic substrates were most readily phosphorylated (20-28% of the value for the parent ligand thymidine), whereas for the N3-functionalized derivatives, cationic and neutral complexes were apparently better substrates for the enzyme (14-18%) than anionic derivatives (9%).
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Compuestos Organometálicos/química , Renio/química , Tecnecio/química , Timidina Quinasa/química , Timidina Quinasa/metabolismo , Timidina/química , Timidina/metabolismo , Alquinos/química , Azidas/química , Catálisis , Cobre/química , Cristalografía por Rayos X , Ciclización , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Coloración y Etiquetado , EstereoisomerismoRESUMEN
Combined positron emission tomography and computed tomography (PET/CT) scanners play a major role in medicine for in vivo imaging in an increasing number of diseases in oncology, cardiology, neurology, and psychiatry. With the advent of short-lived radioisotopes other than 18F and newer scanners, there is a need to optimize radioisotope activity and acquisition protocols, as well as to compare scanner performances on an objective basis. The Discovery-LS (D-LS) was among the first clinical PET/CT scanners to be developed and has been extensively characterized with older National Electrical Manufacturer Association (NEMA) NU 2-1994 standards. At the time of publication of the latest version of the standards (NU 2-2001) that have been adapted for whole-body imaging under clinical conditions, more recent models from the same manufacturer, i.e., Discovery-ST (D-ST) and Discovery-STE (D-STE), were commercially available. We report on the full characterization both in the two- and three-dimensional acquisition mode of the D-LS according to latest NEMA NU 2-2001 standards (spatial resolution, sensitivity, count rate performance, accuracy of count losses, and random coincidence correction and image quality), as well as a detailed comparison with the newer D-ST widely used and whose characteristics are already published.
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Fantasmas de Imagen , Tomografía de Emisión de Positrones , Electricidad , Humanos , Estándares de Referencia , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos XRESUMEN
Computed tomography (CT) and ultrasonography (US) are commonly employed to guide positioning of radiofrequency electrodes within target tumors. However, this technique cannot be used when the tumor is detectable only by positron emission tomography (PET). In such cases, even the use of intraprocedural coregistered PET/CT will not prevent malpositioning of the electrode tip relative to a lesion visualized only on PET as a result of patient breathing and organ shifts during CT-guided electrode placement. The present report describes a single case of successful targeting and complete ablation of a lesion invisible on CT and US with the use of a method to visualize electrode tip positioning by PET.
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Adenocarcinoma/diagnóstico por imagen , Ablación por Catéter , Neoplasias Hepáticas/diagnóstico por imagen , Tomografía de Emisión de Positrones , Neoplasias del Recto/patología , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Radiografía Intervencional/métodos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVES: Comparison of doxorubicin uptake, leakage and spatial regional blood flow, and drug distribution was made for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), as opposed to intravenous administration in a porcine model. METHODS: White pigs underwent single-pass lung perfusion with doxorubicin (320 mug/mL), labeled 99mTc-microspheres, and Indian ink. Visual assessment of the ink distribution and perfusion scintigraphy of the perfused lung was performed. 99mTc activity and doxorubicin levels were measured by gamma counting and high-performance liquid chromatography on 15 tissue samples from each perfused lung at predetermined localizations. RESULTS: Overall doxorubicin uptake in the perfused lung was significantly higher (P = .001) and the plasma concentration was significantly lower (P < .0001) after all isolated lung perfusion techniques, compared with intravenous administration, without differences between them. Pulmonary artery infusion (blood flow occlusion) showed an equally high doxorubicin uptake in the perfused lung but a higher systemic leakage than surgical isolated lung perfusion (P < .0001). The geometric coefficients of variation of the doxorubicin lung tissue levels were 175%, 279%, 226%, and 151% for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), respectively, compared with 51% for intravenous administration (P = .09). 99mTc activity measurements of the samples paralleled the doxorubicin level measurements, indicating a trend to a more heterogeneous spatial regional blood flow and drug distribution after isolated lung perfusion and blood flow occlusion compared with intravenous administration. CONCLUSIONS: Cytostatic lung perfusion results in a high overall doxorubicin uptake, which is, however, heterogeneously distributed within the perfused lung.
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Antibióticos Antineoplásicos/farmacocinética , Quimioterapia del Cáncer por Perfusión Regional/métodos , Doxorrubicina/farmacocinética , Pulmón/metabolismo , Animales , Cateterismo de Swan-Ganz , Infusiones Intravenosas , Pulmón/irrigación sanguínea , Pulmón/diagnóstico por imagen , Microesferas , Modelos Animales , Compuestos de Organotecnecio , Arteria Pulmonar , Cintigrafía , Flujo Sanguíneo Regional , Porcinos , Distribución TisularRESUMEN
PURPOSE: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated 131I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkin's lymphoma (NHL). METHODS: Patients received standard weekly therapy with rituximab (375 mg/m2) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq 131I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131I-rituximab injection prior to the second and third injections, respectively. RESULTS: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T(1/2)beta, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T(1/2) of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48-0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. CONCLUSION: These results show that the biodistribution and tissue kinetics of 131I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.
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Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Linfoma no Hodgkin/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Carga Corporal (Radioterapia) , Esquema de Medicación , Femenino , Humanos , Infusiones Intralesiones , Inyecciones Intralesiones , Cinética , Linfoma no Hodgkin/radioterapia , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Especificidad de Órganos , Radiometría , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Dosificación Radioterapéutica , Efectividad Biológica Relativa , Rituximab , Distribución Tisular , Recuento Corporal TotalRESUMEN
UNLABELLED: As part of a search for optimal conditions for radioimmunotherapy of lymphoma, rituximab was labeled with 2 different specific activities of 131I and immunoreactivity was comparatively measured. METHODS: Labeling was performed with chloramine T using as starting conditions 185 MBq of 131I per 1 mg and per 5 mg of antibody for labelings A and B, respectively. Six comparative labelings were performed over a period of 10 mo with similar efficacy and purified by anion-exchange chromatography. Immunoreactivity was determined immediately after labeling in parallel assays using different concentrations of fresh Raji and Daudi cells. Results were compared at maximal observed specific binding on 10(7) cells and after extrapolation to infinite antigen excess. A statistical analysis was performed to predict the frequency of radiolabeled mono- and polyiodinated antibodies: First, a gaussian distribution predicted the number of iodine atoms per antibody in labelings A and B, respectively; then, the radiolabeling probability was developed according to the Newton binome. RESULTS: Final radiochemical purity was >98.4% for all labelings. The final mean specific activities were 169.7 MBq/mg and 32.8 MBq/mg, corresponding to 0.87 and 0.17 iodine atoms per antibody in labelings A and B, respectively. Labeling B showed a significantly higher immunoreactivity than did labeling A, the mean relative increase in binding being > or =28% for both Raji cells and Daudi cells. The predictive statistical analysis indicated that 57.3% and 15.4% of radiolabeled antibodies in labelings A and B, respectively, were polyiodinated. CONCLUSION: The low specific activity of 131I-rituximab allowed preservation of a high immunoreactivity and correlated with the prediction of a low percentage of polyiodinated radiolabeled antibodies.
Asunto(s)
Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Linfoma de Burkitt/inmunología , Radioisótopos de Yodo/química , Radioisótopos de Yodo/inmunología , Marcaje Isotópico/métodos , Radioinmunoterapia/métodos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Linfoma de Burkitt/radioterapia , Línea Celular Tumoral , Humanos , Radioisótopos de Yodo/uso terapéutico , Cinética , Radiofármacos/química , Radiofármacos/inmunología , Radiofármacos/uso terapéutico , RituximabRESUMEN
Intratumoural (i.t.) injection of radio-iododeoxyuridine (IdUrd), a thymidine (dThd) analogue, is envisaged for targeted Auger electron- or beta-radiation therapy of glioblastoma. Here, biodistribution of [(125)I]IdUrd was evaluated 5 hr after i.t. injection in subcutaneous human glioblastoma xenografts LN229 after different intravenous (i.v.) pretreatments with fluorodeoxyuridine (FdUrd). FdUrd is known to block de novo dThd synthesis, thus favouring DNA incorporation of radio-IdUrd. Results showed that pretreatment with 2 mg/kg FdUrd i.v. in 2 fractions 0.5 hr and 1 hr before injection of radio-IdUrd resulted in a mean tumour uptake of 19.8% of injected dose (% ID), representing 65.3% ID/g for tumours of approx. 0.35 g. Tumour uptake of radio-IdUrd in non-pretreated mice was only 4.1% ID. Very low uptake was observed in normal nondividing and dividing tissues with a maximum concentration of 2.9% ID/g measured in spleen. Pretreatment with a higher dose of FdUrd of 10 mg/kg prolonged the increased tumour uptake of radio-IdUrd up to 5 hr. A competition experiment was performed in FdUrd pretreated mice using i.t. co-injection of excess dThd that resulted in very low tumour retention of [(125)I]IdUrd. DNA isolation experiments showed that in the mean >95% of tumour (125)I activity was incorporated in DNA. In conclusion, these results show that close to 20% ID of radio-IdUrd injected i.t. was incorporated in tumour DNA after i.v. pretreatment with clinically relevant doses of FdUrd and that this approach may be further exploited for diffusion and therapy studies with Auger electron- and/or beta-radiation-emitting radio-IdUrd.
Asunto(s)
Neoplasias Encefálicas/radioterapia , ADN/metabolismo , Glioblastoma/radioterapia , Idoxuridina/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Timidina/biosíntesis , Animales , Neoplasias Encefálicas/metabolismo , Floxuridina/uso terapéutico , Glioblastoma/metabolismo , Humanos , Idoxuridina/farmacocinética , Ratones , Trasplante de Neoplasias , Distribución Tisular , Trasplante HeterólogoRESUMEN
BACKGROUND AND METHODS: 5-Iodo-2'-deoxyuridine (IdUrd) radiolabelled with the positron emitter I or with the gamma and Auger electron emitters I or I has been proposed for cancer diagnosis and therapy. We modified the synthesis to reliably obtain [I]IdUrd and [I]IdUrd by using an Iodogen supported destannylation reaction of 5-(tri-n-butylstannyl)-2'-deoxyuridine (Bu3SndUrd) which meets the requirements for good laboratory practice (GLP) and good clinical practice (GCP). A method of purification was developed to eliminate by-products as well as any unreacted starting material. RESULTS: [I]IdUrd, which originated from a trace of iodide in the Bu3SndUrd precursor, was identified as the unknown by-product reported for this method. This trace could be eliminated by modified purification of Bu3SndUrd. Stabilization of pH was essential for unequivocal identification of radiolabelled IdUrd and possible degradation products in the different systems tested for quality control. Biodistribution in tumour bearing nude mice was measured as early as 3 and 6 h after i.v. injection of [I]IdUrd. This compound showed high and specific activity uptake in tumour and dividing tissues when combined with 5-fluoro-2'-deoxyuridine pre-treatment. Uptake was specifically inhibited by injection of excess thymidine.
Asunto(s)
Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/metabolismo , Idoxuridina/farmacocinética , Animales , División Celular , Estudios de Factibilidad , Femenino , Humanos , Idoxuridina/síntesis química , Radioisótopos de Yodo/química , Radioisótopos de Yodo/farmacocinética , Marcaje Isotópico/métodos , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Estadificación de Neoplasias/métodos , Especificidad de Órganos , Cintigrafía , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución TisularRESUMEN
UNLABELLED: The study aim was to assess the safety, biodistribution, tissue kinetics, and tumor uptake of the (99m)Tc-labeled neurotensin (NT) analog NT-XI. METHODS: Four patients presenting ductal pancreatic adenocarcinoma were studied with (99m)Tc-NT-XI. Patients were followed by scintigraphy up to 4 h and by continued blood and urinary sampling until surgery 18-22 h after injection. Surgical tissue samples were analyzed for radioactivity uptake and NT receptor expression. RESULTS: No side effects were observed on injection of (99m)Tc-NT-XI. Blood biologic half-lives alpha and beta were 35 min (range, 17-62 min) and 230 min (range, 107-383 min), respectively. Repeated whole-body scintigraphy performed in 2 patients showed a single exponential decrease of whole-body activity with half-lives of 101 and 232 min. Tracer elimination was mainly renal, with 92% and 98% of activity counted in urine in the first 20 h. Kidney, liver, spleen, and bone marrow activity uptake was observed in all patients. Tumor was not visualized in the first 3 patients but could be localized by tomoscintigraphy in the pancreas head region of patient 4. In vitro tissue analysis showed high expression of NT receptor in the tumor of patient 4, correlated with the highest tumor radioactivity uptake and the highest tumor-to-fat radioactivity ratio. In vitro receptor expression was also positive in a second patient having a tumor characterized by very low cellularity; however, the remaining 2 tumors lacked NT receptor expression. CONCLUSION: Injection of (99m)Tc-NT-XI was well tolerated. The in vivo tumor uptake appeared specific as it was observed in the 1 patient with a pancreatic tumor that expressed high amounts of NT receptor. The results are compatible with preclinical animal results and in favor of further development of radiolabeled NT analogs for diagnosis or therapy of cancer.
Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/metabolismo , Neurotensina/farmacocinética , Compuestos de Organotecnecio/farmacocinética , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/metabolismo , Recuento Corporal Total , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/metabolismo , Adulto , Anciano , Femenino , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neurotensina/análogos & derivados , Valor Predictivo de las Pruebas , Dosis de Radiación , Radiometría , Cintigrafía , Radiofármacos/farmacocinéticaRESUMEN
In tissue engineering, degradable or non-degradable polymer matrices can act as cell-carrier-scaffolds. Cell adhesion and growth on these scaffolds can be promoted by immobilizing extracellular matrix proteins. Therefore, in this study, polymer poly(ethylene terephthalate) (PET) films were surface modified by graft polymerization of acrylic acid, to subsequently allow collagen (types I and III) immobilization and human smooth muscle cell expansion. The surfaces of PET were activated by plasma, followed by acrylic acid graft polymerization, resulting in covalently bound brushes, containing an average of either 0.22+/-0.1 or 5.93+/-0.87 microg/cm2 of poly(acrylic acid) (PAA). Subsequent electrostatic adsorption of collagen gave a surface concentration of 4.96 and 17.2 microg/cm2, respectively, as determined using radiolabelled 125I collagen. Both PET films grafted with 0.22 microg/cm2 of PAA with or without adsorbed collagen were apt for smooth muscle cell adhesion and proliferation. However, films grafted with 5.93 microg/cm2 were not. PAA-grafted PET films, onto which serum proteins of the culture medium adsorbed spontaneously, proved to be better matrices than films on which collagen has been immobilized. It, therefore, can be speculated that other serum proteins are more important than collagen for the human smooth muscle cell adhesion and growth on surface-modified polymer matrices.