RESUMEN
Purpose: Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs.Experimental Design: Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia.Results: Hypoxia was sufficient to drive the formation of CC-ICs and colorectal cancer cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide not only inhibits tumor growth of xenografts compared with 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, noninvasive FAZA-PET hypoxia imaging was predictive of a tumor's response to evofosfamide.Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach. Clin Cancer Res; 24(9); 2116-27. ©2018 AACR.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Hipoxia/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Nitroimidazoles/administración & dosificación , Mostazas de Fosforamida/administración & dosificación , Profármacos/administración & dosificación , Animales , Biomarcadores , Caspasas/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimioradioterapia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Masculino , Ratones , Fenotipo , Tomografía de Emisión de Positrones , Nivel de Atención , Vía de Señalización Wnt , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Peer-reared (PR) rhesus monkeys with early maternal separation later exhibit aggressiveness, impaired impulse control, alcohol abuse, and low CSF 5-hydroxyindoleacetic acid. This study compared regional brain serotonin transporter (SERT) binding between nine PR and seven mother-reared rhesus monkeys with [11C]DASB positron emission tomography (PET) imaging. Parametric images of binding potential (BP) (which is proportional to Bmax/KD, in which Bmax is transporter density and KD is dissociation constant) and relative blood flow (R1) were generated by the two-parameter multilinear reference tissue model. R1 images were used for coregistration and normalization of PET parametric data to the magnetic resonance imaging template space. Group BP differences were analyzed voxelwise by Student's t test in SPM2. Region of interest-based parameter values were also calculated to obtain the magnitude of regional BP differences between the two groups. For the PR group, SERT BP was decreased by 10-23% across a range of brain areas consisting of the raphe, thalamus, hypothalamus, caudate and putamen, globus pallidum, anterior cingulate gyrus, and medial temporal regions, including amygdala and hippocampus (cluster-level corrected p = 0.002). For the latter three regions, BP was decreased in the right hemisphere. These results agree with the hypothesis that early maternal deprivation affects the development of the serotonergic system and suggest that decreased serotonergic innervations in the critical brain regions may explain some of the behavioral and biochemical abnormalities in PR monkeys.
Asunto(s)
Compuestos de Anilina/farmacocinética , Animales Recién Nacidos/metabolismo , Ansiedad de Separación/metabolismo , Encéfalo/metabolismo , Privación Materna , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estrés Psicológico/metabolismo , Sulfuros/farmacocinética , Envejecimiento/metabolismo , Animales , Macaca mulatta , Masculino , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
UNLABELLED: This study evaluated the use of gated versus nongated PET acquisitions for absolute quantification of radioisotope concentration (RC) in a respiratory motion-simulated moving phantom filled with radioactive spheres and background for both 2-dimensional (2D) and 3-dimensional (3D) acquisitions. METHODS: An image-quality phantom with all 6 spheres filled with the same (18)F RC (range, 19-62 kBq/mL) was scanned with PET/CT at rest and in motion with and without gating. The background was filled with (18)F solution to yield sphere-to-background ratios of approximately 5, 10, 15, and 20 to 1. Both 2D and 3D acquisitions were used for all combinations. Respiratory motion was simulated by using a motor-driven plastic platform to move the phantom periodically with a displacement of 2 cm and a cycle time of 5.8 s. For gated acquisitions, the phantom was tracked using a real-time position management system. Images were reconstructed, and regions of interest with the same sizes as the actual spheres were manually placed on axial slices to determine maximum and mean pixel RC. A threshold method (70% and 94% for 2D and 3D modes) was also used to determine a mean voxel RC. All values were compared with the expected RC; percentage differences were calculated for each sphere. To reduce partial-volume effects, only data for the 4 largest spheres were analyzed. RESULTS: The mean pixel method was the only method with linear responses for all 3 scan types, enabling direct comparisons. The ranges of RC percentage differences were underestimated for all scan types (using the mean pixel method). The overall mean percentage differences were 37, 49, and 41 in 2D mode and 40, 51, and 41 in 3D mode for static, nongated, and gated acquisitions, respectively. Gated acquisitions improved quantification (by reducing underestimation) over nongated acquisitions by 8% and 10% for 2D and 3D modes. CONCLUSION: In the presence of motion, the use of gated PET acquisitions appears to improve quantification accuracy over nongated acquisitions, almost restoring the results to those observed when the phantom is static.
Asunto(s)
Análisis de Elementos Finitos , Fantasmas de Imagen/normas , Tomografía de Emisión de Positrones/métodos , Técnica de Sustracción , Artefactos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Movimiento (Física) , Fantasmas de Imagen/estadística & datos numéricos , Tomografía de Emisión de Positrones/normas , Dosis de Radiación , Valores de Referencia , Reproducibilidad de los Resultados , Respiración , Sensibilidad y EspecificidadRESUMEN
Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.
Asunto(s)
Radioisótopos de Galio/farmacocinética , Neuroblastoma/diagnóstico por imagen , Receptores de Somatostatina/análisis , Animales , Línea Celular Tumoral , Quelantes , Radioisótopos de Galio/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo , Xenoinjertos , Humanos , Lutecio/uso terapéutico , Ratones , Neuroblastoma/radioterapia , Tomografía de Emisión de Positrones/métodos , Radioisótopos/uso terapéutico , Radiofármacos/farmacocinética , Receptores de Somatostatina/metabolismoRESUMEN
UNLABELLED: Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. METHODS: We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer (18)F-fluoroazomycin arabinoside (or (18)F-1-α-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [(18)F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. RESULTS: Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. CONCLUSION: Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents.
Asunto(s)
Hipoxia/diagnóstico por imagen , Nitroimidazoles/farmacocinética , Neoplasias Pancreáticas/diagnóstico por imagen , Radiofármacos/farmacocinética , Anciano , Anciano de 80 o más Años , Algoritmos , Femenino , Humanos , Hipoxia/etiología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Metástasis de la Neoplasia/diagnóstico por imagen , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/complicaciones , Tomografía de Emisión de Positrones , Flujo Sanguíneo RegionalRESUMEN
INTRODUCTION: Treatment of locally advanced non-small cell lung cancer with chemoradiotherapy (CRT) is limited by development of toxicity in normal tissue, including radiation esophagitis (RE). Increasingly, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is being used for adaptive planning. Our aim was to assess changes in esophageal FDG uptake during CRT and relate the changes to the onset and severity of RE. METHODS: This prospective study in patients with stage II-III non-small cell lung cancer involved serial four-dimensional computed tomography and PET scans during CRT (60-74Gy). RE was recorded weekly using the Common Terminology Criteria for Adverse Events (v4.0), and imaging was performed at weeks 0, 2, 4, and 7. Changes in the esophagus's peak standard uptake value (SUVpeak) were analyzed for each time point and correlated with grade of RE using the Wilcoxon rank-sum test. The volume of esophagus receiving 50 Gy (V50) and volume of esophagus receiving 60 Gy (V60) were correlated with the development of RE, and the C-statistic (area under the curve [AUC]) was calculated to measure predictivity of grade 3 RE. RESULTS: RE developed in 20 of 27 patients (74%), with grade 3 reached in 6 (22%). A significant percentage increase in SUVpeak in the patients with RE was noted at week 4 (p = 0.01) and week 7 (p = 0.03). For grade 3 RE, a significant percentage increase in SUVpeak was noted at week 2 (p = 0.01) and week 7 (p = 0.03) compared with that for less than grade 3 RE. Median V50 (46.3%) and V60 (33.4%) were significantly higher in patients with RE (p = 0.04). The AUC measurements suggested that the percentage change in SUVpeak at week 2 (AUC = 0.69) and V50 (AUC = 0.67) and V60 (AUC = 0.66) were similarly predictive of grade 3 RE. CONCLUSIONS: Serial FDG-PET images during CRT show significant increases in SUVpeak for patients in whom RE develops. The changes at week 2 may predict those at risk for the development of grade 3 RE and may be informative for adaptive planning and early intervention.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/efectos adversos , Esofagitis/etiología , Fluorodesoxiglucosa F18 , Neoplasias Pulmonares/terapia , Tomografía de Emisión de Positrones , Traumatismos por Radiación/etiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
UNLABELLED: The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice by use of (18)F-FDG and a small animal PET scanner. rCMR(glc) determined with (18)F-FDG PET was compared with values determined simultaneously by the autoradiographic 2-(14)C-DG method. In addition, we compared the rCMR(glc) values under isoflurane, ketamine and xylazine anesthesia, and awake states. METHODS: Immediately after injection of (18)F-FDG and 2-(14)C-DG into mice, timed arterial samples were drawn over 45 min to determine the time courses of (18)F-FDG and 2-(14)C-DG. Animals were euthanized at 45 min and their brain was imaged with the PET scanner. The brains were then processed for 2-(14)C-DG autoradiography. Regions of interest were manually placed over cortical regions on corresponding coronal (18)F-FDG PET and 2-(14)C-DG autoradiographic images. rCMR(glc) values were calculated for both tracers by the autoradiographic 2-(14)C-DG method with modifications for the different rate and lumped constants for the 2 tracers. RESULTS: Average rCMR(glc) values in cerebral cortex with (18)F-FDG PET under normoglycemic conditions (isoflurane and awake) were generally lower (by 8.3%) but strongly correlated with those of 2-(14)C-DG (r(2) = 0.95). On the other hand, under hyperglycemic conditions (ketamine/xylazine) average cortical rCMR(glc) values with (18)F-FDG PET were higher (by 17.3%) than those with 2-(14)C-DG. Values for rCMR(glc) and uptake (percentage injected dose per gram [%ID/g]) with (18)F-FDG PET were significantly lower under both isoflurane and ketamine/xylazine anesthesia than in the awake mice. However, the reductions of rCMR(glc) were markedly greater under isoflurane (by 57%) than under ketamine and xylazine (by 19%), whereas more marked reductions of %ID/g were observed with ketamine/xylazine (by 54%) than with isoflurane (by 37%). These reverse differences between isoflurane and ketamine/xylazine may be due to competitive effect of (18)F-FDG and glucose uptake to the brain under hyperglycemia. CONCLUSION: We were able to obtain accurate absolute quantification of rCMR(glc) with mouse (18)F-FDG PET imaging as confirmed by concurrent use of the autoradiographic 2-(14)C-DG method. Underestimation of rCMR(glc) by (18)F-FDG in normoglycemic conditions may be due to partial-volume effects. Computation of rCMR(glc) from (18)F-FDG data in hyperglycemic animals may require, however, alternative rate and lumped constants for (18)F-FDG.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Fluorodesoxiglucosa F18/farmacocinética , Glucosa/metabolismo , Tomografía Computarizada de Emisión/métodos , Anestésicos/farmacología , Animales , Autorradiografía , Encéfalo/citología , Encéfalo/efectos de los fármacos , Mapeo Encefálico/métodos , Radioisótopos de Carbono/farmacocinética , Desoxiglucosa/farmacocinética , Estudios de Factibilidad , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos BALB C , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular , Tomografía Computarizada de Emisión/instrumentaciónRESUMEN
This study evaluates effects of anesthesia on (18)F-FDG (FDG) uptake in mouse brain and heart to establish the basic conditions of small animal PET imaging. Prior to FDG injection, 12 mice were anesthetized with isoflurane gas; 11 mice were anesthetized with an intraperitoneal injection of a ketamine/xylazine mixture; and 11 mice were awake. In isoflurane and ketamine/xylazine conditions, FDG brain uptake (%ID/g) was significantly lower than in controls. Conversely, in the isoflurane condition, %ID/g in heart was significantly higher than in controls, whereas heart uptake in ketamine/xylazine mice was significantly lower. Results suggest that anesthesia impedes FDG uptake in mouse brain and affects FDG uptake in heart; however, the effects in the brain and heart differ depending on the type of anesthesia used.
Asunto(s)
Anestesia/métodos , Anestésicos/farmacología , Encéfalo/metabolismo , Fluorodesoxiglucosa F18/farmacocinética , Miocardio/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Corazón/diagnóstico por imagen , Corazón/efectos de los fármacos , Isoflurano/farmacología , Ketamina/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Radiofármacos/farmacocinética , Xilazina/farmacologíaRESUMEN
OBJECTIVE: Scatter correction is an important factor in quantitative SPECT. In this study, we evaluated 2 methods of scatter correction for brain SPECT. The first is based on thresholding the energy spectrum (ES), and the second is based on a modification of the transmission-dependent convolution subtraction (TDCS) method. METHODS: SPECT imaging of a skull striatal phantom was performed using a triple-head camera with and without scatter correction. The striatal compartments were filled with (123)I, and the brain shell cavity (background) was filled with varying concentrations of (123)I to obtain striatal-to-background ratios of 2, 5, 10, 15, 20, and 25 to 1, respectively, which were considered to be the expected ratios. SPECT-measured ratios of striatal-to-background counts were determined with scatter correction (both ES and TDCS methods) and without scatter correction and were then compared with the expected ratios. RESULTS: Without scatter correction, measured striatal-to-background ratios were underestimated by an average of 41.7%, compared with the expected ratios. The ES method of scatter correction underestimated the striatal-to-background ratios by an average of 27.4%, a significant improvement (P < 0.04) over those without scatter correction. With the TDCS method of scatter correction, the ratios were underestimated by only 3.3% (P < 0.03). TDCS ratios were significantly (P < 0.04) higher than ES ratios and were nearly identical to the expected ratios. CONCLUSION: These results suggest that scatter correction significantly improves the striatal-to-background ratios. The TDCS method appears to correct scatter more effectively than does the ES method for the striatal phantom, thus providing more accurate quantification.
Asunto(s)
Algoritmos , Cuerpo Estriado/diagnóstico por imagen , Aumento de la Imagen/instrumentación , Aumento de la Imagen/métodos , Tomografía Computarizada de Emisión de Fotón Único/instrumentación , Tomografía Computarizada de Emisión de Fotón Único/métodos , Humanos , Fantasmas de Imagen , Dispersión de RadiaciónRESUMEN
Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.
Asunto(s)
Región CA1 Hipocampal/ultraestructura , Hemorragia Subaracnoidea/patología , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiopatología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Modelos Animales de Enfermedad , Potenciación a Largo Plazo/fisiología , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína Básica de Mielina/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/fisiopatologíaRESUMEN
The present study aims to image the 18-kDa translocator protein (TSPO; formerly known as the peripheral benzodiazepine receptor) in a preclinical human breast cancer (BC) xenograft mouse model with positron-emission tomography (PET). An automated radiosynthesis of [(18)F]-N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([(18)F]FEPPA) was validated for human use using a commercial synthesis module and resulted in a high radiochemical yield (30%±8%, uncorrected; n=54) and specific activity (6±4 Ci/µmol). Tumor uptake of [(18)F]FEPPA in mice bearing subcutaneous MDA-MB-231 BC xenografts was evaluated by PET-computed tomography imaging and ex vivo biodistribution studies. Although the tumor was successfully visualized, ex vivo biodistribution studies revealed low tumor uptake (0.7%ID/g), with the majority of radioactivity distributed in the spleen, muscle, and heart despite high TSPO expression in this cell line. Our laboratory routinely prepares [(18)F]FEPPA for human-imaging studies in the central nervous system, and we envision that radiopharmaceuticals that target the TSPO have the potential for imaging macrophages in the tumor microenvironment.
Asunto(s)
Anilidas , Neoplasias de la Mama/diagnóstico por imagen , Radioisótopos de Flúor , Piridinas , Radiofármacos , Receptores de GABA/análisis , Anilidas/farmacocinética , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones/métodos , Piridinas/farmacocinética , Radiofármacos/farmacocinética , Receptores de GABA/metabolismoRESUMEN
UNLABELLED: Quantitative small-animal PET of mice requires successful delivery of radiotracers into the venous system. Intravenous injection of radiotracers via lateral tail veins is the most commonly used method of administration and can be technically challenging. Evaluation of the quality of an intravenous injection is necessary to determine whether small-animal PET is quantitatively accurate. The purpose of this study was to evaluate and compare the quality of 50 consecutive intravenous injections into mouse tail veins using both quantitative and qualitative methods. METHODS: During (18)F-FDG intravenous injection, qualitative assessment of the injection was performed and classified according to specific criteria as good, intermediate, or poor. Small-animal PET scans of the body and tail were acquired, and tail injection sites were quantitatively assessed in terms of percentage injected dose per gram and classified as low, medium, or high uptake of (18)F-FDG. Qualitative and quantitative methods were compared. To assess baseline amounts of (18)F-FDG in the tail without a tail injection, 3 additional mice were injected by the intraperitoneal method, imaged, and quantitatively assessed in the same manner. The in vivo imaging data were validated on 7 additional mice by sacrificing them after scans, removing their tails, rescanning the tails, and then measuring the tail radioactivity ex vivo in a γ-counter and correlating it with the in vivo amount. RESULTS: Validation of in vivo imaging to ex vivo data yielded an excellent correlation, with an r(2) value of 0.95. Comparison of qualitative and quantitative methods yielded 45 matching results (42 good and low, 2 intermediate and medium, and 1 poor and high). There were 5 cases of mismatching results (1 false-negative and 4 false-positive) between qualitative and quantitative methods. Low-uptake tail injections were comparable to the intraperitoneal injection values. Using qualitative methods, accuracy was true 90% (45/50) of the time. The overall rate of successful intravenous injections was 92% (46/50) using quantitative methods. CONCLUSION: Qualitative assessment is all that is necessary if the intravenous injection is classified as good. In intermediate, poor, or uncertain classifications, a scan of the tail should be performed for quantitative assessment.
Asunto(s)
Fluorodesoxiglucosa F18/administración & dosificación , Tomografía de Emisión de Positrones/veterinaria , Cola (estructura animal)/irrigación sanguínea , Cola (estructura animal)/diagnóstico por imagen , Imagen de Cuerpo Entero/veterinaria , Animales , Inyecciones Intravenosas/veterinaria , Ratones , Radiofármacos/administración & dosificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To quantify, in a feasibility study, metabolic and volumetric response to fractionated radiation therapy (RT) using weekly (18)F fluoro-deoxyglucose positron emission tomography (PET) imaging for 10 non-Hodgkin lymphoma (NHL) patients, and to correlate them to clinical outcome. METHODS AND MATERIALS: Ten patients with chemotherapy-refractory NHL planned for radical RT were prospectively entered into a research study. PET/computed tomography (CT) scans were acquired before RT, and repeated weekly during the 3- to 4-week course of RT, and at 1 and 3 months after therapy. Gross tumor volumes were contoured on CT scans and the corresponding maximum standardized uptake values (SUV(max)) determined in the coregistered PET images. The clinical outcomes of interest were local tumor response at 3 months post-RT and local tumor status at last follow-up or time of death. RESULTS: (18)F fluoro-deoxyglucose uptake from inflammation was rarely observed. The responses showed a large variability between patients. SUV(max) decreased consistently with a median of -2.1% per Gy (range, -3.3 to -0.7) and the median of the volumetric response was -2.2% per Gy (range, -2.8 to +0.5). Initial SUV(max) was not correlated with local control, whereas smaller initial tumor volume was, with smaller tumors more likely to achieve local control. The responses after treatment were also correlated to local control, but not the responses during treatment. CONCLUSIONS: Radiation does not confound the FDG uptake in the NHL tumor and normal tissues. Only smaller initial tumor volume and metabolic and volumetric response after completion of radiation therapy significantly correlated with eventual local control.
Asunto(s)
Fluorodesoxiglucosa F18 , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/radioterapia , Radiofármacos , Fraccionamiento de la Dosis de Radiación , Estudios de Factibilidad , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Radiofármacos/farmacocinética , Inducción de Remisión , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodos , Carga TumoralRESUMEN
UNLABELLED: Breast cancers (BCs) with high human epidermal growth factor receptor type 2 (HER2) expression are most likely to respond to trastuzumab; however, the mechanisms of action of trastuzumab are complex and there are no established biomarkers to accurately monitor treatment outcome in individual patients. Therefore, our aim was to determine, in human BC xenografts in athymic mice treated with trastuzumab, whether there were any changes in (18)F-FDG uptake that were associated with response to the drug and that could have utility in monitoring response in patients. METHODS: Baseline tumor uptake of (18)F-FDG was measured in mice with MDA-MB-361 HER2-overexpressing xenografts and MDA-MB-231 xenografts with low HER2 expression by small-animal PET imaging on day 0. Mice were treated with phosphate-buffered saline (PBS) or trastuzumab (4 mg/kg), and small-animal PET was repeated 2 d after treatment. Maintenance doses of trastuzumab (2 mg/kg) or PBS were administered on days 7 and 14, and mice were imaged again on days 9 and 16. Tumor uptake was measured as percentage injected dose per gram (%ID/g) by volume-of-interest analysis on days 0 (baseline), 2, 9, and 16, followed by biodistribution studies on day 16. Tumor growth was measured, and a tumor growth index was calculated. RESULTS: The treatment of mice with trastuzumab, compared with control mice treated with PBS, resulted in a significant decrease in tumor uptake of (18)F-FDG in HER2-overexpressing MDA-MB-361 xenografts after 16 d of treatment (2.6 +/- 0.8 %ID/g vs. 4.6 +/- 1.8 %ID/g, respectively; P < 0.03) but not after 2 or 9 d of treatment (P = 0.28-0.32). In contrast, there was no significant change in the tumor uptake of MDA-MB-231 xenografts with low HER2 expression during the entire course of therapy (4.4 +/- 1.7 %ID/g vs. 3.6 +/- 1.1 %ID/g, respectively; P = 0.31). Trastuzumab treatment, compared with PBS treatment of controls, resulted in significant growth inhibition of MDA-MB-361 xenografts as early as 10 d from the initiation of treatment (tumor growth index, 0.7 +/- 0.2 vs. 1.7 +/- 0.3, respectively; P < 0.0005), whereas no tumor growth inhibition was observed for MDA-MB-231 xenografts (5.3 +/- 2.7 and 5.2 +/- 3.0; P = 0.95). CONCLUSION: Changes in the tumor uptake of (18)F-FDG after therapy accurately identified responding and nonresponding human BC xenografts in athymic mice treated with trastuzumab; however, diminished glucose utilization did not precede changes in tumor volume.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Fluorodesoxiglucosa F18 , Animales , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Transformación Celular Neoplásica , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Regulación Neoplásica de la Expresión Génica , Genes erbB-2/genética , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones , Sensibilidad y Especificidad , Distribución Tisular , Tomografía Computarizada por Rayos X , Trastuzumab , Resultado del TratamientoRESUMEN
A novel PET radiotracer, [18F]-1-deoxy-1-fluoro-scyllo-inositol, was synthesized via a one-pot reaction in 16 +/- 3% uncorrected radiochemical yield within 80 minutes; although this compound revealed low brain penetration it shows promise in rodent tumour models for breast cancer imaging.
Asunto(s)
Inositol/análogos & derivados , Radiofármacos/síntesis química , Animales , Línea Celular Tumoral , Radioisótopos de Flúor/química , Humanos , Inositol/síntesis química , Inositol/química , Masculino , Ratones , Tomografía de Emisión de Positrones , Radiofármacos/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Trasplante HeterólogoRESUMEN
OBJECTIVE: Nicotinic acetylcholine receptors have close interactions with the dopaminergic system and play critical roles in cognitive function. The purpose of this study was to compare these receptors between living PD patients and healthy subjects. METHODS: Nicotinic acetylcholine receptors were imaged in 10 nondemented Parkinson's disease patients and 15 age-matched healthy subjects using a single-photon emission computed tomography ligand [(123)I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus nondisplaceable), as well as the delivery (K(1)). RESULTS: Parkinson's disease showed a widespread significant decrease (approximately 10%) of V in both cortical and subcortical regions without a significant change in K(1). INTERPRETATION: These results indicate the importance of extending the study to demented patients.
Asunto(s)
Enfermedad de Parkinson , Receptores Nicotínicos/metabolismo , Anciano , Azetidinas/química , Azetidinas/metabolismo , Femenino , Humanos , Radioisótopos de Yodo/química , Radioisótopos de Yodo/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Piridinas/química , Piridinas/metabolismo , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
PURPOSE: The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). METHODS: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. RESULTS: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. CONCLUSION: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.