RESUMEN
PURPOSE: 3-[18F]Fluoro-α-methyl-L-tyrosine ([18F]FAMT) is an amino acid positron emission tomography (PET) tracer specific for cancer detection by assessment of tumor amino acid metabolism. Little is known on whether or not the uptake of [18F]FAMT within cancer cells is associated with the expression of programmed death ligand-1 (PD-L1), a predictor of anti-PD-1 antibody efficacy. We conducted a clinicopathological study to assess the expression of PD-L1 and the presence of tumor-infiltrating lymphocytes (TILs) in patients with non-small cell lung cancer (NSCLC) diagnosed by PET. PROCEDURES: A total of 75 patients with NSCLC who underwent [18F]FAMT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET were enrolled in the study. Tumor specimens were stained by immunohistochemistry for glucose transporter 1 (Glut1), PD-L1 (using different antibody clones including E1L3N and 28-8), CD3, CD4, and CD8. The uptake of [18F]FAMT was correlated with clinicopathological variables. RESULTS: High uptake of [18F]FAMT was significantly associated with disease staging, initial treatment (surgical resection or chemotherapy), and the expression of PD-L1 (E1L3N). The value of the maximum standardized uptake value (SUVmax) for [18F]FAMT was significantly correlated with PD-L1 (E1L3N) expression, Glut1, and the SUVmax for [18F]FDG in patients with histological results of adenocarcinoma (AC) and advanced disease. A validation cohort for anti-PD-L1 using clone 28-8 showed a statistically significant correlation between SUVmax for [18F]FAMT and the expression of PD-L1 (28-8) and between the expression of PD-L1 (E1L3N) and PD-L1 (28-8). CONCLUSIONS: The uptake of [18F]FAMT on PET imaging was significantly correlated with PD-L1 expression in NSCLC, especially in patients with AC and advanced disease.
Asunto(s)
Biomarcadores de Tumor/inmunología , Radioisótopos de Flúor/farmacocinética , Neoplasias Pulmonares/inmunología , alfa-Metiltirosina/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Antígeno B7-H1/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Curva ROCRESUMEN
AIMS: L-[3-(18)F]-α-Methyltyrosine ((18)F-FAMT) has high specificity for malignant tumors on positron emission tomography (PET), and its role and potential usefulness has been previously investigated in operable esophageal carcinoma. We aimed to assess the ability of (18)F-FAMT PET to predict the response of esophageal cancer to definitive chemoradiotherapy. PATIENTS AND METHODS: We retrospectively reviewed 40 patients with esophageal cancer imaged with (18)F-FAMT PET. The relationship between (18)F-FAMT PET uptake before chemoradiotherapy and clinical outcomes was assessed. RESULTS: The primary tumor was visualized in 95% patients. (18)F-FAMT uptake was significantly positively correlated with lymph node metastasis. The low-(18)F-FAMT accumulation group had significantly higher complete response (CR) rates than did the high-accumulation group. The addition of a lymph node metastasis category with low (18)F-FAMT uptake provides a more precise predictor of CR. CONCLUSION: (18)F-FAMT uptake prior to treatment is a good predictor of CR rate after CRT for esophageal cancer.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Radiofármacos/farmacocinética , alfa-Metiltirosina/farmacocinética , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Quimioradioterapia , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Femenino , Radioisótopos de Flúor , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Estudios RetrospectivosRESUMEN
PURPOSE: This study was to develop an efficient synthesis of (99m)Tc-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-α-methyl tyrosine ((99m)Tc-N4-AMT) and evaluate its potential in cancer imaging. METHODS: N4-AMT was synthesized by reacting N4-oxalate and 3-bromopropyl AMT (N-BOC, ethyl ester). In vitro cellular uptake kinetics of (99m)Tc-N4-AMT was assessed in rat mammary tumor cells. Tissue distribution of the radiotracer was determined in normal rats at 0.5-4 h, while planar imaging was performed in mammary tumor-bearing rats at 30-120 min. RESULTS: The total synthesis yield of N4-AMT was 14%. Cellular uptake of (99m)Tc-N4-AMT was significantly higher than that of (99m)Tc-N4. Planar imaging revealed that (99m)Tc-N4-AMT rendered greater tumor/muscle ratios than (99m)Tc-N4. CONCLUSIONS: N4-AMT could be synthesized with a considerably high yield. Our in vitro and in vivo data suggest that (99m)Tc-N4-AMT, a novel amino acid-based radiotracer, efficiently enters breast cancer cells, effectively distinguishes mammary tumors from normal tissues, and thus holds the promise for breast cancer imaging.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Compuestos de Organotecnecio/síntesis química , Cintigrafía/métodos , Radiofármacos/síntesis química , alfa-Metiltirosina/síntesis química , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Femenino , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Ratas Endogámicas F344 , Distribución Tisular , alfa-Metiltirosina/química , alfa-Metiltirosina/farmacocinéticaRESUMEN
A sensitive and selective LC-MS-MS method for the isolation and quantification of alpha-methyltyrosine (AMT) from human plasma is described. The method employs a simple protein precipitation using zinc sulfate and sodium hydroxide. This precipitation procedure produced samples with high aqueous content that could be directly injected into a LC-MS-MS system without compromising reverse-phase chromatographic performance. Chromatographic separation was performed on a MetaChem MonoChrom C(18) column (2.0 mm x 50 mm; 5 microm) at a flow rate of 1 mL/min. Compounds were eluted using a gradient mixture of water-acetic acid (100:0.1, v/v) and acetonitrile-acetic acid (100:0.1, v/v). The structural analog alpha-hydroxymethyltyrosine was used as the internal standard. Mass spectrometric detection was carried out with a triple quadrupole mass spectrometer. The method was validated and used to determine human plasma AMT concentrations, and has been implemented to derive pharmacokinetic parameters.
Asunto(s)
Inhibidores Enzimáticos/sangre , alfa-Metiltirosina/sangre , Área Bajo la Curva , Calibración , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Indicadores y Reactivos , Masculino , Espectrometría de Masas , Control de Calidad , Reproducibilidad de los Resultados , Solventes , Manejo de Especímenes , alfa-Metiltirosina/farmacocinéticaRESUMEN
PURPOSE: To compare the accuracy of magnetic resonance (MR) imaging scores with that of 3-(iodine 123)-L-alpha-methyltyrosine ((123)I-IMT) single photon emission computed tomography (SPECT) in the noninvasive grading of untreated gliomas. MATERIALS AND METHODS: The study comprised 15 patients with low-grade gliomas (grades I-II, according to World Health Organization criteria) and 33 patients with high-grade gliomas (grades III-IV). The lesions were evaluated by using an MR imaging score based on nine criteria. The (123)I-IMT uptake was quantified as the ratio between the amino acid uptake in the tumor and that in the contralateral hemisphere. To test for potentially significant differences in diagnostic performance between contrast material-enhanced MR imaging and (123)I-IMT SPECT, binormal receiver operating characteristic curves were fitted to the data and compared by using the area test. RESULTS: The accuracy of MR imaging in the noninvasive grading of untreated gliomas was higher than that of (123)I-IMT SPECT (88% vs 79%). However, the difference in diagnostic performance was not significant on the basis of findings at receiver operating characteristic analysis (P >.2). Neither MR imaging nor (123)I-IMT SPECT allowed differentiation between high-grade gliomas (grades III and IV). CONCLUSION: Although (123)I-IMT uptake is significantly higher in high-grade gliomas than in low-grade gliomas, the performance of (123)I-IMT SPECT adds little to the accuracy of determining tumor grade when MR imaging is performed.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Imagen por Resonancia Magnética , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Anciano , Anciano de 80 o más Años , Astrocitoma/diagnóstico , Astrocitoma/patología , Biopsia , Encéfalo/patología , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/patología , Femenino , Glioblastoma/diagnóstico , Glioblastoma/patología , Glioma/clasificación , Glioma/patología , Humanos , Radioisótopos de Yodo/farmacocinética , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , alfa-Metiltirosina/farmacocinéticaRESUMEN
PURPOSE: Scintigraphy using I-123-iodo-alpha-methyl tyrosine (IMT) is useful in the preoperative characterization of gliomas, in detecting recurrent glioma and in the biological re-evaluation of residual or recurrent tumours. A systematic evaluation of non-parenchymal brain tumours has not yet been performed. The aim of the present study was to evaluate IMT SPECT in the management of intracerebral metastases and lymphomas. PATIENTS AND METHODS: IMT uptake was analyzed in 31 patients with 28 metastases of extracerebral solid tumours and 7 cerebral lymphomas. Histology revealed high grade lymphomas, melanomas, and carcinomas of the following origin: lung, unknown primary, breast, colon, renal cell, ovary, vagina, frontal sinus. IMT uptake was quantified as ratio between maximal tumour accumulation and average uptake in the contralateral hemisphere. RESULTS: All tumours except two renal cell and one small cell lung carcinoma metastases accumulated IMT (91%). The highest IMT uptake was found in a metastasis of lung carcinoma. IMT uptake was highly variable and was similar in primary and in recurrent tumours. CONCLUSION: Significant accumulation of IMT is seen in the majority of tumours, so that this technique might be helpful for the management of cerebral metastases and lymphomas.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Radioisótopos de Yodo , Linfoma/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodos , alfa-Metiltirosina , Adulto , Anciano , Transporte Biológico , Biopsia , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Femenino , Glioma/clasificación , Glioma/diagnóstico por imagen , Glioma/patología , Glioma/cirugía , Humanos , Radioisótopos de Yodo/farmacocinética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , alfa-Metiltirosina/farmacocinéticaRESUMEN
Brain and tumor uptake of [18F-alpha-methyl]tyrosine (18F-AMT) and the incorporation into each of four fractions (lipid, RNA, DNA and protein) were investigated in mice bearing LS180 colorectal carcinoma. Homogenized tissues were analyzed by the fractionation method into an acid-soluble fraction (ASF) and an acid-precipitable fraction (APF). The APF was further investigated to assess the incorporation of 18F-AMT into each fraction. Incorporation into four fractions of brain and tumor at 60 min post-injection was 20 and 12%, respectively; 10% of the activity was incorporated to lipid in brain and 5% in tumor. There was 5, 2 and 2% incorporation with RNA, DNA and protein, respectively. Metabolites in ASF were analyzed by high-performance liquid chromatography and thin-layer chromatography. There was only one radioactive peak, which corresponded to 18F-AMT. The incorporation of 18F-AMT into lipid was twice that of 18F-AMT in tumor. The uptake of 18F-AMT in tissues was rapid and accomplished before 30 min, and then slowly diffused in blood. These results implied that 18F-AMT was metabolized to protein to only a small extent and trapped as intact 18F-AMT in cells up to 60 min. We conclude that 18F-AMT is a promising tracer for tumor imaging and quantification of the transport rate using two-compartment models.
Asunto(s)
Encéfalo/metabolismo , Neoplasias Colorrectales/metabolismo , Inhibidores Enzimáticos/metabolismo , Radiofármacos/metabolismo , alfa-Metiltirosina/metabolismo , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Neoplasias Colorrectales/diagnóstico por imagen , Inhibidores Enzimáticos/farmacocinética , Femenino , Radioisótopos de Flúor , Ratones , Ratones Endogámicos BALB C , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Tomografía Computarizada de Emisión , Células Tumorales Cultivadas , alfa-Metiltirosina/farmacocinéticaRESUMEN
UNLABELLED: We have developed 18F-labeled alpha-methyl tyrosine (FMT) for PET imaging. The aim of this study was to evaluate the clinical application potential of FMT for patients with brain tumors. METHODS: Eleven healthy volunteers and 20 patients with brain tumors were injected with 185 MBq (5 mCi) FMT. In 3 healthy volunteers, whole-body imaging and urinary and plasma analysis were conducted for the assessment of the biodistribution of FMT. The normal range of cortical standardized uptake value (SUV) as a reference for comparing tumor SUV of FMT was estimated by using PET data obtained at 30 min postinjection in 8 healthy volunteers. Dynamic PET scans were conducted for 100 min in 4 healthy volunteers and for 30 min in 15 patients with brain tumors. The 10-min static images in another 4 volunteers and all patients were obtained at 30 min postinjection. In 13 patients, FMT uptake in the brain tumor was compared with 18F-fluorodeoxyglucose (FDG). Tumor-to-normal cortex count (T/N) ratio and tumor-to-white matter count (T/W) ratio and SUVs of brain tumors were determined on FMT and FDG PET images. RESULTS: Approximately 1480 MBq (40 mCi) FMT were produced in one radiosynthesis. Percentage injected dose (%ID) of FMT in the brain ranged from 2.8% to 4.9%, and approximately 50%ID of FMT was excreted in urine during 60 min postinjection, of which 86.6% was unmetabolized FMT. A faint physiological brain uptake with SUV of 1.61 +/- 0.32 (mean +/- SD, n = 8) was observed in healthy volunteers. Tumor SUV of FMT ranged from 1.2 to 8.2, with mean value of 2.83 +/- 1.57 (n = 23), which was significantly higher than that of the cortical area in healthy volunteers (P < 0.01). T/N and T/W ratios of FMT were significantly higher than those of FDG (2.53 +/- 1.31 versus 1.32 +/- 1.46, P < 0.001; 3.99 +/- 2.10 versus 1.39 +/- 0.65, P < 0.0001, respectively). CONCLUSION: FMT, like other radiolabeled amino acids, can provide high-contrast PET images of brain tumors.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor , Radiofármacos , Tomografía Computarizada de Emisión , alfa-Metiltirosina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Radioisótopos de Flúor/farmacocinética , Fluorodesoxiglucosa F18 , Humanos , Lactante , Masculino , Persona de Mediana Edad , alfa-Metiltirosina/farmacocinéticaRESUMEN
UNLABELLED: Various radiopharmaceuticals for breast cancer detection have been used for scintimammography and PET. However, few comparative studies have described the uptake of radiopharmaceuticals as a method of detecting breast cancer. The aim of this study was to assess the radiopharmaceuticals for breast cancer imaging in experimental mice implanted with breast cancer cells. METHODS: Six radiopharmaceuticals were studied: three for PET [18F-fluorodeoxyglucose (FDG), L-18F-alpha-methyltyrosine (FMT) and 11C-methionine (C-Met)] and three for scintimammography [99mTc-tetrofosmin (TF), 99mTc-sestamibi (MIBI) and 201Tl-chloride (Tl)]. Biodistributions of six different tracers in mice implanted with MCF-7 breast cancer cells were studied 1 and 3 hr after injection. RESULTS: Tumor uptake 1 hr after injection was FMT = C-Met > FDG = TF > MIBI = Tl. Thallium-201-chloride showed the highest tumor-to-blood ratio (T/B) among all radiopharmaceuticals because of its fast clearance from circulation. The T/B of the six radionuclides used in this study ranged from 1.26 for C-Met to 12.83 for Tl. Tumor-to-muscle ratio (T/M) revealed FMT = C-Met > FDG > MIBI > TF = Tl. The T/M ranged from 0.20 for TF to 2.29 for FMT. Tumor-to-lung ratio (T/L) varied from 0.45 for TF to 2.41 for FMT. FMT revealed the highest T/L of all six radiopharmaceuticals. CONCLUSION: Among radiopharmaceuticals for PET, FMT seemed to be suitable in detecting MCF-7 tumor; whereas for scintimammography, MIBI, TF and Tl appeared to have almost the same detectability of MCF-7 tumor. The results of this study strongly suggest that FMT may have a potential in breast cancer imaging.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Radiofármacos , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada de Emisión , Animales , Neoplasias de la Mama/metabolismo , Femenino , Radioisótopos de Flúor/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Radiofármacos/farmacocinética , Distribución Tisular , alfa-Metiltirosina/farmacocinéticaRESUMEN
Ethylene vinylacetate polymer (EVA) has been used for many years to fabricate controlled-release polymeric implant devices with which drugs of high or low molecular weight compounds could be delivered with zero-order kinetics. However, because the known fabrication methods such as solvent evaporation, casting and possible shrinkage are not sufficiently controllable we have now developed the microextrusion method with which even small amount of clinically important and expensive drugs can be incorporated into EVA with high reproducibility. We show here that devices produced by the microextrusion method allows for a controlled delivery of several neurotoxic and neurotherapeutic compounds such as alpha-methyl-p-tyrosine, diazepam, quinolinic acid, and phencyclidine. Each substance is slowly released from the polymer, as evidenced by spectrophotometric data, for up to 120 days at daily rates varying from 18.4 microg of phencyclidine to 97.6 microg/day of diazepam. Thus, microextrusion is a valuable method for fabricating controlled-release polymers in which small amounts of scarce drugs can be incorporated. Another advantage of the current procedure is that polymers can be fabricated with very little amount of solvent.