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UNLABELLED: The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa). METHODS: Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new (18)F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with (18)F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software. RESULTS: Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7-4.9 mSv). CONCLUSION: BAY 864367, a novel (18)F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging.
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Bombesina/análogos & derivados , Radioisótopos de Flúor , Neoplasias de la Próstata/diagnóstico por imagen , Radiometría/métodos , Administración Intravenosa , Anciano , Algoritmos , Biopsia , Péptido Liberador de Gastrina/química , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico por imagen , Tomografía de Emisión de Positrones , Antígeno Prostático Específico/metabolismo , Radiofármacos , Programas Informáticos , Tomografía Computarizada por Rayos XRESUMEN
UNLABELLED: (D)-(18)F-fluoromethyltyrosine (d-(18)F-FMT), or BAY 86-9596, is a novel (18)F-labeled tyrosine derivative rapidly transported by the l-amino acid transporter (LAT-1), with a faster blood pool clearance than the corresponding l-isomer. The aim of this study was to demonstrate the feasibility of tumor detection in patients with non-small cell lung cancer (NSCLC) or head and neck squamous cell cancer (HNSCC) compared with inflammatory and physiologic tissues in direct comparison to (18)F-FDG. METHODS: 18 patients with biopsy-proven NSCLC (n = 10) or HNSCC (n = 8) were included in this Institutional Review Board-approved, prospective multicenter study. All patients underwent (18)F-FDG PET/CT scans within 21 d before d-(18)F-FMT PET/CT. For all patients, safety and outcome data were assessed. RESULTS: No adverse reactions were observed related to d-(18)F-FMT. Fifty-two lesions were (18)F-FDG-positive, and 42 of those were malignant (34 histologically proven and 8 with clinical reference). Thirty-two of the 42 malignant lesions were also d-(18)F-FMT-positive, and 10 lesions had no tracer uptake above the level of the blood pool. Overall there were 34 true-positive, 8 true-negative, 10 false-negative, and only 2 false-positive lesions for d-(18)F-FMT, whereas (18)F-FDG was true-positive in 42 lesions, with 10 false-positive and only 2 false-negative, resulting in a lesion-based detection rate for d-(18)F-FMT and (18)F-FDG of 77% and 95%, respectively, with an accuracy of 78% for both tracers. A high d-(18)F-FMT tumor-to-blood pool ratio had a negative correlation with overall survival (P = 0.050), whereas the (18)F-FDG tumor-to-blood pool ratio did not correlate with overall survival. CONCLUSION: d-(18)F-FMT imaging in patients with NSCLC and HNSCC is safe and feasible. The presented preliminary results suggest a lower sensitivity but higher specificity for d-(18)F-FMT over (18)F-FDG, since there is no d-(18)F-FMT uptake in inflammation. This increased specificity may be particularly beneficial in areas with endemic granulomatous disease and may improve clinical management. Further clinical investigations are needed to determine its clinical value and relevance for the prediction of survival prognosis.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Células Escamosas/diagnóstico por imagen , Radioisótopos de Flúor/química , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Tirosina/análogos & derivados , Tirosina/química , Adulto , Anciano , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Reacciones Falso Positivas , Femenino , Fluorodesoxiglucosa F18/química , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Inflamación , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Pronóstico , Estudios Prospectivos , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos XRESUMEN
UNLABELLED: Targeting cancer cells with vitamin B12 (cobalamin) is hampered by unwanted physiologic tissue uptake mediated by transcobalamin. Adhering to good manufacturing practice, we have developed a new (99m)Tc-cobalamin derivative ((99m)Tc(CO)3-[(4-amido-butyl)-pyridin-2-yl-methyl-amino-acetato] cobalamin, (99m)Tc-PAMA-cobalamin). The derivative shows no binding to transcobalamin but is recognized by haptocorrin, a protein present in the circulation and notably expressed in many tumor cells. In this prospective study, we investigated cancer-specific uptake of (99m)Tc-PAMA-cobalamin in 10 patients with various metastatic tumors. METHODS: Ten patients with biopsy-proven metastatic cancer were included. Dynamic imaging was started immediately after injection of 300-500 MBq of (99m)Tc-PAMA-cobalamin, and whole-body scintigrams were obtained at 10, 30, 60, 120, and 240 min and after 24 h. The relative tumor activity using SPECT/CT over the tumor region after 4 h was measured in comparison to disease-free lung parenchyma. Patients 3-10 received between 20 and 1,000 µg of cobalamin intravenously before injection of (99m)Tc-PAMA-cobalamin. The study population comprised 4 patients with adenocarcinomas of the lung, 3 with squamous cell carcinomas of the hypopharyngeal region, 1 with prostate adenocarcinoma, 1 with breast, and 1 with colon adenocarcinoma. RESULTS: The median age of the study group was 61 ± 11 y. Six of 10 patients showed positive tumor uptake on (99m)Tc-PAMA-cobalamin whole-body scintigraphy. The scan was positive in 1 patient with colon adenocarcinoma, in 3 of 4 lung adenocarcinomas, in 1 of 3 hypopharyngeal squamous cell carcinomas, and in 1 breast adenocarcinoma. Renal uptake was between 1% and 3% for the left kidney. Predosing with cobalamin increased the tumor uptake and improved blood-pool clearance. The best image quality was achieved with a predose of 20-100 ug of cold cobalamin. The mean patient dose was 2.7 ± 0.9 mSv/patient. CONCLUSION: To our knowledge, we report for the first time on (99m)Tc-PAMA-cobalamin imaging in patients with metastatic cancer disease and show that tumor targeting is feasible.
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Neoplasias/diagnóstico por imagen , Compuestos de Organotecnecio/farmacología , Radiofármacos/farmacología , Tecnecio/farmacología , Vitamina B 12/análogos & derivados , Vitamina B 12/química , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Metástasis de la Neoplasia , Estudios Prospectivos , Cintigrafía , Sensibilidad y Especificidad , Factores de Tiempo , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Vitamina B 12/farmacología , Imagen de Cuerpo EnteroRESUMEN
PURPOSE: To compare the accuracy of PET/MR imaging with that of FDG PET/CT and to determine the MR sequences necessary for the detection of liver metastasis using a trimodality PET/CT/MR set-up. METHODS: Included in this single-centre IRB-approved study were 55 patients (22 women, age 61 ± 11 years) with suspected liver metastases from gastrointestinal cancer. Imaging using a trimodality PET/CT/MR set-up (time-of-flight PET/CT and 3-T whole-body MR imager) comprised PET, low-dose CT, contrast-enhanced (CE) CT of the abdomen, and MR with T1-W/T2-W, diffusion-weighted (DWI), and dynamic CE imaging. Two readers evaluated the following image sets for liver metastasis: PET/CT (set A), PET/CECT (B), PET/MR including T1-W/T2-W (C), T1-W/T2-W with either DWI (D) or CE imaging (E), and a combination (F). The accuracy of each image set was determined by receiver-operating characteristic analysis using image set B as the standard of reference. RESULTS: Of 120 liver lesions in 21/55 patients (38%), 79 (66%) were considered malignant, and 63/79 (80%) showed abnormal FDG uptake. Accuracies were 0.937 (95% CI 89.5 - 97.9%) for image set A, 1.00 (95% CI 99.9 - 100.0%) for set C, 0.998 (95% CI 99.4 - 100.0%) for set D, 0.997 (95% CI 99.3 - 100.0%) for set E, and 0.995 (95% CI 99.0 - 100.0%) for set F. Differences were significant for image sets D - F (P < 0.05) when including lesions without abnormal FDG uptake. As shown by follow-up imaging after 50 - 177 days, the use of image sets D and both sets E and F led to the detection of metastases in one and three patients, respectively, and further metastases in the contralateral lobe in two patients negative on PET/CECT (P = 0.06). CONCLUSION: PET/MR imaging with T1-W/T2-W sequences results in similar diagnostic accuracy for the detection of liver metastases to PET/CECT. To significantly improve the characterization of liver lesions, we recommend the use of dynamic CE imaging sequences. PET/MR imaging has a diagnostic impact on clinical decision making.
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Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Anciano , Protocolos Clínicos , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: Computed tomography perfusion (CTP) can provide information about angiogenesis and blood-flow characteristics in tumours. [18F]Fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) is one of the major oncological imaging techniques which provides information about viability of the tumour cell and partly also about its aggressiveness. The aim of the study was to investigate the relationship between FDG and CTP data in patients with head and neck cancers. MATERIALS AND METHODS: Forty-one patients with a clinically suspected head and neck cancer were prospectively included. All patients underwent a combined PET/CT with an integrated CTP examination in the area of the head and neck tumour. CTP data (BF, BV and MTT) and PET data (SUVmax, SUVmean, TLG, PETvol) were compared between tumours and (1) healthy contralateral tissue, (2) inflammatory lesions, (3) metastatic lymph nodes, and CTP data and PET data were correlated in tumours. RESULTS: Thirty-five patients had a head and neck cancer. All CTP data were statistically different between tumours, inflammatory lesions, healthy tissue and metastatic lymph nodes; PET/CT data were in part significantly different. CTP and PET parameters were not significantly correlated. CONCLUSION: CTP and PET parameters were not significantly correlated; thus, the additional CTP values provide additional insights into tumour behaviour and their glycolytic status.
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Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adulto , Anciano , Biopsia , Medios de Contraste , Diatrizoato de Meglumina , Femenino , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/terapia , Humanos , Yohexol/análogos & derivados , Metástasis Linfática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Radiofármacos , Estadísticas no ParamétricasRESUMEN
PURPOSE: To investigate the clinical value of (18)F-fluorocholine PET/CT (CH-PET/CT) in treatment decisions in patients with recurrent prostate cancer (rPCA). METHODS: The study was a retrospective evaluation of 156 patients with rPCA and CH-PET/CT for restaging. Questionnaires for each examination were sent to the referring physicians 14-64 months after examination. Questions included information regarding initial extent of disease, curative first-line treatment, and the treatment plan before and after CH-PET/CT. Additionally, PSA values at diagnosis, after initial treatment, before CH-PET/CT and at the end of follow-up were also obtained from the questionnaires. RESULTS: Mean follow-up was 42 months. The mean Gleason score was 6.9 at initial diagnosis. Initial treatment was: radical prostatectomy in 110 patients, radiotherapy in 39, and combined prostatectomy and radiotherapy in 7. Median PSA values before CH-PET/CT and at the end of follow-up were 3.40 ng/ml and 0.91 ng/ml. PSA levels remained stable, decreased or were below measurable levels in 108 patients. PSA levels increased in 48 patients. In 75 of the 156 patients (48%) the treatment plan was changed due to the CH-PET/CT findings. In 33 patients the therapeutic plan was changed from palliative treatment to treatment with curative intent. In 15 patients treatment was changed from curative to palliative. In 8 patients treatment was changed from curative to another strategy and in 2 patients from one palliative strategy to another. In 17 patients the treatment plan was adapted. CONCLUSION: CH-PET/CT has an important impact on the therapeutic strategy in patients with rPCA and can help to determine an appropriate treatment.
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Colina/análogos & derivados , Imagen Multimodal , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Recurrencia , Estudios RetrospectivosRESUMEN
PURPOSE: To prospectively analyze different FDG-PET/CT-parameters (modified RECIST, SUVmax, TLG, PETvol) in patients with malignant pleural mesothelioma (MPM) under continued pemetrexed and platin based treatment. METHODS: Patients with biopsy proven MPM undergoing treatment with pemetrexed and platin based treatment were prospectively included in the study. Integrated FDG-PET/CT imaging was performed within 2 weeks before therapy and after every three consecutive cycles of combined chemotherapy. All CT-images were evaluated according to the modified RECIST (modRECIST) criteria. All FDG-PET/CT images were analyzed using SUVmax (maximum Standard Uptake Value) according to the EORTC criteria, change in Total Lesion Glycolysis (TLG) and FDG volume (PETvol). Percent change in all parameters compared to the initial, pre-therapeutic and the previous FDG-PET/CT scan. ModRECIST, EORTC guidelines, increase or decrease in TLG and PETvol was correlated with overall survival (OS) using the Log Rank Test. RESULTS: 41 patients with MPM were prospectively included in this study. The median OS of the study population is 439 days (111-1128). 41 patients had initial staging, 41 patients completed 3 cycles, 28 patients completed 6 cycles, 19 patients completed 9 cycles, 11 patients completed 12 cycles, 5 patients completed 15 cycles, 4 patients completed 18 cycles and 1 patient completed 21 cycles of chemotherapy. Chemotherapy was well tolerated up to 21 cycles. SUVmax showed a high variance over time for individual patients and change in SUVmax using EORTC guidelines did not predict OS at any time point. Ongoing morphological response in CT using modRECIST had highest correlation with OS and predicted survival up to the 15th cycle of continued permetrexed and platin based treatment. The correlations of response of the volume based PET parameters (TLG and PETvol) and OS are inferior to the morphological modRECIST parameter. CONCLUSION: Permetrexed and platin based treatment in MPM patients can be given over a prolonged time with good tolerance. Therapy response should be assessed by modRECIST in CT but not with SUVmax in FDG-PET. Long term permetrexed and platin therapy should be considered in MPM patients with good tolerance of treatment and ongoing morphological response in CT.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Fluorodesoxiglucosa F18 , Mesotelioma/diagnóstico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Pemetrexed , Tomografía de Emisión de Positrones , Pronóstico , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Técnica de Sustracción , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
The Warburg hypothesis states that aggressive cancers obtain much of their adenosine triphosphate (ATP) by metabolizing glucose directly to lactic acid. As a result of its high tumor selectivity, 3-bromopyruvic acid (3-BrPA), a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. We investigated the effect of 3-BrPA in a mouse model of aggressive metastatic lymphoma. Epstein-Barr-virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase were incubated with RPMI/fetal bovine serum, and various concentrations of 3-BrPA were used to determine the LD50 in vitro. In total, 18 severely combined immunodeficient mice were injected with 1 million human Raji lymphoma cells via the tail vein. Using bioluminescent imaging, tumor growth was measured daily for 12 days to determine the tumor burden. At day 0 (start of treatment), the mice were randomized. Six mice received 10 mg/kg 3-BrPA i.p. daily for 7 days, 6 mice received 1 treatment at day 0, and 6 mice received the control buffer. Tumor growth was assessed daily from day 0 until day 7 using bioluminescent imaging. All data were normalized to acquisition time (luminescence/second; L/s). Body weight was measured daily to determine the toxicity of 3-BrPA. The LD50 for Raji lymphoma cells exposed to 3-BrPA in vitro was 11 µM with an extremely steep dose response curve. At day 0, tumor activity medians in the group with daily treatment was 2131 L/s (244-12,725), with a 1-day dose of 3095 L/s (523-9650) and in the nontreated control group, 2997 L/s (1521-6911). In mice treated with a daily dose of 10 mg/kg 3-BrPa for 7 days, a significant reduction in tumor activity was found during the whole treatment period compared with the control mice (P = 0.0043 at day 7). In mice with a single treatment at day 0, growth delay was only evident at day 2 (P = 0.0152 at day 2) but not for the rest of the observation period. The only manifestation of toxicity of the daily administration of 10 mg/kg 3-BrPA was a reduction in body weight. Body weight at day 0 was 17.22 g ± 0.84 g in the treatment group and 17.58 g ± 0.86 g in the control group. Body weight at day +6 was 15.02 g ± 2.04 g in the treated group and 19.4 g ± 0.63 g in the control group. 3-BrPA demonstrated a significant positive tumor response both in vitro and in vivo. This, to our knowledge, is the first report of the use of 3-BrPA in a systemic tumor model. Based on these data, 3-BrPA holds promise for treatment of systemic metastatic cancers.
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Antineoplásicos/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Glucólisis/efectos de los fármacos , Linfoma no Hodgkin , Piruvatos/administración & dosificación , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Dosificación Letal Mediana , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/metabolismo , Masculino , Ratones , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To analyze the effect of H1N1 influenza A virus vaccination in patients referred for staging or follow-up F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for different malignant tumors. METHOD AND MATERIALS: Medical history of all patients scheduled for FDG PET/CT during the national vaccination campaign against H1N1 was evaluated for recent vaccination. Site of injection and time between PET/CT and the date of vaccination (dTime) was determined. A difference in the maximum SUV between ipsi- and contralateral deltoid muscle or axillary lymph node of more than 0.5 was determined as positive reaction. The best cut-off dTime for still visible reaction was calculated. All patients with positive ipsilateral lymph node were clinically followed. Institutional Review Board approval was waived. RESULTS: Of 269 patients, 58 (21.5%) were vaccinated for the H1N1 within 4 weeks prior to PET/CT (mean, 14.5 ± 8.7 days). Of them, 17 (29.3%) patients had FDG-positive lymph nodes (mean SUV, 1.43 ± 1.06), with a dTime range from 1 to 14 days. Only 2 of them had no increased FDG uptake in the ipsilateral deltoid muscle. The area under the receiver operator characteristic curve revealed a strong relation between time delay (dTime) and axillary activity (AUC, 0.9; 95% confidence interval, 0.816-0.983) with a cutoff at 8 days (Youden Index). At follow-up (mean, 183 days; range, 173-196 days), no patient was found to have required treatment or signs of axillary lymphadenopathy. CONCLUSIONS: H1N1 vaccination can cause false-positive FDG PET/CT findings, when administered less than 14 days before the test, with the highest probability if the vaccination was administered less than 8 days ago. Increased FDG activity in the ipsilateral deltoid muscle is a key finding for accurate interpretation of increased FDG activity in axillary lymph nodes.
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Fluorodesoxiglucosa F18/farmacocinética , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunación , Femenino , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Imagen Multimodal , Tomografía de Emisión de Positrones , Curva ROC , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: To assess the possible radiosensitizing capabilities of two different poly(ADP-ribose) polymerase (PARP) inhibitors in combination with external beam and I-tositumomab in a non-Hodgkin's lymphoma cell line. METHODS AND MATERIALS: Epstein-Barr virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase in log-phase growth were incubated with various doses of AZD-2281 and ABT-888 24 h before external beam radiation exposure. A 500 nmol/l concentration of AZD-2281 and ABT-888 was used to assess the growth curve of Raji lymphoma cells over 5 days. The number of double-stranded breaks was visually assessed using a H2AX antibody and confocal microscopy. Intracellular PARP activity was measured 2 h after incubation with AZD-2281 (500 nmol/l) and ABT-888 using a colorimetric PARP assay kit. The radiosensitizing effect of AZD-2281 (500 nmol/l) with various doses of I-tositumomab was assessed after 24 h. RESULTS: A volume of 500 nmol/l of AZD-2281 and 500 nmol/l of ABT-888, in combination with 0, 4, 8, and 12 Gy external beam radiation, showed a 5.2, 7.1, 10.1, and 33.1% radiosensitization. A measure of 500 nmol/l AZD-2281 and ABT-888 significantly reduced the percentage of viable cells on days 3-5 compared with controls. The maximal relative reduction in viable cells was 78.5%, and this occurred with AZD-2281 (500 nmol/l) on day 5. AZD-2281 revealed a higher number of double-stranded breaks with confocal microscopy than did ABT-888. Two hours after incubation of Raji cells with 500 nmol/l of AZD-2281 or ABT-888, the colorimetric PARP activity assay showed a reduction of 30.36% with ABT-888 and of 47.8% with AZD-2281. Combining AZD-2281 (500 nmol/l) with 0, 5 µCi (0.185 MBq), 10 µCi (0.37 MBq) and 20 µCi (0.74 MBq) ¹³¹I-tositumomab revealed a significant reduction in cell viability after 24 h with 5 µCi (0.185 MBq) (P<0.01) and 10 µCi (0.37 MBq) (P<0.01) radiation dose. CONCLUSION: PARP inhibitors AZD-2281 and ABT-888 are highly radiosensitizing agents when used before external beam radiation and ¹³¹I-tositumomab.
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Quimioradioterapia , Linfoma no Hodgkin/terapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Radioinmunoterapia , Anticuerpos Monoclonales/administración & dosificación , Bencimidazoles/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Inhibidores Enzimáticos/uso terapéutico , Humanos , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Radiación IonizanteRESUMEN
UNLABELLED: Despite approval by the Food and Drug Administration and consistent reports of the efficacy and safety of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, these therapies are infrequently used. This study investigates the opinions and patterns of the use of radioimmunotherapy by nuclear physicians, affiliated researchers, nuclear medicine technologists, and radiation oncologists and aims to identify possible barriers to the use of this promising therapy. METHODS: An e-mail-based survey with 13 broad questions related to radioimmunotherapy was sent electronically to 13,221 Society of Nuclear Medicine members and radiation oncologists throughout the United States. RESULTS: Six hundred thirteen individuals (4.6%) responded to the electronic survey. Two hundred fifty-one responders (40.9%) had treated patients with non-Hodgkin lymphoma (NHL) with radioimmunotherapy in the last 24 mo. Of the responders, 29.5% used only (90)Y-ibritumomab tiuxetan, 7.6% used only (131)I-tositumomab, and 24.9% used both radiopharmaceuticals; 37.9% did not treat NHL with radioimmunotherapy. Most responders said their patients came from university hospitals (33.9%) or private offices (25.6%), and they mainly treated in a second-line (42.9%), third-line (35.6%), or consolidation (23.5%) setting. Major concerns were that referring oncologists and hematologists wanted to treat by themselves with nonradioactive compounds (mean ± SD, 3.418 ± 1.49) and that (90)Y-ibritumomab tiuxetan and (131)I-tositumomab were expensive (mean ± SD, 3.413 ± 1.35). Of the responders and involved physicians, 40.4% and 35.2%, respectively, did not know if their institution accepted Medicare patients for radioimmunotherapy. Almost 30% (29.6%) of the responders thought radioimmunotherapy would probably grow and 38.0% thought it would grow in importance in the future. Responders who did not administer radioimmunotherapy for NHL thought it took too much time to administer radioimmunotherapy (P < 0.01) and had concerns about the dosimetry procedure (P < 0.01) and radiation safety (P < 0.01). Individuals who perceived a negative future for radioimmunotherapy had significantly more concerns about the time-consuming administration process (P < 0.05) and the high cost of radioimmunotherapy (P < 0.05). Responders from academic centers had significantly fewer concerns about payment (P < 0.01), dosimetry (P < 0.01), and radiation safety (P < 0.01). CONCLUSION: Radioimmunotherapy was generally viewed positively by the surveyed population. However, limited referrals due to alternative nonradioactive therapies and logistic, educational, and economic concerns played an important role for subgroups in the perception of radioimmunotherapy for NHL.
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Linfoma no Hodgkin/radioterapia , Medicina Nuclear/estadística & datos numéricos , Médicos/estadística & datos numéricos , Oncología por Radiación/estadística & datos numéricos , Radioinmunoterapia/estadística & datos numéricos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/inmunología , Recolección de Datos , Demografía , Medicina Basada en la Evidencia/estadística & datos numéricos , Hematología/estadística & datos numéricos , Humanos , Percepción , Radioinmunoterapia/efectos adversos , Radioinmunoterapia/economía , Radiofármacos/uso terapéutico , Derivación y Consulta/estadística & datos numéricosRESUMEN
Antibody responses to tumor antigens play an important role in initiating a cellular antitumor response with respect to antigen cross-presentation and T cell cross-priming. Successful vaccination strategies rely on an optimally timed activation of the humoral and cellular immune system by using appropriate adjuvant stimulation. The LUD99-008 trial used the cancer testis antigen NY-ESO-1 formulated with ISCOMATRIX adjuvant injected into patients intramuscularly. It was shown that this vaccination strategy is a safe and highly potent activator of the humoral and cellular immune system. Using the RAYS technology, we analyzed in detail the humoral immune response in these patients before and after vaccination: during the course of repeated vaccinations with the adjuvant, antibody titers against NY-ESO-1 and cross-reactivity to LAGE 1A and B increased as an indicator of an enhanced immune response, whereas no antibody response could be detected after vaccination without the adjuvant. Analysis of single fragments of the NY-ESO-1 protein revealed that the humoral response was almost exclusively directed against the N-terminal fragments and the number of fragments and their length being recognized by the NY-ESO-1-specific antibodies increased during the course of vaccination. The humoral immune response mainly consisted of antibodies of the IgG1 and IgG3 subclass. We rarely found IgG2 and IgG4 subclass antibodies. Our results support the implication that target-specific antibodies raised after vaccination contribute to the stimulation of an effective T cell response against the target antigen.
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Adyuvantes Inmunológicos/farmacología , Formación de Anticuerpos/efectos de los fármacos , Antígenos de Neoplasias/farmacología , Vacunas contra el Cáncer/farmacología , Colesterol/farmacología , Proteínas de la Membrana/farmacología , Fosfolípidos/farmacología , Saponinas/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Formación de Anticuerpos/inmunología , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/uso terapéutico , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Colesterol/uso terapéutico , Reactividad Cruzada/inmunología , Combinación de Medicamentos , Epítopos/inmunología , Humanos , Inmunoensayo , Inmunoglobulina G/inmunología , Inmunoterapia , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/uso terapéutico , Neoplasias/terapia , Fosfolípidos/uso terapéutico , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Saponinas/uso terapéutico , Linfocitos T/inmunología , Levaduras/genética , Levaduras/metabolismoRESUMEN
OBJECTIVE: To assess the clinical value of multi-phase, contrast-enhanced DOPA-PET/CT with emphasis on the diagnostic CT component in patients with neuroendocrine tumours (NET). METHODS: Sixty-five patients with NET underwent DOPA-cePET/CT. The DOPA-PET, multi-phase CT and combined DOPA cePET/CT data were evaluated and diagnostic accuracies compared. The value of ceCT in DOPA cePET/CT concerning lesion detection and therapeutic impact was evaluated. Sensitivities, specificities and accuracies were calculated. Histopathology and clinical follow-up served as the standard of reference. Differences were tested for statistical significance by McNemar's test. RESULTS: In 40 patients metastatic and/or primary tumour lesions were detected. Lesion-based analysis for the DOPA-PET showed sensitivity, specificity and accuracy of 66%, 100% and 67%, for the ceCT data 85%, 71% and 85%, and for the combined DOPA cePET/CT data 97%, 71% and 96%. DOPA cePET/CT was significantly more accurate compared with dual-phase CT (p < 0.05) and PET alone (p < 0.05). Additional lesion detection was based on ceCT in 12 patients; three patients underwent significant therapeutic changes based on the ceCT findings. CONCLUSION: DOPA cePET/CT was significantly more accurate than DOPA-PET alone and ceCT alone. The CT component itself had a diagnostic impact in a small percentage but contributed to the therapeutic strategies in selected patients.
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Dihidroxifenilalanina/análogos & derivados , Yohexol/análogos & derivados , Tumores Neuroendocrinos/diagnóstico , Tomografía de Emisión de Positrones/métodos , Técnica de Sustracción , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Medios de Contraste , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
UNLABELLED: Radioimmunotherapy is approved by the Food and Drug Administration for CD20 antigen-positive follicular and transformed non-Hodgkin lymphoma. The goal of this study was to obtain the opinion of hematologists and medical oncologists about CD20-directed radioimmunotherapy in the United States. METHODS: An e-mail-based survey with 8 questions was sent to 4,239 oncologists and hematologists throughout the United States. RESULTS: Two hundred sixteen (5.0%) oncologists and hematologists responded to our survey. One hundred fifty-seven (72.7%) said they had referred patients with non-Hodgkin lymphoma for radioimmunotherapy in the last 24 mo. Different types of practices had significantly different concerns regarding this treatment. Compared with referring physicians from academic centers, those from nonacademic centers reported significantly higher concerns about the lack of a site to which to refer patients for treatment (P < 0.01), the lack of interest by nuclear physicians in this type of treatment (P < 0.01), and a referral process that they felt was too complicated (P < 0.01). They were also more concerned about an economically adverse effect on their own practices if they referred patients for radioimmunotherapy (P < 0.01). Referring physicians who perceived consolidation as a possible indication for radioimmunotherapy had significantly fewer concerns about an adverse effect on their own practice (P < 0.01) and about nonradioactive alternatives (P < 0.01). Seventy-nine (36.6%) responders thought radioimmunotherapy would probably grow in importance, and 52 (24.1%) responders thought it would definitely grow in importance. However, the group with a positive outlook about the future of radioimmunotherapy predicted a higher growth of radioimmunotherapy if they could administer it in their own offices (P < 0.05). CONCLUSION: Radioimmunotherapy was generally viewed positively by referring physicians. However, in addition to scientific concerns, barriers to the use of radioimmunotherapy included difficulty in referral, perceptions of a high cost of the treatment, concerns about negative financial outcomes related to referral, and an opinion that the treatment would be used more if given by medical oncologists in their own offices. For the growth of radioimmunotherapy, it appears crucial not only to demonstrate the treatment's safety and efficacy but also to streamline the referral process, to enhance collaboration between specialists, and-it appears-to develop economic incentives for the referring physician.
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Testimonio de Experto , Hematología/estadística & datos numéricos , Linfoma no Hodgkin/radioterapia , Oncología Médica/estadística & datos numéricos , Radioinmunoterapia/estadística & datos numéricos , Antígenos CD20/inmunología , Recolección de Datos , Demografía , Hematología/organización & administración , Oncología Médica/organización & administración , Radioinmunoterapia/tendencias , Derivación y Consulta , Estados UnidosRESUMEN
UNLABELLED: Our objective was to investigate the use of bowel preparation before (18)F-FDG PET/CT to reduce intestinal (18)F-FDG uptake. METHODS: Sixty-five patients with abdominal neoplasias were assigned either to a bowel-preparation group (n = 26) or to a native group (n = 39). (18)F-FDG activity was measured in the small intestine and the colon. RESULTS: In the 26 patients with bowel preparation, average maximal standardized uptake value (SUVmax) was 3.5 in the small intestine and 4.4 in the colon. In the 39 patients without bowel preparation, average SUVmax was 2.6 in the small intestine and 2.7 in the colon. (18)F-FDG activity impaired diagnosis in 6 patients (23%) in the bowel-preparation group and 11 patients (28%) in the native group (P = 0.5). SUVmax in the colon was significantly higher in the bowel-preparation group (P = 0.002), but SUVmax in the small intestine did not significantly differ between the 2 groups (P = 0.088). CONCLUSION: Bowel preparation increases (18)F-FDG activity in the large intestine and is therefore not useful before PET/CT.
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Fluorodesoxiglucosa F18/metabolismo , Mucosa Intestinal/metabolismo , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Anciano , Artefactos , Transporte Biológico , Colon/metabolismo , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Intestino Delgado/metabolismo , Intestinos/diagnóstico por imagen , Masculino , Método Simple CiegoRESUMEN
Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[(18)F]fluor-2-deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15%) patients received statins throughout therapy. Five-year EFS was 67.3% in patients without statins compared with 79% in patients receiving statins during R-CHOP (HR, 0.47; 95% CI, 0.15-1.54, p = 0.2). Five-year OS was 81.4% for patients without statins compared with 93.3% for patients taking statins (HR, 0.58; 95% CI 0.07-4.55, p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75% in the non-statin group versus 86% in the statin group, p = 0.45). A trend toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84% versus 92%, p = 0.068). Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBCL.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Interacciones Farmacológicas , Humanos , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Estudios Retrospectivos , Rituximab , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
OBJECTIVE: To integrate CT-perfusion into a routine, clinical contrast-enhanced (ce) PET/CT protocol for the evaluation of liver metastases and to compare functional CT and PET parameters. MATERIALS AND METHODS: Forty-six consecutive patients (mean age: 60 (34-82) years; 20 f, 26 m) with known liver lesions (colorectal metastases (n = 34), primary liver cancer (n = 4), breast cancer (n = 3), anal cancer, gastric cancer, esophageal cancer, GIST, duodenal cancer (all: n = 1) who were referred for staging or therapy follow-up by [18F]-Fluoro-2-deoxy-D-glucose-positron-emission-tomography/computed-tomography imaging (FDG-PET/CT) were included. After acquisition of a low-dose PET/CT, a split-injection (70-90 mL) ce-CT-protocol, including a 35-s CT-perfusion scan of the liver and a diagnostic ce-CT of the thorax and/or abdomen (70 s delay, iv-contrast volume: 90 mL, 4 mL/s) was performed. CT-perfusion parameters (BF, BV, MTT,) and semi-quantitative PET-parameters (SUVmax, SUVmean, TLG, PETvol) were analyzed and compared. RESULTS: CT-perfusion data could be obtained in all but one patient with shallow breathing. In all patients, diagnostic ce-PET/CT quality was adequate without the use of additional contrast media. Significant correlations (P < 0.05) were found for each of BF, BV, MTT, and SUVmax, further, BF and MTT correlated with TLG. Several other correlations were seen for other perfusion and PET-parameters. CONCLUSION: Combined CT-perfusion/PET/CT-protocol without the use of additional contrast media is feasible and can be easily integrated in clinical routine. Perfusion parameters and PET-parameters are only partly correlating and therefore have to be investigated further at fixed time points during the course of disease and therapy.
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Neoplasias Hepáticas/diagnóstico por imagen , Imagen de Perfusión/métodos , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Medios de Contraste , Estudios de Factibilidad , Femenino , Fluorodesoxiglucosa F18 , Neoplasias Gastrointestinales/patología , Humanos , Yohexol/análogos & derivados , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Interpretación de Imagen Radiográfica Asistida por Computador , Radiofármacos , Estadísticas no ParamétricasRESUMEN
PURPOSE: Based on the complex growth pattern of MPM, conventional response evaluation in this cancer entity is challenging. Therefore, there is growing interest in therapy response evaluation with FDG-PET/CT. The aim of the study was to evaluate the value of several FDG-PET/CT-parameters in therapy response evaluation concerning prediction of survival at baseline and after three cycles of therapy. PATIENTS AND METHODS: The study was performed in accordance with the regulations of the local ethics committee. Forty-one patients with proven MPM and treated with palliative pemetrexed and platinum-based chemotherapy were included. All patients were evaluated by FDG-PET/CT at baseline and after three cycles of chemotherapy. Responders and non-responders were evaluated based on modified RECIST- and EORTC-criteria. Additional PET-parameters (SUVmean, tumor lesion glycolysis (TLG) and tumor volume (PETvol)) were evaluated. Results were evaluated using the COX regression and the Kaplan-Meier method. RESULTS: None of the baseline CT-measurements or the initial PET-parameters were predictive for survival. Based on CT, after three cycles of therapy 10 patients were categorized as responders, 30 were classified as stable disease and 1 had progressive disease. Based on PET-evaluation, 14 responders were identified, 23 patients with stable disease and 4 patients were progressive. CT-response after 3 cycles of chemotherapy was significantly related to overall survival (p=0.001). However, neither SUVmax-response (p=0.61) nor SUVmean-response (p=0.68) were related to survival. A decrease of TLG and PETvol, however, was found to be predictive (TLG: p=0.01; PETvol: p=0.002). CONCLUSION: Response evaluation based on modified RECIST by CT as well as response evaluation by TLG and PETvol in FDG-PET, but not SUVmax-measurements are predictive for survival in MPM.
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Antineoplásicos/uso terapéutico , Mesotelioma/mortalidad , Neoplasias Pleurales/mortalidad , Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Femenino , Fluorodesoxiglucosa F18 , Glutamatos/uso terapéutico , Glucólisis/efectos de los fármacos , Guanina/análogos & derivados , Guanina/uso terapéutico , Humanos , Masculino , Mesotelioma/diagnóstico por imagen , Mesotelioma/tratamiento farmacológico , Cuidados Paliativos , Pemetrexed , Neoplasias Pleurales/diagnóstico por imagen , Neoplasias Pleurales/tratamiento farmacológico , Tomografía de Emisión de Positrones , Pronóstico , Resultado del TratamientoRESUMEN
Rapidly growing cells show an increased demand for nutrients and vitamins. The objective of our work is to exploit the supply route of vitamin B12 to deliver new derivatives of this vital vitamin to hyperproliferative cells. To date, radiolabeled ((57)Co and (111)In) vitamin B12 derivatives showed labeling of tumor tissue but also undesired high accumulation of radioactivity in normal tissue. By abolishing the interaction of a tailored vitamin B12 derivative to its transport protein transcobalamin II and therefore interrupting transcobalamin II receptor and megalin mediated uptake in normal tissue, preferential accumulation of a radiolabeled vitamin in cancer tissue could be accomplished. We identified transcobalamin I on tumors as a possible new receptor for this preferential accumulation of vitamin-mediated targeting. The low systemic distribution of radioactivity and the high tumor to blood ratio opens the possibility of a more successful clinical application of vitamin B12 for imaging or therapy.
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Antineoplásicos/uso terapéutico , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapéutico , Transporte Biológico/efectos de los fármacos , Carcinoma , Línea Celular Tumoral , Humanos , Neoplasias Renales , Melanoma , Transcobalaminas/efectos de los fármacos , Transcobalaminas/metabolismo , Neoplasias de la Vejiga UrinariaRESUMEN
PURPOSE: To retrospectively determine the sensitivity and specificity of co-registered fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in patients with Hodgkin lymphoma after first-line therapy, with use of clinical follow-up or biopsy results as the reference standard. MATERIALS AND METHODS: Informed consent was obtained for imaging and included consent to use patient data for research purposes. Institutional review board approval was obtained. Between May 2001 and July 2005, the data for all patients (n=66) at the authors' institution with proved Hodgkin lymphoma after first-line therapy were retrospectively reviewed. PET/CT scans were evaluated for the presence of abnormal FDG uptake and residual masses after the end of treatment and at further follow-up. All patients with pathologic FDG lesions underwent surgical biopsy for histopathologic confirmation. All patients with negative PET/CT scans at follow-up were evaluated for disease-free survival. RESULTS: An FDG-avid lesion was detected at PET/CT in 27 of the 66 patients (mean age +/- standard deviation, 33.0 years +/- 12.2). Recurrence of Hodgkin lymphoma was confirmed with biopsy in 23 of the 27 patients. The mean maximum standardized uptake value (SUV) of the histopathologically proved lesions was 7.32 (+/-2.01). Four patients had false-positive findings at PET/CT: Biopsy revealed only inflammatory changes, and the mean maximum SUV was 7.30 (+/-2.53). Thirty-nine patients (mean age, 36.7 years +/- 10.8) did not have FDG-avid lesions and remained free of disease after a mean clinical follow-up of 26.2 months (+/-12.5) (specificity, 91% [39 of 43 patients]; sensitivity, 100% [23 of 23 patients]). The presence of bulky disease (>5 cm) after the end of treatment was a significant predictor of recurrent disease (P<.05). CONCLUSION: The authors conclude that FDG PET/CT can help exclude persistent and/or recurrent Hodgkin lymphoma after first-line therapy. Because of the false-positive results and the toxicity of salvage chemotherapy, including high-dose chemotherapy with autologous stem cell support, biopsy of the FDG-avid lesion is still needed.