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PURPOSE: Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results. METHODS: Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals. CONCLUSION: Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.
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Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Medicina Nuclear/normas , Feocromocitoma/diagnóstico por imagen , Tomografía de Emisión de Positrones/normas , Guías de Práctica Clínica como Asunto , Neoplasias de las Glándulas Suprarrenales/radioterapia , Unión Europea , Humanos , Radioisótopos de Yodo/uso terapéutico , Medicina Nuclear/organización & administración , Feocromocitoma/radioterapia , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Radiofármacos/normas , Radiofármacos/uso terapéutico , Sociedades Médicas/normas , Somatostatina/análogos & derivadosRESUMEN
PURPOSE: This study was designed to determine safety, tolerability, and radiation burden of a [(68)Ga]NODAGA-RGD-PET for imaging integrin αvß3 expression in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Moreover, metabolic stability and biokinetic data were compiled. METHODS: After injection of 154-184 MBq [(68)Ga]NODAGA-RGD three consecutive PET/CT scans were acquired starting 8.3 ± 2.1, 36.9 ± 2.8, and 75.1 ± 3.4 min after tracer injection. For metabolite analysis, blood and urine samples were analyzed by HPLC. For dosimetry studies, residence time VOIs were placed in the corresponding organs. The OLINDA/EXM program was used to estimate the absorbed radiation dose. RESULTS: The radiopharmaceutical was well tolerated and no drug-related adverse effects were observed. No metabolites could be detected in blood (30 and 60 min p.i.) and urine (60 min p.i.). [(68)Ga]NODAGA-RGD showed rapid and predominantly renal elimination. Background radioactivity in blood, intestine, lung, and muscle tissue was low (%ID/l 60 min p.i. was 0.56 ± 0.43, 0.54 ± 0.39, 0.22 ± 0.05, and 0.16 ± 0.8, respectively). The calculated effective dose was 21.5 ± 5.4 µSv/MBq, and the highest absorbed radiation dose was found for the urinary bladder wall (0.26 ± 0.09 mSv/MBq). No increased uptake of the tracer was found in HCC compared with the background liver tissue. CONCLUSIONS: [(68)Ga]NODAGA-RGD uptake in the HCCs lesions was not sufficient to use this tracer for imaging these tumors. [(68)Ga]NODAGA-RGD was well tolerated and metabolically stable. Due to rapid renal excretion, background radioactivity was low in most of the body, resulting in low radiation burden and indicating the potential of [(68)Ga]NODAGA-RGD PET for non-invasive determination of integrin αvß3 expression.
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Carcinoma Hepatocelular/metabolismo , Complejos de Coordinación/farmacocinética , Integrina alfaVbeta3/metabolismo , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Péptidos Cíclicos/farmacocinética , Exposición a la Radiación/análisis , Anciano , Carcinoma Hepatocelular/diagnóstico por imagen , Femenino , Humanos , Cirrosis Hepática/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Imagen Molecular/métodos , Especificidad de Órganos , Tomografía de Emisión de Positrones/métodos , Dosis de Radiación , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular , Recuento Corporal TotalRESUMEN
PURPOSE: PET/CT with (68)Ga-labelled [DOTA(0),Tyr(3)]-octreotide ((68)Ga-DOTA-TOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTR). Recent studies have shown SSTR expression in head and neck squamous cell carcinoma, albeit lower than in highly differentiated neuroendocrine tumours. We sought to determine whether nasopharyngeal carcinoma (NPC) positive for Epstein-Barr virus (EBV), a rare subtype of head and neck cancer, shows increased (68)Ga-DOTA-TOC uptake indicating expression of SSTR. METHODS: Five patients with untreated, histologically proven EBV-positive NPC were referred for (68)Ga-DOTA-TOC PET/CT. Tracer uptake in tumour lesions was assessed visually and semiquantitatively measuring maximum standardized uptake values (SUVmax) and tumour to background ratios. RESULTS: Increased tumour-specific uptake was detected in all five patients with a median SUVmax of 10.6 (range 3.6 - 17.1) in the primary tumour and 13.2 (range 6.1 - 14.5) in cervical lymph node metastases. CONCLUSION: (68)Ga-DOTA-TOC PET/CT demonstrated tracer uptake in EBV-positive NPC comparable to that in highly differentiated neuroendocrine tumours. This observation is consistent with increased SSTR expression in EBV-positive NPC and may open new diagnostic and therapeutic windows in NPC.
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Carcinoma/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Octreótido/análogos & derivados , Compuestos Organometálicos , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Anciano , Carcinoma/virología , Femenino , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/virología , Octreótido/farmacocinética , Compuestos Organometálicos/farmacocinética , Radiofármacos/farmacocinética , Distribución Tisular , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: To assess the association between PSA levels, PSA kinetics and other factors and a pathological (68)Ga-PSMA PET/CT scan in patients with recurrent prostate cancer (rPCa) with biochemical relapse (BR) after radical therapy. METHODS: Seventy consecutive rPCA patients referred for (68)Ga-PSMA PET/CT, matching all the following criteria, were retrospectively evaluated: (a) previous radical prostatectomy or primary radiotherapy with curative intent; (b) BR or persisting high PSA levels after primary treatment; and (c) complete clinical and imaging information. The mean ± SD PSA level was 3.5 ± 5.3 ng/mL (median 1.7, range 0.2 - 32.2 ng/mL), the mean ± SD PSA doubling time (PSAdt) was 6.5 ± 5.5 months (median 5.5, range 1.3 - 31.6 months), and the mean ± SD PSA velocity was 7.9 ± 20.5 (median 2.1, range 0.2 - 147.5 ng/mL/year). Statistical analysis was performed to assess which factors were associated with the detection of rPCa on (68)Ga-PSMA PET/CT. RESULTS: (68)Ga-PSMA PET/CT was positive in 52 of 70 patients (74.2%). In 30 patients (42.8%) lesions limited to the pelvis were detected. Distant lesions were observed in 8 of patients (11.4%). Local plus systemic lesions were detected in 14 patients (20%). PSA level (p = 0.017) and PSAdt (p = 0.0001) were significantly different between PET-positive patients (higher PSA level, shorter PSAdt) and PET-negative patients (lower PSA, longer PSAdt). ROC analysis showed that PSAdt 6.5 months and PSA 0.83 ng/mL were optimal cut-off values. In multivariate analysis PSAdt was associated with (68)Ga-PSMA PET/CT positivity. (68)Ga-PSMA PET/CT was positive in 17 of 20 patients (85%) with PSA <2 ng/mL and PSAdt <6.5 months, and in 3 of 16 patients (18.7%) with PSA <2 ng/mL and PSAdt ≥6.5 months. CONCLUSION: The great potential of (68)Ga-PSMA PET/CT in patients with rPCa and BR was confirmed. PSA and PSAdt were valuable predictors of pathological (68)Ga-PSMA PET/CT findings.
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Ácido Edético/análogos & derivados , Recurrencia Local de Neoplasia/diagnóstico por imagen , Oligopéptidos , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Radiofármacos , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Isótopos de Galio , Radioisótopos de Galio , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias de la Próstata/patología , Sensibilidad y EspecificidadRESUMEN
PURPOSE: 68Ga-labelled DOTA°-Tyr³-octreotide positron emission tomography (PET)/CT (68Ga-DOTATOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTRs). Recent studies have shown that SSTRs are also expressed in head and neck squamous cell carcinoma (HNSCC). This is the first prospective clinical trial investigating SSTR expression in patients with HNSCC using 68Ga-DOTATOC. METHODS: Patients with previously untreated HNSCC underwent 68Ga-DOTATOC PET/CT (120 MBq, range 81-150 MBq). Tumour tracer uptake was scored, the maximum standardized uptake value (SUVmax) was measured and the tumour to background uptake ratio was calculated. For each patient, PET/CT findings were correlated with immunohistochemical SSTR expression in tumour specimens. RESULTS: Fifteen HNSCC patients were included in the study from May 2011 to May 2012. Tumour-specific 68Ga-DOTATOC uptake was detected in all patients with an median SUVmax of 4.0 (range 2.2-6.5). Uptake was weak in seven (47%), moderate in five (33%) and strong in three (20%) patients. All tumour specimens were SSTR positive on immunohistochemistry. Of the 15 patients, 14 were positive for SSTR subtype 2, characterized by the highest affinity to octreotide. CONCLUSION: SSTR expression in HNSCC can be visualized clinically using 68Ga-DOTATOC PET/CT. SSTR expression in HNSCC could provide a potential target for SSTR-based therapy in patients not amenable to standard treatment modalities, but this cannot be predicted by SSTR immunohistochemistry.
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Carcinoma de Células Escamosas/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Octreótido/análogos & derivados , Compuestos Organometálicos , Tomografía de Emisión de Positrones , Radiofármacos , Adolescente , Adulto , Anciano , Carcinoma de Células Escamosas/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Octreótido/farmacocinética , Compuestos Organometálicos/farmacocinética , Radiofármacos/farmacocinética , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismoRESUMEN
PURPOSE: The hepatic asialoglycoprotein receptor is responsible for degradation of desialylated glycoproteins through receptor-mediated endocytosis. It has been shown that imaging of the receptor density using [(99m)Tc]diethylenetriamine pentaacetic acid (DTPA) galactosyl human serum albumin ([(99m)Tc]GSA) allows non-invasive determination of functional hepatocellular mass. Here we present the synthesis and evaluation of [(68)Ga]GSA for the potential use with positron emission tomography (PET). METHODS: Labelling of GSA with (68)Ga was carried out using a fractionated elution protocol. For quality control thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and size exclusion chromatography (SEC) techniques were evaluated. Stability of [(68)Ga]GSA was studied in phosphate-buffered saline (PBS) and human serum. For in vivo evaluation [(68)Ga]GSA distribution in Lewis rats was compared with [(99m)Tc]GSA by using a dual isotope protocol. PET and planar imaging studies were performed using the same scaled molar dose of [(68)Ga]GSA and [(99m)Tc]GSA. Time-activity curves (TAC) for heart and liver were generated and corresponding parameters calculated (t50, t90). RESULTS: [(68)Ga]GSA can be produced with high radiochemical purity. The best TLC methods for determining potential free (68)Ga include 0.1 M sodium citrate as eluent. None of the TLC methods tested were able to determine potential colloids. This can be achieved by SEC. HPLC confirmed high radiochemical purity (>98%). Stability after 120 min incubation at 37 °C was high in PBS (>95% intact tracer) and low in human serum (â¼27% intact tracer). Biodistribution studies simultaneously injecting both tracers showed comparable liver uptake, whereas activity concentration in blood was higher for [(68)Ga]GSA compared to [(99m)Tc]GSA. The [(99m)Tc]GSA TACs exhibited a small degree of hepatic metabolism compared to the [(68)Ga]GSA curves. The mean [(68)Ga]GSA t90 was higher than the mean t90 for [(99m)Tc]GSA. The mean [(68)Ga]GSA t50 was not significantly different from the mean t50 for [(99m)Tc]GSA. CONCLUSION: This study provides a promising new (68)Ga-labelled compound based on a commercially used kit for imaging the functional hepatocellular mass.
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Albúminas/síntesis química , Radioisótopos de Galio/química , Hígado/diagnóstico por imagen , Compuestos Organometálicos/síntesis química , Radiofármacos/síntesis química , Albúminas/química , Albúminas/farmacocinética , Animales , Radioisótopos de Galio/farmacocinética , Humanos , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Ácido Pentético/química , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Ratas , Agregado de Albúmina Marcado con Tecnecio Tc 99m/farmacocinética , Pentetato de Tecnecio Tc 99m/farmacocinética , Distribución TisularRESUMEN
PET/CT with the new 68Ga-labeled minigastrin analog DOTA-dGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2 (68Ga-DOTA-MGS5) was performed on patients with advanced medullary thyroid cancer (MTC) to evaluate cholecystokinin-2 receptor expression status. Methods: Six patients with advanced MTC underwent PET/CT with 68Ga-DOTA-MGS5. From the images acquired 1 and 2 h after injection, preliminary data on the biodistribution and tumor-targeting properties were evaluated in a retrospective analysis. Results: In total, 87 lesions with increased radiotracer uptake considered malignant were detected (2 local recurrences, 8 lymph node lesions, 27 liver lesions, and 50 bone lesions). In general, radiotracer accumulation in lesions was higher at 2 h than at 1 h after injection (mean SUVmax, 7.2 vs. 6.0, respectively; mean SUVmean, 4.4 vs. 3.6, respectively). Conclusion: The preliminary results clearly demonstrate the potential of 68Ga-DOTA-MGS5 PET/CT in detecting local recurrence and metastases in patients with advanced MTC.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Tiroides , Humanos , Receptor de Colecistoquinina B/metabolismo , Radioisótopos de Galio/química , Distribución Tisular , Estudios Retrospectivos , Radiofármacos , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/metabolismoRESUMEN
Background: Gastrin-releasing peptide receptors (GRPRs) are molecular imaging targets in multiple malignancies. Recently, NeoBOMB1, a 68Ga-labelled antagonist to GRPRs, was developed for PET. Here we report the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) describing diagnostic properties and covariates influencing uptake of 68Ga-NeoBOMB1 in oligometastatic gastrointestinal stromal tumor (GIST) patients. Methods: Nine patients with advanced GIST using PET/CT (computed tomography) were included. After kit-based 68Ga-NeoBOMB1 preparation with a licensed 68Ge/68Ga generator, 3 MBq/kg body weight were injected intravenously. PET/CT included dynamic and static PET scans 5, 12 and 18 min and 1, 2, and 3−4 h post injection (first six patients) and static PET scans 2 and 3−4 h post injection (last three participants). Tumor targeting was assessed on a per-lesion and per-patient basis. Results: Six patients showed visible radiotracer uptake in at least one tumor lesion. Seventeen out of 37 tumor lesions exhibited significant 68Ga-NeoBOMB1 uptake (median SUVmax 11.8 [range 2.8−51.1] 2 h p.i. and 13.2 [range 2.5−53.8] 3−4 h p.i) and improved lesion-to-background contrast over time. Five lesions (13.5%) were identified only by 68Ga-NeoBOMB1-PET, with no correlation on contrast-enhanced CT. Three patients showed no radiotracer accumulation in any lesions. Tracer uptake correlated with male sex (p < 0.0001), higher body mass index (p = 0.007), and non-necrotic lesion appearance (p = 0.018). There was no association with whole-lesion contrast enhancement, hepatic localization, mutational status, or disease duration. Conclusions: 68Ga-NeoBOMB1-PET exhibits variable tumor uptake in advanced-stage GIST patients, correlating with lesion vitality based on CT contrast uptake, opening the possibility of a theragnostic approach in selected cases.
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The new minigastrin analog DOTA-MGS5 is a promising new candidate for targeting cholecystokinin-2 receptor (CCK2R)-expressing tumors. To enable the clinical translation of PET/CT imaging using 68Ga-labeled DOTA-MGS5, different quality and safety aspects need to be considered to comply with the regulatory framework for clinical trial application. The preparation of the radiopharmaceutical was established using a cassette-based automated synthesis unit. Product specifications, including analytical procedures and acceptance criteria, were adopted from Ph. Eur. monographs for other 68Ga-labeled radiopharmaceuticals. Non-clinical studies included receptor affinity and cell uptake studies using two different CCK2R-expressing cell lines, as well as pharmacokinetic biodistribution studies in BALB/c mice for dosimetry calculations and toxicological studies in Wistar rats. The produced masterbatches fulfilled the defined acceptance criteria. DOTA-MGS5, with confirmed affinity to the CCK2R, showed a high specific cell uptake and no interaction with other receptors in vitro when radiolabeled with gallium-68. Favorable in vivo properties were observed in biodistribution and dosimetry studies. An effective dose of ~0.01 mSv/MBq was estimated for humans utilizing OLINDA/EXM software. A maximum peptide dose of 50 µg was established for the initial clinical dose based on the toxicity study in rats. The standardized production of [68Ga]Ga-DOTA-MGS5 using an automated synthesis module and the performed non-clinical safety studies support a first exploratory clinical trial with this new PET imaging agent.
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Ácido Edético/análogos & derivados , Radioisótopos de Flúor , Oligopéptidos , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Radiofármacos , Adulto , Isótopos de Galio , Radioisótopos de Galio , Humanos , Masculino , Neoplasias de la Próstata/radioterapia , Radiofármacos/uso terapéutico , Radio (Elemento)/uso terapéuticoRESUMEN
UNLABELLED: (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide (DOTA-TOC) PET has proven its usefulness in the diagnosis of patients with neuroendocrine tumors. Radionuclide therapy ((90)Y-DOTA-TOC or (177)Lu-DOTA-octreotate) is a choice of treatment that also requires an accurate diagnostic modality for early evaluation of treatment response. Our study compared (68)Ga-DOTA-TOC PET with CT or MRI using the Response Evaluation Criteria in Solid Tumors. Furthermore, standardized uptake values (SUVs) were calculated and compared with treatment outcome. METHODS: Forty-six patients (29 men, 17 women; age range, 34-84 y) with advanced neuroendocrine tumors were investigated before and after 2-7 cycles of radionuclide therapy. Long-acting somatostatin analogs were not applied for at least 6 wk preceding the follow-up. Data were acquired with a dedicated PET scanner. Emission image sets were acquired at 90-100 min after injection. (68)Ga-DOTA-TOC PET images were visually interpreted by 2 experienced nuclear medicine physicians. For comparison, multislice helical CT scans and 1.5-T MRI scans were obtained. Attenuation-corrected PET images were used to determine SUVs. Repeated CT evaluation and other imaging modalities, for example, (18)F-FDG, were used as the reference standard. RESULTS: According to the reference standard, (68)Ga-DOTA-TOC PET and CT showed a concordant result in 32 patients (70%). In the remaining 14 patients (30%), discrepancies were observed, with a final outcome of progressive disease in 9 patients and remission in 5 patients. (68)Ga-DOTA-TOC PET was correct in 10 patients (21.7%), including 5 patients with progressive disease. In these patients, metastatic spread was detected with the follow-up whole-body PET but was missed when concomitant CT was used. On the other hand, CT confirmed small pulmonary metastases not detected on (68)Ga-DOTA-TOC in 1 patient and progressive liver disease not detected on (68)Ga-DOTA-TOC in 3 patients. Quantitative SUV analysis of individual tumor lesions showed a large range of variability. CONCLUSION: (68)Ga-DOTA-TOC PET shows no advantage over conventional anatomic imaging for assessing response to therapy when all CT information obtained during follow-up is compared. Only the development of new metastases during therapy was detected earlier in some cases when whole-body PET was used. SUV analysis of individual lesions is of no additional value in predicting individual responses to therapy.
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Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/radioterapia , Octreótido/análogos & derivados , Compuestos Organometálicos/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/metabolismo , Octreótido/farmacocinética , Octreótido/uso terapéutico , Compuestos Organometálicos/farmacocinética , Pronóstico , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Receptores de Somatostatina/metabolismo , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Peptide receptor radionuclide therapy (PRRT) has been used for more than 20 y as a systemic treatment approach in inoperable or metastatic somatostatin receptor-positive tumors. The purpose of this study was to analyze the long-term outcome of PRRT with regard to the most commonly used radiopharmaceuticals, 90Y-DOTATOC and 177Lu-DOTATATE. Methods: This retrospective clinical study included a total of 44 consecutive patients (27 men) with advanced tumors and enhanced somatostatin receptor expression. Mean age at initial diagnosis was 60 y (SD, 11.3 y; range, 40-84 y). Median follow-up was 80 mo. For 177Lu-PRRT, the mean number of cycles administered was 5.3 ± 2.5 and the mean activity was 27.2 ± 14.9 GBq per patient. For 90Y-PRRT, the mean number of cycles administered was 5.5 ± 2.6 and the mean activity was 14.7 ± 7.3 GBq per patient. Overall, 378 cycles were administered (mean, 8.6 ± 3.4 cycles per patient), with an overall cumulative activity of 1,514.1 GBq. Results: Median overall survival was 79 mo. Twenty-one (77.8%) of the 27 men and 9 (52.9%) of the 17 women had died 12 y after commencement of PRRT. The shortest duration of illness was 8 mo and the longest 155 mo. Severe side effects (World Health Organization grades III and IV) were seen in 9 of the 14 patients still alive. Chronic kidney disease in combination with anemia was the most common finding in the 9 patients with severe side effects. A poor prognosis was found for those patients who showed progressive disease, in comparison with patients with cumulative disease control after initial PRRT (log rank, P < 0.001), whereas women and patients with no more than 2 tumor sites seemed to especially benefit from PRRT (not reaching significance levels). Conclusion: PRRT is encouraging in terms of long-term outcome. Thirty-two percent (14/44 patients) of the patients with metastatic or inoperable disease were still alive more than 12 y after the beginning of radionuclide therapy. Possible predictors for favorable outcome are having an initial response to PRRT, having a low number of affected sites, and being female.
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Octreótido/análogos & derivados , Receptores de Péptidos/metabolismo , Receptores de Somatostatina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Neoplasias/radioterapia , Octreótido/efectos adversos , Octreótido/uso terapéutico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: As radionuclide therapy is gaining importance in palliative treatment of patients suffering from neuroendocrine tumour (NET) as well as castration resistant prostate cancer (CRPC), the radiation protection of patients, staff, family members and the general public is of increasing interest. Here, we determine patient discharge dates according to European guidelines. METHODS: In 40 patients with NET and 25 patients with CRPC organ and tumour doses based on the MIRD concept were calculated from data obtained during the first therapy cycle. Planar whole body images were recorded at 0.5, 4, 20, 68 und 92 h postinjection. Residence times were calculated from the respective time-activity-curves based on the conjugated view method. Residence times for critical organs were fitted into the commercially available OLINDA software to calculate the organ doses. The doses of tumours and salivary glands were calculated via their self-irradiation by approximation with spheres of equivalent volume. Kidney volumes were gained by organ segmentation, volumes of all other organs were estimated by means of OLINDA and hence were lean body mass corrected. Out of the whole body curves reference points for patient discharge were estimated. RESULTS: In patients with NET discharge dates could be properly estimated from dosimetric data, which is not only crucial for radiation protection, but also makes therapy planning easier. For 177Lu-PSMA-617 ligand therapy it is difficult to seriously estimate a generalized discharge date due to large interpatient variation resulting from different tumor loads and heavy pre-treatment. CONCLUSION: Patient release is predictable for 177Lu-DOTATATE therapy but not for 177Lu-PSMA ligand therapy.
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Dipéptidos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Neoplasias/radioterapia , Octreótido/análogos & derivados , Compuestos Organometálicos/uso terapéutico , Dosificación Radioterapéutica , Humanos , Riñón/diagnóstico por imagen , Riñón/efectos de la radiación , Lutecio , Neoplasias/diagnóstico por imagen , Octreótido/uso terapéutico , Órganos en Riesgo , Antígeno Prostático Específico , Radiometría , Glándulas Salivales/diagnóstico por imagen , Glándulas Salivales/efectos de la radiación , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Imagen de Cuerpo EnteroRESUMEN
UNLABELLED: The aim of this study was to evaluate the diagnostic value of a new somatostatin analog, (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ((68)Ga-DOTA-TOC), for PET in patients with known or suspected neuroendocrine tumors. PET was compared with conventional scintigraphy and dedicated CT. METHODS: Eighty-four patients (48 men, 36 women; age range, 28-79 y; mean age +/- SD, 58.2 +/- 12.2 y) were prospectively studied. For analysis, patients were divided into 3 groups: detection of unknown primary tumor in the presence of clinical or biochemical suspicion of neuroendocrine malignancy (n = 13 patients), initial tumor staging (n = 36 patients), and follow-up after therapy (n = 35 patients). Each patient received 100-150 MBq (68)Ga-DOTA-TOC. Imaging results of PET were compared with (99m)Tc-labeled hydrazinonicotinyl-Tyr(3)-octreotide ((99m)Tc-HYNIC-TOC) and (111)In-DOTA-TOC. CT was also performed on every patient using a multidetector scanner. Each imaging modality was interpreted separately by observers who were unaware of imaging findings before comparison with PET. The gold standard for defining true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) results was based on all available histologic, imaging, and follow-up findings. RESULTS: PET was TP in 69 patients, TN in 12 patients, FP in 1 patient, and FN in 2 patients, indicating a sensitivity of 97%, a specificity of 92%, and an accuracy of 96%. The FP finding was caused by enhanced tracer accumulation in the pancreatic head, and the FN results were obtained in patients with a tumor of the gastrointestinal tract displaying liver metastases. (68)Ga-DOTA-TOC showed higher diagnostic efficacy compared with SPECT (TP in 37 patients, TN in 12 patients, FP in 1 patient, and FN in 34 patients) and diagnostic CT (TP in 41 patients, TN in 12 patients, FP in 5 patients, and FN in 26 patients). This difference was of statistical significance (P < 0.001). However, the combined use of PET and CT showed the highest overall accuracy. CONCLUSION: (68)Ga-DOTA-TOC PET shows a significantly higher detection rate compared with conventional somatostatin receptor scintigraphy and diagnostic CT with clinical impact in a considerable number of patients.
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Radioisótopos de Galio/farmacocinética , Octreótido/análogos & derivados , Octreótido/química , Cintigrafía/métodos , Receptores de Somatostatina/metabolismo , Tomografía Computarizada por Rayos X/métodos , Tirosina/química , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Octreótido/farmacocinética , Tomografía de Emisión de Positrones/métodos , Estudios ProspectivosRESUMEN
PURPOSE: Non-invasive techniques allowing quantitative determination of the functional liver mass are of great interest for patient management in a variety of clinical settings. Recently, we presented [68Ga]DTPA-GSA to target the hepatic asialoglycoprotein receptor for this purpose. Here, we introduce [68Ga]NOTA-GSA to improve metabolic stability of the radiopharmaceutical and compare the imaging properties with [68Ga]DTPA-GSA. PROCEDURES: Labeling of the compounds was carried out at room temperature using 1.9 M sodium acetate as buffer. For quality control, thin-layer, high-performance liquid, and size exclusion chromatographies were used. Metabolic stability was studied in rat and human serums. For in vivo evaluation, Fischer rats were scanned by positron emission tomography and magnetic resonance imaging and subsequently sacrificed for biodistribution studies. Time activity curves (TACs) for heart and liver were generated and corresponding parameters (T50, T90, LHL15, HH15) were calculated. RESULTS: [68Ga]NOTA-GSA can be produced in high radiochemical yield and purity (>95 %) within 15 min. Stability studies revealed almost no metabolite formation over the 2-h observation period. Analysis of the TACs showed comparable results for most of the investigated parameters. The only significant difference was found in the T90 value, where [68Ga]NOTA-GSA showed slower uptake in comparison with 68Ga-DTPA-GSA (123 ± 10 vs. 89 ± 3 s, p < 0.01). CONCLUSIONS: [68Ga]NOTA-GSA showed a significant increase of the metabolic stability and in most organs lower background activity. However, comparison of LHL15 and HH15 indicates that the increased stability did not further improve the diagnostic value. Thus, [68Ga]NOTA-GSA and [68Ga]DTPA-GSA can be used equivalent for imaging hepatic function with positron emission tomography.
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Complejos de Coordinación/química , Gadolinio/química , Hígado/fisiología , Imagen Molecular/métodos , Albúmina Sérica Humana/química , Animales , Complejos de Coordinación/síntesis química , Humanos , Pruebas de Función Hepática , Masculino , Ácido Pentético/química , Ratas Endogámicas F344 , Distribución TisularRESUMEN
AIM: The aim of this study was to compare C-choline PET/CT, prostate-specific antigen (PSA), PSA kinetics, and C-choline uptake in recurrent metastatic prostate cancer patients with osteoblastic and osteolytic bone metastases. PATIENTS AND METHODS: We retrospectively analyzed 140 patients with the following criteria: (a) positive bone lesions identified with C-choline PET/CT and validated as true positive by histology (14.2%), correlative imaging (33.4%), or clinical follow-up (52.4%); (b) after radical prostatectomy (67.9%) or primary radiotherapy (22.1%); (c) proven biochemical relapse with rising PSA levels; (d) no chemotherapy, zoledronic acid, or palliative bone external beam radiation therapy previously administrated during biochemical relapse; and (f) asymptomatic for bone pain. Lesions were categorized as osteoblastic, osteolytic, or bone marrow lesions. Patients were divided into osteoblastic and osteolytic patient groups. RESULTS: C-Choline PET/CT detected oligometastatic bone disease (1-3 lesions) in 98 (70%) of the 140 patients and multiple bone lesions in 42 (30%) of the 140 patients. By per-lesion analysis of 304 lesions, there were 184 osteoblastic, 99 osteolytic, and 21 bone marrow lesions.By per-patient analysis, 97 (69.3%) of the 140 patients were in the osteoblastic group, whereas 43 (30.7%) of the 140 patients were in the osteolytic group. Statistically significant differences in SUVmax (P < 0.001), fast PSA doubling time (P = 0.01), and PSA velocity (P = 0.01) were observed between osteoblastic (lower values) and osteolytic (higher values) groups. By multivariate analysis, fast PSA doubling time was a significant predictor for osteolytic lesions. CONCLUSIONS: We demonstrated differences in PSA kinetics and SUVmax between osteolytic and osteoblastic lesions. C-Choline PET/CT may identify patients that could benefit from early targeted therapies, depending on the type of bone lesions expressed.
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Neoplasias Óseas/diagnóstico por imagen , Colina , Imagen Multimodal , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Radiofármacos , Tomografía Computarizada por Rayos X , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/secundario , Radioisótopos de Carbono , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patologíaRESUMEN
Imaging of angiogenic processes is of great interest in preclinical research as well as in clinical settings. The most commonly addressed target structure for imaging angiogenesis is the integrin α(v)ß(3). Here we describe the synthesis and evaluation of [(18)F]FProp-Cys(*)-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys(*)-OH, a radiolabelled peptide designed to selectively target the integrin α(5)ß(1). Conjugation of 4-nitrophenyl-(RS)-2-[(18)F]fluoropropionate provided [(18)F]FProp-Cys(*)-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys(*)-OH in high radiochemical purity (>95%) and a radiochemical yield of approx. 55%. In vitro evaluation showed α(5)ß(1) binding affinity in the nanomolar range, whereas affinity to α(v)ß(3) and α(IIb)ß(3) was >50 µM. Cell uptake studies using human melanoma M21 (α(v)ß(3)-positive and α(5)ß(1)-negative), human melanoma M21-L (α(v)ß(3)-negative and α(5)ß(1)-negative), and human prostate carcinoma DU145 (α(v)ß(3)-negative and α(5)ß(1)-positive) confirmed receptor-specific binding. The radiotracer was stable in human serum and showed low protein binding. Biodistribution studies showed tumour uptake ranging from 2.5 to 3.5% ID/g between 30 and 120 min post-injection. However, blocking studies and studies using mice bearing α(5)ß(1)-negative M21 tumours did not confirm receptor-specific uptake of [(18)F]FProp-Cys(*)-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys(*)-OH, although this radiopeptide revealed high affinity and substantial selectivity to α(5)ß(1) in vitro. Further experiments are needed to study the in vivo metabolism of this peptide and to develop improved radiopeptide candidates suitable for PET imaging of α(5)ß(1) expression in vivo.
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Integrina alfa5beta1/metabolismo , Péptidos Cíclicos/síntesis química , Péptidos/síntesis química , Radiofármacos/síntesis química , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Endocitosis , Citometría de Flujo , Radioisótopos de Flúor , Humanos , Proteínas Inmovilizadas/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Datos de Secuencia Molecular , Péptidos/sangre , Péptidos/química , Péptidos Cíclicos/sangre , Péptidos Cíclicos/química , Unión Proteica , Estabilidad Proteica , Radiofármacos/química , Distribución TisularRESUMEN
BACKGROUND: The significant progress in nanotechnology provides a wide spectrum of nanosized material for various applications, including tumor targeting and molecular imaging. The aim of this study was to evaluate multifunctional liposomal nanoparticles for targeting approaches and detection of tumors using different imaging modalities. The concept of dual-targeting was tested in vitro and in vivo using liposomes derivatized with an arginine-glycine-aspartic acid (RGD) peptide binding to αvß3 integrin receptors and a substance P peptide binding to neurokinin-1 receptors. METHODS: For liposome preparation, lipids, polyethylene glycol building blocks, DTPA-derivatized lipids for radiolabeling, lipid-based RGD and substance P building blocks and imaging labels were combined in defined molar ratios. Liposomes were characterized by photon correlation spectroscopy and zeta potential measurements, and in vitro binding properties were tested using fluorescence microscopy. Standardized protocols for radiolabeling were developed to perform biodistribution and micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies in nude mice bearing glioblastoma and/or melanoma tumor xenografts. Additionally, an initial magnetic resonance imaging study was performed. RESULTS: Liposomes were radiolabeled with high radiochemical yields. Fluorescence microscopy showed specific cellular interactions with RGD-liposomes and substance P-liposomes. Biodistribution and micro-SPECT/CT imaging of (111)In-labeled liposomal nanoparticles revealed low tumor uptake, but in a preliminary magnetic resonance imaging study with a single-targeted RGD-liposome, uptake in the tumor xenografts could be visualized. CONCLUSION: The present study shows the potential of liposomes as multifunctional targeted vehicles for imaging of tumors combining radioactive, fluorescent, and magnetic resonance signaling. Specific in vitro tumor targeting by fluorescence microscopy and radioactivity was achieved. However, biodistribution studies in an animal tumor model revealed only moderate tumor uptake and no additive effect using a dual-targeting approach.
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Liposomas/farmacocinética , Imagen Molecular/métodos , Nanopartículas/química , Péptidos/farmacocinética , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Línea Celular , Femenino , Liposomas/química , Ratones , Ratones Desnudos , Microscopía Fluorescente , Neoplasias Experimentales/patología , Neoplasias Experimentales/radioterapia , Péptidos/química , Polietilenglicoles , Radiofármacos/química , Radiofármacos/farmacocinética , Distribución Tisular , Tomografía Computarizada por Rayos X/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Vasoactive intestinal peptide (VIP) receptors are overexpressed in a broad variety of tumours. For the detection of these tumours, novel chemically modified and shortened VIP derivatives were designed. MATERIALS AND METHODS: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-derivatised VIP analogues were radiolabelled with (111)In and in vitro and in vivo behaviour was evaluated using stability and internalisation assays, as well as an initial biodistribution study. RESULTS: Radiolabelling of the VIP analogues resulted in high radiochemical yields, without need for further purification steps. Stability of the VIP derivatives was variable and cell uptake studies in VIP receptor-positive cell lines revealed that only a limited number of derivatives were internalised. In the tumour mouse model, no specific tumour targeting was shown. CONCLUSION: Since the tested VIP derivatives exhibited impaired in vitro and in vivo characteristics alternative modifications to increase their stability while retaining receptor affinity should be considered to enable the use of synthetic VIP analogues for tumour targeting.
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Carcinoma Ductal Pancreático/metabolismo , Diseño de Fármacos , Compuestos Heterocíclicos con 1 Anillo/química , Radioisótopos de Indio , Neoplasias Pancreáticas/metabolismo , Fragmentos de Péptidos/farmacocinética , Radiofármacos , Receptores de Péptido Intestinal Vasoactivo/metabolismo , Péptido Intestinal Vasoactivo/farmacocinética , Animales , Unión Competitiva , Células CHO , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/radioterapia , Células Cultivadas , Cricetinae , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/radioterapia , Fragmentos de Péptidos/metabolismo , Cintigrafía , Distribución Tisular , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
BACKGROUND: To assess the sensitivity and specificity of [(18)F]-fluoro-ethyl-l-tyrosine ((18)F-FET) PET in brain tumors and various non-neoplastic neurologic diseases. METHODS: We retrospectively evaluated (18)F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). (18)F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense). RESULTS: Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed (18)F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher (18)F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). (18)F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions. CONCLUSIONS: (18)F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood-brain barrier and (18)F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.