RESUMEN
BACKGROUND: Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. METHODS: Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68Ga and the ß- emitting nuclide 177Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [18F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. RESULTS: The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68Ga and >98 % with 177Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [68Ga]DOTAZOL (SUV Femur = 5.4 ± 0.6) followed by [18F]NaF (SUV Femur = 4.8 ± 0.2), [68Ga]DOTAPAM (SUV Femur = 4.5 ± 0.2) and [68Ga]BPAPD (SUV Femur = 3.2 ± 0.3). [177Lu]DOTAZOL showed a similar distribution as the diagnostic 68Ga complex. CONCLUSION: The 68Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [68Ga]DOTAZOL, which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177Lu. The therapeutic compound [177Lu]DOTAZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [68Ga/177Lu]DOTAZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.
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BACKGROUND: Neuroendocrine Neoplasms of the small intestine have been noticed more frequently over the past 35 years. They constitute about 25% of all NENs and 29% of all tumors of the small intestine. Due to the predominantly indolent nature and overall good prognosis, the benefit of surgical treatment is still debated. METHODS: In a retrospective study, data of 83 surgically treated patients with neuroendocrine neoplasms of the small intestine, 48 males and 35 females with a median age of 62 years (range 25-86 years) were analyzed. Patient data were documented in the MaDoc database for neuroendocrine tumors of the University Medical Center of Mainz. IBM SPSS Statistics 20 was used for statistical analysis. Kaplan-Meier survival curves and Log-Rank tests, censoring patients at the time of last follow-up, were used to compare the overall survival depending on potential prognostic factors (stage, grade, surgical treatment). RESULTS: At the time of diagnoses, the most common clinical symptoms were abdominal pain (n = 31, 37.3%), bowel obstruction (n = 11, 13.3%), bowel perforation and peritonitis (n = 3, 3.6%), gastrointestinal bleeding (n = 9, 10.8%), weight loss (n = 11, 13.3%), and carcinoid syndrome (n = 27, 32.5%). 65 patients (78.3%) had lymph node metastasis and in 58 patients (69.9%) distant metastasis were present. Segmental bowel resection (44) was the most common surgical procedure, followed by right hemi-colectomy (32) and explorative laparotomy (7). In most patients (78.9%), lymphadenectomy (systematic/selective) was performed. The 5-year survival of patients who underwent a systematic or a selective lymphadenectomy differed significantly (82.2 vs. 40.0%). The overall 3-, 5-, and 10-year survival rates were 88.2, 80.3, and 71.0%, respectively. CONCLUSION: Mesenteric lymph node metastases are almost invariably present and have significant impact on patients' prognosis. Systematic lymphadenectomy prevents complications and improves the survival. Early surgical treatment should be the goal in order to prevent complications.
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Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Intestino Delgado/patología , Tumores Neuroendocrinos/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Intestino Delgado/cirugía , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/mortalidad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendenciasRESUMEN
UNLABELLED: In patients with metastasized, castration resistant prostate cancer (mCRPC) treatment with radium-223 (Xofigo) is an attractive therapeutic option. In particular, patients with high tumour load seem to profit from this treatment in regard of survival and quality of live. Aim of this study was to stratify mCRPC patients according to a quantitative imaging marker derived from routine bone scans (EXINI bone) and analyze haematopoietic toxicity of Xofigo in these patients. PATIENTS, METHODS: Toxicity and oncologic outcome were investigated in a cohort of 14 patients with high tumour load. Additionally, based on a web survey, experience of toxicity in 41 high tumour load patients in Germany in 2014 was collected. RESULTS: In patients with a bone scan index (BSI) greater than 5, significant toxicity occurred in more patients than expected from the ALSYMPCA trial. This was associated with application of fewer cycles. Similar experiences have been made in other centers in Germany. Approximately 7% of these patients will need very long time or will not recover from grade ≥ 3 toxicity. CONCLUSION: Close follow-up of haematopoietic indices and, in case of toxicity, early termination of therapy is in particular necessary in late stage disease where limited bone marrow reserve is likely.
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Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/etiología , Neoplasias Óseas/radioterapia , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/etiología , Radio (Elemento)/efectos adversos , Enfermedades de la Médula Ósea/prevención & control , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico por imagen , Femenino , Humanos , Masculino , Traumatismos por Radiación/prevención & control , Radioisótopos/efectos adversos , Radioisótopos/uso terapéutico , Cintigrafía , Radiofármacos/efectos adversos , Radiofármacos/uso terapéutico , Radio (Elemento)/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with neuroendocrine neoplasms (NEN) develop hepatic metastases in 50-95 %. The aims of this study were to evaluate the outcome/prognosis of patients following hepatic surgery and to identify predictive factors for the selection of patient that benefit from hepatic tumor resection. PATIENTS AND METHODS: In a retrospective single-center study (1990 to 2014), 204 patients with hepatic metastasis of NEN were included. Ninety-four were subjected to various forms of liver resection. According to the overall survival, the influence of several prognostic factors like the Ki-67 index, stage of disease, and resection status was evaluated. RESULTS: The primary tumor was located in the small intestine (n = 73), pancreas (n = 58), colon (n = 26), esophagus or stomach (n = 9) and in 38 patients the primary site was unknown. The Ki-67 index was associated with significant different overall survival. Patients with an R0 resection (n = 38) of their hepatic metastasis had a very good 10-year survival of 90.4 %. Patients in whom an R1 (n = 23) or R2 (n = 33) resection of their hepatic metastasis could be achieved had a 10-year survival of 53.4 and 51.4 %, respectively. The majority of the patients (53.9 %) could not be resected and had a poor 10-year survival rate of 19.4 %. Partial or complete control of endocrine-related symptoms was achieved in all patients with functioning tumors following surgery. The overall 5- and 10-year survival rates were 77.9 and 65.2 %, respectively. CONCLUSION: Surgical resection of hepatic NEN metastases can reduce symptoms and improve the survival in selected patients with a Ki-67 index less than 20 %. The expected outcome has to be compared to the outcome of alternative treatment strategies. An R0 situation should be the aim of hepatic surgery, but also patients with R1 or R2 resection show a good survival benefit.
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Hepatectomía/métodos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Tumores Neuroendocrinos/patología , Selección de Paciente , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Femenino , Humanos , Antígeno Ki-67/sangre , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Pulmonary imaging using ventilation/perfusion (V/P) single-photon emission tomography (V/P scan) with Tc-99m-labeled radiotracers is a well-established diagnostic tool for clinically suspected pulmonary embolism (PE). Ga-68 aerosol (Galligas) and Ga-68-labeled macroaggregated albumin (MAA) are potential tracers for positron emission tomography (PET) lung V/P imaging and could display an advantage over conventional V/P scans in terms of sensitivity and specificity. After radiochemical and animal studies, the clinical applicability of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was investigated in an exploratory study in patients with clinical suspicion of PE. PET scans were acquired using a 16-slice Gemini TF positron emission tomography/computed tomography (PET/CT) scanner. The acquisition protocol included low-dose computed tomography (CT) for attenuation correction (AC). Dosimetry calculations and continuative phantom measurements were performed. Structural analyses showed no modification of the particles due to the labeling process. In addition, in vitro experiments showed stability of Ga-68 MAA in various media. As expected, Ga-68-labeled human serum albumin microspheres (HSAM) were completely retained in the lung of the animals. In clinical use, PET lung ventilation and perfusion imaging using Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was successful in all cases. In one case a clinically suspected PE could be detected and verified. The administered activity of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA may be reduced by more than 50%, resulting in comparable radiation exposure to conventional V/P scans. In conclusion, Ga-68 aerosol (Galligas) and Ga-68-labeled MAA are efficient substitutes for clinical use and could be an interesting alternative with high accuracy for lung V/P imaging with Tc-99m-labeled radiotracers, especially in times of Mo-99 shortages and increasing use and spread of PET/CT scanners and Ga-68 generators, respectively.
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Radioisótopos de Galio , Tomografía de Emisión de Positrones/métodos , Relación Ventilacion-Perfusión , Aerosoles , Anciano , Anciano de 80 o más Años , Animales , Femenino , Humanos , Masculino , Microesferas , Radiometría , Ratas , Ratas Sprague-Dawley , Albúmina SéricaRESUMEN
Neuroendocrine tumors (NET) are defined by biochemical characteristics and structures which can be specifically addressed by radioligands for diagnostic imaging as well as radionuclide therapy in nuclear medicine. Somatostatin receptor imaging has been shown to be an important part of the diagnostic process in the management of NET for a long time. In recent years a number of tracers enabling PET-based imaging of somatostatin receptors and amine precursor uptake have been developed. By combining the specific functional information of the PET signal with anatomical information by CT imaging using PET-CT hybrid scanners, primary tumors and metastases can be detected with high resolution and high sensitivity. Compared with conventional indium-111 octreotide scintigraphy PET-CT has a higher resolution and also a lower radiation exposure. In addition, quantification of the tracer uptake allows therapy monitoring. By labelling with therapeutic beta-emitters, such as lutetium-177 or yttrium-90, a systemic internal radiotherapy with somotostatin analogues (peptide radionuclide radiation therapy, PRRT) can be provided as a therapeutic option for patients with unresectable and metastasized neuroendocrine tumors.
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Neoplasias del Sistema Digestivo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Tumores Neuroendocrinos/diagnóstico por imagen , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Neoplasias del Sistema Digestivo/patología , Neoplasias del Sistema Digestivo/radioterapia , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Estadificación de Neoplasias , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/radioterapia , Pronóstico , Dosis de Radiación , Radioisótopos/efectos adversos , Sensibilidad y Especificidad , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Imagen de Cuerpo EnteroRESUMEN
Using PET with the opioidergic ligand [11C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biologic clock.
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Cefalalgia Histamínica/diagnóstico por imagen , Diprenorfina/farmacocinética , Hipotálamo/diagnóstico por imagen , Antagonistas de Narcóticos/farmacocinética , Glándula Pineal/diagnóstico por imagen , Adulto , Radioisótopos de Carbono , Cefalalgia Histamínica/patología , Lateralidad Funcional , Humanos , Hipotálamo/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Glándula Pineal/patología , Tomografía de Emisión de Positrones , RadiografíaRESUMEN
This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10(6) Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 micro g unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%+/-4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%+/-2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with (149)Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach.
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Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Leucemia/metabolismo , Leucemia/radioterapia , Radioinmunoterapia/métodos , Partículas alfa/uso terapéutico , Animales , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/uso terapéutico , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos/métodos , Medicina Basada en la Evidencia/métodos , Femenino , Leucemia/tratamiento farmacológico , Ratones , Ratones SCID , Especificidad de Órganos , Radiofármacos/uso terapéutico , Reproducibilidad de los Resultados , Rituximab , Sobrevida , Distribución Tisular , Resultado del TratamientoRESUMEN
A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.
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Actinio/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias/radioterapia , Radioinmunoterapia/métodos , Actinio/administración & dosificación , Actinio/farmacocinética , Partículas alfa/uso terapéutico , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Femenino , Semivida , Compuestos Heterocíclicos con 1 Anillo , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacocinética , Transferencia Lineal de Energía , Linfoma/radioterapia , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/radioterapia , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
A monoclonal antibody (E-cadherin delta 9-1) directed against a characteristic E-cadherin mutation (in-frame deletion of exon 9), found in diffuse-type gastric cancer but not in any normal tissue, was conjugated with the high linear energy transfer alpha-emitter 213Bi and tested for its binding specificity in s.c. and i.p. nude mice tumor models. After intratumoral application in s.c. tumors expressing mutant E-cadherin, the 213Bi-labeled antibody was specifically retained at the injection site as shown by autoradiography. After injection into the peritoneal cavity, uptake in small i.p. tumor nodules expressing mutant E-cadherin was 17-fold higher than in tumor nodules expressing wild-type E-cadherin (62% injected dose/g versus 3.7% injected dose/g). 78% of the total activity in the ascites fluid was bound to free tumor cells expressing mutant E-cadherin, whereas in control cells, binding was only 18%. The selective binding of the 213Bi-labeled, mutation-specific monoclonal antibody E-cadherin delta 9-1 suggests that it will be successful for alpha-radioimmunotherapy of disseminated tumors after locoregional application.