RESUMEN
Surgery remains the only curative treatment of pancreatic neuroendocrine neoplasms (pNEN). Here, we report the outcome after surgery for non-functional pNEN at a European Neuroendocrine Tumor Society (ENETS) center in Germany between 2000 and 2019; cases were analyzed for surgical (Clavien-Dindo classification; CDc) and oncological outcomes. Forty-nine patients (tumor grading G1 n = 25, G2 n = 22, G3 n = 2), with a median age of 56 years, were included. Severe complications (CDc ≥ grade 3b) occurred in 11 patients (22.4%) and type B/C pancreatic fistulas (POPFs) occurred in 5 patients (10.2%); in-hospital mortality was 2% (n = 1). Six of seven patients with tumor recurrence (14.3%) had G2 tumors in the pancreatic body/tail. The median survival was 5.7 years (68 months; [1-228 months]). Neither the occurrence (p = 0.683) nor the severity of complications had an influence on the relapse behavior (p = 0.086). This also applied for a POPF (≥B, p = 0.609). G2 pNEN patients (n = 22) with and without tumor recurrence had similar median tumor sizes (4 cm and 3.9 cm, respectively). Five of the six relapsed G2 patients (83.3%) had tumor-positive lymph nodes (N+); all G2 pNEN patients with recurrence had initially been treated with distal pancreatic resection. Pancreatic resections for pNEN are safe but associated with relevant postoperative morbidity. Future studies are needed to evaluate suitable resection strategies for G2 pNEN.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Tumores Neuroendocrinos/cirugía , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Estudios RetrospectivosRESUMEN
This recommendation is intended to provide a guideline for radiosynoviorthesis (RSO) in the effective local treatment of chronic inflammatory (non-infectious) joint diseases. It was developed in an interdisciplinary manner and describes the general objectives, definitions, clinical background information, indication and contraindications of this radionuclide therapy. The requirements to be met by a treatment center, the results of pretherapeutic examinations as well as recommendations on how the treatment should be carried out. Here, organizational and technical issues have been considered. Furthermore, information on the surveillance and follow-up of the treated patients can be found. In general, treatment and follow-up should be done in in close cooperation of the participating disciplines.
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Artropatías , Humanos , Artropatías/radioterapiaRESUMEN
PURPOSE: Pheochromocytomas/paragangliomas (PPGLs) and their metastases are tumors that predominantly express somatostatin receptor 2 (SSR2). (68)Ga-DOTA(0)-Tyr(3)-octreotate ((68)Ga-DOTATATE) is a PET radiopharmaceutical with both high and selective affinity for SSRs. The purpose of this study was to evaluate the utility of (68)Ga-DOTATATE in comparison with other specific and nonspecific radiopharmaceuticals recommended in the current guidelines for the localization of metastatic sporadic PPGL by PET/CT. METHODS: This prospective study included 22 patients (15 men, 7 women; aged 50.0 ± 13.9 years) with confirmed metastatic PPGL, a negative family history for PPGL, and negative genetic testing, who underwent (68)Ga-DOTATATE, (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT, and CT/MRI. Only 12 patients underwent an additional (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET/CT scan and only 11 patients underwent an additional (18)F-fluorodopamine ((18)F-FDA) PET/CT scan. The rates of detection of metastatic lesions were compared among all the imaging studies. A composite of all functional and anatomical imaging studies served as the imaging comparator. RESULTS: (68)Ga-DOTATATE PET/CT showed a lesion-based detection rate of 97.6 % (95 % confidence interval, CI, 95.8 - 98.7 %). (18)F-FDG PET/CT, (18)F-FDOPA PET/CT, (18)F-FDA PET/CT, and CT/MRI showed detection rates of 49.2 % (CI 44.5 - 53.6 %; p < 0.01), 74.8 % (CI 69.0 - 79.9 %); p < 0.01), 77.7 % (CI 71.5 - 82.8 %; p < 0.01), and 81.6 % (CI 77.8 - 84.8 %; p < 0.01), respectively. CONCLUSION: The results of this study demonstrate the superiority of (68)Ga-DOTATATE PET/CT in the localization of sporadic metastatic PPGLs compared to all other functional and anatomical imaging modalities, and suggest modification of future guidelines towards this new imaging modality.
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Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos , Paraganglioma/diagnóstico por imagen , Paraganglioma/secundario , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
UNLABELLED: Pheochromocytomas/paragangliomas overexpress somatostatin receptors, and recent studies have already shown excellent results in the localization of sympathetic succinate dehydrogenase complex, subunit B, mutation-related metastatic pheochromocytomas/paragangliomas using (68)Ga-DOTATATE PET/CT. Therefore, the goal of our study was to assess the clinical utility of this functional imaging modality in parasympathetic head and neck paragangliomas (HNPGLs) compared with anatomic imaging with CT/MRI and other functional imaging modalities, including (18)F-fluorohydroyphenylalanine ((18)F-FDOPA) PET/CT, currently the gold standard in the functional imaging of HNPGLs. METHODS: (68)Ga-DOTATATE PET/CT was prospectively performed in 20 patients with HNPGLs. All patients also underwent (18)F-FDOPA PET/CT, (18)F-FDG PET/CT, and CT/MRI, with 18 patients also undergoing (18)F-fluorodopamine ((18)F-FDA) PET/CT. (18)F-FDOPA PET/CT and CT/MRI served as the imaging comparators. RESULTS: Thirty-eight lesions in 20 patients were detected, with (18)F-FDOPA PET/CT identifying 37 of 38 and CT/MRI identifying 23 of 38 lesions (P < 0.01). All 38 and an additional 7 lesions (P = 0.016) were detected on (68)Ga-DOTATATE PET/CT. Significantly fewer lesions were identified by (18)F-FDG PET/CT (24/38, P < 0.01) and (18)F-FDA PET/CT (10/34, P < 0.01). CONCLUSION: (68)Ga-DOTATATE PET/CT identified more lesions than other imaging modalities. With the results of the present study, and the increasing availability and use of DOTA analogs in the therapy of neuroendocrine tumors, we expect that (68)Ga-DOTATATE PET/CT will become the preferred functional imaging modality for HNPGLs in the near future.
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Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos , Paraganglioma/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Dihidroxifenilalanina/análogos & derivados , Femenino , Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Paraganglioma/genética , Paraganglioma/patología , Estudios Prospectivos , Succinato Deshidrogenasa/genéticaRESUMEN
OBJECTIVE: To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers. DESIGN: Prospective multimodal clinical and neuroimaging study. SETTING: University of Lübeck, Lübeck, Germany. PARTICIPANTS: Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS). INTERVENTIONS: Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS). MAIN OUTCOME MEASURES: Frequency of parkinsonian signs, brain structure, and functional alterations. RESULTS: The only available patient with compound heterozygous KRS showed a markedly reduced striatal DAT density bilaterally. Magnetic resonance imaging revealed severe global brain atrophy as well as iron deposition in the basal ganglia. The heterozygous mother had definite parkinsonism with reduced DAT density in both putamina. While all asymptomatic heterozygous siblings displayed subtle extrapyramidal signs, DAT imaging revealed striatal tracer uptake within physiological levels. Voxel-based morphometry revealed an increase in gray matter volume in the right putamen and a decrease in the cerebellum of the heterozygous carriers. In all mutation carriers, the substantia nigra had a normal appearance on TCS. CONCLUSIONS: Single ATP13A2 heterozygous mutations may be associated with clinical signs of parkinsonism and contribute to structural and functional brain changes. Lack of hyperechogenicity in the substantia nigra may be a distinctive feature of this form of genetic parkinsonism. This, along with the finding of iron in the basal ganglia in our patient with KRS, implies a different underlying pathophysiology compared with other monogenic forms of parkinsonism and idiopathic PD and may place KRS among the syndromes of neurodegeneration with brain iron accumulation (NBIA).
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Mutación , Degeneración Nerviosa/genética , ATPasas de Translocación de Protón/genética , Anciano , Encéfalo/patología , Encéfalo/fisiopatología , Mapeo Encefálico , Percepción de Color/fisiología , Discriminación en Psicología/fisiología , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/patología , Percepción Olfatoria/fisiología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Linaje , Fenotipo , Estudios ProspectivosRESUMEN
BACKGROUND AND PURPOSE: The addition of systemic drugs to whole-brain irradiation has not improved the survival of patients with multiple brain metastases, most likely because the agents did not readily cross the blood-brain barrier (BBB). Radiolabeling of cetuximab was performed to investigate whether this antibody crosses the BBB. CASE REPORT: A patient with multiple brain lesions from non-small cell lung cancer was investigated. The largest metastasis (40 x 33 x 27 mm) was selected the reference lesion. On day 1, 200 mg/m(2) cetuximab (0.25% hot and 99.75% cold antibody) were given. On day 3, 200 mg/m(2) cetuximab (cold antibody) were given. Weekly doses of 250 mg/m(2) cetuximab were administered for 3 months. RESULTS: The reference lesion showed enhancement of radiolabeled cetuximab ((123)I-Erbi) on scintigraphy; (123)I-Erbi crossed the BBB and accumulated in the lesion. The reference lesion measured 31 x 22 x 21 mm at 4 months. Enhancement of contrast medium was less pronounced. CONCLUSION: This is the first demonstration of cetuximab crossing the BBB and accumulating in brain metastasis.
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Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Barrera Hematoencefálica/diagnóstico por imagen , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/secundario , Irradiación Craneana , Radioisótopos de Yodo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Cetuximab , Humanos , Procesamiento de Imagen Asistido por Computador , Neoplasias Pulmonares/diagnóstico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Cintigrafía , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Patients with oral squamous cell carcinoma (OSCC) and poor prognosis may benefit from an intensification of the initial therapy scheme. To improve the clinical management of these patients, there is a strong requirement for an accurate assessment of the malignant properties of the individual lesion. The objective of the present analysis was to define the potential value of 2-[(18)F]fluoro-2-deoxy-d-glucose ((18)FDG) uptake in the tumor measured by positron emission tomography (PET) in predicting patients' outcome in the clinical course of OSCC. In this respect, a clinically well-defined cohort of 79 patients with primary OSCC was retrospectively evaluated. (18)FDG uptake in the primary tumor site was quantified by calculation of the maximum standardized uptake values (SUV(max)). Subsequent statistical analyses found, that (18)FDG uptake of the primary tumor was significantly higher in stage T3/T4 vs. T1/T2 (p<0.001), in UICC stage IV vs. stage I-III (p=0.01), and in N1-3 vs. N0 tumors (p<0.001), respectively. To define SUV(max) cut-off values for survival analyses, receiver operating curves (ROC) were calculated for overall and disease-free survival after 36 and 60 months, respectively. Univariate survival analysis showed that high SUV(max) was significantly associated with shortened overall survival after 36 (p=0.026) and 60 months (p=0.02). Subsequent multi-variate Cox regression analysis including SUV(max), age, gender and UICC stage as co-variables determined that, high SUV(max) was the only predictor of inferior overall survival after 60 months (p=0.035) in this model. In conclusion, (18)FDG uptake detected by PET predicts adverse outcome of patients with OSCC in this retrospective analysis. (18)FDG-PET might be a promising tool to contribute to therapeutic decisions and should be evaluated in future prospective studies.
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Carcinoma de Células Escamosas , Fluorodesoxiglucosa F18/farmacocinética , Neoplasias de la Boca , Radiofármacos/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/diagnóstico por imagen , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/mortalidad , Estadificación de Neoplasias/métodos , Tomografía de Emisión de Positrones/métodos , Pronóstico , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
High-dose radio-/chemotherapy in the context of autologous and allogeneic haematopoietic stem cell transplantation is a double-edged sword. The requirement for dose intensification is linked to an increase in toxicity to noninvolved organs. Particularly for older patients and patients with comorbidities, efficient but toxicity-reduced schemes are needed. Myeloablative radioimmunotherapy is a targeted, internal radiotherapy that uses radiolabelled monoclonal antibodies (mAb) with affinity to the bone marrow. It involves the administration of high radiation doses (up to 30 Gy) to the bone marrow and spleen but without exposing radiosensitive organs to doses higher than 1-7 Gy. Added to conventional or intensity-reduced conditioning, myeloablative radioimmunotherapy may achieve a pronounced antileukaemic effect with tolerable toxicities. A rational and individual design of the ideal nuclide-antibody combination optimizes therapy. The anti-CD33, anti-CD45 and anti-CD66 mAbs appear to be ideal tracers so far. The beta-emitter (90)Y is coupled by DTPA and is the best nuclide for myeloablation. Approval trials for DTPA anti-CD66 mAb are underway in Europe, and in the near future these therapies may become applicable in practice. This review gives an overview of current myeloablative conditioning radioimmunotherapy. We discuss the selection of the optimal radioimmunoconjugate and discuss how radioimmunotherapy might be optimized in the future by individualization of therapy protocols. We also highlight the potential advantages of combination therapies.
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Trasplante de Células Madre Hematopoyéticas/métodos , Agonistas Mieloablativos/uso terapéutico , Radioinmunoterapia/métodos , Acondicionamiento Pretrasplante/métodos , Ensayos Clínicos como Asunto , Terapia Combinada , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Leucemia/terapia , Mieloma Múltiple/terapia , Agonistas Mieloablativos/efectos adversos , Defectos del Tubo Neural/terapia , Radioinmunoterapia/efectos adversos , Dosificación Radioterapéutica , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
PURPOSE: We investigated the influence of cell proportions and proliferation activities on tumor maximum standard uptake value (SUV(max)) in patients with squamous-cell esophageal cancer (SCEC). METHODS: Sixteen (16) patients with untreated SCEC were examined with (18)F-flourodeoxyglucose positron emission tomography (FDG-PET). The tumor SUV(max) were calculated. Tumors were resected by transthoracic esophagectomy. Tissues were stained with hematoxylin and eosin for the measurement of cell proportions and MIB-1 for measurement of proliferation indices (PIs). Tumor SUV and histologic data were related by using multiple linear regression analysis. RESULTS: The mean proportion of tumor cells in the tumor site was 58.1% (+/-12.1%); the proportion of inflammatory cells was 34.2% (+/-14.2%); the PI of tumor cells was 70.5% (+/-11.8%); and the PI of inflammatory cells was 22.2% (+/-7.6%). The tumor PI was the only variable that was significantly associated with the FDG uptake in the tumor site (p = 0.04). The correlation was low (Pearson-coefficient Gamma = 0.51). The Pearson-correlation-coefficient between tumor SUV and the fraction of inflammatory cells was Gamma = 0.37 and between tumor SUV and PI of inflammatory cells Gamma = 0.13. CONCLUSIONS: In untreated SCEC-patients, the tumor maximum FDG uptake is weakly associated with the proliferation rate of tumor cells. In contrast, neither the proportion nor the PI of inflammatory cells in the tumor site significantly correlates with the maximum SUV and should not profoundly affect PET interpretations.
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Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Fluorodesoxiglucosa F18/metabolismo , Anciano , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular , Tamaño de la Célula , Neoplasias Esofágicas/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Tomografía de Emisión de PositronesRESUMEN
PURPOSE: Breast carcinomas express the Na(+)/I() symporter and may-albeit not a routine procedure-be imaged with (123)iodide ((123)I) and (99m)technetium-pertechnetate ((99m)TcO(4)(-)) scintigraphy. The aim of our prospective study was the comparison of (99m)TcO(4)(-)--and (123)I-single-photon emission computed tomography (SPECT) with (18)F-2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in patients suspicious for breast cancer. METHODS: Twenty-nine (29) untreated patients suspected of having breast carcinoma were prospectively examined with thorax SPECT with (99m)TcO(4)(-) (n=19) or (123)I (n=10), respectively, and FDG-PET (n=29) prior to biopsy. Tumor-to-background ratios (TBRs) were calculated for SPECT findings. Mean and maximum standardized uptake values (SUVs) were calculated for PET findings. Findings were compared in an intra-individual lesion-to-lesion analysis. RESULTS: In 28 of 29 patients, malignancy was verified with histopathology. In imaging the primary tumor, sensitivities of (99m)TcO(4)(-)-SPECT, (123)I-SPECT, and FDG-PET were 63%, 67%, and 89%, respectively. TBR maximum was 2.6+/-1.1 in (99m)TcO(4)()-SPECT and 2.3+/-0.6 in (123)I-SPECT. In FDG-PET, mean tumor SUV was 4.1+/-4 and maximum tumor SUV was 5.4+/-5.1. In contrast to FDG-PET, (99m)TcO(4)()-SPECT was ineffective in imaging nodal and distant metastases in the thorax, and (123)I-SPECT failed in imaging lymph node infiltrations. Distant metastases were not present in patients of the (123)I group, and the value of (123)I-SPECT was not evaluated. CONCLUSIONS: In contrast to FDG-PET, (99m)TcO(4)(-) and (123)I-SPECT are ineffective in imaging breast carcinoma in clinical practice.
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Neoplasias de la Mama/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Radioisótopos de Yodo , Tomografía de Emisión de Positrones/métodos , Pertecnetato de Sodio Tc 99m , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Reacciones Falso Negativas , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Posición Prona , Sensibilidad y Especificidad , Posición Supina , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/diagnóstico por imagen , Neoplasias Torácicas/secundarioRESUMEN
With the advances in genomics, molecular biology including gene vector technologies today's molecular imaging modalities have strongly been improved. The major progress is based on peptide and antibody targeting vectors. When labeled with beta(-)-emitting radioisotopes these agents are applicable for endoradiotherapy and exploit the targeting potential for highly specific therapeutic applications. This novel class of pharmaceuticals offers the potential to develop patient specific therapies and might provide the means to go beyond the possibilities of current chemotherapy and radiation therapy. In this review the basic principles of endoradiotherapeutics based on peptides and proteins are presented. Several of these drugs such as (90)Y-rituximab (Zevalin), (131)I-tositumomab (Bexxar) and the somatostatin receptor binding (90)Y-DOTATOC that are nowadays successfully applied in oncological therapy are discussed. Future generations of endoradiopharmaceuticals will address yet unknown targets which might be identified by screening techniques such as ribosome and phage display peptide libraries.
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Neoplasias/radioterapia , Péptidos/uso terapéutico , Proteínas/uso terapéutico , Radioinmunoterapia , Radioisótopos/uso terapéutico , Secuencia de Aminoácidos , Animales , Anticuerpos Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Marcaje Isotópico/métodos , Modelos Biológicos , Datos de Secuencia Molecular , Neoplasias/inmunología , Péptidos/química , Conformación ProteicaRESUMEN
We treated 20 adult patients with a (188) Re-labeled anti-CD66 antibody (mean marrow dose 13.3 Gy) prior to allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia or advanced chronic myeloid leukemia. The intensified conditioning was not associated with increased non-relapse mortality. No reduction in the incidence of relapse was observed in the context of a T-cell depleted graft (4-year overall survival: 29%).
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Trasplante de Células Madre Hematopoyéticas/métodos , Inmunoconjugados/administración & dosificación , Leucemia/terapia , Adulto , Antígenos CD/inmunología , Médula Ósea/efectos de la radiación , Moléculas de Adhesión Celular/inmunología , Humanos , Persona de Mediana Edad , Radioisótopos/uso terapéutico , Renio/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Trasplante HomólogoRESUMEN
UNLABELLED: Intensification of the conditioning regimen with a radioactively labeled anti-CD66 antibody is feasible before allogeneic stem cell transplantation. The use of radioimmunotherapy may deliver a significant dose of radiation to the kidneys. We therefore studied the incidence and clinical picture of bone marrow transplantation (BMT) nephropathy in our patients receiving radioimmunotherapy before allogeneic stem cell transplantation. METHODS: This study was a clinical trial of 114 consecutive patients who received conditioning with a radiolabeled anti-CD66 antibody-188Re (n = 93) or 90Y (n = 21)-between 1998 and 2003. RESULTS: Although BMT nephropathy has developed in none of the patients in the [90Y]anti-CD66 group, 6 of 93 patients receiving [188Re]anti-CD66 presented with signs of BMT nephropathy at a median of 11.5 mo after stem cell transplantation. The absorbed renal dose was significantly lower in the 90Y group (4 vs. 7 Gy, P < 0.0001). Of the patients receiving [188Re]anti-CD66 who are alive, BMT nephropathy developed in 19% (6/32). Five of 6 patients with BMT nephropathy received total-body irradiation. The patients presented with elevated serum creatinine, proteinuria, anemia, hypertension, and signs of microangiopathy. All 6 patients in whom BMT nephropathy has developed are alive at a median follow-up of 58 mo after stem cell transplantation, and 1 patient has entered a dialysis program. CONCLUSION: BMT nephropathy appears to be a significant problem after allogeneic stem cell transplantation with intensified conditioning using the 188Re-labeled anti-CD66 applied in this study, particularly when combined with total-body irradiation.
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Trasplante de Médula Ósea/efectos adversos , Médula Ósea/efectos de la radiación , Enfermedades Renales/etiología , Leucemia/radioterapia , Traumatismos por Radiación/etiología , Radioinmunoterapia/efectos adversos , Trasplante de Células Madre , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Enfermedades Renales/diagnóstico , Leucemia/complicaciones , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Traumatismos por Radiación/diagnóstico , Radioinmunoterapia/métodos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
In a phase I-II study for patients aged 55-65 years, we employed radioimmunotherapy using an anti-CD-66 antibody as part of a dose-reduced conditioning regimen, which was followed by a T-cell-depleted graft. 20 patients with a median age of 63 years suffering from acute leukaemia (n=17) or myelodysplastic syndrome (n=3) received the antibody labelled either with 188Rhenium (n=8) or with 90Yttrium (n=12) during conditioning. Radioimmunotherapy provided a mean dose of 21.9 (+/-8.4) Gy to the bone marrow with a significantly higher dose when 90Yttrium was used. Additional conditioning was fludarabine-based plus anti-thymocyte globulin in matched related donor transplants (n=11), or plus melphalan in matched unrelated donor transplants (n=9). Regimen-related toxicity was low, with two patients developing three episodes of grade III organ toxicity. All patients engrafted, grade II-IV acute graft-versus-host disease (GvHD) was observed in one patient (5%) and chronic GvHD in three patients (15%). The cumulative incidence of non-relapse mortality was 25%, the cumulative incidence of relapse 55%. The probability of survival was estimated to be 70% at 1 year and 52% at 2 years post-transplant, although no plateau was reached afterwards. In conclusion, radioimmunotherapy using the anti-CD66 antibody was feasible and safe in our elderly patient group and provided a high marrow dose.
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Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antígenos de Diferenciación/inmunología , Enfermedades Hematológicas/terapia , Radioinmunoterapia/métodos , Radioisótopos/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Anciano , Suero Antilinfocítico/uso terapéutico , Antineoplásicos/uso terapéutico , Moléculas de Adhesión Celular , Femenino , Estudios de Seguimiento , Enfermedades Hematológicas/radioterapia , Enfermedades Hematológicas/cirugía , Humanos , Inmunosupresores/uso terapéutico , Leucemia/radioterapia , Leucemia/cirugía , Leucemia/terapia , Depleción Linfocítica , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Síndromes Mielodisplásicos/radioterapia , Síndromes Mielodisplásicos/cirugía , Síndromes Mielodisplásicos/terapia , Radiometría , Renio/uso terapéutico , Trasplante de Células Madre , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Radioisótopos de Itrio/uso terapéuticoRESUMEN
OBJECTIVE: The nucleoside 3'-deoxy-3'-fluorothymidine (alovudine) is an antiviral agent accumulating in proliferating cells. We prospectively evaluated the biodistribution of the PET tracer [18F]3'-deoxy-3'-fluorothymidine (FLT) and its value in detecting manifestations of non-Hodgkin's lymphoma (NHL). METHODS: In this pilot study, 7 patients (6 male, 1 female) with indolent NHL (2), NHL in transformation (2) or aggressive NHL (3) were examined. Patients received initial staging or restaging with an interval of at least 10 weeks between therapy and positron emission tomography (PET). Mean doses of 324 +/- 165 MBq FLT were injected intravenously. Static PET scans were performed 50-70 minutes after application. Maximum standardized uptake values (SUV) of organs and NHL manifestations were calculated. FLT-positive lesions were verified by biopsies (3 lesions) or aspiration smears (5 lesions in 4 patients). RESULTS: Biodistribution: The tracer accumulated physiologically in hematopoietic marrow and in the liver. It was renally excreted. SUV of organs 1 hour after injection were: bones with hematopoietic marrow, 9.9 +/- 4.7; liver, 5.2 +/- 1.0; kidneys, 4.0 +/- 1.7; spleen, 3.0 +/- 1.2; bones without hematopoietic marrow, 1.9 +/- 1.1; lungs, 0.8 +/- 0.3. NHL manifestations: In 7 patients, diagnosis was verified as true positive by histology/cytology. Maximum lymphoma SUV of FLT positive lesions were 6 for the indolent group and 8-11 for lymphoma in transformation. In the aggressive group, SUV were 6, 14, and 17. The low SUV in this group was found in a highly proliferate large-cell anaplastic lymphoma combined with marked sclerosis of 30%. CONCLUSIONS: In this pilot study, FLT-PET was suitable in the imaging of NHL manifestations. In NHL with normal cellularity, FLT accumulated more intensely in aggressive NHL and NHL in transformation than in indolent NHL. Bones with hematopoietic marrow and the liver were the organs with the highest physiological uptake.
Asunto(s)
Didesoxinucleósidos , Radioisótopos de Flúor , Linfoma no Hodgkin/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Anciano , Didesoxinucleósidos/farmacocinética , Femenino , Humanos , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Radiofármacos/farmacocinéticaRESUMEN
A 61-year-old man with Hodgkin lymphoma (mixed type), with lymph node manifestations and extranodal and bone marrow involvement in both supra- and infradiaphragmatic locations (stage 4), had dyspnea and tachycardia on echocardiography. There were pleural and pericardial effusions and thickening of the epicardium and pericardium. These findings and computed tomographic findings were suspicious for manifestations of Hodgkin lymphoma. The pericardial findings were demonstrated on F-18 fluorodeoxyglucose positron emission tomographic imaging.
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Fluorodesoxiglucosa F18 , Neoplasias Cardíacas/diagnóstico por imagen , Enfermedad de Hodgkin/diagnóstico por imagen , Pericardio , Tomografía Computarizada de Emisión , Humanos , Masculino , Persona de Mediana Edad , RadiofármacosRESUMEN
The nucleoside 5-fluoro-2-deoxyuridine is a pyrimidine analogue accumulating in proliferative cells. We prospectively evaluated biodistribution of the PET tracer [(18)F]5-fluoro-2-deoxyuridine (FdUrd), its value for imaging malignant tumors, and its correlation to both [(18)F]2-fluoro-2-deoxyglucose (FDG)-PET findings and histological proliferation indices. In 11 previously untreated patients (5 lung carcinoma; 3 soft tissue sarcoma; 2 gastrointestinal carcinoma; 1 non-Hodgkin lymphoma [NHL]), mean doses of 290 MBq FdUrd and 390 MBq FDG were administered intravenously on subsequent days. Static PET scans were initiated 50-70 min after administration and the mean standardized uptake values (SUV) were calculated. Dynamic emission FdUrd scans were performed in 8/11 patients. Time-activity curves of blood and tumors as well as SUV of tumor lesions and organs were calculated. Proliferative activity was evaluated by Ki-67 immunohistostaining of biopsies. Tracer accumulated physiologically in liver, kidney, and bladder. SUVs were: kidney, 4.8 +/- 0.66; liver, 4.1 +/- 0.36; vertebrae, 0.70 +/- 0.17; spleen, 0.37 +/- 0.06; lungs, 0.19 +/- 0.05; femora/humeri, 0.14 +/- 0.03. Five patients exhibited significant intratumoral FdUrd-uptake (2 sarcomas; 1 NHL; 2 lung carcinomas) with mean SUVs ranging from 0.7 to 10.5. Metastases were not detected. Time-activity curves showed a rapid initial increase of intratumoral activity followed by activity retention. FDG-PET was positive in 10/11 patients. Correlation between the SUV of FdUrd-PET and FDG-PET or the tissue proliferation index, respectively, was not significant. FdUrd was a suitable tracer for imaging malignant tumors only in exceptional cases: Sarcoma, NHL, and some lung carcinomas were detected. FdUrd-PET was less effective than FDG-PET. In this group of patients, it was not useful in measuring tissue proliferation.
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Fluorodesoxiglucosa F18/farmacocinética , Neoplasias/diagnóstico por imagen , Radiofármacos/farmacocinética , Adulto , Anciano , Huesos/metabolismo , División Celular/efectos de los fármacos , Femenino , Neoplasias Gastrointestinales/diagnóstico por imagen , Neoplasias Gastrointestinales/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/metabolismo , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Neoplasias/metabolismo , Estudios Prospectivos , Sarcoma/diagnóstico por imagen , Sarcoma/metabolismo , Distribución Tisular , Tomografía Computarizada de Emisión/métodos , Vejiga Urinaria/metabolismoRESUMEN
Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-x(L), a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies.
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Apoptosis/efectos de la radiación , Partículas beta , Caspasas/metabolismo , Leucemia-Linfoma de Células T del Adulto/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Receptor fas/metabolismo , Línea Celular Tumoral/metabolismo , Línea Celular Tumoral/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Activación Enzimática/efectos de la radiación , Rayos gamma , Células HL-60 , Humanos , Dosis de Radiación , Tolerancia a Radiación , Radioinmunoterapia/métodos , Radiometría/métodosRESUMEN
Radioimmunotherapy (RIT) with radiolabelled monoclonal antibodies (mAbs) is an effective method of achieving myeloablation in leukaemia patients prior to stem cell transplantation (SCT). We wished to compare the approaches of specific binding to leukaemic blasts and non-specific binding to benign red marrow cells, which results in a myeloablative "cross-fire" effect. Therefore, we prospectively evaluated the biodistribution and biokinetics of the anti-CD45 mAb YTH 24.5 and the anti-CD66 mAb BW 250/183 with regard to their suitability for myeloablative RIT. The red marrow selective anti-CD66 mAb BW 250/183 (IgG1) binds to normal granulopoietic cells. In contrast, the anti-CD45 mAb YTH 24.5 (IgG2b) binds to 85-90% of acute leukaemic blasts and almost all haematopoietic white cells. Patients with leukaemic blast infiltration of the marrow <25% and assigned for RIT and SCT were included. Twelve patients (eight male, four female; median age 46+/-7 years) with AML (5), CML (5) or ALL (2) were examined. Both mAbs were labelled with technetium-99m. Within 48 h, 906+/-209 MBq (99m)Tc-anti-CD66 mAb and 760+/-331 MBq (99m)Tc-anti-CD45 mAb were injected consecutively. Scintigraphic and urinary measurements were performed 1, 2, 4 and 24 h after injection. Serum activities were evaluated 2, 5, 10, 15, 30 and 60 min and 2, 4 and 24 h after injection. Compared with the anti-CD45 mAb, the anti-CD66 mAb showed an approximately fourfold higher accumulation in the red marrow, a 2.5-fold lower accumulation in the liver and similar accumulation in the kidneys. The serum activity (% of the injected dose) initially decreased faster for the anti-CD45 mAb but was similar for the two mAbs 24 h after injection: 3.3%+/-1.2% (anti-CD66 mAb) and 2.4%+/-1.1% (anti-CD45 mAb). The cumulated urinary excretion was 17%+/-6.6% (anti-CD66 mAb) and 27.3%+/-7.9% (anti-CD45 mAb) 24 h after application. In these patients with low tumour load, the anti-CD66 mAb BW 250/183 showed more favourable properties in terms of biodistribution and pharmacokinetics. Thus, it appears superior to anti-CD45 mAb YTH 24.5 in selectively increasing the marrow dose and avoiding extramedullary organ toxicity.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Médula Ósea/metabolismo , Compuestos de Organotecnecio/farmacocinética , Recuento Corporal Total/métodos , Adolescente , Adulto , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/orina , Femenino , Humanos , Cinética , Leucemia/radioterapia , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Agonistas Mieloablativos/sangre , Agonistas Mieloablativos/farmacocinética , Agonistas Mieloablativos/orina , Especificidad de Órganos , Compuestos de Organotecnecio/sangre , Compuestos de Organotecnecio/uso terapéutico , Compuestos de Organotecnecio/orina , Radioinmunoterapia/métodos , Radiofármacos/sangre , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Radiofármacos/orina , Distribución TisularRESUMEN
BACKGROUND: Stem cell transplantation (SCT) is potentially curative for high-risk leukemia patients. Conditioning regimens affect relapse rate and treatment-related mortality. We evaluated biodistribution, radiation absorbed organ doses and immediate toxicities of myeloablative radioimmunotherapy with marrow selective 188rhenium (188Re)-labeled anti-CD66 monoclonal antibody (mAb). METHODS: Fifty high-risk leukemia patients were treated 14 +/- 2 days prior to SCT. Dosimetric measurements were performed at 1.5, 3, 20, 26, and 44 hours after about 1 GBq of 188Re followed by radioimmunotherapy with about 10 GBq 188Re. Standard conditioning consisted of high-dose chemotherapy and 12 Gy total-body irradiation. Forty-six patients received allogenic, and four received autologous, stem cell grafts. RESULTS: The mean radiation absorbed doses (in Gy) were: marrow, 13.9 +/- 4.6; liver, 5.7 +/- 2.7; spleen, 22.6 +/- 25.5; kidneys, 6.8 +/- 2.6; lungs, 0.8 +/- 0.7; total body, 1.4 +/- 0.3. The tumor-to-organ-ratios were 2.4 for liver, 0.6 for the spleen, 2.0 for the kidneys and 17.8 for the lungs. Type of leukemia did not affect radiation absorbed doses of marrow, lungs, kidneys and liver. Mean marrow dose of transplanted patients in complete remission was 1.37 +/- 0.43 Gy/GBq, compared with 1.34 +/- 0.29 Gy/GBq for patients with leukemic blast marrow infiltration of 5-25%. Immediate side effects were moderate. All patients showed primary engraftment. After a median follow-up of 11.0 +/- 7.4 months 28/50 patients (56%) are in ongoing complete remission. Nine patients (5%) have relapsed, seven (4%) of them have died. Another 13 patients (7%) died of treatment-related causes. CONCLUSIONS: Due to its biodistribution, radiation absorbed organ doses, low toxicity and clinical data, myeloablative radioimmunotherapy with 188Re-labeled anti-CD66 mAb seems to be a promising method for improving standard conditioning of high-risk leukemia patients prior to SCT.