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1.
J Nucl Med ; 55(2): 183-90, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24434296

RESUMO

UNLABELLED: Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival. METHODS: We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with (177)Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan-Meier curve method (log-rank test) and multivariate analysis (P < 0.05). RESULTS: The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3-33.7) and 55 mo (95% confidence interval, 48.8-61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1-3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively. CONCLUSION: The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient's performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2-in particular, between G1 (Ki-67 index of 1%-2%) and low-range G2 (Ki-67 index of 3%-10%)-provides prognostic stratification.


Assuntos
Neoplasias Intestinais/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Radioisótopos/uso terapêutico , Receptores de Peptídeos/química , Neoplasias Gástricas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Intestinais/mortalidade , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/mortalidade , Octreotida/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Fatores de Tempo , Resultado do Tratamento
2.
Eur J Nucl Med Mol Imaging ; 41(2): 205-10, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24030668

RESUMO

PURPOSE: We assessed the outcome and toxicity of salvage therapy (repeat treatment) with (177)Lu-octreotate and high cumulative activities in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NET). METHODS: We retrospectively analysed a consecutive cohort of 33 patients with metastatic GEP-NET who underwent salvage peptide receptor radionuclide therapy (PRRT) in our institution. All patients had progressive NET prior to salvage treatment and had shown an initial response to PRRT. The mean cumulative activity was 44.3 GBq (30.0-83.7 GBq). Radiographic response was assessed using CT and/or MRI according to modified SWOG criteria. Toxicity was evaluated using laboratory data, including complete blood counts and renal function tests using CTCAE 3.0. Survival analysis was performed with the Kaplan-Meier curve method and a significance level at p < 0.05. RESULTS: Radiographic responses consisted of complete response in 1 patient (3.0%), partial response in 6 patients (18.2%), minor response in 1 patient (3.0%), stable disease in 14 patients (42.4%), and progressive disease in 11 patients (33.3%). Median progression-free survival (PFS) from the start of salvage therapy was 13 months (95% CI 9-18) and patients with a history of a durable PFS after initial PRRT tended to have long-lasting PFS after salvage treatment (p = 0.04). None of the patients developed severe nephrotoxicity (grade 3/4) or a myelodysplastic syndrome during follow-up. Relevant albeit reversible haematotoxicity (grade 3/4) occurred in 7 patients (21.2%). The cumulative administered activity was not associated with an increased incidence of haematotoxicity. CONCLUSION: PRRT with (177)Lu-octreotate in the re-treatment setting is safe and effective in patients with metastatic GEP-NET.


Assuntos
Neoplasias do Sistema Digestório/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Neoplasias do Sistema Digestório/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Metástase Neoplásica/radioterapia , Tumores Neuroendócrinos/patologia , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
3.
Clin Oral Investig ; 18(2): 461-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23604700

RESUMO

OBJECTIVES: Intermittent parathyroid hormone (PTH) exerts anabolic effects on bone and has been approved for osteoporosis therapy. The dual actions of PTH are mediated primarily through the parathyroid hormone 1 receptor (PTH1R). Upon ligand binding, PTH1R activates diverse signaling pathways, including cAMP/protein kinase A (PKA)- and phospholipase C/protein kinase C (PLC/PKC)-dependent pathways. PTH1R has been abundantly studied in bone cells. Knowledge on PTH1R characteristics and physiology in periodontal ligament (PDL) cells is still in its infancy. MATERIALS AND METHODS: We characterized PTH1R in PDL cells in terms of its cellular localization, binding affinity, and signal transduction and compared these characteristics to those of MG63 osteoblast-like cells. RESULTS: PTH1R mRNA/protein was identified in PDL and MG63 cells. PTH1R was mainly localized on the plasma membrane, in vesicular structures inside the cell, and, to some extent, in the nucleus of both cell types. Binding characteristics of PTH1R were cell type specific, with PDL cells demonstrating a lower binding affinity. The response of cAMP and active PKC production in MG63 cells was dose dependent with increasing PTH(1-34) concentration, whereas in PDL cells, it was regulated biphasically. However, we observed a cross talk between the cAMP/PKA and PLC/PKC signaling pathways, which were regulated diametrically opposed at a given concentration of PTH(1-34). CONCLUSION: These data indicate that, albeit the similarity in its subcellular distribution, PTH1R in PDL cells exhibits characteristics different from those in MG63 cells, pointing to the cell type specificity of this receptor. CLINICAL RELEVANCE: The findings further elucidate the characteristics of PTH action in dental tissues and widen the theoretical basis for the development of anabolic treatment strategies.


Assuntos
Ligamento Periodontal/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Células Cultivadas , Humanos , Ligamento Periodontal/citologia , Ligação Proteica , Transdução de Sinais
4.
EJNMMI Res ; 3(1): 82, 2013 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-24369053

RESUMO

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) with 177Lu-[DOTA0,Tyr3]octreotate (177Lu-octreotate) is generally performed using a fixed activity of 7.4 GBq (200 mCi) per course bound to 180 to 300 µg of the peptide. While this single activity may lead to suboptimal radiation doses in neuroendocrine tumors (NET) with advanced or bulky disease, dose escalation has been withheld due to concerns on potential tumor somatostatin receptor saturation with reduced efficacy of the added activity. In vivo saturation effects during standard-dose PRRT based on quantification of pre- and intra-therapeutic 68Ga-DOTATOC positron emission tomography (PET) imaging might guide potential dose escalation. METHODS: Five patients with metastatic NET of the pancreas underwent 68Ga-DOTATOC PET/CT before and directly after standard-dose PRRT with 177Lu-octreotate. In each patient, four target tumor lesions, normal liver parenchyma, and the spleen were evaluated and the ratios of SUVmax of the target lesions to liver (SUVT/L) and spleen (SUVT/S) were calculated; paired Student's t test was performed with p < 0.05 for pre-/intra-PRRT comparisons. RESULTS: The mean intra-therapeutic tumor SUVmax showed no significant change (per-lesion paired t test) compared to pretreatment values (-9.1%, p = 0.226). In contrast, the SUVmax of the normal liver parenchyma and spleen were significantly lower directly after infusion of 7.4 GBq 177Lu-octreotate. Consequently, SUVT/L and SUVT/S increased significantly from pretreatment to intra-therapeutic examination: SUVT/L (p < 0.001) from 2.8 ± 1.3 (1.3 to 5.8) to 4.7 ± 3.0 (2.1 to 12.7) and SUVT/S (p < 0.001) from 1.2 ± 0.7 (0.4 to 3.0) to 3.5 ± 1.5 (1.6 to 7.9). CONCLUSIONS: This small retrospective study provides preliminary evidence for the absence of relevant in vivo saturation of somatostatin receptor subtype 2 (sst2) in tumor lesions during PRRT with standard activities of 177Lu-octreotate in contrast to normal tissue (liver, spleen) showing limited receptor capacity. After being confirmed by larger series, this observation will have significant implications for PRRT: (1) Higher activities of 177Lu-octreotate might be considered feasible in patients with high tumor disease burden or clinical need for remission, and (2) striving to reduce the amount of peptide used in standard preparations of 177Lu-octreotate appears futile.

5.
J Nucl Med ; 54(11): 1857-61, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24009272

RESUMO

UNLABELLED: Myelosuppression may be the dose-limiting toxicity in peptide receptor radionuclide therapy (PRRT). The aim of this study was to investigate the incidence, severity, and reversibility of long-term hematotoxicity in a large cohort of patient undergoing PRRT with (177)Lu-octreotate for metastatic neuroendocrine tumors. The impact of potential risk factors, including initial cytopenia, advanced bone metastatic disease, previous chemotherapy, and cumulative administered activity, and the protective effects of splenectomy were of particular interest. METHODS: A total of 632 PRRT courses were performed in 203 patients with metastatic neuroendocrine tumors. A mean activity of 7.9 GBq of (177)Lu-octreotate was administered per treatment cycle, with a goal of 4 courses at standard intervals of 3 mo. Hematologic parameters were determined before each treatment course, at 2- to 4-wk intervals between the courses, 8-12 wk after the last course of PRRT, and at 3-month intervals for further follow-up. Toxicity was recorded with Common Terminology Criteria for Adverse Events (version 3.0). RESULTS: Myelodysplastic syndrome as a delayed adverse event was documented in 3 patients (1.4%). Relevant but reversible hematotoxicity (grade 3 or 4) occurred in 23 patients (11.3%) and 29 administrations (4.6%), with leukopenia in 2.7% and thrombocytopenia in 1.7%. The mean time to blood count recovery was 12 mo after the termination of PRRT (range, 3-22 mo). The only preexisting factor that contributed to hematotoxicity was initial cytopenia (P < 0.001). A high level of cumulative administered activity (>29.6 GBq) was associated with relevant leukopenia (P < 0.001). None of the patients with a history of splenectomy developed grade 3 or 4 hematotoxicity, and splenectomy was inversely associated with the incidence and degree of leukopenia (P = 0.02) and thrombocytopenia (P = 0.03). CONCLUSION: PRRT-induced myelosuppression is almost invariably reversible and rarely requires clinical measures. Administered activity and initial cytopenia are the only factors contributing to myelosuppression, whereas splenectomy may exert a protective effect.


Assuntos
Eritrócitos/efeitos da radiação , Neoplasias Intestinais/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Receptores de Peptídeos/metabolismo , Neoplasias Gástricas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/efeitos da radiação , Feminino , Humanos , Neoplasias Intestinais/sangue , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/patologia , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Fatores de Tempo
6.
PLoS One ; 7(9): e44482, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028547

RESUMO

Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+) Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.


Assuntos
Doença de Hodgkin/imunologia , Doença de Hodgkin/terapia , Interleucina-12/imunologia , Interleucina-2/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Antígeno Ki-1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/metabolismo
7.
Clin Nucl Med ; 37(6): e141-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22614212

RESUMO

PURPOSE: Selection of candidates for peptide receptor radionuclide therapy (PRRT) is increasingly based on receptor positron emission tomography (PET) imaging, including the common tracer 68Ga DOTATOC. However, no studies have yet compared standardized uptake values (SUVs) and absorbed doses in this field. MATERIALS AND METHODS: We retrospectively analyzed a consecutive cohort of 21 patients with 61 evaluable tumor lesions undergoing both pretherapeutic 68Ga DOTATOC-PET/CT (Biograph Duo [Siemens Medical Solutions, Erlangen, Germany]; PET acquisition, 75.3 ± 15.4 minutes postinjection; 117.3 ± 33.9 MBq 68Ga DOTATOC) and PRRT with Lu octreotate (7.47 ± 1.39 GBq; intratherapeutic tumor dosimetry with serial whole-body scans; 1, 2, and 4 days postinjection) at our institution. SUVs were compared with the tumor-absorbed doses per injected activity (D/A0) of the subsequent first treatment cycle. RESULTS: The correlation of SUV and D/A0 was r = 0.72 (SUVmean) and r = 0.71 (SUVmax), both P < 0.001. Pancreatic origin and hepatic localization were associated with higher D/A0, and chromogranin A level and Ki-67 index had no influence on SUV or D/A0. High-SUV lesions (SUVmean >15; SUVmax >25) resulted in high D/A0 (>10 Gy/GBq) in 66.7% to 70.8% and low D/A0 (<5 Gy/GBq) in only 8.3% to 12.5% on subsequent PRRT. The mentioned low D/A0 range, on the other hand, was achieved by all lesions with SUVmean <7 or SUVmax <9. CONCLUSIONS: Somatostatin receptor PET imaging may predict tumor-absorbed doses. The ability to indicate insufficient target irradiation by a low SUV could aid in selection of appropriate candidates for PRRT. However, larger series are needed to confirm and validate these initial findings.


Assuntos
Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/radioterapia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos/metabolismo , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/radioterapia , Tomografia por Emissão de Pósitrons , Doses de Radiação , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/radioterapia , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Feminino , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Octreotida/metabolismo , Octreotida/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de Peptídeos/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Resultado do Tratamento
8.
J Nucl Med ; 52(11): 1721-6, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21976530

RESUMO

UNLABELLED: This retrospective study compared the effects of single and multiple administrations of (186)Re-hydroxyethylidenediphosphonate ((186)Re-HEDP) on palliation and survival of prostate cancer patients presenting with more than 5 skeletal metastases. METHODS: A total of 60 patients were divided into 3 groups. Group A (n = 19) consisted of patients who had received a single injection; group B (n = 19), patients who had 2 injections; and group C (n = 22), patients who had 3 or more successive injections. The (188)Re-HEDP was prepared using non-carrier-added (188)Re obtained from an in-house (188)W/(188)Re generator after dilution with carrier perrhenate. Patients' data available from the referring physicians-including prostate-specific antigen levels-were entered into a Windows-based matrix and analyzed using a statistical program. The Gleason scores were similar for all 3 groups. RESULTS: Mean survival from the start of treatment was 4.50 ± 0.81 mo (95% confidence interval [CI], 2.92-6.08) for group A, 9.98 ± 2.21 mo (95% CI, 5.65-14.31) for group B, and 15.66 ± 3.23 (95% CI, 9.33-22.0) for group C. Although the 3 groups did not differ in Gleason score, the number of lost life-years was significantly lower in group C than in groups A and B. Pain palliation was achieved in 89.5% of group A, 94.7% of group B, and 90.9% of group C. CONCLUSION: Posttreatment overall survival could be improved from 4.50 to 15.66 mo by multiple-injection bone-targeted therapy with (188)Re-HEDP, when compared with a single injection. Significant pain palliation was common and independent of administration frequency.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Ácido Etidrônico/uso terapêutico , Hormônios/farmacologia , Compostos Organometálicos/uso terapêutico , Cuidados Paliativos/métodos , Neoplasias da Próstata/patologia , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/radioterapia , Ácido Etidrônico/administração & dosagem , Seguimentos , Hormônios/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Estudos Retrospectivos , Análise de Sobrevida
9.
J Nucl Med ; 52(8): 1197-203, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21764798

RESUMO

UNLABELLED: Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NETs), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastasis (BM). METHODS: We retrospectively analyzed a consecutive subgroup of 42 patients with BM of GEP NETs treated with PRRT ((177)Lu-octreotate, 4 intended cycles at 3 monthly intervals [10-14 wk]; mean activity per cycle, 8.1 GBq). Availability of restaging and outcome data was required for patient inclusion. Baseline characteristics, including age, tumor origin, performance score, Ki-67 index, tumor load, tumor uptake, plasma chromogranin A, and neuron-specific enolase, were analyzed regarding impact on tumor regression (modified M.D. Anderson criteria) and time to progression. Survival analyses were performed using Kaplan-Meier curves, log-rank test at a significance level of P less than 0.05, and Cox proportional hazards model for uni- and multivariate analyses. RESULTS: Median follow-up was 32 mo. The observed response of BMs consisted of complete remission in 2 (4.8%), partial remission in 14 (33.3%), minor response in 5 (11.9%), stable disease in 16 (38.1%), and progressive disease in 5 (11.9%) patients. Median progression-free survival and overall survival (OS) were 35 mo (26-44, 95% confidence interval) and 51 mo (37-65, 95% confidence interval), respectively. Patients with responding BMs (complete remission, partial remission, or minor response) exhibited a trend toward better OS (median OS not reached after 53 mo) when compared to nonresponding patients (39 mo, P = 0.076). Only Ki-67 index (>10%) and chromogranin A level (>600 ng/mL) contributed to regression analysis. CONCLUSION: BM of GEP NETs is effectively controlled by PRRT, with long progression-free survival and OS. Poor patient condition and multifocality of BMs do not clearly affect treatment efficacy, possibly encouraging the use of PRRT in advanced bone metastatic disease. Larger studies are needed to assess predictors of treatment outcome in these patients.


Assuntos
Neoplasias Ósseas/secundário , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Radioisótopos/uso terapêutico , Receptores de Peptídeos/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/patologia , Octreotida/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
10.
Nucl Med Biol ; 38(2): 165-70, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21315271

RESUMO

INTRODUCTION: 2-[(18)F]Fluoroethyl-choline ([(18)F]FECH) is a promising tracer for the detection of prostate cancer as well as brain tumors with positron emission tomography (PET). [(18)F]FECH is actively transported into mammalian cells, becomes phosphorylated by choline kinase and gets incorporated into the cell membrane after being metabolized to phosphatidylcholine. So far, its synthesis is a two-step procedure involving at least one HPLC purification step. To allow a wider dissemination of this tracer, finding a purification method avoiding HPLC is highly desirable and would result in easier accessibility and more reliable production of [(18)F]FECH. METHODS: [(18)F]FECH was synthesized by reaction of 2-bromo-1-[(18)F]fluoroethane ([(18)F]BFE) with dimethylaminoethanol (DMAE) in DMSO. We applied a novel and very reliable work-up procedure for the synthesis of [(18)F]BFE. Based on a combination of three different solid-phase cartridges, the purification of [(18)F]BFE from its precursor 2-bromoethyl-4-nitrobenzenesulfonate (BENos) could be achieved without using HPLC. Following the subsequent reaction of the purified [(18)F]BFE with DMAE, the final product [(18)F]FECH was obtained as a sterile solution by passing the crude reaction mixture through a combination of two CM plus cartridges and a sterile filter. The fully automated synthesis was performed using as well a Raytest SynChrom module (Raytest, Germany) or a Scintomics HotboxIII module (Scintomics, Germany). RESULTS: The radiotracer [(18)F]FECH can be synthesized in reliable radiochemical yields (RCY) of 37±5% (Synchrom module) and 33±5% (Hotbox III unit) in less than 1 h using these two fully automated commercially available synthesis units without HPLC involvement for purification. Detailed quality control of the final injectable [(18)F]FECH solution proved the high radiochemical purity and the absence of Kryptofix2.2.2, DMAE and DMSO used in the course of synthesis. Sterility and bacterial endotoxin testing following standard procedures verified that the described production method for [(18)F]FECH is suitable for human applications. CONCLUSIONS: The routine production of [(18)F]FECH with sufficient RCYs was established by reliable and fast solid-phase extraction purifications of both the secondary labeling precursor [(18)F]BFE and the final product [(18)F]FECH, avoiding complex and sensitive HPLC equipment. The purity of the product was >95%, rendering the tracer suitable for human application. The newly developed purification procedure for [(18)F]BFE significantly reduces the complexity of the automated synthesis unit, hence reducing the cost for routine production in a clinical setup and allowing easy transfer to different synthesis modules.


Assuntos
Colina/análogos & derivados , Extração em Fase Sólida/métodos , Automação , Colina/síntese química , Colina/isolamento & purificação , Deanol/química , Fluorocarbonos/química , Humanos , Radioquímica , Segurança
11.
Eur J Nucl Med Mol Imaging ; 38(3): 459-66, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20852858

RESUMO

PURPOSE: The role of the Ki-67 tumour proliferation index (PI) in predicting the efficacy of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic tumours (GEP-NET) remains undetermined. This single-centre analysis focused on the potential therapeutic impact of this immunohistochemical parameter. METHODS: A total of 81 consecutive GEP-NET patients treated with (177)Lu-DOTA-octreotate (mean activity of 7.9 GBq per cycle, usually four treatment cycles at standard intervals of 3 months) were retrospectively analysed. Both an evaluable PI and tumour response (modified SWOG criteria) were required for patient inclusion. RESULTS: Response of tumours with a PI of ≤20% (partial response 40%, minor response 15%, stable disease 34%, progressive disease 11%) was comparable in all PI subsets, including those with a PI of 20%. However, G3 tumours (PI > 20%) showed progression in 71% of patients. CONCLUSION: Response to PRRT is consistent over the PI range of ≤20% (G1 + G2). Contrary to preliminary previous suggestions, a PI of 15% or 20% should not preclude candidates from somatostatin receptor-targeted radiotherapy.


Assuntos
Neoplasias do Sistema Digestório/patologia , Neoplasias do Sistema Digestório/radioterapia , Antígeno Ki-67/metabolismo , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Receptores de Peptídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Estudos de Coortes , Neoplasias do Sistema Digestório/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Estudos Retrospectivos , Resultado do Tratamento
12.
Eur J Nucl Med Mol Imaging ; 35(4): 815-20, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18183393

RESUMO

PURPOSE: Recently published data indicated (18)F-fluorocholine to be feasible for imaging vulnerable atherosclerotic plaques in an animal model. METHODS: Five patients undergoing whole-body (18)F-fluoromethylcholine-((18)F-FMCH-) PET/CT for imaging of prostate cancer disease were retrospectively evaluated. Whole-body PET scans were started immediately after i.v. injection of (18)F-FMCH. About 5-15 min after tracer injection, acquisition of scans of the pelvis and abdomen was performed. PET, CT, and PET/CT slices were generated for review and visual analyses of the abdominal aorta and the common iliac arteries were performed. Vascular findings in examined arteries and surrounding structures due to artifacts were excluded from further analysis. The lower threshold of (18)F-FMCH uptake was set above the background activity within the examined vessels. Morphological classification of vessel wall alterations (WA) included structural wall alterations without additional calcification (SWA), structural wall alterations associated with calcifications (SWC), and solely calcified lesions (CL). They were correlated with (18)F-FMCH uptake qualified as present and vice versa. RESULTS: A total of 31 WA were identified. Positive (18)F-FMCH uptake was found in 14 lesions (SWA: n = 5; SWC: n = 9). Sixteen of 17 (18)F-FMCH negative lesions were identified as CL without additional structural vessel wall alteration. One SWA did not show any (18)F-FMCH accumulation. None of the CLs as well as unaltered parts of the vessel wall showed (18)F-FMCH uptake. CONCLUSIONS: Our initial data in five patients with a total of 31 vessel wall alterations show promising results indicating for the first time the feasibility of (18)F-FMCH for in vivo imaging of structural WA in humans.


Assuntos
Aorta Abdominal/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Colina/análogos & derivados , Radioisótopos de Flúor , Angiografia/métodos , Artérias/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Cintilografia
13.
Nucl Med Biol ; 33(3): 305-9, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16631078

RESUMO

Nicotinic acetylcholine receptors (nAChR) are involved in many physiological functions and appear to be affected in neurodegenerative diseases like Alzheimer's disease and Parkinson's disease (PD). Here, we describe the in vitro evaluation of nAChRs in PD with 2-[18F]F-A85380, a ligand with high affinity to the beta2 nAChR subunit. Autoradiography with 2-[18F]F-A85380 in untreated rat brain corresponded to the known distribution of alpha4beta2 nAChRs with high uptake in the thalamus, moderate uptake in the striatum and cortex and low uptake in the cerebellum (47%, 43% and 19% of the thalamus, respectively). The localization of alpha4beta2 nAChRs in the striatum was investigated in rodents with unilateral lesion of the substantia nigra. 2-[18F]F-A85380 binding was significantly reduced in the striatum ipsilateral to the lesion side (to 64% of the contralateral side), indicating that a fraction of alpha4beta2 nAChRs is located on dopaminergic terminals, whereas another fraction resides on striatal interneurons or cortical afferents. Similarly, in human brain sections of PD patients, 2-[18F]F-A85380 uptake was significantly reduced not only in the caudate and putamen but also in the thalamus (approximately 30% of the binding of control brain in all three regions); within the striatum, nAChRs in the putamen were significantly more severely affected as in the caudate. The observed pattern of alpha4beta2* nAChR loss demonstrates the potential of 2-[18F]F-A85380 for further investigations of this positron emission tomography ligand for in vivo studies of alpha4beta2* nAChRs in PD.


Assuntos
Azetidinas , Encéfalo/metabolismo , Radioisótopos de Flúor , Doença de Parkinson/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Autorradiografia , Azetidinas/farmacocinética , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/farmacocinética , Humanos , Técnicas In Vitro , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
14.
Ann Nucl Med ; 20(10): 663-70, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17385304

RESUMO

OBJECTIVE: 99mTc-tetrofosmin and 99mTc-sestamibi are approved tracers for myocardial perfusion studies. Recently, a 99mTc-MIBI preparation from a different manufacturer (99mTc-cardiospect-MIBI) has been introduced to the market. Therefore, the aim of this study was the evaluation of 99mTc-tetrofosmin as well as of two different 99mTc-labeled MIBI tracers with regard to differences in imaging quality under resting conditions. METHODS: Sixty patients (mean age 63.8 years +/- 1.25) with known or suspected coronary artery disease but without evidence of rest-ischemia were included. Twenty patients in each group were examined by a two-day-rest-stress protocol using the three 99mTc-labeled tracers. Visual analysis of all images was performed by two experienced physicians blinded with regard to the applied tracer. Regions of interest (ROI) were defined over the heart, lung and whole body only in the rest imaging in order to calculate heart-to-lung, lung-to-whole body-, and heart-to-whole body-ratios. RESULTS: The heart-to-lung ratio was statistically significant higher for 99mTc-cardiospect-MIBI as compared to 99mTc-sestamibi as well as to 99mTc-tetrofosmin. Furthermore, a significantly higher heart-to-lung ratio was found for 99mTc-sestamibi as compared to 99mTc-tetrofosmin. The heart-to-whole body-ratio and the lung-to-whole body-ratio were equivalent between all tracers. Visual analysis revealed only slight differences regarding image quality between all tracers. CONCLUSIONS: ROI analysis surprisingly revealed a significant higher myocardial uptake and consequently a higher heart-to-lung ratio for 99mTc-cardiospect-MIBI. Whether this leads to a better visual image quality has to be evaluated in future studies with larger study populations as well as semiquantitative segmental analysis of the myocardial perfusion images.


Assuntos
Doença da Artéria Coronariana/metabolismo , Miocárdio/metabolismo , Compostos Organofosforados/farmacocinética , Compostos de Organotecnécio/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Tecnécio Tc 99m Sestamibi/farmacocinética , Disfunção Ventricular Esquerda/metabolismo , Imagem Corporal Total/métodos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Coração/diagnóstico por imagem , Humanos , Injeções Intra-Arteriais , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Perfusão/métodos , Compostos Radiofarmacêuticos/farmacocinética , Descanso , Distribuição Tecidual , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia
16.
Appl Radiat Isot ; 62(4): 577-86, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15701412

RESUMO

UNLABELLED: For the purpose of implementing steam sterilization of 2-[18F]FDG (FDG) in the final container into routine production, we have validated and established a fully automated dispensing and sterilization system, thereby considerably reducing the radiation burden to the personnel. METHODS: The commercially available system combines aseptic dispensing of the product solution under a miniaturized laminar flow unit with subsequent steam sterilization, realized by heating of the product in the final containers by an autoclave included in the dispensing unit, thus incorporating current pharmaceutical manufacturing standards for the production of parental radiopharmaceuticals. The efficiency of the used sterilization cycle, the stability of FDG under the conditions of sterilization and the stability of the final product towards radiolysis was investigated with respect to various pH-formulations. RESULTS: The system was found to be fully valid for filling of vials in a laminar flow class A (US-class 100) environment and for sterilization of FDG in the final container. The pH for sterilizing FDG solutions must be slightly acidic to avoid decomposition. A pH of 5.5 appears to be optimal and gives FDG of very high radiochemical purity (approximately 99%). In addition, radiolysis of FDG in solutions of high activity concentration was significantly lower at pH 5.5 than at neutral pH. CONCLUSION: Terminal sterilization enables the production of FDG in full compliance with GMP-regulations even in Class C or D (US class 10,000 or 100,000) laboratories.


Assuntos
Fluordesoxiglucose F18/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Esterilização/métodos , Fluordesoxiglucose F18/normas , Humanos , Concentração de Íons de Hidrogênio , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos/normas , Vapor , Esterilização/instrumentação
17.
Int J Cancer ; 110(3): 386-94, 2004 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-15095304

RESUMO

The pathogenesis of Hodgkin's disease (HD) is associated with the accumulation of functionally anergic T cells in the near vicinity of the malignant Hodgkin/Reed-Sternberg (H/RS) cell. To stimulate locally the anti-tumour immunity in Hodgkin's disease, we generated an anti-CD30-antibody-interleukin-2 fusion protein (HRS3-scFv-Fc-IL-2) that binds to CD30 constitutively expressed on H/RS cells. The fusion protein is composed of a CD30 binding domain (HRS3-scFv) that is linked via the human IgG hinge-CH2/CH3 domain to human IL-2. The HRS3-scFv-Fc-IL-2 fusion protein is expressed as a 140 kDa homodimer, has binding specificities to both the CD30 antigen and the IL-2 receptor and stimulates proliferation of preactivated T cells in vitro, demonstrating its IL-2 bioactivity. After binding to CD30+ Hodgkin lymphoma cells, HRS3-scFv-Fc-IL-2 moreover induces resting NK cells, but not T cells, to lyse the lymphoma cells with high efficiency. Recruitment of resting NK cells towards a cytolytic immune response against CD30+ lymphoma cells has the potential to build up an effective anti-tumour response despite of Hodgkin's disease associated T-cell anergy and makes the HRS3-scFv-Fc-IL-2 fusion protein suitable for the specific immunotherapy of Hodgkin's lymphoma.


Assuntos
Citocinas/química , Doença de Hodgkin/metabolismo , Fragmentos de Imunoglobulinas/química , Imunoterapia/métodos , Interleucina-2/química , Antígeno Ki-1/biossíntese , Células Matadoras Naturais/metabolismo , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Separação Celular , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Humanos , Interleucina-2/imunologia , Interleucina-2/metabolismo , Células Jurkat , Antígeno Ki-1/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Modelos Genéticos , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Linfócitos T/metabolismo , Distribuição Tecidual
19.
J Clin Oncol ; 21(15): 2869-75, 2003 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12885803

RESUMO

PURPOSE: We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death. RESULTS: In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2). The effectiveness of rhenium-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P =.006 and P =.001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P =.0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P =.043). CONCLUSION: Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP.


Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Ácido Etidrônico/uso terapêutico , Neoplasias da Próstata/patologia , Rênio/uso terapêutico , Idoso , Progressão da Doença , Relação Dose-Resposta à Radiação , Humanos , Masculino , Compostos Organometálicos , Medição da Dor , Dor Intratável/radioterapia , Cuidados Paliativos , Estudos Prospectivos , Dosagem Radioterapêutica , Resultado do Tratamento
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