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1.
J Radiat Res ; 62(3): 483-493, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33899102

RESUMO

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose-volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance-covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child-Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74-0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.


Assuntos
Hepatopatias/etiologia , Neoplasias Hepáticas/complicações , Modelos Biológicos , Probabilidade , Lesões por Radiação/complicações , Intervalos de Confiança , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada
2.
Phys Med Biol ; 65(10): 105011, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32235057

RESUMO

Positron emission tomography (PET) has been used for dose verification in charged particle therapy. The causes of washout of positron emitters by physiological functions should be clarified for accurate dose verification. In this study, we visualized the distribution of irradiated radioactive beams, 11C and 15O beams, in the rabbit whole-body using our original depth-of-interaction (DOI)-PET prototype to add basic data for biological washout effect correction. Time activity curves of the irradiated field and organs were measured immediately after the irradiations. All data were corrected for physical decay before further analysis. We also collected expired gas of the rabbit during beam irradiation and the energy spectrum was measured with a germanium detector. Irradiated radioactive beams into the brain were distributed to the whole body due to the biological washout process, and the implanted 11C and 15O ions were concentrated in the regions which had high blood volume. The 11C-labelled 11CO2 was detected in expired gas under the 11C beam irradiation, while no significant signal was detected under the 15O beam irradiation as a form of C15O2. Results suggested that the implanted 11C ions form molecules that diffuse out to the whole body by undergoing perfusion, then, they are incorporated into the blood-gas exchange in the respiratory system. This study provides basic data for modelling of the biological washout effect.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/efeitos da radiação , Radioisótopos de Carbono/metabolismo , Modelos Biológicos , Radioisótopos de Oxigênio/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Oxigênio/farmacocinética , Coelhos , Distribuição Tecidual
3.
Radiother Oncol ; 135: 100-106, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31015154

RESUMO

PURPOSE: To predict the probability of radiation-induced liver toxicity (RILT) and implement the normal tissue complication probability (NTCP) model-based approach considering confidence intervals (CIs) to select patients for new treatment techniques, such as proton beam therapy, based on a certain NTCP reduction (ΔNTCP) threshold for primary liver cancer patients. METHODS AND MATERIALS: Common Toxicity Criteria for Adverse Events (CTCAE) grade ≥2 RILT was scored. The Lyman NTCP models predicting the probability of CTCAE grade ≥2 RILT as a function of the fraction-size adjusted mean liver dose (MLD), using reference fraction size = 2 Gy/fraction and α/ß ratio = 2 Gy, were fitted using the maximum likelihood method. At certain combinations of MLDs, ΔNTCP with a CI was evaluated by the delta method. RESULTS: Of the 239 patients, the incidence of CTCAE grade ≥2 RILT was 55% (46% in the Child-Pugh (CP)-A vs. 81% in the CP-B/C, p < 0.001). Among 180 CP-A patients, 40% who had viral hepatitis infections experienced toxicity vs. 32% in the nonhepatitis subgroup. The MLD was 18 Gy in the toxicity group vs. 16.1 Gy in the nontoxicity group (p = 0.002). The estimated NTCP model parameters specific to the patient subgroups and the ΔNTCP with CI assuming a particular CP classification and viral hepatitis infection status were considerably different which possible changed treatment decision. CONCLUSIONS: Patients with CP-A and viral hepatitis infection or CP-B/C cirrhosis had greater susceptibility to CTCAE grade ≥2 RILT. The estimated NTCP and ΔNTCP for individual patients along with a consideration of uncertainties improve the reliability of the NTCP model-based approach.


Assuntos
Neoplasias Hepáticas/radioterapia , Fígado/efeitos da radiação , Lesões por Radiação/epidemiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Probabilidade , Incerteza
4.
J Radiat Res ; 59(suppl_1): i50-i57, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29538699

RESUMO

Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (∆NTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance-covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ∆NTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ∆NTCP threshold.


Assuntos
Neoplasias Hepáticas/terapia , Fígado/patologia , Fígado/efeitos da radiação , Probabilidade , Terapia com Prótons/efeitos adversos , Lesões por Radiação/etiologia , Incerteza , Terapia por Raios X , Algoritmos , Humanos
5.
Phys Med Biol ; 61(24): 8664-8675, 2016 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-27880740

RESUMO

In charged particle therapy with pencil beam scanning (PBS), localization of the dose in the Bragg peak makes dose distributions sensitive to lateral tissue heterogeneities. The sensitivity of a PBS plan to lateral tissue heterogeneities can be reduced by selecting appropriate beam angles. The purpose of this study is to develop a fast and accurate method of beam angle selection for PBS. The lateral tissue heterogeneity surrounding the path of the pencil beams at a given angle was quantified with the heterogeneity number representing the variation of the Bragg peak depth across the cross section of the beams using the stopping power ratio of body tissues with respect to water. To shorten the computation time, one-dimensional dose optimization was conducted along the central axis of the pencil beams as they were directed by the scanning magnets. The heterogeneity numbers were derived for all possible beam angles for treatment. The angles leading to the minimum mean heterogeneity number were selected as the optimal beam angle. Three clinical cases of head and neck cancer were used to evaluate the developed method. Dose distributions and their robustness to setup and range errors were evaluated for all tested angles, and their relation to the heterogeneity numbers was investigated. The mean heterogeneity number varied from 1.2 mm-10.6 mm in the evaluated cases. By selecting a field with a low mean heterogeneity number, target dose coverage and robustness against setup and range errors were improved. The developed method is simple, fast, accurate and applicable for beam angle selection in charged particle therapy with PBS.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Terapia com Prótons , Planejamento da Radioterapia Assistida por Computador/métodos , Algoritmos , Humanos , Dosagem Radioterapêutica , Estudos Retrospectivos
6.
Phys Med ; 32(9): 1095-102, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27567089

RESUMO

PURPOSE: This treatment planning study was conducted to determine whether spot scanning proton beam therapy (SSPT) reduces the risk of grade ⩾3 hematologic toxicity (HT3+) compared with intensity modulated radiation therapy (IMRT) for postoperative whole pelvic radiation therapy (WPRT). METHODS AND MATERIALS: The normal tissue complication probability (NTCP) of the risk of HT3+ was used as an in silico surrogate marker in this analysis. IMRT and SSPT plans were created for 13 gynecologic malignancy patients who had received hysterectomies. The IMRT plans were generated using the 7-fields step and shoot technique. The SSPT plans were generated using anterior-posterior field with single field optimization. Using the relative biological effectives (RBE) value of 1.0 for IMRT and 1.1 for SSPT, the prescribed dose was 45Gy(RBE) in 1.8Gy(RBE) per fractions for 95% of the planning target volume (PTV). The homogeneity index (HI) and the conformity index (CI) of the PTV were also compared. RESULTS: The bone marrow (BM) and femoral head doses using SSPT were significantly lower than with IMRT. The NTCP modeling analysis showed that the risk of HT3+ using SSPT was significantly lower than with IMRT (NTCP=0.04±0.01 and 0.19±0.03, p=0.0002, respectively). There were no significant differences in the CI and HI of the PTV between IMRT and SSPT (CI=0.97±0.01 and 0.96±0.02, p=0.3177, and HI=1.24±0.11 and 1.27±0.05, p=0.8473, respectively). CONCLUSION: The SSPT achieves significant reductions in the dose to BM without compromising target coverage, compared with IMRT. The NTCP value for HT3+ in SSPT was significantly lower than in IMRT.


Assuntos
Neoplasias dos Genitais Femininos/radioterapia , Doenças Hematológicas/etiologia , Pelve/efeitos da radiação , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Medula Óssea/efeitos da radiação , Feminino , Cabeça do Fêmur/efeitos da radiação , Neoplasias dos Genitais Femininos/complicações , Humanos , Modelos Teóricos , Recidiva Local de Neoplasia , Órgãos em Risco , Probabilidade , Lesões por Radiação , Radiometria/métodos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Tomografia Computadorizada por Raios X
7.
J Radiat Res ; 56(1): 186-96, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25129556

RESUMO

In the real-time tumor-tracking radiotherapy system, a surrogate fiducial marker inserted in or near the tumor is detected by fluoroscopy to realize respiratory-gated radiotherapy. The imaging dose caused by fluoroscopy should be minimized. In this work, an image processing technique is proposed for tracing a moving marker in low-dose imaging. The proposed tracking technique is a combination of a motion-compensated recursive filter and template pattern matching. The proposed image filter can reduce motion artifacts resulting from the recursive process based on the determination of the region of interest for the next frame according to the current marker position in the fluoroscopic images. The effectiveness of the proposed technique and the expected clinical benefit were examined by phantom experimental studies with actual tumor trajectories generated from clinical patient data. It was demonstrated that the marker motion could be traced in low-dose imaging by applying the proposed algorithm with acceptable registration error and high pattern recognition score in all trajectories, although some trajectories were not able to be tracked with the conventional spatial filters or without image filters. The positional accuracy is expected to be kept within ±2 mm. The total computation time required to determine the marker position is a few milliseconds. The proposed image processing technique is applicable for imaging dose reduction.


Assuntos
Artefatos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Proteção Radiológica/métodos , Radioterapia Guiada por Imagem/métodos , Técnicas de Imagem de Sincronização Respiratória/métodos , Sistemas Computacionais , Marcadores Fiduciais , Fluoroscopia/instrumentação , Fluoroscopia/métodos , Humanos , Aumento da Imagem/instrumentação , Aumento da Imagem/métodos , Movimento (Física) , Imagens de Fantasmas , Doses de Radiação , Proteção Radiológica/instrumentação , Radioterapia Guiada por Imagem/instrumentação , Reprodutibilidade dos Testes , Mecânica Respiratória , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador
8.
Med Phys ; 40(7): 071729, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23822433

RESUMO

PURPOSE: In spot-scanning proton therapy, the interplay effect between tumor motion and beam delivery leads to deterioration of the dose distribution. To mitigate the impact of tumor motion, gating in combination with repainting is one of the most promising methods that have been proposed. This study focused on a synchrotron-based spot-scanning proton therapy system integrated with real-time tumor monitoring. The authors investigated the effectiveness of gating in terms of both the delivered dose distribution and irradiation time by conducting simulations with patients' motion data. The clinically acceptable range of adjustable irradiation control parameters was explored. Also, the relation between the dose error and the characteristics of tumor motion was investigated. METHODS: A simulation study was performed using a water phantom. A gated proton beam was irradiated to a clinical target volume (CTV) of 5 × 5 × 5 cm(3), in synchronization with lung cancer patients' tumor trajectory data. With varying parameters of gate width, spot spacing, and delivered dose per spot at one time, both dose uniformity and irradiation time were calculated for 397 tumor trajectory data from 78 patients. In addition, the authors placed an energy absorber upstream of the phantom and varied the thickness to examine the effect of changing the size of the Bragg peak and the number of required energy layers. The parameters with which 95% of the tumor trajectory data fulfill our defined criteria were accepted. Next, correlation coefficients were calculated between the maximum dose error and the tumor motion characteristics that were extracted from the tumor trajectory data. RESULTS: With the assumed CTV, the largest percentage of the data fulfilled the criteria when the gate width was ± 2 mm. Larger spot spacing was preferred because it increased the number of paintings. With a prescribed dose of 2 Gy, it was difficult to fulfill the criteria for the target with a very small effective depth (the sum of an assumed energy absorber's thickness and the target depth in the phantom) because of the sharpness of the Bragg peak. However, even shallow targets could be successfully irradiated by employing an adequate number of paintings and by placing an energy absorber of sufficient thickness to make the effective target depth more than 12 cm. The authors also observed that motion in the beam direction was the main cause of dose distortion, followed by motion in the lateral plane perpendicular to the scan direction. CONCLUSIONS: The results suggested that by properly adjusting irradiation control parameters, gated proton spot-scanning beam therapy can be robust to target motion. This is an important first step toward establishing treatment plans in real patient geometry.


Assuntos
Movimento , Neoplasias/fisiopatologia , Neoplasias/radioterapia , Imagens de Fantasmas , Terapia com Prótons/instrumentação , Humanos , Dosagem Radioterapêutica , Respiração , Fatores de Tempo , Água
9.
Radiat Oncol ; 8: 48, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23497543

RESUMO

BACKGROUND: We performed a dosimetric comparison of spot-scanning proton therapy (SSPT) and intensity-modulated radiation therapy (IMRT) for hepatocellular carcinoma (HCC) to investigate the impact of tumor size on the risk of radiation induced liver disease (RILD). METHODS: A number of alternative plans were generated for 10 patients with HCC. The gross tumor volumes (GTV) varied from 20.1 to 2194.5 cm3. Assuming all GTVs were spherical, the nominal diameter was calculated and ranged from 3.4 to 16.1 cm. The prescription dose was 60 Gy for IMRT or 60 cobalt Gy-equivalents for SSPT with 95% planning target volume (PTV) coverage. Using IMRT and SSPT techniques, extensive comparative planning was conducted. All plans were evaluated by the risk of RILD estimated using the Lyman-normal-tissue complication probability model. RESULTS: For IMRT the risk of RILD increased drastically between 6.3-7.8 cm nominal diameter of GTV. When the nominal diameter of GTV was more than 6.3 cm, the average risk of RILD was 94.5% for IMRT and 6.2% for SSPT. CONCLUSIONS: Regarding the risk of RILD, HCC can be more safely treated with SSPT, especially if its nominal diameter is more than 6.3 cm.


Assuntos
Carcinoma Hepatocelular/radioterapia , Hepatopatias/etiologia , Neoplasias Hepáticas/radioterapia , Terapia com Prótons/efeitos adversos , Lesões por Radiação/etiologia , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada/efeitos adversos , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Seguimentos , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
10.
Med Phys ; 39(9): 5584-91, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22957624

RESUMO

PURPOSE: In accurate proton spot-scanning therapy, continuous target tracking by fluoroscopic x ray during irradiation is beneficial not only for respiratory moving tumors of lung and liver but also for relatively stationary tumors of prostate. Implanted gold markers have been used with great effect for positioning the target volume by a fluoroscopy, especially for the cases of liver and prostate with the targets surrounded by water-equivalent tissues. However, recent studies have revealed that gold markers can cause a significant underdose in proton therapy. This paper focuses on prostate cancer and explores the possibility that multiple-field irradiation improves the underdose effect by markers on tumor-control probability (TCP). METHODS: A Monte Carlo simulation was performed to evaluate the dose distortion effect. A spherical gold marker was placed at several characteristic points in a water phantom. The markers were with two different diameters of 2 and 1.5 mm, both visible on fluoroscopy. Three beam arrangements of single-field uniform dose (SFUD) were examined: one lateral field, two opposite lateral fields, and three fields (two opposite lateral fields + anterior field). The relative biological effectiveness (RBE) was set to 1.1 and a dose of 74 Gy (RBE) was delivered to the target of a typical prostate size in 37 fractions. The ratios of TCP to that without the marker (TCP(r)) were compared with the parameters of the marker sizes, number of fields, and marker positions. To take into account the dependence of biological parameters in TCP model, α∕ß values of 1.5, 3, and 10 Gy (RBE) were considered. RESULTS: It was found that the marker of 1.5 mm diameter does not affect the TCPs with all α∕ß values when two or more fields are used. On the other hand, if the marker diameter is 2 mm, more than two irradiation fields are required to suppress the decrease in TCP from TCP(r) by less than 3%. This is especially true when multiple (two or three) markers are used for alignment of a patient. CONCLUSIONS: It is recommended that 1.5-mm markers be used to avoid the reduction of TCP as well as to spare the surrounding critical organs, as long as the markers are visible on x-ray fluoroscopy. When 2-mm markers are implanted, more than two fields should be used and the markers should not be placed close to the distal edge of any of the beams.


Assuntos
Marcadores Fiduciais , Método de Monte Carlo , Terapia com Prótons , Doses de Radiação , Radioterapia/normas , Humanos , Masculino , Probabilidade , Neoplasias da Próstata/radioterapia , Dosagem Radioterapêutica
11.
Ann Nucl Med ; 23(2): 183-90, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19225942

RESUMO

OBJECTIVE: One trend in positron emission tomography (PET) instrumentation over the last decade has been the development of scanners dedicated to small animals such as rats and mice. Thicker crystals, which are necessary to obtain higher sensitivity, result in degraded spatial resolution in the peripheral field-of-view (FOV) owing to the parallax error. On the other hand, we are developing the jPET-D4, which is a dedicated human brain PET scanner that has a capability for depth-of-interaction (DOI) measurement. Although its crystal width is about twice that of commercially available small animal PET scanners, we expect the jPET-D4 to have a potential for small animal imaging by making full use of the DOI information. In this article, we investigate the jPET-D4's potential for small animal imaging by comparing it with the microPET Focus220, a state-of-the-art PET scanner dedicated to small animals. METHODS: The jPET-D4 uses four-layered GSO crystals measuring 2.9 mm x 2.9 mm x 7.5 mm, whereas the microPET Focus220 uses a single layer of LSO crystals measuring 1.5 mm x 1.5 mm x 10.0 mm. First, the absolute sensitivity, counting rate performance and spatial resolution of both scanners were measured. Next a small hot-rod phantom was used to compare their imaging performance. Finally, a rat model with breast tumors was imaged using the jPET-D4. RESULTS: Thanks to the thicker crystals and the longer axial FOV, the jPET-D4 had more than four times higher sensitivity than the microPET Focus220. The noise equivalent counting-rate performance of the jPETD4 reached 1,024 kcps for a rat-size phantom, whereas that of the microPET Focus220 reached only 165 kcps. At the center of the FOV, the resolution was 1.7 mm for the microPET Focus220, whereas it was 3.2 mm for the jPET-D4. On the other hand, the difference of resolution became smaller at the off-center position because the radial resolution degraded faster for the microPET Focus220. The results of phantom imaging showed that the jPET-D4 was comparable to the microPET Focus220 at the off-center position even as the microPET Focus220 outperformed the jPET-D4 except for the peripheral FOV. CONCLUSIONS: The jPET-D4 human brain PET scanner, which was designed to achieve not only high resolution but also high sensitivity by measuring DOI information, was proven to have a potential for small animal imaging.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Aumento da Imagem/instrumentação , Tomografia por Emissão de Pósitrons/instrumentação , Tomografia por Emissão de Pósitrons/veterinária , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Feminino , Humanos , Aumento da Imagem/métodos , Imagens de Fantasmas , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
J Cereb Blood Flow Metab ; 29(3): 504-11, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18985052

RESUMO

Multidrug resistance-associated protein 1 (MRP1) acts as a defense mechanism by pumping xenobiotics and endogenous metabolites out of the brain. The currently available techniques for studying brain-to-blood efflux have significant limitations related to either their invasiveness or the qualitative assessment. Here, we describe an in vivo method, which overcomes these limitations for assessing MRP1 function, using positron emission tomography (PET) and a PET probe. 6-Bromo-7-[(11)C]methylpurine was designed to readily enter the brain after intravenous administration and to be efficiently converted to its glutathione conjugate (MRP1 substrate) in situ. Dynamic PET scan provided the brain time-activity curve after injection of 6-bromo-7-[(11)C]methylpurine into mice. The efflux rate of the substrate was kinetically estimated to be 1.4 h(-1) with high precision. Moreover, knockout of Mrp1 gene caused approximately a 90% reduction of the efflux rate, compared with wild-type mice. In conclusion, our method allows noninvasive and quantitative assessment for MRP1 function in the living brain.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Radioisótopos de Carbono , Glutationa/metabolismo , Masculino , Camundongos , Camundongos Knockout , Sondas Moleculares/síntese química , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Purinas/síntese química , Purinas/química , Purinas/farmacocinética , Sensibilidade e Especificidade , Especificidade por Substrato , Fatores de Tempo
13.
Nucl Med Biol ; 35(1): 67-74, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18158945

RESUMO

This study reports on the radiosynthesis and feasibility studies of 4'-[methyl-(11)C]thiothymidine ([methyl-(11)C]S-dThd) as a tumor proliferation imaging agent. [Methyl-(11)C]S-dThd was synthesized by rapid methylation of corresponding 5-trimethylstannyl- or 5-tributylstannyl-precursor via a palladium-promoted Stille cross-coupling reaction with [(11)C]methyl iodide. The decay-corrected radiochemical yields of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor based on [(11)C]CO(2) were 18.9% and 14.5%, respectively. The radiochemical purity of [methyl-(11)C]S-dThd was always greater than 99%. The specific activities of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor were 47 GBq/mumol and 121 GBq/mumol, respectively, at the end of the synthesis. The total synthesis time was 30 min after the end of bombardment. The comparison between in vivo distribution of [methyl-(14)C]S-dThd and that of [methyl-(3)H]FLT showed that tracer uptake was comparable in nonproliferating tissues. In contrast, [methyl-(14)C]S-dThd showed significantly higher uptake in proliferating tissues than did [methyl-(3)H]FLT. [Methyl-(11)C]S-dThd uptake levels in five different tumor tissues were well correlated with the DNA synthesis levels determined by [2-(14)C]thymidine DNA incorporation. At 30 min after injection, plasma analysis found 95% of the activity in unmetabolized form. The microPET imaging of the C6 glioma xenograft showed significantly high uptake in the tumor and urinary bladder, followed by the intestine and marrow. Our results demonstrated that the tumor uptake of [methyl-(11)C]S-dThd was higher than that of [methyl-(3)H]FLT and was well correlated with the DNA synthesis level. Consequently, 4'-[methyl-(11)C]thiothymidine has promise for the imaging of tumor cell proliferation by positron emission tomography.


Assuntos
Radioisótopos de Carbono , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/patologia , Compostos Radiofarmacêuticos , Tionucleosídeos , Timidina/análogos & derivados , Animais , Proliferação de Células , DNA/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Tionucleosídeos/síntese química , Tionucleosídeos/metabolismo , Timidina/síntese química , Timidina/metabolismo , Distribuição Tecidual
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