引言与常规的医学影像诊断技术(超声、X线CT、及MRI等)不同，核医学显像(或核素显像) 需要特定放射性核素标记的显像剂即放射性药物，显像 ... 另一些PET肿瘤显像剂正在发展 中，其中18F标记5-氟尿嘧啶(5-FU)有望很快应用于临床，指导胃肠道肿瘤的术后化疗.

医瘤网的留言簿- Welcome !
是否有脑转移应该通过脑部CT或MRI检查确定，出现脑转移的治疗方法有伽马刀局部 ... 对于浑身骨头胀痛这一症状建议去做个骨扫描，判断是否有骨转移，再作进一步治疗。 ...
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医瘤网的留言簿- Welcome !
左肩和脚踝处痛建议作个骨扫描排除骨转移的可能性。祝顺利。（丁医生） ... 你好， 如果您母亲的一般情况良好，肝肾功能、血象正常，建议可以用5-fu+cf+顺铂+E-ADM ...
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[DOC] 生命科学研究快报
Format de fichier: Microsoft Word - Version HTML
通过扫描，研究人员发现，这些胶原质条在角膜表面错落有致地排列。 ... SHIVER JW; FU TM; CHEN L; ET AL. REPLICATION-INCOMPETENT ADENOVIRAL VACCINE VECTOR ...
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[PPT] 投影片1
Format de fichier: Microsoft Powerpoint - Version HTML
正子断层扫描. 检查前6小时需禁食; 扫描结束后多喝水、多排尿. 常见脑部造影方式 ... Lin KJ, Yen TC, Wey SP, Hwang JJ, Ye XX, Tzen KY, Fu YK, Chen JC. ...
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《电脑爱好者》索引摘录--关键词：fu
赛门铁克：扫描RAR文件竟会遭黑客攻击_软件·防黑_电脑爱好者网站 ... 可以消除脑部 疲劳的MP3播放器_数码_电脑爱好者网站 functionfontzoom(size) ...
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Chemical Bond : My name is Bond, Chemical Bond... - 文学城博客blog ...
The father , Lan Fu , returned to China from Australia in February 2000 . ... 要是真有 ， 不妨等她睡着时 ， 悄悄 地 扫描 几 下 : - ) 不过 ...
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成大核医部[ 繁体 ]
Ming-Che Wu, Nan-Tsing Chiu, An-Chy- Chen, Bing-Fu Shih. ... 高血糖高渗透压非酮 性病症并发癫痫之鎝-99m HMPAO脑部单光子电脑断层扫描表现. 中华民国核子医学年会. ...
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FU Wai Hospital Xi Gui WP - 5in1996 ， in Bei Jing . 2 吴清玉 ， 孟强 ， 胡盛寿 ， 等 . ... 近 红外线 扫描 对 乳腺 增生 程度 和 癌 前 病 . ...
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黄金书屋
国王写到："吸烟的习惯看起来非常恶心，闻起来令人反胃，"还会危及脑部；毒害肺部， ... Cigffette），但在意大利文中只是简单的"香烟"（II fu －mo）。 ...
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好医生继续医学教育中心
先将部分血液抽空，然后注入5-FU常可使血胸迅速稳定和吸收， ... （3） 全身化疗：脑 转移患者，几乎100%有肺转移，证明脑转移是肺内病灶的脑部扩散的结果。 ...
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第十四卷第六期[ 繁体 ]
大部分急性脑中风病患在急诊室所接受的脑部影像扫描都是电脑断层(97.5%)，因其简单 ... Chin-Hua Fu, Wen-Long Tsao Department of Neurology, Buddhist Dalin Tzu Chi ...
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肿瘤_浏览留言
另外，我想将检查结果用电子邮件发给长命锁您们看一下，我已扫描好，能告诉我邮箱的 地址吗：我的电话 ... 经复查，肺部肿瘤缩小约80%，脑部较大肿瘤缩小约50%，最小的1 ...
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[转帖]情绪的精灵@ 意识流实验室
带着这样的疑问 ， 研究者 在 下 丘脑 以外 的 其它 脑 部 埋 上 电极 ... 社团事工, | | - 在线求职, | | - 慈善论坛, | | - 合译 《 奥修传 》, | | - 扫描 工程 ...
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④消化道癌肿：5-fu及糖胞苷（arabinosylcytosine， ara-c）。⑤黑色素瘤： 氮烯咪胺（dtic）、ccnu、光辉霉素、干扰素等。脑部弥漫性病灶有用ommaya贮液囊，脑室内用药 ...
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91, 医学院, 医学图象暨放射科学系, 萧颖聪, 加速射出断层扫描图象重建的统计图 ... 含5-FU药物的聚甲壳醣微胶囊之制备及其在大肠癌之治疗(1/2), 2003/8/1, 2004/7/31 ...
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:校园艳事第二十一章怎么可能 作者： 寂寞剑客[煞更新 ...
模拟脑部思维活动的映象图屏幕上，居然什么也没有，只有一片雪花！ 5`!`ア[ ... 事实上，整个包围着意斯特恩的扫描仪整个都被一团诡异的蓝芒包裹其中， ...
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甲状腺核素扫描示甲状腺右叶肿大、变形，内有“冷结节”，右叶下界平胸骨切迹。 ... 术后1～5天予5-FU+丝裂霉素入1 000m1生理盐水腹腔灌洗化疗，腹胀好转。 ...
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GE Healthcare - Brochure -
图16 真正的全身PET/CT应从病人的头顶扫描到脚,在这研究中,揭示78%病人常规区域(颅底 到大腿上部) ... 然而脑部的其他部位经过抗胆碱治疗后脑血流量没有得到改善。 ...
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手术后规范的治疗是以 5 － FU 为主的化疗 ， 6 个疗程 。 ... 我父亲左肺叶尖发现癌变 3cm 左右 , 发现 时 已 转移 至 脑 部 约 2 - 3 处肿瘤 ， 肺 部 无 症状 ...
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CT 显示 脑 部 右 额 叶 有 病变 ， 在西安交通大学附属医院做过伽马刀手术后 ... 如果 没有 做 甲状腺 同位素 扫描 ， 应该做 ， 对诊断和治疗都有很大的帮助 ...
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[ Autres résultats, domaine www.chinaonco.net ]



http://www.jco.org/cgi/content/full/17/5/1580

Tumor, Normal Tissue, and Plasma Pharmacokinetic Studies of Fluorouracil Biomodulation With N-Phosphonacetyl-L-aspartate, Folinic Acid, and Interferon Alfa
Robert J.A. Harte, Julian C. Matthews, Susan M. O'Reilly, D.W. Owen Tilsley, Safiye Osman, Gavin Brown, Sajinder J. Luthra, Frank Brady, Terry Jones, Patricia M. Price
From the Medical Research Council (MRC) Cyclotron Unit and the Cancer Research Campaign Positron Emission Tomography (CRC PET) Research Group, Section of Cancer Therapeutics, Imperial College School of Medicine, Hammersmith Campus, London, United Kingdom.

Address reprint requests to R.J.A. Harte, c/o Pat M. Price, MD, MRC Cyclotron Unit and CRC PET Research Group, Section of Cancer Therapeutics, Imperial College School Medicine, Hammersmith Campus, Du Cane Rd, London W12 0NN, United Kingdom

PURPOSE: To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration.

PATIENTS AND METHODS: Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN- in recognized schedules.

RESULTS: TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN- had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow.

CONCLUSION: The administration of PALA and IFN- produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.


FLUOROURACIL (5FU) REMAINS the most widely prescribed anticancer drug for colorectal cancer, with response rates of 10% to 40% in cases of advanced disease.1 Its biochemistry and pharmacology have been well characterized, confirming that thymidylate synthase (TS) is the key target enzyme involved.2 Several approaches have been developed that aim to increase the therapeutic ratio, including biochemical modulation (biomodulation), dose and schedule modification, pharmacokinetically guided dosing, and regional drug-delivery systems.3-7

Biomodulation is the pharmacologic manipulation of an anticancer drug by another compound with the goal of enhancing antitumor activity. The biomodulating agent may or may not have anticancer activity. Although a number of such interactions have been described with various antimetabolites, those with 5FU have most clinical importance.8,9 The combination of 5FU and folinic acid (5FU/FA) has entered widespread clinical use; however, the translation of other biomodulating strategies from the laboratory has often failed to confirm in vitro or early clinical promise.

The 5FU/FA combination is based on the postulated folate depletion of tumor cells and evidence that increased intratumoral–reduced folates can overcome multiple mechanisms of 5FU resistance.1 The mechanism requires that exogenous folate be metabolized to 5,10-methylene tetrahydrofolate, which acts as a methyl donor, stabilizing the reaction between fluorodeoxyuridylate (FdUMP) and TS and thus inhibiting the production of thymidylate, a key element in the synthesis and repair of DNA.3,10,11 The greatest amount of clinical experience has accrued with 5FU/FA but in a wide range of dose/schedule combinations; the optimal dose/schedule combination remains uncertain.12,13 The combinations used have increased response rates in advanced disease in comparison to 5FU alone. In a minority of studies, this has translated into a modest survival benefit.14,15

N-Phosphonacetyl-L-aspartate (PALA) and the interferons have been studied with 5FU. PALA is an aspartate transcarbamylase inhibitor that interrupts the de novo pyrimidine synthesis pathway.16 By a decrease in the amount of uridine nucleotide pools, the incorporation of 5FU into RNA is facilitated. Inhibiting pyrimidine synthesis decreases concentrations of deoxyuridine monophosphate and therefore decreases competition with FdUMP for TS binding.17,18 Clinical trials with 5FU/PALA have demonstrated the activity of the combination, but there appears to be no clear advantage of this combination over 5FU regimens, even with optimal scheduling.19-22

Several mechanisms of interaction between 5FU and the interferons have been identified, including thymidine phosphorylase regulation (leading to increased intracellular levels of FdUMP), inhibition of adaptive upregulation of TS expression, and an increase in DNA damage.23-28 Additionally, some pharmacokinetic studies have shown a decrease in 5FU clearance after IFN treatment, in contrast to FA and PALA treatment, for which there is no evidence of plasma pharmacokinetic effects on 5FU.29-31 Phase III clinical trials utilizing 5FU ± IFN and 5FU/FA ± IFN provide mixed evidence of survival advantage with IFN, suggesting that sequence and schedule are critical in explaining the apparent inconsistencies.23,32,33

The rational development of biomodulation strategies would be facilitated by having means for their evaluation in vivo. Nuclear magnetic resonance (NMR) spectroscopy and positron emission tomography (PET) are complementary techniques for the in vivo assessment of tumor and tissue pharmacokinetics, and 5FU is the most extensively investigated chemotherapy agent for both modalities. NMR spectroscopy lacks the sensitivity and spatial resolution of PET but can distinguish between chemical forms (ie, PET cannot differentiate labeled parent drug from labeled metabolite).34,35 Evidence has been accumulating from [19F]-NMR spectroscopy that knowledge of intratumoral 5FU kinetics assists our understanding of the determinants of clinical response.36-39 Similarly, PET studies have focused on pharmacokinetic analysis as a means of predicting chemotherapy response.39,40 The aims of this PET study were (1) to evaluate the effect of biomodulation by PALA, FA, and IFN on plasma, tumor, and liver 5FU pharmacokinetics, (2) to investigate the determinants of any changes observed, and (3) to consider whether in vivo pharmacokinetic data helped to explain activity data in clinical trials.

Patient Selection
Twenty patients from the Department of Clinical Oncology, Hammersmith Hospital, were studied at the MRC Cyclotron Unit over a 20-month period (Table 1). All were scheduled to receive 5FU-based chemotherapy as either adjuvant or palliative therapy for histologically confirmed colorectal (18 patients), gastric (one patient), or hepatocellular (one patient) cancer. Eighteen patients were chemotherapy-naive, and the remaining two had had no chemotherapy in the preceding 3 weeks. One patient had an FA study 14 months after a PALA study (studies no. 13 and 1, respectively). Twelve male and eight female patients were studied, with ages ranging from 42 to 80 years (median, 59 years). Eligibility criteria included a life expectancy of greater than 12 weeks, performance status of 0 to 2, and adequate renal and hepatic function (ie, serum creatinine, < 125 µmol · L-1; bilirubin, < 17 mmol · L-1; and aspartate transaminase, < 35 mmol · L-1). All gave written, informed consent to the study, which had Hammersmith Hospital Research Ethics Committee and Administration of Radioactive Substances Advisory Committee (UK) approval.




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Table 1. Patient and Study Characteristics in 5-[18F]-FU Biomodulation Studies




Study Design
Patients underwent two pharmacokinetic studies 1 week apart: the first on day 1, while biomodulator-naive, and the second on day 8, after the administration of either PALA, FA, or IFN (IFN-2a or -2b) before the study. PALA (250 mg · m-2 intravenously [IV]) was administered in 100 mL N saline over 20 minutes on day 7; FA (30 mg IV bolus) was given on days 1 through 4, 7, and 8 (days 5 and 6 were the weekend); and IFN (3 millon units subcutaneously) was administered on days 1, 4, 7, and 8. FA and IFN were given after the PET study on day 1 and 30 minutes before the 5-[18F]-FU injection on day 8. Scans were carried out at approximately the same time of day (injection times are listed in Table 1). Patients were advised to have only a light breakfast on the day of scanning.

During each complete pharmacokinetic study, two PET scans were performed: (1) a C15O2 scan to measure tissue perfusion, and (2) a 5-[18F]-FU scan to measure tumor (ie, hepatic metastasis) and liver 5FU pharmacokinetics. Additionally, 5-[18F]-FU plasma pharmacokinetics were measured. For six studies, perfusion measurements were not obtained, and for five studies, plasma kinetic data measurements were not obtained, because of technical difficulties. For 15 of the paired studies (nine PALA, three FA, and three IFN), only the radiolabeled 5-[18F]-FU was injected (ie, tracer studies, delivering 5FU doses of between 1.4 and 10.8 mg · m-2). In six studies (three FA and three IFN), the 5-[18F]-FU was coinjected with 375 to 400 mg · m-2 unlabeled 5FU (ie, full-dose studies; Table 1).

Patient Repositioning
Patients were repositioned in the scanner on successive weeks, using anatomical landmarks and a pilot positioning scan. Because this method is not exact, the second images were shifted and rotated (rigid transformation) using a program that corrected for minor PET to PET misalignment to ensure that identical tissue volumes were sampled on successive weeks.41

Tissue-Perfusion Measurement
Tissue-perfusion scans were conducted immediately before the 5-[18F]-FU scans. For tissue-perfusion scans, the patient inhaled C15O2 that had been synthesized on-site and delivered via a light face mask at an activity of 4 MBq · mL-1 and a constant flow rate of 500 mL · min-1 for 3.5 minutes. For 10 minutes, dynamic measurements were made of the radioactivity in arterial blood, tumor, and normal liver, and from these data, tumor blood flow per unit volume of tissue (TBF)—a measure of tumor perfusion—was calculated using established methodology.42-44 In these calculations, the fraction of the tumor volume into which H215O diffuses, ie, the fractional volume of distribution, was also estimated (ie, a value of between 0 and 1). Because similar calculations for hepatic perfusion have not been validated, liver-perfusion measurements were restricted to a qualitative measurement, ie, Flow index = mean tissue radioactivity concentrationmean blood radioactivity concentration

{smtxt}with the mean concentrations calculated over the duration of the 3.5-minute infusion. The FI value will range from 0 to the fractional volume of distribution, with higher-perfusion regions having higher values. The short half-life of 15O (2.04 minutes) allowed the 5-[18F]-FU scan to follow 10 minutes after the C15O2 scan.

5-[18F]-FU Data Acquisition and Processing
Data acquisition, processing, and analysis followed previously developed protocols.45 A rapid and efficient synthesis of 5-[18F]-FU was developed using high-performance liquid chromatography for purification.46 In the 42 5-[18F]-FU syntheses, the median radiochemical purity was 98.1% (range, 84.2% to 100.0%), with uracil the only identified impurity. The median injected radioactivity dose was 321 MBq (range, 117 to 437 MBq), associated with a median 5FU dose of 5.3 mg · m-2 (range, 0.6 to 10.8 mg · m-2).

The 5-[18F]-FU solution, either alone or mixed with a therapeutic dose of 5FU, was injected via a venous line inserted into the right antecubital fossa. After the injection, the venous line was flushed with 5 mL of saline to ensure that all of the 5FU had entered the patient; this procedure was completed within 60 seconds.

After 5-[18F]-FU injection, dynamic PET data were acquired for 1 hour, using an ECAT 931-08/12 PET scanner (CTI, Knoxville, TN), with data collected into discrete time frames ranging from 30 to 600 seconds. This resulted in images detailing the biodistribution of radioactivity in the camera's field of view for each time frame. The image-analysis software program Analyze (Mayo Clinic, Rochester, MN) was used to define sample volumes in tumor and normal liver.47 This was done in conjunction with computed tomography or ultrasound films, and to minimize sampling error, only tumor deposits greater than 3 cm in diameter were sampled. Because of this effect and the 10.8-cm axial field of view of the PET camera, tumor data were acquired from 12 of 17 patients who had computed tomographic evidence of disease, and normal liver data were acquired from all patients. Mean radioactivity in the sample volumes for each of the time frames was then calculated, creating representative radioactivity versus time curves (ATCs) for the tumor and liver. These ATCs were then corrected for radioactive decay and radioactivity dose injected using the formula Corrected ATC = ATC (MBq |mZ ml-1) x etRadioactive dose (MBq)

{smtxt}where = 0.0001053 · s-1 is the decay constant of 18F and t is the midframe time, measured from injection time. Areas under these corrected ATCs were then calculated: AUC500, during the first 500 seconds, and AUC3,600, during the entire 1-hour scan (3,600 seconds).

Plasma Sampling and Assay
Continuous sampling of arterial blood radioactivity concentrations were performed simultaneously with PET data acquisition.48 Additionally, up to six discrete samples were taken for measurement of (1) the ratio of radioactivity in plasma/radioactivity in whole blood and (2) the contribution of 5-[18F]-FU to the total radioactivity in plasma (which is a composite signal of 5-[18F]-FU and [18F]-metabolites). The plasma/whole-blood radioactivity ratio was determined by measurement in a well counter after the blood was centrifuged for 2 minutes at 2000 x g. High-performance liquid chromatography analytical techniques were used to calculate the contribution of 5-[18F]-FU to the total activity in plasma. The discrete measurements were then extrapolated to the entire duration of the study by regressing a delayed exponential function through data points of radioactivity in plasma/radioactivity in whole blood and by regressing a sigmoid-type function through data points of the fraction of activity in plasma attributed to 5-[18F]-FU. These functions were chosen because they best described the population data and assumed no a priori knowledge. Application of these continuous corrections to the continuous measurements of radioactivity in blood produces the ATC of 5-[18F]-FU in plasma. After decay correction, areas under these curves were calculated numerically, from which estimates of the clearance of 5FU from plasma could be derived using the formula Clearance (L |mZ min-1 |mZ m-2) = Radioactive dose (MBq)AUC (MBq |mZ min |mZ L-1 x Body surface area (m2)

{smtxt}No extrapolation of the time activity curves was required because the levels of 5-[18F]-FU in plasma were negligible by the end of the 1-hour data-acquisition period.

Statistical Analysis
The effects of biomodulation on TBF, hepatic flow index (HFI), liver and tumor AUCs, whole body clearance, plasma/whole-blood radioactivity partitioning, and plasma 5-[18F]-FU/radioactivity partitioning were examined. Statistically significant changes in these parameters were examined using paired t tests. Data were also pooled (combining PALA, FA, and IFN data) for the examination of relationships between pharmacokinetic parameters, and correlation coefficients (Pearson's) were calculated. Significant relationships were then determined by rejecting the null hypothesis that there is no relationship.49