188Re—HEDP治疗肿瘤骨转移痛药代动力学研究

目的研究188Re标记的1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）在肿瘤骨转移患者体内的分布和排泄,分析不同剂量188Re—HEDP在患者体内的药代动力学特点。方法将40例肿瘤骨转移患者分为4组,每组10例,4组分别按体质量“弹丸”式经肘静脉注射188Re—HEDP20,30,40和50MBq／kg,给药时及给药后1,2,4,5,12,24,36,48,60和72h分别用SPECT仪采集胸前区和前后位、后前位全身图像,并收集患者尿液,测量放射性。利用感兴趣区（ROI）技术在左心室区测得经本底校正的放射性,作为血液放射性。将1h全身前位、后位放射性总计数率经死时间和时间衰减校正后的几何平均值设定为100％注射剂量（ID）,据此估算上述各时间点全身和各器官的百分注射剂量率（％ID）。各组间的计量资料采用元、中位数、范围等表示,组间比较采用方差分析或t检验。结果20～50MBq／kg范围内,188Re—HEDP在体内的时间-放射性曲线下面积（AUC）与其剂量呈线性关系,r^2=0．9376。4组均符合静脉给药二室模型,AUC值中位数分别为3．32×10^5,3．97×10^5,7．83×10^5,8．58×10^5;分布速度常数（α值）中位数分别为0．06,0．05,0．04,0．06;消除速度常数（B值）中位数分别为1．16×10^-3,1．16×10^-3,1．03×10^-3,1．15×10^-3;指数项系数A值中位数分别为3591．21,4858．23,5642．48,4167．05;指数项系数B值中位数分别为293．97,352．95,614．41,1063．82;药物分布相半衰期T1/2值中位数分别为12．51,12．83,15．41,12．02min;药物消除相半衰期T1／2（β）中位数分别为595．47,596．50,673．09,600．93min。骨组织是摄取188Re—HEDP的主要组织,给药后4h放射性摄取高,约为40％ID,其他组织未见明显摄取188Re—HEDP0188Re．HEDP主要通过泌尿系统排泄,给药后24h排出66．79％ID,其中74％在给药后5h内排出。结论20～50MBq／kg范围内,188Re—HEDP在机体内的药代动力学符合血管给药二室模型。188Re—HEDP T1/2（β）平均为616．50min。188Re—HEDP主要通过泌尿系统排泄;骨组织是摄取188Re—HEDP的主要组织。     

Skeletal uptake and soft-tissue retention of 186Re-HEDP and 153Sm-EDTMP in patients with metastatic bone disease.

The aim of this study was to introduce a new quantification method for 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) and 186Re-(tin)1,1-hydroxyethylidene diphosphonate (HEDP) to separately measure bone uptake and soft-tissue retention of these radiopharmaceuticals. METHODS: Studies were performed on 23 men and 6 women undergoing radionuclide therapy for palliation of bone pain. Whole-body images were acquired at 3 min, 3-4 h, and 24-72 h after injection of 1,295 MBq 186Re-HEDP and 37 MBq 153Sm-EDTMP per kilogram of body weight. The activities for whole body, urinary bladder, and both thighs, as representative of soft tissue, were measured by region-of-interest technique. A background region of interest adjacent to the head was used to correct for bremsstrahlung. Bone uptake was calculated as initial whole-body activity minus urinary excretion and remaining soft-tissue activity. RESULTS: For 186Re-HEDP (n = 11) the mean bone uptake at 3 h after injection was 13.7% +/- 8.6% of initial whole-body activity. The remaining soft-tissue activity was 49.4% +/- 16.9%, and urinary excretion was 36.9% +/- 14.4%. At 24 h after injection, bone uptake reached a value of 21.8% +/- 9.0%. Urinary excretion increased to 65.3% +/- 12.8% according to a decreasing soft-tissue remainder activity of 12.8% +/- 5.4%. The corresponding results for 153Sm-EDTMP (n = 18) at 3 h after injection were 29.2% +/- 15.5% for bone uptake, 32.3% +/- 12.9% for urinary excretion, and 38.4% +/- 14.5% for soft tissue. At 24 h after injection, we calculated values of 47.7% +/- 11.2% for bone uptake, 39.5% +/- 13.8% for urinary excretion, and 12.7% +/- 4.7% for soft tissue. CONCLUSION: Bone uptake and soft-tissue retention for both 186Re-HEDP and 153Sm-EDTMP as obtained in this study agree well with the conventional 24-h whole-body retention measurements for these tracers. However, by this new scintigraphic quantification method, bone uptake and soft-tissue retention can be calculated separately, thus providing more detailed kinetic data and potentially improving the dosimetry of these radiopharmaceuticals in, for example, assessment of radiation dosage to bone and bone marrow.     

Radiation dosimetry of a 99mTc-labeled IgM murine antibody to CD15 antigens on human granulocytes.

99mTc-labeled anti-stage specific embryonic antigen-1 (anti-SSEA-1) is an injectable IgM antibody derived from mice. It binds to CD15 antigens on some granulocytic subpopulations of human white blood cells in vivo after systemic administration. The purpose of this study was to measure biodistribution of 99mTc-labeled anti-SSEA-1 and perform radiation dosimetry in 10 healthy human volunteers. METHODS: Transmission scans and whole-body images were acquired sequentially on a dual-head camera for 32 h after the intravenous administration of about 370 MBq (10.0 mCi) of the radiopharmaceutical. Renal excretion fractions were measured from 10 to 14 discrete urine specimens voided over 27.9 +/- 2.0 h. Multiexponential functions were fit iteratively to the time-activity curves for 17 regions of interest using a nonlinear least squares regression algorithm. The curves were integrated numerically to yield source organ residence times. Gender-specific radiation doses were then estimated individually for each subject, using the MIRD technique, before any results were averaged. RESULTS: Quantification showed that the kidneys excreted 39.5% +/- 6.5% of the administered dose during the first 24 h after administration. Image analysis showed that 10%-14% of the radioactivity went to the spleen, while more than 40% went to the liver. Residence times were longest in the liver (3.37 h), followed by the bone marrow (1.09 h), kidneys (0.84 h) and the spleen (0.65 h). The dose-limiting organ in both men and women was the spleen, which received an average of 0.062 mGy/MBq (0.23 rad/mCi, range 0.08-0.30 rad/mCi), followed by the kidneys (0.051 mGy/MBq), liver (0.048 mGy/MBq) and urinary bladder (0.032 mGy/MBq). The effective dose equivalent was 0.018 mSv/MBq (0.068 rem/mCi). CONCLUSION: The findings suggest that the radiation dosimetry profile for this new infection imaging agent is highly favorable.     

Bone uptake studies in rabbits before and after high-dose treatment with 153Sm-EDTMP or 186Re-HEDP.

The aim of this animal study was to measure the bone uptake of (99m)Tc-hydroxymethylene diphosphonate (HDP) before and after high-dose treatment with (153)Sm-ethylenediaminetetramethylenephosphonate (EDTMP) or (186)Re-(tin)1,1-hydroxyethylidene diphosphonate (HEDP) to prove or disprove post-therapeutic alterations of bone uptake of radiolabeled bisphosphonates. METHODS: Quantitative bone scanning using 100 MBq (99m)Tc-HDP was performed on 12 rabbits before and 8 wk after radionuclide therapy with 1,000 MBq of either (153)Sm-EDTMP or (186)Re-HEDP. Whole-body images were acquired at 3 min, 3 h, and 24 h after injection, and the activities for the whole body, urinary bladder, and soft tissue were measured by region-of-interest technique. From these data, bone uptake was calculated as initial whole-body activity minus urinary excretion and remainder soft-tissue activity. RESULTS: In animals treated with (153)Sm-EDTMP (n = 6), no differences could be proven for the bone uptake of (99m)Tc-HDP at 24 h after injection before and after therapy (51.1% +/- 5.5% vs. 48.0% +/- 6.1%, P > 0.05). There were also no significant differences for the remainder soft-tissue activities and the urinary excretion rates before and after therapy. Similar results were obtained in rabbits treated with (186)Re-HEDP: Bone uptake (44.8% +/- 6.7% vs. 40.4% +/- 4.9%, P > 0.05) and urinary excretion revealed no significant differences before and after treatment. CONCLUSION: No significant impairment of bone uptake of (99m)Tc-HDP could be observed 8 wk after high-dose radionuclide bone therapy. Because both the biokinetic data obtained for (186)Re-HEDP and (153)Sm-EDTMP and the myelotoxic effects were quite similar in rabbits to those in patients, it seems justifiable to expect the same result (i.e., no significant alteration of bone uptake of radiolabeled bisphosphonates) in patients undergoing a second radionuclide therapy within 2-3 mo after standard treatment with (186)Re-HEDP or (153)Sm-EDTMP.     

Preparation and evaluation of the rhenium-188-labelled anti-NCA antigen monoclonal antibody BW 250/183 for radioimmunotherapy of leukaemia.

Anti-NCA antigen antibody BW 250/183 (Anti-Granulocyte) localizes more than 50% of injected antibody dose to the bone marrow. Therefore, this antibody is promising for adjuvant conditioning radioimmunotherapy of bone marrow before bone marrow transplantation. To examine its potential use for radioimmunotherapy, we developed an efficient and reproducible technical protocol for labelling anti-NCA antigen antibody BW 250/183 with generator-produced rhenium-188, aiming at both high radiochemical yield and high specific activity. (188)Re-labelled BW 250/183 antibody was used in 12 patients with advanced leukaemia. Labelling of BW 250/183 with (188)Re was accomplished by the direct radiolabelling method using tris-(2-carboxyethyl) phosphine (TCEP) as the reducing agent. Twelve patients with recurrent acute or chronic leukaemia were treated with activities of 6.5-12.4 GBq of (188)Re-labelled BW 250/183. Standard gamma camera scintigraphy was used to evaluate the biodistribution, and a region of interest analysis together with the MIRDOSE 3.1 software was applied to determine the radiation doses to relevant tissues. The (188)Re-BW 250/183 antibody was labelled in high radiochemical yield, with high radiochemical purity (94%+/-3%) and specific activity (5.55-7.4 GBq/mg) within 1 h. The preliminary biodistribution studies showed persistent uptake of (188)Re-BW 250/183 in bone marrow. The radiation absorbed doses (mGy/MBq) delivered to the total body, red marrow, liver, spleen and kidneys were 0.13+/-0.02, 1.45+/-0.71, 0.43+/-0.21, 1.32+/-0.99 and 0.71+/-0. 17, respectively. TCEP reduction enabled the direct, fast and effective labelling of the monoclonal antibody BW 250/183 with (188)Re. Preliminary clinical results suggest delivery of a significant radiation dose to bone marrow and thus the potential for adjuvant conditioning therapy before BMT.     

A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases

AIM: The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. METHOD: The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. RESULTS: In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). CONCLUSION: All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.     

18F-Fluorothymidine radiation dosimetry in human PET imaging studies.

3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a PET imaging agent that shows promise for studying cellular proliferation in human cancers. FLT is a nucleoside analog that enters cells and is phosphorylated by human thymidine kinase 1, but the 3' substitution prevents further incorporation into DNA. We estimated the radiation dosimetry for this tracer from data gathered in patient studies. METHODS: Time-dependent tissue concentrations of radioactivity were determined from blood samples and PET images of 18 patients after intravenous injection of (18)F-FLT. Radiation-absorbed doses were calculated using the MIRD Committee methods, taking into account variations that were based on the distribution of activities observed in the individual patients. Effective dose equivalent (EDE) was calculated using International Commission on Radiological Protection Publication 60 tissue weighting factors for the standard man and woman. RESULTS: For a single bladder voiding at 6 h after (18)F-FLT injection, the (18)F-FLT EDE (mean +/- SD) was 0.028 +/- 0.012 mSv/MBq (103 +/- 43 mrem/mCi) for a standard male patient and 0.033 +/- 0.012 mSv/MBq (121 +/- 43 mrem/mCi) for a standard female patient. The organ that received the highest dose was the bladder (male, 0.179 mGy/MBq [662 mrad/mCi]; female, 0.174 mGy/MBq [646 mrad/mCi]), followed by the liver (male, 0.045 mGy/MBq [167 mrad/mCi]; female, 0.064 mGy/MBq [238 mrad/mCi]), the kidneys (male, 0.035 mGy/MBq [131 mrad/mCi]; female, 0.042 mGy/MBq [155 mrad/mCi]), and the bone marrow (male, 0.024 mGy/MBq [89 mrad/mCi]; female, 0.033 mGy/MBq [122 mrad/mCi]). CONCLUSION: Organ dose estimates for (18)F-FLT are comparable to those associated with other commonly performed nuclear medicine tests, and the potential radiation risks associated with (18)F-FLT PET imaging are within accepted limits.     

Radioimmunotherapy for the intensification of conditioning before stem cell transplantation: differences in dosimetry and biokinetics of 188Re- and 99mTc-labeled anti-NCA-95 MAbs.

A new concept is the intensification of preparative regimens for patients with advanced leukemia using monoclonal antibodies (MAbs) with an affinity for beta emitter-labeled bone marrow. 188Re is a high-energy beta emitter that has therapeutic promise. Our first aim was to clarify whether the therapeutic application of 188Re-MAb against nonspecific cross-reacting antigen 95 (NCA-95) can be predicted from biokinetic data derived from 99mTc-labeled NCA-95. Our second aim was to show that a radiation absorbed dose of > or =12 Gy in the bone marrow can be achieved using 188Re-MAb. METHODS: Dosimetric data were obtained for both radiotracers from multiple planar whole-body scans (double-head gamma camera), blood samples, and urine measurements from 12 patients with advanced leukemia. Radiation absorbed doses were calculated using MIRDOSE 3 software. RESULTS: Radiation absorbed doses to bone marrow, liver, spleen, lung, and kidney were 2.24, 0.50, 1.93, 0.05, and 0.90 mGy/MBq, respectively, using 99mTc-MAb and 1.45, 0.43, 1.32, 0.07, and 0.71 mGy/MBq, respectively, using 188Re-MAb. These differences were statistically significant for bone marrow, spleen, and kidney. The main differences were less accumulation of 188Re-MAb in bone marrow (31%+/-13% compared with 52%+/-13%) and faster elimination through urine (25%+/-3% compared with 15%+/-5% after 24 h). On the basis of these data, a mean marrow dose of 14+/-7 Gy was achieved in 12 patients suffering from leukemia after application of approximately 10+/-2 GBq 188Re-MAb. CONCLUSION: Myeloablative radiation absorbed doses can easily be achieved using 188Re-MAb. 99mTc- and 188Re-MAb showed similar whole-body distributions. However, direct prediction of radiation absorbed doses from the 99mTc-MAb, assuming identical biokinetic behavior, is not valid for the 188Re-MAb in a single patient. Therefore, individual dosimetry using 188Re-MAb is needed to calculate therapeutic activity.     

Anti-CD45 monoclonal antibody YAML568: A promising radioimmunoconjugate for targeted therapy of acute leukemia.

The outcome of hematopoietic cell transplantation for hematologic malignancies may be improved by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the biodistribution of 111In-labeled anti-CD45 antibody in humans using the rat IgG2a monoclonal antibody YAML568 that recognizes a common CD45 epitope present on all human leukocytes. METHODS: Eight patients undergoing bone marrow transplantation received YAML568 labeled with 122 +/- 16 MBq of 111In intravenously followed by serial blood sampling, urine collection, and conjugated view planar gamma-camera imaging up to 144 h after injection. Time-activity curves were obtained using region-of-interest analysis in the accumulating organs and residence times were calculated. An estimate for the radiation-absorbed doses for each organ per unit of administered activity of 90Y was calculated using software for internal dose assessment. The first patient received no unlabeled antibody preloading. The second 2 patients received a preloading dose of 10 mg (0.15 mg/kg). The last 5 patients received a preloading dose of 30-47 mg (0.5 mg/kg). RESULTS: No significant administration-related side effects were seen. The 3 patients receiving no antibody or low antibody preloading had an unfavorable biodistribution with a high initial accumulation of activity in the liver (37%) and the spleen (34%). For the patients receiving 0.5-mg/kg antibody preloading, the estimated radiation-absorbed doses for red bone marrow, spleen, liver, kidney, and total body were 6.4 +/- 1.2, 19 +/- 5, 3.9 +/- 1.4, 1.1 +/- 0.4, and 0.6 +/- 0.1 mGy/MBq, respectively, demonstrating preferential red marrow targeting. A linear regression model showed that the amount of unlabeled antibody preloading per body weight has a strong influence on the estimated red marrow absorbed dose (P = 0.003, R2 = 0.80). CONCLUSION: This study shows that the anti-CD45 monoclonal antibody YAML568 is suitable for delivering selectively radiation to hematopoietic tissues when labeled with 90Y provided that a preloading dose of about 0.5 mg/kg unlabeled antibody is given.     

Can bone marrow scintigraphy predict platelet toxicity after treatment with 186Re-HEDP?

The toxicity of 186Re-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) therapy in patients with painful bone metastases is mainly limited to thrombocytopaenia. The aim of this study was to investigate the influence of bone marrow scintigraphy on the prediction of decreased platelet counts after 186Re-HEDP therapy. Twenty-nine prostatic cancer patients with multiple painful bone metastases were included in the study. From a pre-therapy nanocolloid bone marrow scintigram, the bone marrow index (BMI) was determined as an indicator of the extent of bone marrow involvement. The influence of the BMI on the prediction of percent decrease in platelet counts was investigated. The mean BMI was 59 +/- 20. Regression analysis showed that the BMI does not improve the relationship between percent reduction in platelet count and administered dose. In contrast, we previously showed that the bone scan index (BSI) does predict the percent reduction in platelet counts before treatment. We conclude that bone marrow scintigraphy does not provide any additional information on platelet toxicity after a therapeutic dose of 186Re-HEDP. Bone scintigraphy is preferred in the prediction of reduced platelet counts.     

Biodistribution and radiation dosimetry of [<Superscript>123</Superscript>I]ADAM in healthy human subjects: preliminary results

[(123)I]ADAM [2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM)] has recently been shown to be a very promising imaging ligand for the detection of serotonin transporters (SERT) in human brain, because of its high specificity for SERT. [(123)I]ADAM has previously been used only for animal studies. In this work, we investigated the radiation dosimetry and biodistribution of [(123)I]ADAM based on whole-body scans in healthy human volunteers. Following the administration of 196+/-20 MBq (range 157-220 MBq) [(123)I]ADAM, serial whole-body images were performed up to 24 h. Estimates of radiation absorbed dose were calculated using the MIRDOSE 3.0 program with a dynamic bladder model. Twelve source organs were considered in estimating absorbed radiation doses for organs of the body. The highest absorbed organ doses were found to the lower large intestine wall (8.3.10(-2) mGy/MBq), kidneys (5.2.10(-2) mGy/MBq), urinary bladder wall (4.9.10(-2) mGy/MBq) and thyroid (4.3.10(-2) mGy/MBq). The effective dose was estimated to be 2.2.10(-2) mSv/MBq. The results suggest that [(123)I]ADAM is of potential value as a tracer for single-photon emission tomography imaging of serotonin receptors in humans, with acceptable dosimetry and high brain uptake.     

In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia

Alemtuzumab (Campath, Berlex) is a humanized IgG1 rat monoclonal antibody directed against the cell surface CD52 antigen, found on lymphocytes and monocytes. It is being developed for the treatment of chronic lymphocytic leukemia (CLL), autoimmune disease and for the prevention of transplant rejection. This study focused on synthesis, quality control, in vitro evaluation and biodistribution of (188)Re-labeled alemtuzumab for radioimmunotherapy of B-cell CLL. (188)Re-alemtuzumab was synthesized using a direct radiolabeling method. Reduction of the intramolecular disulfide bonds of the antibody was performed with tris-(carboxyethyl)-phosphine (Pierce), using a 1:60 molar excess. Reaction took place at room temperature for 20 min. A PD-10 desalting column was used to purify the reduced antibody from excess phospine. Complexation and transchelation of (188)ReO(4)(-) was achieved using sodium gluconate as weak chelator and SnCl(2) as reducing agent. Quality control was done using instant thin-layer chromatography. Binding assays were performed on a CD52-positive cell line (HuT-78). Female NMRI mice were injected intravenously with 20 microg radiolabeled alemtuzumab and killed at preset time intervals for biodistribution studies. Tissues were dissected, weighed and counted for determination of radioactivity. Data were expressed as percentage injected activity per gram of tissue (% IA/g tissue) or as percentage injected activity (% IA). (188)Re-alemtuzumab was prepared achieving high radiochemical yields. Labeling efficiency of more than 95% can be obtained using optimal reaction conditions. (188)Re-alemtuzumab showed good in vitro stability, remaining intact at 24 h after radiolabeling. In mice, (188)Re-alemtuzumab showed high uptake in the blood (25.10+/-1.36% IA at 1 h p.i.), followed by a biexponential clearance (t(1/2alpha)=4.790 h and t(1/2beta)=55.45 h). Increased uptake was observed in kidneys and heart (9.29+/-0.46% IA/g in kidneys and 6.10+/-1.82% IA/g in heart at 1 p.i.). The highest absorbed radiation dose was received by the kidneys (0.159-3.26 mGy/MBq) and heart wall (0.0705-0.132 mGy/MBq). The predicted radiation dose for the total body was in the range of 0.0459-0.0529 mGy/MBq. The effective dose for the human reference adult was estimated to be approximately 0.0486-0.195 mSv/MBq. (188)Re-alemtuzumab can be prepared with high radiochemical yield and purity and showed good in vitro behavior and favorable biodistribution. Therefore, (188)Re-alemtuzumab would be an ideal candidate for radioimmunotherapy of chronic lymphocytic leukemia.     

Patient-specific dosimetry calculations using mathematic models of different anatomic sizes during therapy with 111In-DTPA-D-Phe1-octreotide infusions after catheterization of the hepatic artery.

The aim of the study was to provide dosimetric data on intrahepatic (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide therapy for neuroendocrine tumors with overexpression of somatostatin receptors. METHODS: A dosimetric protocol was designed to estimate the absorbed dose to the tumor and healthy tissue in a course of 48 treatments for 12 patients, who received a mean activity of 5.4 +/- 1.7 GBq per session. The patient-specific dosimetry calculations, based on quantitative biplanar whole-body scintigrams, were performed using a Monte Carlo simulation program for 3 male and 3 female mathematic models of different anatomic sizes. Thirty minutes and 2, 6, 24, and 48 h after the radionuclide infusion, blood-sample data were collected for estimation of the red marrow radiation burden. RESULTS: The mean absorbed doses per administered activity (mGy/MBq) by the critical organs liver, spleen, kidneys, bladder wall, and bone marrow were 0.14 +/- 0.04, 1.4 +/- 0.6, 0.41 +/- 0.08, 0.094 +/- 0.013, and (3.5 +/- 0.8) x 10(-3), respectively; the tumor absorbed dose ranged from 2.2 to 19.6 mGy/MBq, strongly depending on the lesion size and tissue type. CONCLUSION: The results of the present study quantitatively confirm the therapeutic efficacy of transhepatic administration; the tumor-to-healthy-tissue uptake ratio was enhanced, compared with the results after antecubital infusions. Planning of treatment was also optimized by use of the patient-specific dosimetric protocol.     

PET-based radiation dosimetry in man of 18F-fluorodihydrotestosterone, a new radiotracer for imaging prostate cancer.

16 beta-fluoro-5 alpha-dihydrotestosterone (FDHT) is a promising new PET radiopharmaceutical for the imaging of prostate cancer. A recent clinical trial provided the opportunity for refinement of normal-tissue radiation-absorbed dose estimates based on quantitative PET. The objective of the current study was to derive estimates of normal-tissue absorbed doses for (18)F-FDHT administered to patients with advanced prostate cancer. METHODS: Absorbed dose estimates were derived from 10 (18)F-FDHT PET studies (administered activity, 111-407 MBq) of 7 prostate cancer patients. Activity concentrations in plasma and red marrow (assuming a plasmacrit of 0.58, an extracellular fluid fraction of 0.40, and equilibration of activity between plasma and marrow extracellular fluid) were measured ex vivo from a peripheral blood sample. Liver, spleen, urinary bladder contents, and total-body activities were measured by region-of-interest analysis of quantitative whole-body studies acquired with a dedicated PET scanner. Total organ activities and residence times were calculated from the respective PET scan-derived activity concentrations assuming standard (70 kg) man organ masses. Urinary excretion was corrected for hepatobiliary excretion (liver activity), and a first-order adjustment was made for the bladder-wall mass based on the patient's total-body mass. Mean organ absorbed doses were calculated with the MIRD formalism and the standard man model using the MIRDOSE3 software program. RESULTS: The absorbed doses (mean +/- SD) ranged from 0.00057 +/- 0.000281 cGy/MBq (to skin) to 0.00868 +/- 0.00481 cGy/MBq (to bladder wall) (voiding intervals, 1-2 h), and the effective dose equivalent was 0.00177 +/- 0.000152 cSv/MBq. CONCLUSION: The maximum absorbed dose among all tissues in all 10 studies, 0.0151 cGy/MBq, occurred for the urinary bladder wall (with hydration and 1- to 2-h voiding intervals). To ensure that the maximum normal-tissue absorbed dose is kept below the recommended maximum permissible dose of 5 cGy per single administration, a maximum administered activity of 331 MBq (5 cGy/[0.0151 cGy/MBq]) is recommended for (18)F-FDHT.     

A phase I trial combining high-dose 90Y-labeled humanized anti-CEA monoclonal antibody with doxorubicin and peripheral blood stem cell rescue in advanced medullary thyroid cancer.

This trial determined the pharmacokinetics, dosimetry, and dose-limiting toxicity of 90Y-hMN-14 IgG (humanized anticarcinoembryonic antigen [CEA, or CEACAM5] monoclonal antibody; labetuzumab), combined with doxorubicin and peripheral blood stem cell (PBSC) support in advanced medullary thyroid cancer (MTC) patients. METHODS: Fifteen patients received an infusion of 111In-hMN-14 IgG. One to 2 wk later, 14 patients received 90Y-hMN-14 IgG, starting at 740 MBq/m2, followed 24 h later with a fixed intravenous bolus dose of doxorubicin (60 mg/m2). Preharvested PBSCs were reinfused when the 90Y activity in the body was < or =111 MBq/m2. RESULTS: The mean red marrow dose estimated for the 90Y-hMN-14 IgG was 1.65 +/- 0.59 mGy/MBq (n = 11), with normal organs ranging from approximately 2.3 to 4.4 mGy/MBq. Eighty percent of all known lesions (125/156), including 78 of 79 bone and 16 putatively occult lesions, were targeted. The average radiation dose to the tumor was 15.1 +/- 10.8 mGy/MBq (55.8 +/- 39.8 cGy/mCi) 90Y-hMN-4 IgG (n = 29 tumors in 8 patients), with a majority of the lesions receiving >2,000 cGy at an administered dose of < or =1,480 MBq/m2. The average tumor-to-red marrow, tumor-to-liver, tumor-to-lungs, and tumor-to-kidneys ratios were 15.0 +/- 11.0, 5.1 +/- 3.6, 6.9 +/- 6.1, and 9.0 +/- 8.7, respectively. Cardiopulmonary toxicity was dose limiting at 1,850 MBq/m2. Minor responses were noted in 2 patients and 1 patient had a partial response (68% reduction in local and hepatic metastatic disease). CONCLUSION: This treatment combination was well tolerated with complete recovery of blood counts and reversible nonhematologic toxicities at the maximum tolerated dose of 1,480 MBq/m2. Evidence of antitumor response in these patients with advanced cancer was modest, but encouraging; this type of treatment may be more successful if applied to more limited, earlier-stage disease.     

肿瘤骨转移疼痛患者对^188Re-HEDP的耐受性研究

目的 评价^188Re-1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）治疗肿瘤骨转移疼痛患者的安全性.方法 符合入选标准的31例患者（前列腺癌10例,乳腺癌9例,肺癌3例,肝癌5例,直肠癌2例,食管癌1例,肾癌1例,均随时间顺序人选）知情同意后接受了按体质量肘静脉单次注射^188ReHEDP,据药物递增剂量分为4个组：20 MBq/kg组6例、30 MBq/kg组6例、40 MBq/kg组9例、50 MBq/kg组10例.低剂量组安全性分析结束并显示安全后,才开始下一剂量组试验.如果患者出现由于用药引起的不可耐受的、WHO公布的Ⅲ或Ⅳ级骨髓毒性,即终止剂量递增,并认为前一组剂量为最大可接受剂量.观察指标包括给药前及给药后8周内每例患者的生命体征（用药后1,6,12,24,48,72 h和1,2,3,4,6,8周）,血细胞计数（用药后1,2,3,4,6和8周）,心电图,肝、肾功能,ALP（用药后4,8周）,＂反跳痛＂以及不良反应等.统计分析主要针对符合方案集（PP）人群,包括统计描述和统计推断（t检验）.结果 31例患者中有27例属于PP人群：20 MBq/kg组5例、30 MBq/kg组5例、40 MBq/kg组8例、50 MBq/kg组9例.在受试剂量范围内,没有观察到188Re-HEDP对患者生命体征、心电图、肝肾功能和ALP的不良影响.20 MBq/kg组的5例患者中仅1例自细胞出现WHO Ⅰ级毒性;30 MBq/kg组5例患者中2例白细胞出现WHO Ⅰ级毒性,其中1例合并血小板Ⅲ级毒性,但给药后8周白细胞和血小板均恢复正常;40 MBq/kg组8例患者中2例白细胞和血小板同时出现毒性反应,分别为WHO Ⅰ级和Ⅱ级,表现为白细胞和血小板同时、同级减低;50 MBq/kg组9例患者中3例白细胞出现WHOⅡ级毒性.全部患者的血小板均在给药后4周达最低水平,平均为143.5×109/L;白细胞均在给药后6周达最低水平,平均为5.4×109/L（两者与给药前基线值比较,t值分别为3.1325和3.3156,P均＜0.05）,给药后8周自细胞和血小板均恢复到基线水平;而血红蛋白在给药后8周最低（与基线值比较,t值为3.4917,P＜0.05）.PP人群27例中有2例出现＂反跳痛＂,发生率7.41%（2/27）.结论 按体质量注射188Re-HEDP 20,30,40和50 MBq/kg对肿瘤骨转移患者均无明显毒性及不良反应,且随着用药剂量增加,188Re-HEDP对骨髓的抑制有增加趋势.     

Whole-body biodistribution and estimation of radiation-absorbed doses of the dopamine D1 receptor radioligand 11C-NNC 112 in humans.

The present study estimated radiation-absorbed doses of the dopamine D(1) receptor radioligand [(11)C]((+)-8-chloro-5-(7-benzofuranyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (NNC 112) in humans, based on dynamic whole-body PET in healthy subjects. METHODS: Whole-body PET was performed on 7 subjects after injection of 710 +/- 85 MBq of (11)C-NNC 112. Fourteen frames were acquired for a total of 120 min in 7 segments of the body. Regions of interest were drawn on compressed planar images of source organs that could be identified. Radiation dose estimates were calculated from organ residence times using the OLINDA 1.0 program. RESULTS: The organs with the highest radiation-absorbed doses were the gallbladder, liver, lungs, kidneys, and urinary bladder wall. Biexponential fitting of mean bladder activity demonstrated that 15% of activity was excreted via the urine. With a 2.4-h voiding interval, the effective dose was 5.7 microSv/MBq (21.1 mrem/mCi). CONCLUSION: (11)C-NNC 112 displays a favorable radiation dose profile in humans and would allow multiple PET examinations per year to be performed on the same subject.     

<Superscript>188</Superscript>Re-HEDP combined with capecitabine in hormone-refractory prostate cancer patients with bone metastases: a phase I safety and toxicity study

Purpose

¹⁸⁸Re-HEDP is indicated for the treatment of pain in patients with painful osteoblastic bone metastases, including hormone-refractory prostate cancer patients. Efficacy may be improved by adding chemotherapy to the treatment regimen as a radiation sensitizer. The combination of ¹⁸⁸Re-HEDP and capecitabine (Xeloda®) was tested in a clinical phase I study.

Methods

Patients with hormone-refractory prostate cancer were treated with capecitabine for 14 days (oral twice daily in a dose escalation regimen with steps of 1/3 of 2,500 mg/m² per day in cohorts of three to six patients, depending on toxicity). Two days later patients were treated with 37 MBq/kg ¹⁸⁸Re-HEDP as an intravenous injection. Six hours after treatment post-therapy scintigraphy was performed. Urine was collected for 8 h post-injection. Follow-up was at least 8 weeks. The primary end-point was to establish the maximum tolerable dose (MTD) of capecitabine when combined with ¹⁸⁸Re-HEDP. Secondary end-points included the effect of capecitabine on the biodistribution and pharmacokinetics of ¹⁸⁸Re-HEDP.

Results

Three patients were treated in the first and second cohorts, each without unacceptable toxicity. One of six patients in the highest cohort experienced unacceptable toxicity (grade 4 thrombopaenia). The MTD proved to be the maximum dose of 2,500 mg/m² per day capecitabine. No unexpected toxicity occurred. Capecitabine had no effect on uptake or excretion of ¹⁸⁸Re-HEDP.

Conclusion

Capecitabine may be safely used in combination with ¹⁸⁸Re-HEDP in a dose of 2,500 mg/m² per day and 37 MBq/kg, respectively. Efficacy will be further studied in a phase II study using these dosages.

     

Radiation absorbed dose calculations for samarium-153-EDTMP localized in bone

Calculations have been undertaken to estimate the likely radiation dose received by patients undergoing treatment with samarium-153-EDTMP. Previously known bone structure parameters have been employed to partition correctly the energy absorbed in the bone matrix between red bone marrow, yellow marrow, and various types of mineral bone. Both uniform surface and volume distribution of the radioactivity are considered. The key findings of the calculations can be stated in terms of the MIRD "S-factors" for red bone marrow and the endosteal layer of cells on bone surfaces. In particular, the S-factor for red bone marrow is either 0.0276 mGy/MBq.h or 0.0077 mGy/MBq.h for surface and volume distributed radioactivity, respectively. For the endosteal layer of thickness (10 microns) on bone surfaces, the corresponding values are 0.0723 mGy/MBq.h and 0.0213 mGy/MBq.h, respectively.     

Biodistribution and radiation dosimetry of the amyloid imaging agent 11C-PIB in humans.

We investigated the biodistribution and radiation dosimetry of the PET amyloid imaging agent (11)C-PIB ((11)C-6-OH-BTA-1) (where BTA is benzothiazole) in humans. Previous radiation exposure estimates have been based on animal experiments. A dosimetry study in humans is essential for a balanced risk-benefit assessment of (11)C-PIB PET studies. METHODS: We used data from 16 different (11)C-PIB PET scans on healthy volunteers to estimate radiation exposure. Six of these scans were dynamic imaging over the abdominal region: 3 covering the upper abdomen and 3 covering the middle abdomen. On average, 489 MBq of (11)C-PIB (range, 416-606 MBq) were injected intravenously, and dynamic emission scans were recorded for up to 40 min. Two subjects had whole-body imaging over the entire body to illustrate the biodistribution. PET brain scans and blood and urine radioactivity measurements from our previous (11)C-PIB studies were also analyzed. Thirteen source organs and the remainder of the body were studied to estimate residence times and mean radiation-absorbed doses. The MIRD method was used to calculate the radiation exposure of selected target organs and the body as a whole. RESULTS: There is a high degree of consistency between our human data and previous biodistribution information based on baboons. In our study, the highest radiation-absorbed doses were received by the gallbladder wall (41.5 microGy/MBq), liver (19.0 microGy/MBq), urinary bladder wall (16.6 microGy/MBq), kidneys (12.6 microGy/MBq), and upper large intestine wall (9.0 microGy/MBq). The hepatobiliary and renal systems were the major routes of clearance and excretion, with approximately 20% of the injected radioactivity being excreted into urine. The effective radiation dose was 4.74 microSv/MBq. CONCLUSION: The established clinical dose of (11)C-PIB required for 3-dimensional PET amyloid imaging has an acceptable effective radiation dose. This dose is comparable with the average exposure expected in other PET brain receptor tracer studies. (11)C-PIB is rapidly cleared from the body, largely by the kidneys. From the viewpoint of radiation safety, these results support the use of (11)C-PIB in clinical PET studies.