The a-emitter 211 At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity. Methods: Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. 211 At was labeled to MX35 F(ab9) 2 using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with 211 At-MX35 F(ab9) 2 (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. g-camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo. Results: Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% 6 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 6 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 6 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 6 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 6 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 6 1.6 mGy/(MBq/L) (mean 6 SD). No adverse effects were observed either subjectively or in laboratory parameters. Conclusion: This study indicates that by intraperitoneal administration of 211 At-MX35 F(ab9) 2 it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity. The lifetime risk of ovarian cancer is 1%22% in European and U.S. women. Despite seemingly successful cytoreductive surgery, followed by systemic chemotherapy, most patients will relapse and succumb. The relapse is most frequently localized in the abdominal cavity. New systemic chemotherapy regimens have not improved the outcome over the past decade, which prompted experimental intraperitoneal treatments, including radioimmunotherapy.Radioimmunotherapy with b-emitters has displayed promising results, although an international randomized phase III study of 90 Y-HMFG1 showed no improvement in survival or time to relapse (1). This disappointing result could be partly explained by the choice of radionuclide. The long range of this b-emitter results in poor irradiation of small tumor clusters, likely insufficient to eradicate peritoneal micrometastases. Furthermore, the relativel...

A formula has been derived for the calculation of renal clearance with the use of a single plasma sample. The formula is based on a one-compartment model. A small correction for non-immediate mixing and non-uniform distribution of the tracer was calculated from empirical data. The accuracy in the calculation method depends on how exactly the distribution volume is known and at what time the blood sample is taken. The expected standard deviation in the clearance value was calculated from data of mean value and spread for the distribution volume of 99Tcm-DTPA. In an investigation of 39 subjects with 99Tcm-DTPA, a standard deviation of 5 to 6 ml/min was obtained in comparison with a standard method for clearance calculation. This value is in good agreement with the expected one.

The present study examines the extent of spinal cerebrospinal fluid (CSF) absorption in healthy individuals in relation to physical activity, CSF production, intracranial pressure (ICP), and spinal CSF movement. Thirty-four healthy individuals aged 21-35 yr were examined by lumbar puncture and radionuclide cisternography with repeated imaging. ICP was registered before and after CSF drainage, and CSF production was calculated. Spinal CSF absorption was calculated as reduction in spinal radionuclide activity. The radionuclide activity in the spinal subarachnoidal space was gradually decreased by 20 Ϯ 13% (mean Ϯ SD) during 1 h. The reduction was higher in active than in resting individuals (27 Ϯ 12% vs. 13 Ϯ 9%). The mean ICP in 19 of the individuals was 13.6 Ϯ 3.1 cmH 2O. B-waves were found in 79% of the individuals, with a mean frequency of 0.6 Ϯ 0.3 min Ϫ1 . The mean CSF production rate was 0.34 Ϯ 0.13 ml/min. There were no correlations between radionuclide reduction, spinal movement of the radionuclide, and CSF production rate. The spinal radionuclide reduction found in this study indicates a spinal CSF absorption of 0.11-0.23 ml/min, more pronounced in active than in resting individuals. arachnoid villi; cerebrospinal fluid spinal flow; cerebrospinal fluid production; cerebrospinal fluid pressure; radionuclide imaging CEREBROSPINAL FLUID (CSF) is mainly produced in the choroid plexus in the lateral, third, and fourth ventricles, and a minor part is derived from the extracellular space of the brain (37). The CSF flows in a to-and-fro movement with a caudaldirected net flow through the aqueduct of Sylvius and foramina of Luschka and Magendie into the spinal subarachnoidal space (SAS) (39). The pulsative brain movements create a "mixing" of CSF in the fourth ventricle, basal cisterns, and upper spinal SAS (17, 23). Older radionuclide cisternographic (RC) studies have shown that radioactively labeled substances move upward when injected in the lumbar region (11) and downward when injected in the ventricles (12). Within the spinal SAS, a pulsatile to-and-fro flow with a caudal-directed net flow in the ventral and a cranial-directed net flow in the lateral cervical SAS has been reported (25, 42). However, the existence of a CSF bulk flow in any direction within the spinal SAS has been questioned, and RC and MRI observations could be explained by mere diffusion (22). The arachnoid villi in the superior sagittal sinus have generally been thought to be the main site for CSF absorption in humans (2, 40). However, lymphatic drainage pathways have been shown in animal studies to play an important role for CSF clearance (5,27,46). The existence of this pathway in humans remains unclear. Spinal CSF absorption through arachnoid granulations located along the nerve roots, morphologically similar to cranial villi, was suggested by Kido et al. (28), and CSF clearance from the spinal SAS has been demonstrated in sheep and cats (6, 31). The extent and importance of the spinal absorption pathway in humans remain unclear and, to ...

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