Rex B. Shafer

Monoclonal antibody-targeted radiotherapy of renal cell carcinoma using a nude mouse model

Radiation dosimetry and monoclonal antibody (MAB)‐targeted radiotherapy studies were performed to evaluate the feasibility of using tumor‐preferential MAB as targeting agents for internal radiotherapy of renal cell carcinoma (RCC). Two human RCC xenograft lines, TK‐177G and TK‐82, were established in nude mice and studied using MAB A6H as a targeting agent. This MAB has previously demonstrated excellent in vivo localization to RCC xenografts. Two doses of A6H (13 to 19 μg) labeled with iodine 131 (110 to 130 μCi) caused the tumor to regress or arrested the tumor growth in both xenografts. Similar doses (18 to 43 μg; 120 μCi) of 131I‐labeled control MAB AFP‐22 or of unlabeled A6H did not inhibit tumor growth. While most mice in the control groups had tumors greater than 250 mg in weight by day 43, none of the tumors in mice treated with 131I‐labeled A6H grew to that size during the 3‐month observation period. Sequential computerized scintigraphy was used to calculate the amount of radioiso‐tope localized in tumor versus normal mouse tissue. Therapeutic doses of 131I‐labeled A6H delivered a median calculated radiation dose of 38 cGy/μCi (range, 28 to 57) injected dose to RCC xenografts, and a median of 0.9 cGy/μCi to normal mouse tissues. These findings suggest that A6H is able to target radioisotopes highly specifically to RCC and achieve a therapeutic effect in the experimental setting.

Effects of opioid blockade with nalmefene in older impotent men.

We evaluated the effect of the opioid antagonist nalmefene on the HPG axis and on food consumption in 14 older impotent men. These patients had low to low normal mean serum testosterone values and normal gonadotrophin levels on screening evaluation. Normal response to GnRH was demonstrated in all the men. The protocol called for 24 hours of evaluation before and during administration of nalmefene 2.0 mg IV every 8 hours for 3 doses. During each 24 hour period, the following determinations were made: serum testosterone, FSH, and LH by five separate determinations between 8 AM and noon; 8 AM and 11 PM serum cortisols; 24 hour urine collections for free cortisol; and nocturnal penile tumescence (NPT). Food consumption was measured from 4 PM to 10 AM during the two periods. Nalmefene resulted in significant rises in testosterone, LH, and FSH. Nalmefene significantly elevated morning and evening cortisol measurements in all the patients. Nalmefene decreased total calorie consumption, principally by decreasing fat consumption. There was no effect on NPT. We conclude that in older impotent men, nalmefene acutely increases activity of the HPG axis and decreases calorie intake predominantly by decreasing fat consumption.

Usefulness of mean aortic valve gradient and left ventricular diastolic filling pattern for distinguishing symptomatic from asymptomatic patients

Consecutive, symptomatic (n = 15) and asymptomatic (n = 25) men with aortic stenosis (valve area < 1.2 cm2) and no clinical evidence of myocardial ischemia underwent radionuclide angiography at rest and during supine bicycle ergometry. Ejection fraction, diastolic filling pattern and aortic valve area/gradient were measured on enrollment and when patients became symptomatic (n = 10) or underwent valve replacement (n = 22) during a 2-year follow-up period. Both groups had similar heart rate, blood pressure and ejection fractions, but mean aortic gradients were higher in symptomatic (53 +/- 4 mm Hg) than asymptomatic (37 +/- 2 mm Hg) subjects p < 0.01. Functional limitation evoked by exercise was prevalent even in the asymptomatic group but symptomatic patients exercised to lower work levels than asymptomatic subjects (184 +/- 27 and 307 +/- 32 kg.m/min, respectively, p = 0.02). Ejection fraction failed to increase with exercise in either group. Symptomatic subjects had supranormalization of early diastolic filling with shorter time to the peak filling rate than asymptomatic subjects (137 +/- 16 and 172 +/- 9 ms, respectively, p < 0.05) and a greater first 1/3 filling fraction. The 10 patients who became symptomatic during follow-up had higher first 1/3 filling fractions (53 +/- 7 and 42 +/- 5%, respectively) and mean gradients (41 +/- 4 and 33 +/- 2 mm Hg, respectively) than subjects who remained asymptomatic, p < 0.05. High mean aortic gradients, impaired exercise tolerance and enhanced early diastolic filling distinguish symptomatic from asymptomatic patients.

Exercise thallium testing in ventricular preexcitation

Ventricular preexcitation, as seen in Wolff-Parkinson-White syndrome, results in a high frequency of positive exercise electrocardiographic responses. Why this occurs is unknown but is not believed to reflect myocardial ischemia. Exercise thallium testing is often used for noninvasive assessment of coronary artery disease in patients with conditions known to result in false-positive electrocardiographic responses. To assess the effects of ventricular preexcitation on exercise thallium testing, 8 men (aged 42 +/- 4 years) with this finding were studied. No subject had signs or symptoms of coronary artery disease. Subjects exercised on a bicycle ergometer to a double product of 26,000 +/- 2,000 (+/- standard error of mean). All but one of the subjects had at least 1 mm of ST-segment depression. Tests were terminated because of fatigue or dyspnea and no patient had chest pain. Thallium test results were abnormal in 5 patients, 2 of whom had stress defects as well as abnormally delayed thallium washout. One of these subjects had normal coronary arteries on angiography with a negative ergonovine challenge, and both had normal exercise radionuclide ventriculographic studies. Delayed thallium washout was noted in 3 of the subjects with ventricular preexcitation and normal stress images. This study suggests that exercise thallium testing is frequently abnormal in subjects with ventricular preexcitation. Ventricular preexcitation may cause dyssynergy of ventricular activation, which could alter myocardial thallium handling, much as occurs with left bundle branch block. Exercise radionuclide ventriculography may be a better test for noninvasive assessment of coronary artery disease in patients with ventricular preexcitation.

Acute effects of nicotinic acid on hepatic transport of 99mTc-PIPIDA

Hepatic injury has been associated with nicotinic acid treatment of schizophrenia and hypercholesterolemia. This association was implicated when the liver and biliary tract were not visualized after 99mTc-HIDA in a patient taking 3 g daily of nicotinic acid. We studied hepatic transport of 99mTc-PIPIDA both in vitro in isolated hepatocytes and in vivo in rabbits pretreated with nicotinic acid to further examine this association. Nicotinic acid increased uptake of PIPIDA by isolated hepatocytes and 7 days of nicotinic acid treatment in rabbits produced no abnormalities in hepatic uptake, gallbladder visualization, or biliary excretion of PIPIDA. We conclude that nicotinic acid does not have an inhibitory effect on uptake of biliary imaging agents and actually may be useful in enhancing hepatic imaging in patients with reduced liver function.

In-111 Pseudomonas aeruginosa: A simple method of labeling live bacteria with a gamma-emitting radioisotope

We describe a simple and reliable technique for labeling Pseudomonas aeruginosa with a readily available commercial preparation of indium-111 (111In) oxine. Labeling of a heavy bacterial suspension with 500 μCi of commercially prepared 111In-oxine resulted in a yield of 0.0004 μCi of cell-associated 111In per 106 colony-forming units (CFU). The label was 88% bacterially associated and did not effect viability of the organism. Radiolabeling a gram-negative organism with 111In-oxine provides a nontoxic, stable gamma-emitting bacterial tracer.

Radioactive Vitamin B12 Absorption Studies: Population Distribution of Plasma B12 Absorption and Serum B12

Summary Simultaneous vitamin B12 plasma absorption levels and serum vitamin B12 levels were measured in 1169 consecutive unselected patients. Analysis of the population distribution confirmed the findings of Gräsbeck et al. (1) of a log-normal distribution of the serum vitamin B12 levels. To the contrary, a plot of the cumulative frequencies for distribution of the vitamin B12 plasma absorption levels showed a normal gaussian distribution, except for slight skewing at both extremes. This skewing would be anticipated because of the impossibility of negative values. The mean vitamin B12 plasma absorption level was 3 ± 3.6 pg/ml with a standard deviation of 2.08 pg/ml. Correlation between the plasma vitamin B12 absorption level and the serum vitamin B12 level was 0.1328. When plasma vitamin B12 absorption levels were compared with the logarithm of the serum vitamin B12 levels, the correlation was 0.3722. Eighteen patients were found who had plasma absorption and serum vitamin B12 levels below the 5 percentile. Eight had plasma absorption and serum vitamin B12 values below the 2.5 percentile. An additional eight had plasma absorption measurements below the 5 percentile, while having serum vitamin B12 levels above the 95 percentile. Seven had plasma B12 absorption and serum vitamin B12 levels above the 95 percentile. In no patient was a high plasma vitamin B12 absorption and a low serum vitamin B12 level found.