Treatment of metastatic bone pain with tin-117m Stannic diethylenetriaminepentaacetic acid: a phase I/II clinical study.

The physical characteristics of Sn-117m combined with the biodistribution of the compound tin-117m (Stannic, 4+) diethylenetriaminepentaacetic acid (Sn-117m DTPA) suggest that it should be an excellent agent for the palliation of pain from bony metastases. Prior work has established the dosimetry and the safety for the material in human beings. The presence of low-energy conversion electrons should result in the relative sparing of the bone marrow while delivering a high radiation dose to sites of bony metastatic disease. Forty-seven patients with painful bone metastases from various malignancies were treated with Sn-117m DTPA. The patients were assigned to five different dose levels ranging from 2.64 to 10.58 MBq (71-286 microCi) per kg of body weight. Follow-up included review of pain diaries, performance scores, analgesic requirements, blood chemistries, and hematological assessment. Three patients received a second treatment. There was an overall response rate for relief of pain of 75% (range, 60-83%) in the 40 treatments that could be evaluated. No correlation was apparent in this limited series between response rate and the five dose levels used. The relief was complete in 12 patients (30%). The time to onset of pain relief was 19 +/- 15 days with doses < or = 5.29 MBq/kg and 5 +/- 3 days with doses > or = 6.61 MBq/kg. Myelotoxicity was minimal, with only one patient having a marginal grade 3 WBC toxicity. On the basis of our data, Sn-117m DTPA should be an effective and safe radiopharmaceutical for palliation of painful bony metastases. A large-scale trial is warranted to evaluate it in comparison to other similar agents.

Radionuclide scanning in the evaluation of Kaposi sarcoma.

A patient with Kaposi sarcoma showed increased uptake of sodium pertechnetate Tc 99m over both clinically evident and occult regions of involvement. The clinically negative but scan-positive regions showed pathologic lesions by biopsy. Gallium citrate Ga 67 and bleomycin sulfate labeled with indium 111 (111In) did not concentrate in the lesions, which suggest that Kaposi sarcoma, despite its resemblance to lymphoma, differs from lymphoma substantially with reference to raionuclide uptake. This report confirms that sodium pertechnetate Tc 99m is the most sensitive agent for diagnostic and therapeutic evaluation of patients with Kaposi sarcoma and suggests taht gallium citrate Ga 67 or bleomycin 111In may be useful in the differentiation of Kaposi sarcoma from lymphoma.

Neutralizing antibodies to bovine thyrotropin in immunized patients with thyroid cancer.

Bovine thyrotropin (bTSH) was administered to 17 patients who had thyroid carcinoma. Anti-bTSH antibodies in the patients' sera were detected by three methods: 1) cross-reaction of sera in a homologous bTSH RIA, 2) [125I]bTSH binding to the patients' sera using charcoal to separate bound from free fractions, and 3) gel filtraton to detect [125I]bTSH bound to anti-bTSH in patients' sera. Immunoreactive anti-bTSH antibodies were thus demonstrated in 14 patients. These patients showed specific binding of their sera to [125I]bTSH with the charcoal separation of free from bound hormone. A high titer of antiserum (1:10,000) was found in those patients whose sera reacted strongly in the bTSH RIA (greater than 50 mu U/ml). The binding capacity of the serum of 1 patient was estimated as 2,600 mu U/ml serum. Ten of the patients' sera which showed immunoreactivity to bTSH neutralized bTSH activity in the McKenzie mouse bioassay but did not neutralize the activity of human TSH in this bioassay. Repeated administration of bTSH to 14 patients resulted in development of immunoreactive and neutralizing anti-bTSH antibodies. Development of immunological resistance to bTSH appears inevitable in patients who receive repeated injections of this hormone. Because of the loss of effectiveness of bTSH by antibody formation, the repeated diagnostic and therapeutic use of bTSH is not recommended.

Human reaction to bovine TSH: concise communication.

The incidence of allergic reactions to bovine TSH and its relation to dose have been studied in 42 patients with thyroid cancer who had total ablation of functioning thyroidal tissue and have been followed prospectively for up to 25 yr. Of these patients, 43% showed an allergic reaction to bovine TSH. The remaining 57% have shown no reaction, even though they have received cumulative TSH doses larger than those who did show a reaction. The reaction rate is linear up to a cumulative dose of 150 units and is not dose-related therafter.

Biliary dyskinesia: role of the sphincter of Oddi, gallbladder and cholecystokinin.

The availability of objective and quantitative diagnostic tests in recent years has allowed more precise documentation of biliary dyskinesia. Biliary dyskinesia consists of two disease entities situated at two different anatomical locations: sphincter of Oddi spasm, at the distal end of the common duct, and cystic duct syndrome, in the gallbladder. Both conditions are characterized by a paradoxical response in which the sphincter of Oddi and the cystic duct contract (and impede bile flow) instead of undergoing the normal dilatation, when the physiological dose of cholecystokinin is infused. Quantitative cholescintigraphy can clearly differentiate one disease entity from the other. The therapies of choice are sphincterotomy, sphincteroplasty or antispasmodics for sphincter of Oddi spasm and cholecystectomy for cystic duct syndrome. After quantitative cholescintigraphy, the final impression should identify the disease entity by name to assist the referring physician in making an appropriate therapeutic decision; a mere statement that a test is consistent with biliary dyskinesia is no longer sufficient.

Identification and differentiation of congenital gallbladder abnormality by quantitative technetium-99m IDA cholescintigraphy.

Failure to visualize the gallbladder in its usual location along the right inferior hepatic border suggests many possibilities including acute cholecystitis. The case described here reveals the importance of proper protocol for hepatobiliary imaging with 99mTC-IDA agents, the necessity of quantification of function as an integral part of imaging to enable proper differential diagnosis. A case of bilobed gallbladder presenting as a Valentine heart in an unusual location in the liver is described. The measurement of the CCK-8 induced gallbladder ejection fraction for each lobe facilitated proper diagnosis.

Scintigraphic variations of normal biliary physiology.

We studied 115 healthy adult volunteers, fasting overnight, to establish the normal scintigraphic variability. Five Tc-99m IDA agents with liver excretion half-times ranging from 18 to 108 min were used. The time of appearance of the common bile duct correlated directly with the liver's excretion half-time. The appearance of the gallbladder and the small intestine were independent of the excretion half-time and showed a reciprocal relationship suggesting a major role for the sphincter of Oddi. In 22% of the subjects, the sphincter tonus was tight enough to divert all of the hepatic bile into the gallbladder, allowing none into the intestine. All of such subjects showed normal dynamic response to intravenous cholecystokinin. The pattern of the bile drainage from the two lobes differed, resulting in asymmetry of the right and left hepatic ducts. It is concluded that the selection of a Tc-99m IDA agent should be based on the clinical problem at hand and that a clinician's understanding of the scintigraphic variability in normal subjects is critical before attempting diagnosis.

Filling, postcholecystokinin emptying, and refilling of normal gallbladder: effects of two different doses of CCK on refilling: concise communication.

A study of 18 normal subjects was undertaken to evaluate the rapidity of gallbladder filling with Tc-99m IDA during fast, and the degree of emptying and incidence of refilling after intravenous infusion of either 20 or 40 ng/kg of octapeptide of cholecystokinin (CCK-8). During fast, the frequency of onset of gallbladder filling with Tc-99m IDA at 20, 30, 40, and 42 min was 68%, 84%, 95%, and 100%, respectively. Following CCK-8 infusion, the gallbladder mean ejection period of 11 +/- 4 (s.d.) min and ejection fraction of 40% +/- 23 were similar in subjects given either a 20 ng/kg or a 40 ng/kg dose. The frequency of onset of refilling at 20, 30, 40, and 50 min after CCK-8 was 33%, 63%, 71%, and 79%, respectively for the combined groups. At 50 min after CCK-8, all subjects given 20 ng/kg refilled, whereas only 63% of the 40-ng/kg group did so. There was no correlation between the degree of emptying (ejection fraction) and onset of refilling. We conclude that the frequency of post CCK-8 onset of gallbladder refilling, which reflects sphincter tone recovery, is widely variable, depending upon both the dose and the duration from the time of infusion of CCK-8 and should be taken into consideration if a pre-emptying procedure is adopted during hepatobiliary imaging with Tc-99m IDA agents.

Radiation dose calculation for Tc-99m HIDA in health and disease.

Radiation dose from Tc-99m HIDA has been calculated for normal subjects and for patients with various hepatobiliary diseases classified into four groups based on serum bilirubin level. The calculation was performed on biokinetic radioactivity data from blood, urine, liver, gallbladder, and intestines, using a biological approach that included a catenary model of the digestive organs. For normal subjects the critical organs were the gallbladder and the upper and lower large intestine, with doses of 910, 300, 200 mrad/mCi, respectively. The bone marrow, ovaries, and testes received 24, 62, and 4 mrad/mCi. For Group 4 patients with severe hepatobiliary disease (bilirubin greater than 10 mg/dl), the critical organs were the kidney, urinary bladder, and gallbladder, with doses of 130, 110, and 100 mrad/mCi. The bone marrow, ovaries, and testes received 9, 13, and 6 mrad/mCi. Thus the critical organs and overall radiation doses to organs change between health and disease.

Technetium-99m-Sn-pyrophosphate pharmaco-kinetics and bone image changes in parathyroid disease.

Skeletal abnormalities in 12 patients with primary hyperparathyroidism, five patients with pseudohypoparathyroidism, and three patients with hypoparathyroidism were studied to compare the diagnostic sensitivity of bone radiologic examination to that of radionuclide studies using 99mTc-Sn-pyrophosphate (99mTc-PPi) a skeletal-seeking radiopharmaceutical. The results were compared with bone mineral content as measrued by the Norland--Cameron densitometer. Kinetic data of the blood disappearance and plasma clearance of 99mTc-PPi were obtained and compared with data of control subjects without evidence of parathyroid disease. Bone imaging with 99mTc-PPi may be more sensitive than routine skeletal radiographs and bone mineral analysis for the evaluation of skeletal abnormalities in patients with parathyroid disfunction. The enhanced plasma clearance of the tracer observed in patients with primary hyperparathyroidism may reflect the direct effect of excessive parathyroid hormone on the renal handling of 99mTc-Sn-pyrophosphate.

Detection, localization, and quantitation of degree of common bile duct obstruction by scintigraphy.

The detection, localization, and quantitation of the degree of obstruction was successfully accomplished by [99mTc]IDA scintigraphy in 13 of 14 patients with cholangiographically documented common bile duct (CBD) obstruction. Ductal dilatation was present on ultrasound examination in only seven patients. The accuracy of biliary scintigraphy was enhanced by several innovations including: (a) selection of a radiopharmaceutical with rapid hepatic uptake and excretion; (b) shorter imaging interval over longer period of time; (c) substitution of image parameter for appearance time; and (d) quantitative measurement of bile emptying parameters following cholecystokinin infusion. Scintigraphically, the partial obstruction was characterized by CBD segmental narrowing or intraluminal filling defects and bile stasis within the area and segmental ducts. The gallbladder mean (+/- s.d.) ejection fraction of 20.0 +/- 17.5%, ejection period of 6.8 +/- 1.6 min, and ejection rate of 3.1 +/- 2.6% per min following 3-min infusion of 10 ng/kg of cholecystokinin octapeptide were reduced significantly when compared to control subjects. The level of CBD obstruction correlated well with the results of cholangiography. It is concluded that quantitative biliary dynamic scintigraphy employing modern techniques can accurately detect and localize CBD obstruction.

Quantification of hepatobiliary function as an integral part of imaging with technetium-99m-mebrofenin in health and disease.

A study was undertaken to check the feasibility of measuring the hepatic extraction fraction (HEF) and excretion T-1/2 values as an integral part of hepatobiliary imaging with technetium-99m-mebrofenin in health and disease. In 18 controls subjects, the HEF was 100% and the T-1/2 excretion mean +/- s.e. value was 15.23 +/- 1.4 min. The mean appearance times of the common bile duct (CBD), gallbladder (GB), and small intestine were 15.8 +/- 1.52, 20.2 +/- 2.7, and 23.8 +/- 3.08 min, respectively. Rising serum bilirubin in patients decreased HEF and increased T-1/2 excretion value resulting in delayed appearance of CBD, GB, and small intestine. In control subjects and patients with bilirubin less than 5 mg%, T-1/2 excretion values at 30, 40, and 50 min were similar to those values calculated using the entire 60 min of data, suggesting that the hepatic phase study time could be reduced to 30-40 min and still use the normal reference values established for 60 min. In patients with bilirubin greater than 5 mg%, the data collection duration should be continued for 60 min.

Hepatocyte versus biliary disease: a distinction by deconvolutional analysis of technetium-99m IDA time-activity curves.

A combination of quantitative hepatobiliary imaging techniques was developed to study normal control subjects and patients with 3 categories of hepatobiliary disease: 1) alcoholic cirrhosis; 2) sclerosing cholangitis; and 3) isolated common bile duct obstruction. Scintigraphic images were supplemented by quantitative measurement of hepatic extraction fraction by deconvolutional analysis and liver excretion T 1/2 by a nonlinear least squares method. In diseases confined primarily to the biliary tract (isolated common bile duct obstruction and sclerosing cholangitis), the mean hepatic extraction fraction as measured by deconvolutional analysis was not different from that in normal controls. In severe alcoholic cirrhosis, considered primarily a hepatocyte disease, the hepatic extraction fraction was markedly reduced. The T 1/2 excretion, compared to normal subjects, was prolonged in all three liver disease categories. We conclude that these quantitative parameters were able to detect hepatobiliary disease and to separate severe hepatocyte disease from biliary tract disease.

Quantitative biliary dynamics: introduction of a new noninvasive scintigraphic technique.

We used a Tc-99m-labeled hepatobiliary agent to measure the partition of hepatic bile between gallbladder and intestine in sixteen normal patients and nine patients with cholelithiasis. In normal subjects, the fractions of the hepatic bile that flow into the gallbladder and the small intestine were widely variable, with mean values of 69 +/- 7% (s.e.) and 31 +/- 7% respectively. Bile reflux into the common hepatic duct was rare, occurring during the first 2/3 of the gallbladder ejection period and only when the ejection fraction was greater than 59%. The gallbladder's mean latent period, ejection period, ejection fraction, and ejection rate were 2 +/- 1 min, 11 +/- 1 min, 59 +/- 4%, and 5.9%/min respectively. In patients with cholelithiasis, the fraction of hepatic bile flowing into the gallbladder was normal, but the ejection fraction was significantly reduced (p less than 0.005). For an equivalent dose of cholecystokinin, the gallbladder in cholelithiasis is less responsive than in normal subjects.

Gallbladder dynamics induced by a fatty meal in normal subjects and patients with gallstones: concise communication.

A study was undertaken to establish the pattern of gallbladder emptying in normal subjects and in patients with gallstones, using a fatty meal as stimulus to release endogenous cholecystokinin. The time from meal ingestion to beginning of gallbladder emptying (latent period), the total duration of emptying (ejection period), degree of emptying (ejection fraction), and the rate of emptying (ejection fraction/ejection period) were measured noninvasively by a nongeometric scintigraphic technique. The mean latent period and ejection rate were similar in normal subjects and patients with gallstones, but the mean ejection period and ejection fraction were significantly reduced in the patients. This study suggests that for an identical stimulus, the gallbladder in cholelithiasis begins to empty at the normal time but empties for a shorter duration; the result is a reduction of ejection fraction but not of ejection rate.

Radiation-dose calculation for five Tc-99m IDA hepatobiliary agents.

The radiation absorbed doses from five commercially available hepatobiliary agents--Tc-99m-tagged analogs of IDA (EIDA, PIPIDA, HIDA, PBIDA, DISIDA) have been calculated from biokinetic data in 41 normal subjects. Serial gamma images, with blood and urine samples, were obtained to calculate cumulated radioactivity in the source organs: blood, kidney, bladder, liver, gallbladder, and intestines. The critical organ was the gallbladder, with an absorbed-dose range of 690 to 780 mrad/mCl. Absorbed doses for other target organs were: upper large intestine 320 to 370 mrad/mCi, lower large intestine 210 to 240, small intestine 170 to 200, liver 65 (DISIDA) to 130 (PBIDA), ovaries 63 to 72, and urinary bladder wall 23 (PBIDA) to 36 (EIDA). The radiation absorbed dose was largely independent of changes in chemical structure except in (a) the liver, where absorbed dose varied by a factor of two in proportion to the rate of excretion of the IDA agent from the liver, and (b) the urinary bladder, where absorbed dose varied by a factor of 1.6 because of differences in rate of excretion. When the stimulus for gallbladder emptying is changed from whole-meal ingestion to cholecystokinin injection, the absorbed dose to the gallbladder increases to approximately 1 rad/mCi; if no gallbladder emptying is assumed, its absorbed dose increases to approximately 1.9 rad/mCi. In the absence of contraindication, the gallbladder absorbed dose may thus be decreased by inducing gallbladder emptying at the end of the imaging study.

Diagnosis of clinically unsuspected gallbladder perforation in an obese patient, by Tc-99m IDA cholescintigraphy.

A male Pickwickian syndrome patient was admitted to the hospital with sudden onset of abdominal pain. Physical examination was equivocal. Due to patient's ileus and morbid obesity (weight 450 lb), neither TCT scan nor ultrasound was possible. A Tc-99m PIPIDA hepatobiliary imaging study revealed intraperitoneal leakage of radioactive bile with collection of the activity in both abdominal gutters, indicating gallbladder rupture. Prompt surgery confirmed the diagnosis.

Kinetics of 99mTc-labeled pyrophosphate and polyphosphate in man.

Thekinetic of 99mTc-labeled pyrophosphate were compared with those of polyphosphate in ten patients in a combined study. Both agents cleared from the blood in a biexpoential fashion. The clearance half-time of Exponent I was the same for both and was shorter than the clearance half-time of Exponent ii. Urinary excretion of both agents was the same during the first hour but during the next 3 hr Tc-pyrophosphate cleared at a slightly more rapid rate, resulting in lower blood background radioactivity. Both agents were bound loosely to plasma proteins, mainly to globulin fractions. The sensitivity of lesion detection was similar for both. Excellent bone images were obtained with both agents. The images with Tc-pyrophosphatewere consistently superior owing to the low blood background and they took less time to accumulate an identical number of counts from identical regions. With the amount of 99mTc-complex used, no hyocalcemia or tetany was noted, nor was there any significant effect on 1-hr serum levels of inorganic phosphours and alkaline phosphatase. Four hours after injection, 9.5% of the dose of Tc-pyrophosphate was circulating in blood, 31.7% was excreted in urine, and the remaining 58.8% was taken up by bone and other tissues. The corresponding values with Tc-polyphosphate were 12.5% in blood, 29.0% in urine, and 58.5% in bone and other tissues. Among the soft tissues, the genitourinary system is most consistently visualized. It is concluded that both Tc-pyroposphate and Tc-polyphosphate are excellent skeletal-imaging agents and that Tc-pyrophosphate appears slightly superior to Tc-polyphosphate.

Tin-117m(4+)DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain.

UNLABELLED: Biokinetics and imaging characteristics of 117mSn(4+)DTPA have been studied in patients with metastatic bone pain. METHODS: Seventeen patients with bone pain due to metastasis were given three dose levels: 180 microCi/kg (6.66 MBq/kg), 229 microCi/kg (8.47 MBq/kg) and 285 microCi/kg (10.55 MBq/kg) body weight. Periodic blood and daily urine samples were collected for 14 days to measure percent injected activity retained in blood and that excreted in urine. Simultaneous anterior and posterior view whole-body images were obtained under identical scan settings at 1, 3.5 and 24 hr and on Days 3 and 7 and between 4-6 and 8-10 wk postinjection. The total body retention was calculated using the geometric mean counts. RESULTS: After intravenous injection, the total body clearance of 117mSn(4+)DTPA shows two components: a soft-tissue component and a bone component. The soft-tissue component accounts for 22.4% of the dose and consists of four subcomponents with an average biologic clearance half-time of 1.45 days (range 0.1-3.2 days). The bone component accounting for the remaining 77.6% of the dose shows no biologic clearance. A mean 22.4% of the dose is excreted in urine in 14 days; 11.4% within 24 hr. The uptake pattern appears similar to that of 99mTc-MDP. Peak uptake is observed in normal bone by 24 hr and metastatic lesions by 3-7 days. Pain palliation was observed with all three doses levels. CONCLUSION: Among the four potential bone pain palliation radionuclides, 117mSn(4+)DTPA demonstrates the highest bone uptake and retention. Some biokinetic and radionuclidic features of 117mSn(4+)DTPA are similar to other agents, but many features are different and unique and may make it an ideal bone pain palliation agent. Double-blind comparative studies are needed to determine its exact role in bone pain palliation.

Left ventricular response to submaximal and maximal exercise in asymptomatic aortic regurgitation.

In patients with chronic aortic regurgitation the quantitative changes in loading conditions and left ventricular performance from rest to submaximal exercise have not been related to the magnitude of change observed from rest to maximal exercise. Changes in end-diastolic volume index, as a measure of preload, and measures of contractile performance (ejection fraction and the systolic blood pressure/end-systolic volume index ratio) were assessed at rest, submaximal and maximal supine bicycle exercise using radionuclide angiography in 74 patients with chronic moderate to severe aortic regurgitation. With exercise, end-diastolic volume index decreased in a stepwise manner from 166 +/- 47 to 152 +/- 41 to 143 +/- 41 ml/m2 at rest, submaximal and maximal exercise, respectively. For the entire group, these changes were not associated with a significant change in ejection fraction but were associated with stepwise increases in systolic blood pressure to end-systolic volume index ratio. However, when patients were divided into 3 subgroups based on an increase (group I), minimal change (group II) or a decrease (group III) in ejection fraction from rest to maximal exercise, stepwise increases in systolic blood pressure to end-systolic volume index were again observed in groups I and II but not in group III. These changes were significantly greater in group I than in group II at submaximal and maximal exercise levels. Differences in ejection fraction response and end-diastolic and end-systolic volumes with exercise in the 3 groups were evident at the submaximal exercise level.(ABSTRACT TRUNCATED AT 250 WORDS)