Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer.

PURPOSE: A large proportion of the practice of radiotherapy in the management of metastatic adenocarcinoma of the prostate is associated with palliation of pain from osseous metastases and improving quality of life. Radiation therapy is well known to be effective in treating painful sites and may also be effective in reducing the propensity for adjuvantly treated disease to become symptomatic. Strontium-89 is a systemic radionuclide that has clinical efficacy in the palliation of pain from bony metastases. METHODS AND MATERIALS: The study was a Phase-III randomized placebo control trial performed in eight Canadian Cancer Centers to evaluate the effectiveness of strontium-89 as an adjunct to local field radiotherapy. Patients with endocrine refractory metastatic prostate cancer received local field radiotherapy and either strontium-89 as a single injection of 10.8 mCi or placebo. RESULTS: One hundred twenty-six patients were recruited. No significant differences in survival or in relief of pain at the index site where noted. Intake of analgesics over time demonstrated a significant reduction in the arm treated with strontium-89. Progression of pain as measured by sites of new pain or the requirement for radiotherapy showed statistically significant differences between the arms in favor of strontium-89. Tumor makers including prostate specific antigen, acid phosphatase, and alkaline phosphatase were also reduced in patients receiving strontium-89. A Quality-of-Life analysis was performed as a multivariate data set and demonstrated an overall superiority of strontium-89 with alleviation of pain and improvement in physical activity being statistically significant. Toxicity was evaluated and demonstrated increased hematological toxicity in the group receiving strontium-89. CONCLUSIONS: It is concluded that the addition of strontium-89 is an effective adjuvant therapy to local field radiotherapy reducing progression of disease as evidenced by new sites of pain and the requirement of further radiotherapy and improving quality-of-life and need for analgesic support in this group of patients.

Routine application of fractionated HMPAO stored at -70 degrees C for WBC scintigraphy.

The radiochemical purity of 99mTc-HMPAO prepared from fractions of reconstituted HMPAO stored at -70 degrees C and its application in the radiolabeling of human granulocytes was investigated. Upon reconstitution of a vial of HMPAO with 1 ml of saline and subsequent freezing at -70 degrees C, small fractions were obtained on each of four consecutive days with the vial being refrozen after each dispensing. Following radiolabeling of the HMPAO fractions with pertechnetate, mean radiochemical purity results met or exceeded manufacturers' specifications for the radiopharmaceutical on each of the four days. Imaging with radiolabeled granulocytes using 99mTc-HMPAO prepared by this technique resulted in high quality clinical studies. These results demonstrate that a vial of HMPAO can be fractionated, after storage at -70 degrees C with no loss of clinical utility for radiolabeling granulocytes and considerable cost savings.

Dose estimation in strontium-89 radiotherapy of metastatic prostatic carcinoma.

Strontium-89 radiotherapy is becoming an important treatment in the palliation of bone pain from osteoblastic metastases. The absorbed dose delivered to bone metastases during 89Sr radiotherapy has been estimated in four patients with metastatic prostatic carcinoma. Patients were injected with a tracer dose of 85Sr-chloride. Blood and urine samples were obtained during the week following injection. Strontium-85 scintigrams of metastases and normal bone were obtained up to 8 wk postinjection. Half of the patients showed elevated whole-body retention; plasma-strontium concentrations were decreased from normal values. Uptake of strontium in metastases was 2-25 times that in normal bone but rates of washout of strontium from metastases were similar to those from normal bone. Absorbed doses delivered in infinite time to the metastases by 89Sr ranged from 21 +/- 4 to 231 +/- 56 cGy/MBq with a median value of 68 cGy/MBq. Doses to red marrow were less by a factor of 2 to 50. These absorbed doses are sufficiently large to be expected to produce a therapeutic benefit.

Radioiodine secretion in tears.

UNLABELLED: Lacrimal secretion of radioiodine has been suspected from previous scintigraphic observations. We semiquantitated radioiodine secretion in the tears of a thyroid-ablated patient with an artificial eye while the patient was on thyroxine treatment. METHODS: After an oral dose of 555 MBq (15 mCi) 123I, 12 tear samples were collected over 24 hr by using Schirmer papers. Radioactivity in each sample was determined in a well counter 27 hr after radioiodine ingestion and was corrected for decay and counting efficiency. RESULTS: Radioactivity was detectable at 15 min and at up to 24 hr after radioiodine ingestion and peaked at around 60 min (215 Bq/microl or 39 x 10(6)% of the administered dose/microl. Considering a tear-flow rate of 1 microl/min, the total radioactivity secreted in the first 4 hr was estimated to be 56 kBq, representing about 0.01% of the administered dose. CONCLUSION: An appreciable amount of ingested radioiodine could be secreted in tears. The potential damage of the lacrimal gland after high doses of 131I treatment deserves further study.

99mTc-human serum albumin scans in children with protein-losing enteropathy.

UNLABELLED: Protein-losing enteropathy (PLE) can be diagnosed scintigraphically using 99mTc-human serum albumin (HSA) scans. METHODS: To evaluate the usefulness of this method in detecting enteric protein loss, we retrospectively reviewed the 99mTc-HSA scans of 18 children presenting consecutively with PLE. RESULTS: Enteric 99mTc-HSA uptake was noted in 12 patients (8 boys, 4 girls) with a mean age of 7.4 y. Early dynamic images showed abdominal uptake that was most likely in the small bowel in 91% of the scans. Delayed images showed abnormal accumulation that was localized in the colon in 73% and in the small bowel in 27% of the scans. A 4-mo follow-up scan obtained in 3 patients showed reduced HSA uptake after a high-protein, low-fat, medium-chain triglyceride oil-based diet and fat-soluble vitamins. Mean serum albumin, total protein, gammaglobulin, and calcium levels were significantly decreased. Ten patients (from 4 families) were diagnosed to have primary intestinal lymphangectasia. One patient had active Salmonella enterocolitis, and 1 had giardiosis. 99mTc-HSA was normal in the remaining 6 patients (3 boys, 3 girls) with a mean age of 3.5 y (range, 2-5 y). Mean serum albumin, total protein, gammaglobulin, and calcium levels were less decreased than those of the first group. Five of these patients had primary intestinal lymphangactesia (associated with infantile systemic hyalinosis in 1 patient). The remaining patient had normal duodenal biopsy, and the cause of protein loss remained unknown. CONCLUSION: The 99mTc-HSA scan is useful in the evaluation of children with PLE, especially those with severe hypoproteinemia and hypoalbuminemia, presumably reflecting a high rate of protein loss.

Hepatic uptake of technetium-99m HM-PAO in a fetus.

The normal biodistribution of technetium-99m HM-PAO ([99mTc]HM-PAO) includes significant uptake in the brain, liver, and kidneys. A pregnant patient studied with [99mTc] HM-PAO to confirm brain death provided an opportunity to examine the transplacental distribution of this radio-pharmaceutical in the unborn fetus. Uptake in the fetus after transplacental delivery is almost exclusively hepatic with a small amount of biliary excretion.

Renal uptake of technetium-99m methylene diphosphonate following therapeutic radiation for vertebral metastases.

Radionuclide bone scans in two patients with breast cancer and concurrent chemotherapy treatment revealed increased band-like uptake of [99mTc]methylene diphosphonate along the medial upper renal cortex corresponding to the portions of the kidneys included within the radiation field. The latency of onset of abnormal uptake was 5 to 9 mo following completion of radiation in one patient, peaked near 13 to 14 mo for both patients, and returned to baseline after 20 to 27 mo. Transient serum creatinine level elevations were also detected. These findings suggest that transient subclinical renal impairment may occur and be detected on bone scans following inadvertent inclusion of renal cortex in radiation fields.

Strontium-89 and low-dose infusion cisplatin for patients with hormone refractory prostate carcinoma metastatic to bone: a preliminary report.

Strontium-89 has been used for the treatment of painful bony metastases in patients suffering from disseminated adenocarcinoma of the prostate, with a variable proportion of patients obtaining clinically significant reductions in analgesic requirements. Based on data revealing enhancement of continuous low-dose rate irradiation by low-dose cisplatin in murine models, a protocol using 148 MBq (4 mCi) of 89Sr and 35 mg/m2 of cisplatin infused over 2 days, 1 and 4 wk after administration of the radioisotope was undertaken. Preliminary data suggest good pain relief with 55% of 18 patients entered thus far obtaining at least a 50% reduction in analgesic requirements. Improvements in total alkaline phosphatase and serum lactate dehydrogenase have consistently been seen, with some patients exhibiting improvements in hemoglobin, tumor markers and bone scans. Toxicity appears to be mild, with no life-threatening complications. In particular, myelosuppression after one course of treatment was modest, but retreatments in two patients has resulted in grade 3 hematologic toxicity. Two patients developed a "pain flare" after administration of cisplatin. Further accrual to this study will allow more accurate determination of pain response rate, and improved evaluation of parameters of objective response.

The VEX-test for myocardial scintigraphy with thallium-201 and sestamibi: effect on abdominal background activity.

UNLABELLED: High abdominal background activity of 99mTc-sestamibi may interfere with the diagnosis in studies in which a coronary vasodilator is used; supplemental dynamic exercise might reduce this problem. METHODS: Clinical and angiographic determinants of subdiaphragmatic-to-myocardial activity ratios were measured on immediate poststress left anterior oblique images and on corresponding tomographic studies 1 hr after injection in 600 sestamibi studies. Similar measurements were made in 550 historic controls with planar 201Tl imaging. Patients performed symptom-limited ergometry when there were no limiting factors, dipyridamole-handgrip in which ergometry was not possible and VEX (vasodilator followed by symptom-limited ergometry) in which exercise capacity was reduced. RESULTS: Abdominal activity was higher with sestamibi than with 201Tl, in women versus men, and with dipyridamole-based tests compared to exercise alone. Compared to the dipyridamole-handgrip, 3 min of ergometry as part of VEX decreased abdominal background (p < or = 0.02) by 18% on immediate 201Tl images, by 13% on immediate sestamibi images and by 12% on 1-hr delayed sestamibi tomoacquisitions. CONCLUSIONS: Poststress abdominal background activity is influenced by similar factors with both agents. Supplemental exercise following dipyridamole reduces potentially interfering abdominal activity but perhaps not as efficiently with sestamibi as with 201Tl.

Cerebral perfusion imaging with technetium-99m HM-PAO in brain death and severe central nervous system injury.

We performed 38 cerebral perfusion studies in 33 patients with brain death or with severe central nervous system injury using technetium-99m hexamethyl-propyleneamine oxime [( 99mTc]HM-PAO). Uptake by the cerebrum and/or cerebellium was present in all patients who were not clinically brain dead (ten studies) although the study was often abnormal. In those patients who were brain dead, 16/17 studies demonstrated no uptake in either the cerebrum or cerebellum. In patients suspected of brain death, but who had conditions interfering with the diagnosis the test demonstrated no uptake in 9/11 studies, confirming brain death. A radionuclide angiogram (RNA) of the head was also performed in 33/38 studies and showed complete agreement with the [99mTc]HM-PAO uptake, except in one case. We conclude that cerebral perfusion imaging with [99mTc]HM-PAO is a simple, noninvasive and reliable test to confirm brain death. By comparison with conventional technetium agents, [99mTc]HM-PAO is not dependent on the quality of the bolus injection, is easier to interpret and allows evaluation of posterior fossa blood flow.

Pulmonary thallium-201 uptake following dipyridamole-exercise combination compared with single modality stress testing.

Angiographic and clinical determinants of pulmonary uptake of thallium-201 were assessed in a laboratory setting where supine bicycle exercise is used for stress testing in the absence of limiting pharmacologic or physical factors, and where symptom-limited exercise is added to intravenous dipyridamole infusion in other cases. Angiographic correlation was available in 400 patients, including 130 tested with exercise, 94 in whom only handgrip or abbreviated bicycle exercise could be used after dipyridamole, and 176 in whom intravenous dipyridamole was combined with a significant level of exercise. For each test mode, lung/myocardial ratios on the immediate image were highly correlated (p less than or equal to 0.001) with a score based on the number of critical coronary artery stenoses, with grading by contrast ventriculography, and with the number of stenosed (greater than or equal to 50%) arteries; relationships (p less than 0.05) to history of myocardial infarction and to gender were also present. Multiple regression analysis showed the critical stenosis score and ventricular dysfunction to be the only significant determinants. When dipyridamole based tests were compared with exercise, curves of receiver-operating characteristics showed a tendency to better diagnostic performance. When dipyridamole is incorporated in stress testing, the value of increased lung uptake as an ancillary diagnostic sign is similar to that established for exercise.

Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI of the brain and biochemical observations in a patient with 4-hydroxybutyric aciduria; a progressive neurometabolic disease.

We report a five-year-old boy with 4-hydroxybutyric aciduria. The child presented with global developmental delay, severe hypotonia and myoclonic seizures. The urine 4-hydroxybutyric acid was 1038 times that of normal, and other organic acids related to its further metabolism were also increased. Electroencephalography showed findings indicative of cerebral dysfunction. However, other neurophysiological studies were normal. Clinical improvement was observed after the administration of vigabatrin and dextromethorphan. Magnetic resonance imaging of the brain revealed cerebellar vermin atrophy and subtle white matter changes in the cerebral hemispheres. Fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomographic (FDG PET) scan of the brain showed a marked decrease in the cerebellar metabolism, probably related to atrophy of cerebellar vermis and secondary cerebellar deafferentation. FDG PET scan is found to be of value in the understanding and assessment of brain functional alterations. It may be useful in monitoring and optimizing treatment strategies of this rare disease.

Clinical and cerebral FDG PET scan in a patient with Krabbe's disease.

A 2-year, 6-month-old Saudi male with infantile Krabbe's disease was studied with fluorine-18-labeled-2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) scan. The patient presented with a gradual loss of developmental milestones, irritability, and crying. At the advanced stage of the disease, he developed tonic-clonic seizures and became a microcephalic, extremely irritable, blind, spastic quadriplegic child, with no deep tendon reflexes. Laboratory studies revealed normal blood chemistry, muscle enzymes, very long chain fatty acids, and acylcarnitines. No abnormal urinary organic acids were detected. The cerebrospinal fluid protein concentration was increased. Magnetic resonance imaging of the brain revealed mild brain atrophy and white matter disease mainly in the centrum semiovale. Electroretinography was normal; however, electroencephalography and visual-evoked potentials were abnormal. Peripheral nerve conduction studies documented a demyelinating neuropathic process. The FDG PET study of the brain demonstrated a marked decrease in the metabolism of the left cerebral cortex and no uptake in the caudate heads. Normal glucose uptake was observed in the thalami, lentiform nuclei, and cerebellum. The patient did not present for subsequent clinic visits and is presumed dead.

Ischemic left ventricular dysfunction assessed on ECG-gated thallium-201 myocardial perfusion images.

Ischemic dysfunction of the left ventricle can be suggested by ancillary data derived from thallium-201 myocardial perfusion images. In this study, qualitative and quantitative assessments of global and segmental contraction derived from ECG-gated left anterior oblique images were analyzed to define more precisely transient ischemic hypokinesis. Immediate (4 mins post stress) and delayed (2 to 4 h) images were compared in 200 patients; 165 had coronary angiography and 35 had a low probability of coronary artery disease based on pretest and test outcome variables. For both immediate and delayed images, a quantitative index of left ventricular contraction (derived from the time-activity curve of the left ventricular cavity and validated in a previous study), correlated well with contrast ventriculography scores. The index derived from the immediate image also was related to the severity/extent of coronary artery lesions and to thallium-201 lung uptake. The ratio of indices (immediate/delayed) was depressed (P less than 0.001) in patients with two or three critically diseased vessels, and reflected the qualitative assessment of stress-induced dysfunction on cinematic images. These data suggest that the quantitative index derived from ECG-gated perfusion scans may be a valuable indicator of stress-induced ventricular contractile dysfunction.

Screening for a renovascular etiology in hypertensive patients undergoing myocardial scintigraphy: differential renal thallium-201 uptake.

In hypertensive patients with target organ damage the search for possible etiologic factors may be particularly relevant. To evaluate renal symmetry, differential renal uptake of thallium-201 was quantified on renal images at 30 mins to 3 h after tracer injection in 112 hypertensive patients undergoing myocardial perfusion scintigraphy for chest pain. In some patients, renal angiographic status was known at the time of thallium-201 scintigraphy (n = 10), or disease was highly suspected (failed angioplasty, n = 6); the remainder (n = 96) were 'screened' for renovascular disease by renal thallium-201 imaging; 32 normotensive patients with no history of renal disease served as controls. Validation of thallium-201 renal imaging was obtained in a total of 17 hypertensive patients who had correlating contrast angiography, confirming eight cases of unilateral or asymmetric bilateral renovascular disease. Renography with technetium-99m DTPA was performed in 28 patients; differential renal function according to this modality correlated well with differential renal uptake of thallium-201 (r = 0.98). Of the screened hypertensives, eight had marked asymmetry of differential renal uptake and eight had possibly significant asymmetry. Renal thallium-201 imaging provided the first evidence of asymmetric renal perfusion in four cases subsequently confirmed by abdominal angiography. In addition, four post angioplasty cases had persistent or progressive asymmetry of renal perfusion disclosed by this technique. Thus, ancillary renal imaging with thallium-201 can be used to identify hypertensive patients who should be considered for renal angiographic evaluation.

Myocardial uptake and washout kinetics of T1-201 with the VEX (vasodilator plus exercise) test: contribution of stress mode components and coronary stenosis severity.

OBJECTIVE: To assess the vasodilator plus exercise (VEX) test as an adjunct to myocardial perfusion imaging with respect to the accuracy of kinetics of thallium-201 (Tl-201) and other indicators of ischemia. SETTING: A nuclear medicine laboratory in which patients referred for myocardial scintigraphy are triaged to undergo the stress component with symptom-limited bicycle exercise, dipyridamole or VEX as appropriate. DESIGN: Cases having correlating scintigraphy and angiography (n = 425) were selected retrospectively. Immediate poststress and redistribution images were quantified using a circumferential profile analysis with interpolative background subtraction. For each of nine sectors on the left anterior oblique image, multivariate analyses were performed, comparing the relative uptake and net washout of Tl-201 to the exercise workload attained, use of dipyridamole, time to redistribution, gender, and the angiographic presence and severity of stenoses at five key sites. Washout values standardized according to gender, exercise level and time to redistribution, were compared with relative uptake profiles and ST depression using receiver operating curves. RESULTS: For each sector, a significant contribution to Tl-201 washout was made by the exercise level (P < 0.001) and by at least one site of stenosis (P < 0.0001), but not by use of dipyridamole (P > 0.5); female gender was associated with increased washout (P < 0.01) except for the three lateral sectors. For each stress modality, standardized washout performed better than ST depression but not as well as relative uptake profiles in detecting coronary artery disease. CONCLUSIONS: For combined pharmacological-exercise stress, quantitative uptake profiles may assist in confirming subjective scan interpretation; washout profiles, even when standardized for gender and stress level, are suboptimal for confirming defect reversibility.

Stress/injection protocols for myocardial scintigraphy with 99Tcm-sestamibi compared with 201Tl: implications of early post-stress kinetics.

Stress/injection protocols developed for myocardial perfusion imaging with 201Tl may not be optimal for 99Tcm-sestamibi (MIBI), an agent with lower myocardial extraction and higher abdominal uptake; prolongation of exercise after radiotracer injection might improve these relative drawbacks of MIBI. We compared the kinetics of MIBI and 201Tl by acquiring dynamic planar images for 5-7 min after a bolus injection (n = 180 studies) with stress performed by supine bicycle exercise alone, intravenous dipyridamole or combined stress. Routine or prolonged protocols involved continuation of exercise for 1 or 2.5 min respectively after tracer appearance in the heart. Subsequently, the perfusion images obtained were categorized as normal or showing significant defects. Myocardial uptake of MIBI, normalized for injected dose, body weight and camera sensitivity, was only 40% of that for 201Tl; there were no differences based on test mode or scan result for either perfusion tracer. During the second minute after injection, the cavity/myocardial ratios, an index of blood pool activity, were elevated with MIBI by 25% when compared with 201Tl (P < 0.001). During the third minute, cavity activity was again higher with MIBI, but only in those subjects with abnormal scans. The prolonged exercise phase did not prevent progressive accumulation in the abdomen, but did allow cavity levels to decline before termination of exercise. The prolonged protocol may ensure that myocardial uptake of MIBI is completed during peak blood flow, and therefore is recommended for stress with exercise or with dipyridamole and exercise in combination.

Pulmonary uptake of sestamibi on early post-stress images: angiographic relationships, incidence and kinetics.

Early post-stress imaging with 99Tcm-sestamibi has the potential to reveal ancillary markers of severe coronary artery disease. Lung/myocardial ratios of sestamibi were assessed after pharmacologic, exercise or combined stress, and these were compared with historical controls who were stressed similarly, but imaged with 201Tl. Forty initial patients had planar imaging and correlating angiograms; pulmonary uptake for sestamibi related to severe coronary artery stenoses when measured on immediate images, started at 4 min post-stress (P = 0.04), but had a poor relationship to angiographic findings when measured on delayed clinical images. Of 180 subsequent studies, increased pulmonary uptake of sestamibi was seen more frequently (incidence = 34%) in those with abnormal tomograms compared to those with normal tomograms (incidence = 13%, P < 0.01), but appeared less frequently than on abnormal 201Tl studies (incidence = 60%). With sequential imaging for 5 min after injection, pulmonary uptake showed a greater fall with time on sestamibi studies than on matched 201Tl studies. No consistent differences were seen among the stress modalities. As an ancillary sign of haemodynamically severe disease, increased pulmonary uptake can be seen after various stress modalities, but may be more difficult to apply with sestamibi than with thallium imaging.

Markers of left ventricular dysfunction induced by exercise, dipyridamole or combined stress on ECG-gated myocardial perfusion scans.

An index of left ventricular contraction can be extracted from the cavitary time-activity curve of electrocardiographic (ECG)-gated myocardial perfusion scans. To assess the induction of stress-induced myocardial depression, we compared contraction indexes derived from immediate poststress and delayed 201Tl images with indexes of ventricular dilation and lung uptake in the prediction of severe coronary artery disease (defined as two or more 90% stenoses). Stress procedures were performed in 93 patients with symptom-limited supine bicycle exercise alone, and in 227 with intravenous dipyridamole, combined where possible with exercise. The immediate and delayed contraction indexes reflected left ventricular dysfunction on ventriculography (P < 0.0001), but additionally the immediate index was reduced (P < 0.0001) in severe coronary disease. Stress-induced hypokinesis was seen frequently after each of the test modes. The relationship with angiographic findings was better defined for indexes of contraction than for lung uptake or ventricular dilation (P < 0.01). The prediction of severe coronary disease was optimized by combining the poststress contraction index and lung uptake. These data support the use of ECG-gated myocardial scans in evaluating the functional consequences of stress/imaging procedures.

Differential renal uptake of 201Tl: requirements for acquisition, display and quantification.

Renal uptake of 201Tl may have a role in screening for renal asymmetry in hypertensive patients (HP) who are referred for myocardial scintigraphy. The qualitative aspects of digitized planar images, and quantified differential renal uptake (DRU) of 201Tl were rated by comparing a simple technique (S) for outlining each kidney with an interpolative background subtracted technique (IB). These parameters were assessed in an initial series of patients by varying the length of acquisition (from 1 to 5 min), delay in acquisition (from 10 to 210 min after injection), and image preparation (nine-point smoothing). Six blinded observers rated the quality of coded images. Image quality was improved (P less than 0.01) by increasing the length of acquisition to at least 2 min, by smoothing of the images and by imaging within 2 h of 201Tl injection. Variability in quantification of DRU was suboptimal with acquisition for only 1 min and was more adversely affected with S than with IB. Clinical application of the quantitative technique was assessed in 180 HP and 32 normotensive controls. With IB, the normal range for DRU was slightly greater than for S. The two techniques were comparable in identifying abnormal cases and found 21 +/- 3% (S) and 19 +/- 3% (IB) of HP as lying outside the normal 99% confidence interval. Both quantitative techniques showed excellent agreement with renal angiography (n = 24). Furthermore, preliminary experience with surface markers and with 180 degrees tomography suggests the potential for simultaneous correction for renal depth. These data justify the use of adjunctive renal imaging during myocardial scintigraphy with 201Tl.