Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of (188)Re-6D2 was escalated to 54 mCi. SPECT/CT revealed (188)Re-6D2 uptake in melanoma metastases. The mean effective half-life of (188)Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that (188)Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

The new technology of combined transmission and emission tomography in evaluation of endocrine neoplasms.

UNLABELLED: The clinical value of a novel technology of combined transmission and emission tomography (TET) was assessed in patients with endocrine tumors. METHODS: TET technology, which combines simultaneous acquisition of SPECT and CT images, using the same imaging device, allows correct fusion of images of both modalities. TET was performed on 27 patients with known or suspected endocrine tumors. The radiopharmaceuticals used for the emission part of the study were chosen according to the tumor type: (111)In-octreotide for patients with neuroendocrine tumors (n = 10), (99m)Tc-sestamibi for patients with primary hyperparathyroidism (n = 8), (131)I for patients with thyroid cancer (n = 4), and (123)I-metaiodobenzylguanidine and (75)Se-cholesterol for patients with adrenal masses (n = 3 and n = 2, respectively). The additional information provided by TET compared with scintigraphy was assessed for both image interpretation and clinical utility. RESULTS: TET did not provide any additional data in 16 patients (59%), including 5 patients with normal scintigraphy. In 11 patients (41%) with abnormal SPECT findings, TET improved image interpretation by providing a better anatomic localization of SPECT-detected lesions. It showed unsuspected bone involvement in 4 patients, it identified the organs involved and the relationship of the lesions to neighboring structures in 5 patients, and it differentiated physiologic uptake from tumor uptake in 2 patients. TET provided additional information of clinical value in 9 patients (33%). It assisted in better planning of surgery in 2 patients with neuroendocrine tumors and in 2 patients with ectopic parathyroid adenomas. It changed the treatment approach in 2 patients with neuroendocrine tumors and 1 patient with thyroid carcinoma, and it altered prognosis in 2 patients with thyroid malignancy. CONCLUSION: TET enhances the already unique role of nuclear medicine procedures in the assessment and management of patients with endocrine neoplasms.

The fusion of anatomic and physiologic imaging in the management of patients with cancer.

Imaging is of major clinical importance in the noninvasive evaluation and management of patients with cancer. Computed tomography (CT) and other anatomic imaging modalities, such as magnetic resonance imaging (MRI) or ultrasound, have a high diagnostic ability by visualizing lesion morphology and by providing the exact localization of malignant sites. Nuclear medicine provides information on the function and metabolism of cancer. Over the last decade, there have been numerous attempts to combine data obtained from different imaging techniques. Fused images of nuclear medicine and CT (or to a lesser extent, MRI) overcome the inherent limitations of both modalities. Valuable physiologic information benefits from a precise topographic localization. Coregistered data have been shown to be useful in the evaluation of patients with cancer at diagnosis and staging, in monitoring the response to treatment, and during follow up, for early detection of recurrence. Time-consuming and difficult realignment and computation for fusion of independent studies have, until now, limited the use of registration techniques to pilot studies performed in a small number of patients. The development of the new technology of single photon emission computed tomography/CT and positron emission tomography/CT that allows for combined functional and anatomic data acquisition has the potential to make fusion an everyday clinical tool.

Prediction of bone loss in patients with primary hyperparathyroidism using quantitative bone SPECT.

UNLABELLED: Bone loss is a major complication of primary hyperparathyroidism (PHPT), and it has significant implications in the treatment of this disease. Bone turnover was measured in patients with PHPT, using quantitative bone SPECT (QBS), to determine if the rate of bone loss could be predicted before a significant decrease in bone mass occurs. METHODS: Forty-six patients were included in the study. QBS and bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) were done at baseline. The percent deviation of QBS in patients with PHPT from the values in normal matched controls was calculated. BMD was measured again after a mean of 17.5 mo in 38 patients, and in 29 patients a repeat BMD study was done after a mean of 41.4 mo. The change in BMD in patients with high and normal QBS values was compared using the nonparametric Mann-Whitney test. Regression analysis tested the correlation between baseline QBS values and BMD changes over time. RESULTS: For the FN, there was a statistically significant difference in the BMD change between patients with high and normal QBS values for short-term follow-up (-2.82%+/-4.80% versus 1.45%+/-4.67%, p < 0.05) and for long-term follow-up (-3.53%+/-5.34% versus 0.92%+/-2.40, p < 0.02). There was a negative correlation in the FN, r=-0.48 between QBS values and the percentage of change in BMD. There was no significant difference between the percentage of change in BMD in the LS in patients with high and normal QBS values for either short- or long-term follow-up. CONCLUSION: The results of this study show that QBS can predict bone loss in the FN in patients with PHPT. QBS can thus indicate the need for surgery at an early stage of the disease to prevent bone loss.

Quantitative bone SPECT in young males with delayed puberty and hypogonadism: implications for treatment of low bone mineral density.

UNLABELLED: Constitutional delayed puberty (DP) and idiopathic hypogonadotropic hypogonadism (IHH) lead to osteoporosis in adult men. We were interested in whether response to treatment of these conditions by testosterone could be predicted by in vivo quantitative bone SPECT (QBS) measurement of bone turnover and whether testosterone administration affects bone mineral density (BMD) in these subjects. METHODS: In vivo QBS and BMD measurements were performed in the lumbar spine (LS) and femoral neck (FN) of 29 young men with DP and 16 young men with IHH. In vivo QBS and BMD values in these patients were compared to the values obtained from 27 age-matched normal controls. The effect of testosterone treatment was determined by measuring changes in QBS and BMD, before and after treatment of 22 patients with DP and of all 16 patients with IHH. Seven patients with DP were not treated. RESULTS: In vivo QBS values in patients with DP were significantly higher than those in controls (8.44% +/- 2.55%ID/ml compared to 5.63% +/- 1.12%ID/ml x 10(-3), p < 0.001, for the LS; and 7.86% +/- 3.01%ID/ml compared to 4.29% +/- 1.25%ID/ml, p < 0.001, for the FN). One year after testosterone treatment, QBS values in DP were significantly reduced. Pretreatment BMD values in patients with DP were significantly lower than those in normal subjects (0.77 +/- 0.11 g/cm2 compared to 1.03 +/- 0.14 g/cm2, p < 0.0001, for the LS; and 0.89 +/- 0.11 g/cm2 compared to 1.08 +/- 0.18 g/cm2, p < 0.006, for the FN). One year after treatment, BMD values increased significantly (0.91 +/- 0.14 g/cm2, p < 0.0001, for the LS; and 0.97 +/- 0.11 g/cm2, p < 0.0001, for the FN). The seven untreated young men with DP still had significantly lower-than-normal BMD values (0.82 +/- 0.08 g/cm2, p < 0.008, for the LS; and 0.89 +/- 0.05 g/cm2, p < 0.04, for the FN). In patients with IHH, QBS values were not significantly different from those found in normal controls. The values for BMD were significantly lower for both the LS (p < 0.0001) and the FN (p < 0.001). After treatment, BMD values in patients with IHH were still significantly lower than those of normals (p < 0.009 for the LS; and p < 0.006 for the FN). CONCLUSION: Young men with maturation abnormalities show low bone density. Patients with DP and high bone turnover, as revealed by high QBS values, respond to testosterone treatment. Patients with IHH have normal bone turnover and do not respond to testosterone.

Bone loss in patients with chronic renal disease: prediction with quantitative bone scintigraphy with SPECT.

PURPOSE: To determine whether quantitative bone scintigraphy (QBS) with single-energy photon emission computed tomography (SPECT) can help predict which patients with chronic renal disease will show bone mineral density (BMD) loss. MATERIALS AND METHODS: In 18 patients, the percentage of injected dose of technetium-99m methylene diphosphonate per cubic centimeter of bone was measured with QBS SPECT in the lumbar vertebrae and femoral neck. The differences in BMD over an average of 20 months were measured and compared with SPECT measurements. QBS values were also compared with serum bone turnover markers. RESULTS: There was a negative correlation (r = -.54, P < .05 for the lumbar spine and r = -.60, P < .01 for the femoral neck) between QBS values and bone loss. Positive and negative predictive values, sensitivity, and specificity of QBS for bone loss in the lumbar spine were 78%, 71%, 78%, and 71%, respectively, and in the femoral neck, 82%, 100%, 100%, and 78%, respectively. Differences between predictive values of serum bone turnover markers were not statistically significant. CONCLUSION: QBS with SPECT enabled prediction of rapid bone loss in patients with renal disease.

Ga-67 scintigraphy with a dual-head camera.

High quality images are necessary for correct interpretation of Ga-67 studies in lymphoma. The authors were interested if there is a significant change in the quality of the Ga-67 images using a newly introduced dual-head camera compared with a conventional single-head camera. The tomographic spatial resolution, full width at half maximum, was found to be 9.63 mm compared with 13.7 for a single-head camera. The volume sensitivity was 380 cps/microCi/ml per axial cm as compared with 333 cps/microCi/ml, and point source sensitivity was 5.6 cps/microCi compared with 3.8. There was a significant difference (P < 0.001), when using the threshold technique, in the number of counts per pixel over a wide range of volumes and concentrations in phantoms when the two cameras were compared. There was also a significant difference (P < 0.001) in Ga-67 uptake in lymphoma lesions in patients when the same parameters were used for both cameras when using SPECT. The average uptake in lymphoma lesions, using a dual-head camera, was 529 counts/pixel with a range of 112 to 1275 counts/pixel in different tumors. With a single-head camera, the average for the same tumor was 216 counts/pixel with a range of 59 to 469 counts/pixel. The high sensitivity of the dual-head camera enabled high-quality, whole body scintigraphy, including the limbs, in 20 minutes compared with the 35 minutes necessary for the single-head camera for images which did not include the legs. Whole body Ga-67 scintigraphy is shown to be important in patients with lymphoma of the upper and lower limbs.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-photon emission computed tomography quantitation of gallium citrate uptake for the differentiation of lymphoma from benign hilar uptake.

PURPOSE: To assess the role of quantitative gallium citrate (Ga 67) single-photon emission computed tomography (SPECT) in differentiating lymphoma from benign hilar uptake, concentrations of Ga 67 in 29 sites of documented lymphoma and in 75 benign lesions were compared. PATIENTS AND METHODS: One hundred seven thoracic Ga 67 SPECT studies obtained in 101 consecutive lymphoma patients were reviewed. Fifty-nine studies detected Ga 67 uptake in the hilar and or mediastinal regions. Forty-eight studies showed no such abnormality. The concentration of Ga 67 in the thoracic lesions was measured using a quantitative SPECT technique and its nature was determined by correlation with computed tomographic (CT) scans and follow-up evaluation of the sites. RESULTS: In 20 of 59 abnormal studies (34%), there was lymphoma in the hilar and or mediastinal regions. In the remaining 39 abnormal studies (66%), Ga 67 uptake was benign. There were 29 sites of lymphoma and 75 benign lesions. The concentration of Ga 67 in lymphoma was significantly higher than in benign hilar uptake (13.2 +/- 5.4 %ID/mL x 10(-3) v 5.6 +/- 1.5 % injected dose (ID)/mL x 10(-3); P < .001). A concentration value of 8.3 %ID/mL x 10(-3) was found to best separate lymphoma and benign uptake, with a sensitivity of 90%, a specificity of 93%, a positive predictive value of 84%, and a negative predictive value of 96%. CONCLUSION: Lymphoma and benign hilar uptake differ significantly in their concentration of Ga 67. The present study shows that quantitative Ga-67 SPECT reliably differentiates lymphoma and benign uptake.

Bone turnover in cortical and trabecular bone in normal women and in women with osteoporosis.

UNLABELLED: This study is based on the assumption that is bone turnover, shown by the uptake of 99mTc-MDP, indicates a high rate of bone loss in patients with osteoporosis, it could potentially predict bone loss in patients at risk before significant bone loss has occurred. METHODS: Quantitative bone SPECT (QBS) using 99mTc-MDP, expressed as the %ID/cc x 10(-3), was performed in 71 women who had osteoporosis in the lumbar vertebrae, the femoral neck or both, and in 54 age-matched normal female controls. Of the women with osteoporosis, 42 had postmenopausal osteoporosis and 29 had primary hyperparathyroidism (HPT) and osteoporosis. RESULTS: QBS increased with age in the cortical bone and decreased in the trabecular bone of the normal women. Quantitative bone SPECT in the femoral neck was 3.18 +/- 1.20 and was 2.73 +/- 1.06 in the femoral shaft in 20 women with postmenopausal osteoporosis of the femoral neck. In 19 women with HPT and osteoporosis of the femoral neck, the QBS value in the femoral neck was 3.57 +/- 0.92 and in the femoral shaft 3.38 +/- 1.12. These values were also significantly higher for the femoral neck and for the femoral shaft than those of normals. Although QBS values were higher in the lumbar region in 39 women with postmenopausal osteoporosis (4.59 +/- 1.45) and in 27 women with HPT (4.30 +/- 1.52), as compared with the normal group (4.28 +/- 1.61), the difference was not statistically significant. CONCLUSION: This study shows that bone turnover is significantly higher in the cortical bone of women with osteoporosis than in normal women.

SPECT quantitation of cobalt-57-bleomycin to predict treatment response and outcome of patients with lung cancer.

UNLABELLED: Our hypothesis is that the concentration of 57Co-bleomycin (Co-bleo) in lung tumors reflects tumor cell kinetics and thus, prognosis. The relationship between the tumor concentration of Co-bleo measured in vivo by quantitative SPECT, response to chemotherapy and survival was investigated. METHODS: Twenty patients with small-cell lung carcinoma (SCLC) and 49 patients with non-small-cell lung carcinoma (NSCLC) were studied. The concentration of Co-bleo was measured by SPECT in vivo in the tumor. The correlation between Co-bleo concentration in the tumor and the fraction of Co-bleo bound to DNA was investigated in an EMT6 murine tumor model and in samples of eight human tumors. RESULTS: Tumors that did not respond to treatment showed a significantly higher Co-bleo concentration 8 hr after injection than tumors that responded (5.83% +/- 1.97% ID/cc * 10(-3) versus 2.55% +/- 1.23% ID/cc * 10(-3), p < 0.001). Values of Co-bleo concentration of 2.97% ID/cc * 10(-3) for SCLC and 2.72% ID/cc * 10(-3) for NSCLC were found to best separate patients into short- and long-term survival groups. In the EMT6 murine tumor model, a good correlation was found between the concentration of Co-bleo in the tumor and the fraction of Co-bleo bound to DNA (r = 0.75). In human tumor samples, a good correlation was found between DNA-bound Co-bleo measured in vitro and the concentration measured in vivo by SPECT (r = 0.85). CONCLUSIONS: SPECT-measured Co-bleo concentration predicts the response to treatment and the outcome in patients with lung tumor by showing Co-bleo binding to DNA and tumor cell kinetics.

In vivo measurements of the fraction of dose of bleomycin labeled with cobalt 57 delivered to human tumors.

Concentrations of bleomycin labeled with cobalt 57 (Co-bleo) over time were measured in vivo in 17 patients with 32 sites of lymphoma and 18 patients with lung tumors after administration of the same dose of bleomycin. There were marked variations in individual tumor drug concentrations even among tumors with the same histologic type, indicating that the tumor concentration of this drug in individuals cannot be predicted from the administered dose. Also, tumor concentration could not be predicted from the area under the concentration over time curve (AUC) of Co-bleo in the blood; there was no correlation (r = 0.53) between the AUC and the concentration in the tumor at any point in time between 30 minutes and 8 hours after injection. There was no significant difference in the percent of the injected dose per milliliter (%ID/ml) which was delivered to the tumor when low and high amounts of bleomycin were administered to the same patient. Also, a good correlation (r = 0.88) between the %ID/ml over time was found when injection of low and high doses of bleomycin were compared. The results indicate that using quantitative single photon emission computed tomography (SPECT) and a labeled tracer dose it is possible to predict what fraction of the dose of a chemotherapeutic drug will concentrate in an individual patient's tumor in vivo. They also show that, for bleomycin, escalation of dose will result in a proportional increase of tumor concentration. This increase depends on individual properties of tumors which can be measured quantitatively in vivo by SPECT and are expressed as percent of %ID/ml of tumor tissue.

SPECT quantitation of iodine-131 concentration in phantoms and human tumors.

The validity of SPECT measurement of iodine-131 (131I) concentration was tested in vitro in phantoms and in vivo by measuring bladder urine concentrations. Phantom studies comparing known and SPECT measured concentrations showed a good correlation for 131I (r = 0.98, s.e.e. = 20.94 counts/voxel) for phantoms of 25 to 127 cc and concentrations of 0.13 to 9.5 microCi/cc. The in vivo, in vitro correlation of 131I concentrations in the urine was also good (r = 0.98, s.e.e. = 0.677 microCi/cc). Quantitative SPECT was used to calculate the effective half-life and dosimetry of radioiodine in 12 sites of thyroid carcinoma in seven patients. SPECT was also used to determine the dosimetry of [131I]MIBG (metaiodobenzylguanidine) in two patients with carcinoid, two with neuroblastoma, and one with pheochromocytoma. The radiation dose for thyroid carcinoma metastases varied between 6.3 and 276.9 rad/mCi. The dose from MIBG varied between 13.4 and 57.8 rad/mCi. These results indicate the validity of quantitative SPECT for in vivo measurement of 131I and the need to measure the concentration of 131I in individual human tumor sites.

Administered dose and tumor dose of bleomycin labeled with cobalt-57 in mice and men.

Tumor concentrations of the chemotherapeutic drug, bleomycin, labeled with cobalt-57 (Co-bleo) were compared in mouse tumor models and in human lung tumors using quantitative single-photon emission computed tomography. Drug concentrations in histologically similar human tumors showed marked variability for the same injected dose (ID). Small cell carcinomas showed concentrations between 1.09 and 8.85 %ID/cc x 10(-3) while non-small cell lung tumors showed a concentration variation between 0.36 and 6.75 %ID/cc x 10(-3). In contrast to the situation in human tumors, uptake in mouse tumors showed only slight variability in animals with the same tumor model. EMT-6 tumors in mice showed at 6 hr significantly higher uptake of Co-bleo (p less than 0.001) and significantly higher tumor-to-lung ratio (p less than 0.001) when compared to murine fibrosarcomas. The EMT-6 tumors in contrast to the fibrosarcomas responded to bleomycin treatment in a dose dependent manner. The results indicate that while in mice the tumor dose closely follows the administered dose, in humans, the tumor dose and the tumor-to-lung ratio in the individual patient cannot be predicted from the administered dose.

Permeability of blood vessels in experimental gliomas: uptake of 99mTc-glucoheptonate and alteration in blood-brain barrier as determined by cytochemistry and electron microscopy.

Experimental gliomas were induced in rats by prenatal exposure to ethyl nitrosourea. Changes in the blood-brain barrier were determined by the uptake of a water-soluble compound, 99mTc-glucoheptonate. Increased uptake of 99mTc-glucoheptonate was measured in intact tumors and in various sectors of dissected tumors. The extent of 99mTc-glucoheptonate uptake greatly varied among different tumors and among different sectors of the same tumor. Ultrastructural and cytochemical analysis of the capillary endothelial wall revealed major alterations in tight junctions, which became permeable to horseradish peroxidase. In brain tissue around the tumors, uptake of 99mTc-glucoheptonate and ultrastructure of tight junctions were comparable to normal brain capillaries. The results of the present study indicate that altered endothelial tight junctions may provide the main route of transport of 99mTc-glucoheptonate through the endothelial wall.

The concentration of bleomycin labeled with Co-57 in primary and metastatic tumors.

The concentration over time of bleomycin labeled with Co-57 was measured in 39 primary and metastatic tumor sites in 16 patients using a newly developed and validated single photon emission computed tomography (SPECT) method. There were nine primary tumors, 15 metastatic tumors, and five multifocal lymphomas. Co-bleomycin concentrations also were measured in primary and metastatic B-16 melanoma tumors in mice. In humans, metastases to lymph nodes (1.58 +/- 0.51 %ID/ml X minutes) showed significantly higher (P less than 0.01) tumor cumulative concentrations of Co-bleomycin than metastases to liver, bone, lung, and brain (0.76 +/- 0.20 %ID/ml X minutes). The cumulative concentrations of Co-bleomycin in human lymphomas (1.1 +/- 0.25 %ID/ml X minutes) also were significantly higher (P less than 0.01) than the concentrations in human metastases other than lymph nodes. The cumulative concentration in cerebral metastases (0.65 +/- 0.18 %ID/ml X minutes) was significantly lower (P less than 0.05) than in noncerebral metastases (1.22 +/- 0.53 %ID/ml X minutes). Primary tumors in humans showed higher concentrations of Co-bleomycin than metastases, except for lymph nodes. In contrast with humans, murine metastases showed higher concentrations of Co-bleomycin (6.20 +/- 2.65 %ID/g) than primary tumors (2.94 +/- 0.90 %ID/g) (P less than 0.001). The concentrations of Co-bleomycin in murine tumors that were affected by bleomycin were about three orders of magnitude higher than in human tumors. The results of this in vivo study document the differences in drug delivery of Co-57-labeled bleomycin to human primary and metastatic tumors and show differences in drug delivery between human and murine tumors.

Quantitation of renal uptake of technetium-99m DMSA using SPECT.

Quantitative single photon emission computed tomography (SPECT) methodology based on calibration with kidney phantoms has been applied for the assessment of renal uptake of [99mTc]DMSA in 25 normals; 16 patients with a single normal kidney; 30 patients with unilateral nephropathy; and 17 patients with bilateral nephropathy. An excellent correlation (r = 0.99, s.e.e. = 152) was found between SPECT measured concentration and actual concentration in kidney phantoms. Kidney uptake at 6 hr after injection in normals was 20.0% +/- 4.6% for the left and 20.8% +/- 4.4% for the right. Patients with unilateral nephropathy had a statistically significant (p less than 0.001) low uptake in the diseased kidney (7.0% +/- 4.7%), but the contralateral kidney uptake did not differ from the normal group (20.0% +/- 7.0%). The method was especially useful in patients with bilateral nephropathy. Significantly (p less than 0.001) decreased uptake was found in both kidneys (5.1% +/- 3.4% for the left and 6.7% +/- 4.2% for the right). The total kidney uptake (right and left) in this group showed to be inversely correlated (r = 0.83) with serum creatinine. The uptake of [99mTc]DMSA in single normal kidney was higher (p less than 0.001) than in a normal kidney (34.7% +/- 11.9%), however, it was lower than the total absolute uptake (RT + LT = 41.5% +/- 8.8%) in the normal group. The results indicate that SPECT is a reliable and reproducible technique to quantitate absolute kidney uptake of [99mTc]DMSA.

Quantitative bone scintigraphy using SPECT.

A quantitative single photon emission computed tomography (SPECT) technique for measuring radiopharmaceutical uptake in humans has been applied to bone scintigraphy. The method was validated by comparing SPECT measured percent of injected [99mTc]MDP in 16 normal skulls with well counter measurements of samples of the same bones obtained at surgery. A very good correlation (r = 0.96) was found. A very good interobserver correlation (r = 0.99) and agreement were also obtained when using quantitative bone scintigraphy (QBS). Control SPECT studies of uptake in the right and left iliac bones and the right and left sacroiliac regions in each patient showed no significant differences between the contralateral sides. Studies done in seven subjects at 2 and 4 hr after the same injection and in nine subjects 4 to 8 mo later in the same subjects showed a very good agreement and no significant differences between the two measurements were found. QBS is suggested as an accurate and reproducible index for assessment of the mass of remodeling bone. Preliminary results showed differences in QBS of normal subjects at different ages. A group of 68 young patients aged 18-26 yr showed a significant higher QBS (p less than 0.001) when compared to an older group of 62 patients aged 50-85 yr. There was, however, a wide range of uptake values for the same bone in the same group, suggesting that the method should best be used for following individual patients over time.

A practical SPECT technique for quantitation of drug delivery to human tumors and organ absorbed radiation dose.

A practical quantitative single photon emission computed tomographic (SPECT) technique based on an empirical threshold analysis permits accurate measurements in humans of drug delivery and absorbed radiation dose. The limits of the method have been explored using a wide range of phantom volumes, concentrations, and target-to-nontarget ratios. A threshold of 43% was found to give the best results using volumes of 30 to 3,800 cc. An excellent correlation (r = .99 with a standard error of estimate [SEE] of 41 cc) was found between SPECT measured volumes and actual phantom volumes. A similarly high correlation (r = .98, SEE = 260 counts/voxel) was found in 77 measurements of concentrations between 0.01 and 3.6 microCi/cc. There was a direct relationship between the target-to-nontarget ratio of phantoms and the accuracy of volume measurements. The technique has been validated by an excellent in vivo/in vitro correlation of uptake in human tumors. The tumor cumulative concentration and tumor-to-blood ratio were used for assessment of drug delivery. In vivo quantitative measurements of the pharmacokinetics of technetium-99m (99mTc) glucoheptonate, cobalt-57 (57Co) bleomycin and platinum-195m (195mPt) cisplatin in human tumors in vivo indicates that, in contrast with tumor models in animals, there is a marked variability in drug delivery even in tumors with the same histology. Future development of labeled drugs should make it possible to use quantitative SPECT for predicting tumor response to therapy and for tailoring chemotherapy for the individual patient under treatment. SPECT quantitation of organ concentration was used for Medical Internal Radiation Dose committee (MIRD) calculations of organ absorbed radiation dose from 99mTc-labeled RBCs. Excellent in vivo/in vitro correlations were obtained between SPECT measured concentrations of blood radioactivity in the heart and in vitro measurements of blood samples. The possibilities and limitations of this technique are discussed and its use for in vivo measurement in humans of absorbed radiation dose from radiopharmaceuticals is suggested.

SPECT quantitation of cobalt-57 bleomycin delivery to human brain tumors.

A newly developed and validated noninvasive quantitative SPECT method was used to measure the in vivo uptake of [57Co]bleomycin (Co-bleo) in 13 human brain tumors and the uptake of [99mTc]glucoheptonate (GH) in 23 brain tumors. Significant differences in tumor uptake were found. The tumor concentration over time, the tumor to blood radio at 30 min and the tumor cumulative concentration of radioactivity showed marked differences even between tumors with the same histology. Only a weak correlation was found between tumor concentration of Co-bleo and of GH. Therefore a simple imaging agent such as GH cannot, at the present time, serve as an indicator of individual tumor uptake and further experience with other agents is still necessary. Contrary to the generally held view, no correlation was found between the concentration of drug in the blood and its tumor concentration. It is suggested therefore that the level of a drug in the blood cannot be used as a criterion of the amount that will penetrate the tumor. Direct SPECT measurement of the concentration of the drug in the tumor itself should be performed. The bioavailability of a drug is critical in order for it to exert it tumoricidal effect. The results, showing marked differences in uptake between brain tumors, suggest that before chemotherapy is administered, uptake of the chemotherapeutic drug in the individual tumor to be treated should be assessed and comparisons should be made between the uptake of a series of drugs to determine which drug would be most efficacious on the basis of its uptake as well as its tumor cell killing potential.

Monitoring of 57Co-bleomycin delivery to brain metastases and their tumors of origin.

The concentration of cobalt-57 (57Co)-labeled bleomycin delivered to three brain metastases and to their tumors of origin in the lungs was measured using a single-photon emission computerized tomography technique. In two brain metastases the 57Co-bleomycin concentration measured at different times after the intravenous injection was significantly lower than that in the originating lung tumors (p less than 0.01 and p less than 0.001). In these two patients, the tumor cumulative concentration (TCC) of drug in the brain neoplasm compared to the lung carcinoma was 12.92 versus 15.12 and 10.30 versus 19.74 micrograms/cc/min. In the third patient there was no significant difference in drug concentration between the tumor in the brain and in the lung (TCC 16.02 vs. 15.09 micrograms/cc/min). There was a significant difference in the drug TCC between the three brain metastases: the difference between the lowest and highest concentrations was more than 50% (10.3 vs. 16.02 micrograms/cc/min). When the concentration in the tumor over time (CT(t)) of the 57Co-bleomycin was compared in the brain and lung tumors, a good correlation was found in each of the three cases (r = 0.93, 0.99, and 0.97). This suggests that the difference in drug uptake between brain metastases and their originating lung tumor is a quantitative rather than a qualitative phenomenon. The results show that the amount of drug to which brain metastases are exposed varies and may be very low in some tumors; therefore, effectiveness of drug delivery may play a role in the nonresponsiveness of brain metastases to treatment.