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Skeletal scintigraphy in children
Skeletal Scintigraphy in Children Larry D. Samuels Skeletal scintigraphy in children has not generally been possible until the past 5 yr, since only sTmsr 18F and the phosphate compounds of 99=Tc are recommended for pediatric use and their availability has been limited until very recently. The literature on pediatric use of 87mSr and lSF is reviewed and compared with a series of 200 children scanned with 87mSr in the author's laboratory. Illustrated examples are given of s7mSr diagnosis of malignant bone disease, metastatic bone, sarcoma, and soft tissue sarcoma. as ~well as the nonmalignant diseases osteoarthritis, osteomyelitis, myositis ossificans, growth deformity,
and nonunion of fracture. The necessity for waiting an adequate period of time between injection of sTmSr and scanning is emphasized: at least 2 hr are required for children and 4-5 hr for adults or teenaged patients. The mechanism of uptake of boneseeking nuclides by bone tumors is not known; several theories are considered. Our recent experience suggests that it may be feasible to exploit 87mSr for its general tumor-localizing properties in addition to its bone-seeking property, as has been done with the radioactive gallium isotopes.
H R O U G H O U T THE EVOLUTION of nuclear medicine as a diagnostic specialty in medicine there has been a continuing search for the optimum bone-seeking radionuclide. Among the available calcium isotopes, only calcium-47 has achieved significant clinical use and its energetic gamma emission ( ~ 1 meV) requires special equipment. Radium and strontium were first studied as calcium-mimetic elements primarily because of their associated tissue injury and value as therapeutic agents. Eventually, 85S came into general clinical use in adults for diagnostic visualization of skeletal lesions, but its long physical half-life of 64 hr has greatly limited its use in children. 1 Not until the advent of 87ms and 181c has skeletal scanning in children become possible as a routine procedure. The more recent introduction of 99mTc-polyphosphate by Subramanian et al. has served to popularize this application even further. 3a Strontium-87m, 2 whose associated radiation exposure is only 0.1%-0.2% as great as that from 8nSr,3 has a gamma emmission of 388 keV, which allows its use with routine equipment. Because of its short half-life, 99.6O/o disappears by physical decay alone during the first 24 hr. This short-lived strontium isotope thus appears ideal for pediatric use in a variety of diagnostic problems. Tluorine-18, although it has a 511 keV gamma emission and twice as much
T
From the Nuclear Medicine Laboratory, Children's Hospital, Columbus, Ohio and the Isotopavdelning, Radiumhemmet, Karolinska Instituter, Stockholm, Sweden. Larry D. Samuels, M.D., M.S. : Former Chief, Nuclear Medicine Laboratory, Children's Hospital; AssiStant Professor of Pathology, Ohio State University; Consultant in Nuclear Medicine, St. Anthony Hospital, Columbus. Reprints: Route 1, Columbia, Mo. 65201. (~ I973 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, Vol. 3, No. 1 (January), 1973
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associated r a d i a t i o n e x p o s u r e as 87mSr, is also a c c e p t a b l e for pediatric use a n d has seen l i m i t e d use i n children. T e c h n e t i u m - 9 9 m p o l y p h o s p h a t e z~ will find g r e a t use i n those l a b o r a t o r i e s u s i n g the A n g e r c a m e r a as their p r i m a r y e q u i p m e n t . T h e 140 k e V p e a k g a m m a p h o t o n is ideal for m a x i m a l i n t e r a c t i o n w i t h the t h i n 1/2-in. crystal. T h e 6 - h r p h y s i c a l half-life as well as the lack of b e t a particles k e e p s the r a d i a t i o n dose low. T h i s r e v i e w will c o n c e n t r a t e p r i m a r i l y o n pediatric d i a g n o s t i c s t u d i e s w i t h 87mSr, b a s e d u p o n the a u t h o r ' s e x p e r i e n c e a n d the r a t h e r l i m i t e d literature. O t h e r r a d i o n u c l i d e s will also b e reviewed. It s h o u l d b e k e p t i n m i n d t h a t the d i a g n o s t i c i m p l i c a t i o n s of all b o n e tracers are similar. T h e p h y s i c a l p r o p e r t i e s a n d the associated r a d i a t i o n b u r d e n d a t a d e t e r m i n e the choice of r a d i o p h a r m a c e u t i c a l . MATERIALS AND METHODS Until 1970, onIy nonsterile 87mSr, available by elution from an 87y generator, was available in the United States. The sterile Stercow* 87mSr generator then became available by special arrangement with the European manufacturer. Shortly thereafter, a 87mSr generator from Englandt was marketed in the United States~ and was converted from a non sterile column to a sealed sterile generator similar to that available from the Netherlands. Fluorine-18 is not readily available except to institutions near production reactors or with cyclotron production facilities. It is not possible to keep 18F available at all times as can be done with 87y/87mSr generator. Either alpha particle bombardment of 160 producing the reactions: 160(a, pn)18F and 160(~, 2n) 18Ne B+ ._~ 18F or intense neutron bombardment of lithium carbonate, as in a production reactor, are used for 18F production. Technetium-99m polyphosphate kits are now available from several commercial sources where the pertechnetate eluted from a 99Mo--90mTc generator can be added easily. The 87raSr scans shown in this article were al] obtained with a commercially available dual headed, rectilinear scanner, using 5-in. crystals, 93-hole collimators of 31/z-in. focal depth and 1 cm resolution, and scanning speeds of 100--300 cm/min.w Electronic contrast enhancement of 10%-30% was frequently employed. Image minification, which allows a whole-body scan to be placed on one 14 X 17-in. film, is a useful accessory for this machine, especially for skeletal scanning. One essential step which is mandatory for skeletal scanning with 8?mSr is an adequate interval between the injection of radionuclide and the time of imaging. This time is essential for adequate clearance of radionuclide from the blood and its skeletal localization. Some reports in the literature4,5 have suggested that the best time for beginning scans with 8?mSr was 30--60 min after injection of the radionuclide. In adults and most children, especially adolescents, there is still a very high blood and soft-tissue background count at this time, and the scans obtained will have too little contrast. Even in young children, whose actively growing skeletons normally have a high affinity for 87mSr and a rapid blood clearance of the radionuclide,6 at least 2 hr waiting time between injection of 8"t'mSr and scanning is desirable. With electronic contrast enhancement adequate studies of the extremities usually are possible after 1 hr. In older children and in adults without skeletal disease, there is a relatively low skeletal affinity for 87mSr and, at least a 4--5 hr wait between injection and scanning is essential if meaningful studies are to be obtained. *Phillips-Duphar Co., Petten, Netherlands. ~'Radiochemical Center, Amersham, England. ~Amersham-Searle, Des Plaines, Ill. w Corp., Cleveland, Ohio, Model 54 or 84D.
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This means up to two half-lives of 87mSr will have elapsed before scanning begins. To compensate for this isotope, enough should be administered to ensure good counting statistics at the time of study: even a dose of 10 mCi of 87mSr has only one-half as much radiation dose to bone as 50/~Ci of 85Sr. The .usual dose range for 87mSr in pediatrics is from 0.25 to 2.5 mCi, with up to S mCi total dose given to older children with proven malignant disease. Using the collimators indicated above, this dose will produce a count rate of 15,000--25,000 cpm, which is enough to allow a reasonable scanning speed while retaining an information density of at least 300 ct/cm2. When using the 2 to I minifying accessory, it is acceptable to double the scanning speed, since the effective statistics are quadrupled on the film by reducing the image by one-half. In the latter case, a whole-body scan can be completed on a child 150 cm tall within 1 hr. A typical area scan, e.g., thorax or pelvis, should be completed easily within 30 min, even at full scale size. This compares favorably with gamma camera imaging time, and has the advantage of having the entire image unified on one film. In addition, the energies of 87mSr and 18F are handled more efficiently by the thicker crystal of the rectilinear scanner. As indicated previously, 09mTc gamma photons may be handled well with either instrument. With 18F the usual administered intravenous dose is from 0.5 to 2.0 mCi, with a subsequent wait before imaging of up to 5 hr. Since this "ideal" incubation time consumes nearly three half-lives of the radionuclide (Tp of 12F, 110 min), one usually settles for a wait of about 1 hr.4 Proper positioning of the patient is as important for good skeletal scanning as it is for roentgenography. With the patient lying supine, his arms usually should be elevated above the head to rotate the scapulae away from the lung fields, and the feet should be taped together to reduce involuntary motion artifact, even in the cooperative patient. It is essential to include normal skeletal structures superior and inferior to the area of interest and to always include the contralateral extremity in scans of long bones. Scans of the bones of the skull are usually best obtained by using the same positioning as for brain scanning, obtaining anterior, posterior, and both lateral views. For whole-body scans, only the anterior and posterior scans are needed usually, and if only a single-headed scanner is available it is possible to have useful information from the posterior scan alone. For the feet and ankles, lateral views are desired and may be obtained with the patient lying on his side with one foot in front of the other. (With this positioning the lateral view of one foot will be on the same film with the medial view of the other foot.) Immobilization is mandatory for interpretable skeletal scans. If the patient is cooperative, simple paper taping to the scanning table may suffice to minimize involuntary muscle twitches and jerks. If the patient is restless, only sedation will allow a satisfactory scan (see ConwayTa).
REVIEW OF REPORTED RESULTS
Historical T h e first r e p o r t e d use of s t r o n t i u m i s o t o p e s for the d i a g n o s i s of b o n e t u m o r s w a s i n 1942. T r e a d w e l l , Low-Beer, Friedell a n d L a w r e n c e 8 u s e d SOSr for this p i o n e e r i n g work. S u b s e q u e n t l y , M u l r y a n d D u d l e y ~ u s e d radiog a l l i u m for the d i a g n o s i s of b o n e t u m o r s , b u t f o u n d t h a t u p t a k e w a s n o t constant. Bauer a n d R a y 1~ s t u d i e d 85Sr m e t a b o l i s m a n d u p t a k e i n skeletal lesions, citing selective u p t a k e of the n u c l i d e i n P a g e t ' s disease, o s t e o m y e l i t i s , fracture, m e t a s t a t i c c a r c i n o m a , a n d b e n i g n b o n e t u m o r s (eosinophilic g r a n u l o m a a n d c h o n d r o m a ) . Lesions were d e m o n s t r a t e d o n l y b y e x t e r n a l c o u n t i n g since g a m m a - i m a g i n g e q u i p m e n t w a s n o t y e t available. 11 F l e m i n g , M c I l r a i t h , a n d K i n g is p u b l i s h e d the first p h o t o s c a n s s h o w i n g skeletal m e t a s t a s e s of cancer a n d fractures. By 1965, the use of 85Sr for i m a g i n g s t u d i e s of m a l i g n a n t b o n e l e s i o n s w a s c o n s i d e r e d r o u t i n e , lz H o w e v e r , u p to t h a t time t h e r e were
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only isolated pediatric cases, since the long 64-day physical half-life of ~Sr precluded its widespread use in children. In 1960, Myers 2 first proposed the use of 87mSr for skeletal scintigraphy, citing the advantages of low radiation dose and better imaging because of imuroved statistics and lower energy gamma emission (388 keV). The detection of pediatric bone tumors was included in the first clinical series of Charkes, Sklaroff, and Bierly, 13 but there were few pediatric cases reported during the next 5 yr. Samuels 14 has suggested the uptake of 87mSr by malignant bone tumors in children is somewhat more intense than in benign lesions. The author has also reported that 87mSr scans could be used for the detection and localization of nonossifying, soft-tissue malignant neoplasms as well as bone tumors. 1~ Briggs and Wegner 16 had reported previously the use of 85Sr in the detection of an ossifying soft tissue metastatic lesion. In 1962, Blau, Nagler, and Bender 17 proposed 18F for skeletal imaging but they apvarentlu studied very few children. During the next 5 yr there was little-published clinical material which used laF, especially in pediatrics. The University of Michigan laboratory was among those using 18F and first reported its uptake in extraosseous metastases of osteosarcoma. 18 As mentioned above, Briggs and Wegner 1~ had previously described the uptake of SSSr in calcifying soft-tissue metastases, while Samuels 1~ and Spencer et al. 2~ reported 87mSr visualization of pulmonary metastases of osteosarcoma in children. Subramanian, Bell, and their co-workers at the Upstate Medical Center in Syracuse, New York have shown very promising results with ~176 phosphate. CLINICAL STUDIES
Malignant Bone Disease There were only four children included in the first report by Charkes et al., 13 three of these with primary bone tumors and one teenage girl with a metastatic teratoma. One of the three primary bone tumors did not visualize with 87mSr. This tumor was a benign eosinophilic granuloma, of the type into which 85Sr uptake had been described by Bauer and Ray. 1~ The somewhat greater uptake of 8VmSr by malignant tumors as compared to benign tumors has been noted by the author. 14 Scheer et al. 21 scanned 125 patients with lSF and 87mSr. Of 39 patients with benign bone lesions, 34 had positive scans. Of these, 11 of 12 primary malignant bone tumors had positive scans, whereas only 46 of 70 secondary bone tumors apparently had increased radionuclide uptake. Of 58 patients with roentgenograms positive for malignant tumors, 49 also had positive scans. In this entire series, the youngest patient mentioned was a 16-yr old girl with metastatic Ewing's tumor. Spencer et al. ~~ reported a series of 50 cases, of which 22 were scanned with 87mSr. However, these was only one pediatric patient with a primary bone tumor scanned with 87mSr. Interestingly, one of two pediatric patients with pulmonary metastases from osteosarcoma showed increased uptake of
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SSSr in the metastases. The author made a similar observation about the same time 19 and subsequently published a series of five such cases scanned with 87mSr in 1968. ~ Spencer et al. 2~ did notice an unusual uptake of 87mSr in a pediatric patient with a chromaffinoma, in that there appeared to be uptake of radiostr0ntium into the tumor itself. Kostamis et al. e3 analyzed 36 patients scanned with 87mSr. Included in this Series were five children, two of whom had primary bone tumors (both osteosarcomas with positive scans). In addition, one case of osteomyelitis, one of gout, and one metastatic carcinoma were found to have positive
87mSr scans. French and McCready9'4 have evaluated 57 18F scans and compared them with 100 85Sr scans and 8VmSr scans, but the ages of their patients are not stated. They found that 13 of 17 patients who had roentgenograms positive for tumors also had positive 18F bone scans, while 10 of 30 with negative X-rays had positive scans. Four scans were equivocal. A positive scan was seen with fibrous dysplasia, as Blau et al. iv had previously observed with 18F. Data on blood clearance of 18F indicate that only about 6% of the injected dose remains in the circulating blood by 1 hr after injection (see BlauZVa). These authors began their scans 1-11/2 hr after injection. Moon et al. 25 reported on patients scanned with 18F for tumor detection, of whom four were within the pediatric range of up to 20 yr. Two cases of Ewings" sarcoma had positive scans. An enchondroma and an osteochondroma with positive localization also were included in their series. Of special note is their assay of the amputation specimen of a 12-yr-old girl with Ewing's tumor, in which the 18F content of the osseous tumor was highest but the radioactivity present in the soft tissue component of the tumor was equal to that in nearby normal bone growth centers and 30 times that in muscle.. Detection of recurrent tumor was the prime value of lSF scans in the series of 150 cases reported by Harmer et al. ~6 Thirty-eight per cent of their
Fig. 1. Strontium-87m scintiscan of pelvis of 12-yr-old girl who had~pain in her left hip. Roentgenograms of pelvis and femurs were interpreted as within normal limits but on the scan there is a focus of intense abnormal Uptake extending superiorly from the left acetabulum toward the iliac crest. This was confirmed to be a reticulum cell sarcoma.
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Fig. 2. Strontium 87m scintiscan (A) of both kness of a boy with pain in his right knee, whose X-ray (B) had revealed a radioTucent focus on the medial aspect of the femur just superior to the distal e p i p h y s i s . There is no increased radionuclide uptake associated with the roentgenographically abnormal focus. This is more typical of benign rather than malignant tumors. This was a benign bone cyst.
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patients with normal or equivocal roentgenograms had positive scans, but all positive scans did not indicate malignant tumors:fibrous dysplasia, hypertrophic pulmonary osteoarthropathy, fracture, and inflammatory disease also had positive scans. The number of pediatric patients in this series is not stated. Blau et alY reported on their studies with 18F and the early detection of bone neoplasms, but their experience appears to have been primarily in adults. The author has accumulated a series of 51 children and one 24-yr-old woman, who were scanned with 87mSr f o r suspected bone tumors. 14 By comparing the intensity of uptake of radiostrontium in the tumor with the intensity of t h e normal uptake in skeletal growth centers, 48 of
Fig. 3. Strontium-87m scintiscan of both knees of 16-yr-old boy who had pain in his left knee. There is normal, minimal epiphyseal uptake on the right side, typical of this age, but there is a prominent focus of abnormal uptake in the distal left femur, involving the ePiPhysis but notextending beyond it. There also is a t0ngue-shaped extension of the tumor superiorly up the shaft of the femur, not visible roentgeno~raphically. The author's experience indicates this pattern is mo~'e typ!ca! of'malignant tumors. This was confirmed to be an osteosarcoma.
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52 (92%) of the tumors were correctly assigned preoperatively to either benign or malignant categories. Those tumors whose intensity of 87mSr uptake equaled or surpassed the intensity of uptake in normal epiphyses and growth centers were considered malignant (Figs. 1-3). No primary malignant bone tumor was missed when this criterion was used, although one metastatic neuroblastoma in a child being treated with cyclophosphamide did not show 87mSr uptake. Although there were no false negative primary bone tumors, there were three false positive scans, one due to an unsuspected fracture through a benign bone cyst, one due to an unknown and atypical mycobacterium osteomyelitis (Fig. 6), and one due to a very vascular osteochondroma. A subseries of 34 patients had been specially studied with comparison of independent interpretations of 87mSr scans, roentgenograms, and microscopic diagnosis. 28 In this series, 32 of 34 scan diagnoses were correct as to malignancy or benignity. The two cases that were missed were the unsuspected fracture and the osteochondroma already mentioned. Following this study, the criteria used were tightened so that in the presence of roentgenographic evidence of fracture no guess as to malignancy or benignity is ventured. Furthermore, the time interval between administration of the s7mSr and the start of the study has been extended beyond the 2-hr limit previously employed. In this manner, highly vascular benign tumors no longer appear to have intense uptake of 87~Sr because of persisting high blood-borne activity (Fig. 4). Recently, Alexander and Gillespie~~ have confirmed that a longer injection to study time interval should be used for 87mSr scans, especially in adults.
Fig. 4. Anterior 87mSr scan of abdomen, performed 30-60 min after injection of radionuclide. There is activity in the bladder from urinary excretion, and prominent residual intravascular activitY within the liver, spleen and heart. Bone scans at this time are confusing because of such high vascular background as this; longer injection scan waiting times are mandatory.
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Fig. 5. Strontium-87m scintiscans of both femurs of 12-yr-old girl with recurrent fever and pain in her left thigh. There is increasing uptake along the shaft of the mid-left-femur. The author's experience has shown this pattern to be common in osteomyelitis, which was the case here.
It is necessary to offer a word of caution concerning the differentiation of osteomyelitis from malignant bone tumors. Although roentgenologically, osteomyelitis frequently involves larger areas (such as the entire shaft of a long bone as in Fig. 5 or both sides of a joint space as in Fig. 6), these factors cannot, at this time, be used as definitive criteria in radionuclide diagnosis. Although the author personally has had some success in differentiating malignant and benign tumors with radionuclide imaging techniques, corroboratory studies have not yet been forthcoming from others. More investigative work, obviously, is needed.
Extraosseous Malignant Tumors In the series just reviewed, there has been occasional mention of apparent uptake of bone-seeking nuclides into noncalcifying tumor tissue. ~L2~ Gallium isotopes have been investigated for their general tumor-localizing properties. Concerning 8~mSr, Papavasilou et al. ~~ in adults and myself 15 in children, have studied its potential use in nonosseous lesions. Uptake into such softtissue malignant processes as a subcutaneous leukemic infiltrate (Fig. 7), a noncalcifying fibrosarcoma (Fig. 8), and a alveolar soft-part" sarcoma led to a systematic study of the diagnosis of soft-tissue malignant tumors by 87mSr scanning, le At the present time, it is apparent that many thoracic tumors can be visualized well with s~mSr even if there is no involvement of bone (Fig. 9). A malignant pleural effusion, e.g., appears to show increased 87mSr uptake.
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Fig. 6. Strontium-87m scintiscans of both knees of a boy with pain in his right knee. There is an apparent increase in radionuclide uptake in the distal right femoral epiphysis, extending into the joint space. Such as extension across the epiphysis is more typical of osteomyelitis rather than tumor. The inflammatory etiology was confirmed in this case. (With permission. 14)
Fig. 7. Lateral 87mSr scintiscans of feet of a child who had a swelling on the dorsum of right foot. There is increased concentration of eTmSr in the area of swelling (arrow), suggesting a metabolically active and probably malignant focus in the soft tissue. This was a subcutaneous leukemic infiltrate.
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Abdominal tumors may likewise be imaged with 87mSr. One child who had no palpable tumor but an unusually prominent abdomen had an abdominal S7mSr scan performed (Fig. 10). The resulting pattern of increased 87mSr uptake throughout the abdomen, except for the areas of spleen and liver, led to the impression of diffuse tumor infiltration which was subsequently confirmed surgically. Except for localized Wilms" tumors, which may not have consistent 87mSr uptake, this technique has subsequently been successful in an on-going series of children with abdominal tumors. ~9b abdominal tumors. ~~
Nonmalignant Skeletal Disease Inflammatory bone and joint disease can be scanned with 87mSr,3~ lsF, or SSSr.31 Acute osteomyelitis is characteristically seen as a focus of intense 87mSr uptake throughout the entire medullary canal of the affected bone, frequently crossing the epiphysis into the joint space (Fig. 6) in contrast to malignant bone tumors (Fig. 3), which generally do not cross over epiphyseal lines. Subacute or chronic osteomyelitis typically has a relatively low intensity STmSr uptake so that exacerbations can frequently be detected if previous scans have shown quiescent disease. Inflammatory joint disease produces a localized increase in s7mSr uptake within the joint space itself (Fig. 14). This is quite intense with acute juvenile rheumatoid arthritis, but may decrease after therapy or remission so that the uptake in inactive juvenile rheumatoid arthritis is similar to the joint uptake seen when there is degenerative or traumatic arthritis, z~ Trauma that produces localized bleeding with formation of periosteal or intramuscular hematomas can lead to an abnormal 87mSr image (Fig. 12), either by direct irritation of the adjacent bone or by secondary calcification of the hematoma itself. 3~ Myositis ossificans that are secondary to previous often unrecognized trauma can be difficult to differentiate from malignant
Fig. 8. Posterior sT=Sr scintiscan of both thighs and lower pelvis of a 12-yr-old boy with a swollen left thigh. There is intense soft tissue uptake of 87=Sr in addition to increased uptake over the proximal femur, ex-
tending into the acetabulum. This was proven on biopsy to be a fibrosarcoma. (With permis-
sion. 14)
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tumors on 87=Sr scans, 3a but the location and configuration may provide important distinguishing information. Any active extraskeletal focus of calcification can be visualized by stronti/Im scanning. This includes a wicle variety of disorders such as calcifying tumors, :8"~2"zs'34 (Fig. 9), benign pulmonary disease, and nephrocalcinosis, zs As with skeletal scans, the intensity of 87mSr uptake is a useful measure of how active the ca]cificafion is at the time of scanning. :SF scintiphotos can also be used to visualize extraosseous tumors, ts'3e Fig. 9. (A) Chest X-ray of a 15-yr-old boy with shortness of breath. Diffuse nodular infiltration is present in both lungs. (B) Strontium-87m lung scintiscan shows diffuse uptake throughout both lungs. Diffuse, infiltrative calcifying metastatic osteosarcoma was subsequently confirmed. A possible metastatic lesion in the vicinity of the right humeral head is also visible on the study. (With permission. 14)
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Fig. 10. Strontium-87m scintiscan of abdomen of 6-yr-old girl who had a prominent abdomen but no palpable tumors. There is no significant isotope uptake in the regions of liver, spleen, or ifiac crests (outlined) but there is abnormal localization throughout the abdominal cavity. The author's experience suggests that such a pattern may be seen in patients with diffuse malignant disease, as was confirmed in this case a t laparotomy. Liver and spleen were not involved, just as is seen on the 87mSr scan.
Fig. 11. Strontium-87m scintiscans of knees, showing increased radioactivity in both joint spaces, compatible with bilateral inflammatory joint disease.
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Fig. 12. Strontium-87m scintiscan (L) and corresponding ro~htgenogram (R) of left femur, revealing minimal isotope uptake in a focus beside the femoral shaft, seen on X-ray as a calcifying mass, and suspected of being an osteosarcoma. The relatively low intensity of radionuclide uptake is more suggestive of a benign process; in this case a calcifying subperiosteal hematoma.
Strontium-87m scans have been used for evaluating growth abnormalities 37 that are clue to both metabolic disorders and to injury. Since the radionuclide uptake in the skeleton is directly proportional to the metabolic rate of the growth centers of the skeleton, the intensity of uptake provides a useful and semiquantitative index of growth rate while the scan image allows visualization of the approximate configuration and size of the maior epiphyses. Differences in growth rate across the epiphyses of a long bone, which can lead to significant bowing of the extremity, can thus be seen on the 87mSr scan. a7 Abnormal skeletal growth secondary to other disease, such as hypertrophic pulmonary osteoarthropathy s8 or acromegaly, can also produce abnormal skeletal scintigrams. There is increased affinity for 87mSr at the site of skeletal fractures, aa beginning within hours after the injury, z~ The rate of uptake has been quantitated with respect to the rate of healing in children. 6 Scan images of fractures are especially useful 4~ when there is uncertainty as to whether healing has occurred or whether there is nonunion, since nonunion produces a characteristic pattern on the 87mSr scan (Fig. 13). The presence of an unsuspected fracture through a benign bone cyst can result in the mistaken scan impression of a malignant tumor, for the increased uptake stimulated b y the fracture may simulate the very intense uptake seen in most malignant bone tumors. 15
THE CHOICE OF RADIONUCLIDE FOR BONE SCANNING
The relative advantages and disadvantages of different radionuclides available or potentially available for bone scanning have been considered by several groups 3'sI'41-47 but only with respect to their use in adults. In this context, SSSr is the usual standard by which other materials are judged. In pediatric use, where skeletal dynamics are so different because of the
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Fig. 13. Strontium-87m scintiscan of shoulders of a girl with history of a recent fracture through left clavicle. There is relatively poor uptake in the region of the distal fragment (arrow), suggesting nonunion and probable nonvascularity.
vastly increased affinity of the rapidly growing skeleton for calcium and calcium-mimetic nuclides, different criteria must be used and different conclusions may be expected. The most fundamental consideration for a bone-seeking nuclide for pediatric use in a variety of diseases is safety. Lack of any acute toxicity and minimal total radiation exposure must be considered first. On the other hand, a material must be adequate to produce satisfactory visualization of pathology or its clinical use for children, no matter how safe, is senseless. The most frequent objection to 8VmSr as it is used in adults is the persistantly high blood background activity. This can be responsible for false positive or false negative interpretations. 4a'49 The author feels that in studies with children, assuming a minimum injection to study time interval of 2-3 hr, this is very rarely a significant problem. The practical considerations of availability, cost, and ease of use also favor aVmSr over 18F in most centers. With a sterile yttrium generator now readily available in the United States, as had been the case in Europe for the past 2 yr, availability of 8VmSr is no longer a problem. As mentioned previously, 99mTc polyphosphate complex 3a and similar technitium-labeled phosphate compounds have gained considerable popularity in the past year. The increasing availability of commercial kits and increasingly favorable reports concerning its usage may help it supplant 87mSr or 18F as the agent of choice for imaging of pediatric skeletal disorders. Its use for imaging extraosseous lesions has yet to be shown. The author has had no experience with this radiopharmaceutical. OTHER BONE-SEEKING RADIONUCLIDES
Dysprosium-157 has been studied by the Berkeley group, 41 who found its cyclotron production similar in cost and difficulty to that of ISF, but its 8.1-hr half-life and 326 keV emission are obviously superior to those of 18F. Localization in tumors of bone approximated that with 18F when the two nuclides were compared at weekly intervals in the same patients. Dysprosium-157 did not have as fast a blood clearance as 18F, and the relative skeletal uptake was not as high, however.
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O'Mara et al.42 have studied the lanthanides 17emLutetium and 177Lu, 153Sm, and 171Er for their potential value in bone scanning. Their advantage is a relatively low-energy gamma emission but the total associated radiation exposure is near that from 85Sr and too excessive to seriously consider their use in pediatrics. The same objections must be raised for 131Ba and laSmBa, whose use was reported by Spencer et al. 43 The argument for their use is their superiority to 85Sr,44 but for pediatric use this is a specious argument. There is prominent gastrointestinal excretion, which interferes with visualization of abdominal and pelvic tumors. Thulium-16745 is similar to 131Ba in the radiation exposure associated with its use but its gamma emission, with major peak at 208 keV, allows better collimation and sharper imaging. In terms of relative radiation exposure, 167Tm has only one-third that of SSSr but this is not good enough to justify recommending its development for pediatric nuclear medicine. An 18F-albumin complex was recently proposed as being superior in animal studies of bone-seeking radionuclides 46 but no clinical data are yet available to support this. THE MECHANISM OF RADIONUCLIDE VISUALIZATION OF BONE LESIONS
The mechanism of uptake of bone-seeking radionuclides into malignant tumors remains unknown. This must be said despite several authors' attempts to explain localization of nuclides in focal skeletal lesions as a reaction of the bone to a focus of disease, 1~176 as a reflection of increased blood flow because of a disease focus, ~1 or as alterations in metabolism produced by the disease process. 15 Strontium isotopes are not calcium-mimetic in their kinetics of uptake and excretion but they do appear to be faithfully calcium-mimetic in their sites of active localization. 37 Fluorine-18 has been shown to be deposited directly on the crystalline lattice of bone mineral and probably would be incorporated directly into the lattice if it were stable, ng Undoubtedly, some form of ion exchange at the crystal surface is involved. Isolated cases of the accumulation of nuclide directly into soft-tissue tumor have been seen over the past decade, 2L~5'53 but not until very recently has this been studied systematically. 15"54 The author could find no data as to whether this has ever been observed with 4rCa or if it represents a unique function for Sr isotopes (and possibly also XSF).~n The similarity of this function to that seen with gallium isotopes, which are also bone seekers ~ but which have more recently won acclaim for their tumor-localizing properties 55"56 is probably no coincidence. Data are being accumulated that could answer this puzzle but a unified hypothesis is not yet possible. It does appear likely that the explanations usually given for localization of boneseeking isotopes into malignant bone tumors do not explain the entire mechanism. The author feels that affinity of the tumor tissue for the radionuclide also is an important possibility to be considered. 14 Data now accumulated appear to indicate that a roentgenographically visible or symptomatic bone lesions that have no significant radionuclide uptake is, in all
SKELETAl.. $CINTIGRAPHY
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likelihood, benign, and very possibly may be followed clinically without biopsy. Since the majority of bone lesions should fit into this category, a great deal of surgery is spared when this criterion is applied. Such an approach is now being evaluated. The exception to this, i.e., little or no radionuclide uptake into a primary malignant bone tumor (the false negative scan) is unknown in the author's experience, and no documented exceptions could be found in the literature as well. Up to 10% false positive scans may be seen because of increased radionuclide uptake into nonmalignant disease, 14 but requiring that these patients have biopsy is far less than demanding routine biopsy of all bone lesions in children. With improved technique for bone scanning, one may hope to reduce the number of false positive bone scans, and this should be the goal of any nuclear medicine laboratory. ACKNOWLEDGMENTS I am indebted to Dr. Edward Eyring and to other referring surgeons for the clinical cases included herein, to Mrs. Cornelia Stewart, Mrs. Mary O'Neil and Emil N e w m a n for technical assistance, to Miss G u n Tegstr6m for art work and to USPHS Institutional G r a n t FR05504 and the Brad Roquet Memorial Fund for financial support.
REFERENCES 1. Tefft, M.: More common radionuclide examinations in children: indications for use with a discussion of radiation dose received. Pediatrics 48:802, 1971. 2. Myers, W. G.: Radiostrontium-87m. J. Nucl. Med. 1:124, 1960. 3. Spencer, R., Herbert, R., Rish, M. W., and Little, W. A.: Bone scanning with Sr-85, Sr-87m and F-18. Br. J. Radiol. 44:984, 1971. 3a. Subramanian, G., and McAfee, J. G.: A new complex of 09mTc for skeletal imaging. Radiology 99, 1972. 4. Charkes, N. D.: In Blahd, W. H., ed. 2. (Ed.): Nuclear Medicine. New York, Blakiston, 1971, p. 453. 5. Bratherton, D. G., and Maysent, A. M.: The use of strontium-87m in bone scanning. In McCready, V. R. (Ed.): Radioactive Isotopes in the Localization of Tumors. London, Heinemann, 1969, p. 118. 6. Season, E. H., Eyring, E. J., and Samuels, L. D.: Uptake of Sr-87m in the knee region of children as a parameter of bone turnover, Clin. Orthoped. (In press). 7. Conway; J. J. : Scientific display, Society of N u c l e a r Medicine, Los Angeles, June 1971. 7a. - - : Considerations for the performance of radionuclide procedures in children. Semin. Nucl. Med. 2:305, 1972. 8. Treadwell, A. deG., Low-Beer, V. L., Friedell, H. L., and Lawrence, J. H.: Meta-
bolic studies on neoplasms of bone with the aid of radioactive strontium. Am. J. Med. Sci. 204:521, 1942. 9. Mulry, W. C., and Dudley, H. C.: Studies of radiogallium as a diagnostic agent in bone tumors. J. Lab. Clin. Med. 37:239, 1951. 10. Bauer, G. C. H., and Ray, R. D.: Kinetics of strontium metabolism in man. J. Bone Joint Surg. 40A:171, 1958. 11. - - , and Wendeberg, B.: External counting of Ca-47 and Sr-85 in studies of localized skeletal lesions in man. J. Bone Joint Surg. 41B:558, 1959. 12. Fleming, W. H., McIlraith, J. D., and King, E. R.: Photoscanning of bone lesions utilizing strontium-85. Radiology 77:635, 1961. 13. Charkes, N. D., Sklaroff, D. M., and Bierly, J.: Detection of metastatic cancer to bone by scintiscanning with strontium87m, Am. J. Roentgeno]. 91:1121, 1964. 14. Samuels, L. D.: Diagnosis of malign a n t bone disease with Sr-87m scans. Can. Med. Ass. J. 104:411, 1971. 15. - - , Detection a n d localization of extraskeletal malignant neoplasms of children with strontium-87m. Am. J. Roentgenol. 115:777, 1972. 16. Briggs, R. C., and Wegner, G. P., Osseous metaplasia in soft tissue, J.A.M.A. 195:185-188, 1966. 17. Blau, M., Nagler, W., and Bender,
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M. A.: F-18: a new isotope for bone scanning, J. Nucl. Med. 3:332-334, 1962. 17a. --:18F-Fluoride Imaging. Sem. Nucl. Med. 2:31, 1972. 18. Woodbury, D. H., and Brierwaltes, W. H.: Fluorine-18 uptake and localization in soft tissue deposits of osteogenic sarcoma in rat and man. J. Nucl. Med. 8:646, 1967. 19. Samuels, L. D.: Lung scanning with radiostrontium in metastatic osteosarcoma, Central Chapter, Society of Nuclear Medicine, 1967. 20. Spencer, R., Herbert, R., Rish, M. W., and Little, W. A.: Bone scanning with Sr-85, Sr-87m and F-18. Physical and radiopharmaceutical considerations and clinical experience in 50 cases. Br. J. Radiol. 40:641, 1967. 21. Scheer, K. E., Harbst, H., Kampmann, H., zum Winkel, K., Maier-Borst, W., Lorenz, W. J., and Bilaniuk, L.: Bone scintigraphy with F-18 and Sr-87m. In Medical Radioisotope Scintigraphy, Vol. II. Vienna, IAEA, 1969, p. 325. 22. Samuels, L. D.: Lung scanning with Sr-87m in metastatic osteosarcoma, Am. J. Roentgenol. 104:766, 1968. 23. Kostamis, P., Constantinides, C., Papavasiliou, C., Binopoulos, D., Sfontouris, J., and Malamos, B.: Early detection of bone lesions by photoscanning with radioactive strontium-87m. In Medical Radioisotope Scintigraphy, Vol. II. Vienna, IAEA, 1969, pp. 349-364. 24. French, R. J., and McCready, V. R.: The use of F-18 for bone scanning, Br. J. Radiol. 40:655, 1967. 25. Moon, N. F., Dworkin, H. J., and LaFluer, P. D.: The clinical use of sodium fluoride F-18 in bone photoscanning, JAMA 204:974, 1968. 26. Harmer, C. L., Burns, J. E., Sams, A., and Spittle, M.: The value of fluorine-18 for scanning bone tumors. Clin. Radiol. 20:204, 1969. 27. Blau, M., Laor, Y., and Bender, M. A.: Isotope scanning with F-18 for the early detection of bone tumors, in Medical Radioisotope Scintigraphy, Vol. II. Vienna, IAEA, 1969, p. 341. 28. Wankel, J., Eyring, E. J., and Samuels, L. D.: Diagnostic preoperative Sr-87m bone scans in malignant bone tumors. J. Nucl. Med. (In press). 29. Alexander, J. L., and Gillespie, P. J.:
LARRY D. SAMUELS
The optimum injection-to-scan interval for spinal scans using Sr-87m, Br. J. Radiol. 44:878, 1971. 29a. Papavasiliou, C., Kostamis, P., Constandinidis, C., GiamareIlou, H., Sfoundouris, J., Binopoulos, D., and Nicolaidis, C.: La valeur de la scintigraphie au Sr-87m dans la radioth6rapie palliative du cancer rectocolique r~cidivant. J. Radiol. Electrol. 52:497, 1971. 29b. Samuels, L. D. : Unpublished data. 30. Samuels, L. D.: Sr-87m bone scans in juvenile rheumatoid arthritis. Ann. AIlerg. 29:246, 1971. 31. Muheim, G., and Crutchlow, W. P.: F-18 and Sr-85 scintimetry in the study of primary arthropathies. Br. J. Radiol. 44:290, 1971. 32. Samuels, L. D.: Unpublished data. 33. Bateson, E. M.: Radiological observation on an alveolar soft-part sarcoma complicated by trauma and myositis ossificans. Clin. Radiol. 19:389, 1968. 34. Schall, G. L., Zeiger, L., Primrack, A., and DeLellis, R.: Uptake of Sr-85 by an osteosarcoma metastatic to lung. J. Nucl. Med. 12:131, 1971. 35. Samuels, L. D.: Nephrocalcinosis in children: diagnosis by Sr-87m scan. J. Urol. (In press). 36. O'Mara, R. E., Brettner, A., Danigelis, J., and Gould, H. W.: F-18 uptake within metastatic osteosarcoma of liver: case report. Radiology 100:113, 1971. 37. Samuels, L. D.: Sr-87m uptake and scans in growth disturbances of childhood. Ohio St. Med. J. (In press). 38. Ilingworth, G. I., and Schiess, F. A.: Sr-87m in the prognosis of fractures of the tibia. Proc. Roy. Soc. Med. 64:633, 1971. 39. Myers, W. G., and Olejar, M.: Radiostrontium-87m in studies of healing bone fracture, J. Nucl. Med. 4:202, 1963. 40. Fueger, G. F.: Private communication. 41. Yano, Y., Van Dyke, D. C., Verdon, T. A., Jr., and Anger, H. O.: Cyclotronproduced Dy-157 compared with F-18 for bone scanning using the whole-body scanner and scintillation camera. J. Nucl. Med. 12:815, 1971. 42. O'Mara, R. E., McAfee, J. G., and Subramanian, G.: Rare earth nuclides as potential agents for skeletal imaging. J. Nucl. Med. 10:49, 1969. 43. Spencer, R. P., Lange, R. C., and Treves, S.: Use of Ba-135m and Ba-131 as
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bone scanning agents, J. Nucl. Med. 12:216, 1971. 44. Hosain, F., Syed, I. B., Wagner, H. N~ Jr., and Poggenburg, J. K.: Ionic Ba-135m: a new agent for bone scanning. Radiology 98:684, 1971. 45. Chandra, g., Hernberg, J., Braunstein, P., and Rosenfeld, W.: Tm-167: a new bone scanning agent. Radiology 100:687, 1971. 46. Lorenz, W. J., Krauss, O., Maier Borst, W., et al., Knochenszintigraphie mit kurzlebigen Radionukliden und der positronen Kamera. Radiobiol. Radiother. (Berlin) 11: 171, 1970. 47. Weber, D. A., Greenberg, E. J., Dimich, A., Kenny, P. J., Rathschild, E. O., Myers, W. P. L., and Laughlin, J. S.: Kinetics of radionuclides used for bone studies. J. Nucl. Med. 10:8, 1969. 48. Charkes, N. D.: Some differences between bone scans made with Sr-87m and Sr-85. J. Nucl. Med. 10:491, 1969. 49. Galasko, C. S. B.: False positive and negatives with Sr-87m. J. Nucl. Med. 12:142, 1971.
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50. Charkes, N. D., Young, J., and Sklaroll, D. M.: The pathologic basis of the strontium bone scan. JAMA 206:2482, 1968. 51. Van Dyke, D., Anger, H. O., Yano, Y., and Bozzini, C.: Bone blood flow shown with F-18 and the positron camera. Am. J. Physiol. 209:65, 1965. 52. Posner, A. S., Eanes, E. D., Harper, R. A., and Zipkin, I.: X-ray diffraction analysis of the effect of fluorite on human bone apatite. Arch. Oral Biol. 8:549, 1963. 53. Papavasiliou, C., Kostamis, P., Angelaskis, P, and Constantinides, C.: Localization of Sr-87m in extraosseous tumors. J. Nucl. Med. 12:265, 1971. 54. Samuels, L. D.: Sr-87m scans in children with extraosseous pathology, Am. J. Roentgenol. 109:813, 1970. 55. Edwards, C. L., and Hayes, R. L.: Scannig malignant neoplasms with gallium67, JAMA 212:1182, 1970. 56. Langhammer, H., Glaubitt, G., Grebe, S. F., et al.: Ga-67 for tumor scanning. J. Nucl. Med. 13:25, 1972.
and nonunion of fracture. The necessity for waiting an adequate period of time between injection of sTmSr and scanning is emphasized: at least 2 hr are required for children and 4-5 hr for adults or teenaged patients. The mechanism of uptake of boneseeking nuclides by bone tumors is not known; several theories are considered. Our recent experience suggests that it may be feasible to exploit 87mSr for its general tumor-localizing properties in addition to its bone-seeking property, as has been done with the radioactive gallium isotopes.
H R O U G H O U T THE EVOLUTION of nuclear medicine as a diagnostic specialty in medicine there has been a continuing search for the optimum bone-seeking radionuclide. Among the available calcium isotopes, only calcium-47 has achieved significant clinical use and its energetic gamma emission ( ~ 1 meV) requires special equipment. Radium and strontium were first studied as calcium-mimetic elements primarily because of their associated tissue injury and value as therapeutic agents. Eventually, 85S came into general clinical use in adults for diagnostic visualization of skeletal lesions, but its long physical half-life of 64 hr has greatly limited its use in children. 1 Not until the advent of 87ms and 181c has skeletal scanning in children become possible as a routine procedure. The more recent introduction of 99mTc-polyphosphate by Subramanian et al. has served to popularize this application even further. 3a Strontium-87m, 2 whose associated radiation exposure is only 0.1%-0.2% as great as that from 8nSr,3 has a gamma emmission of 388 keV, which allows its use with routine equipment. Because of its short half-life, 99.6O/o disappears by physical decay alone during the first 24 hr. This short-lived strontium isotope thus appears ideal for pediatric use in a variety of diagnostic problems. Tluorine-18, although it has a 511 keV gamma emission and twice as much
T
From the Nuclear Medicine Laboratory, Children's Hospital, Columbus, Ohio and the Isotopavdelning, Radiumhemmet, Karolinska Instituter, Stockholm, Sweden. Larry D. Samuels, M.D., M.S. : Former Chief, Nuclear Medicine Laboratory, Children's Hospital; AssiStant Professor of Pathology, Ohio State University; Consultant in Nuclear Medicine, St. Anthony Hospital, Columbus. Reprints: Route 1, Columbia, Mo. 65201. (~ I973 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, Vol. 3, No. 1 (January), 1973
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associated r a d i a t i o n e x p o s u r e as 87mSr, is also a c c e p t a b l e for pediatric use a n d has seen l i m i t e d use i n children. T e c h n e t i u m - 9 9 m p o l y p h o s p h a t e z~ will find g r e a t use i n those l a b o r a t o r i e s u s i n g the A n g e r c a m e r a as their p r i m a r y e q u i p m e n t . T h e 140 k e V p e a k g a m m a p h o t o n is ideal for m a x i m a l i n t e r a c t i o n w i t h the t h i n 1/2-in. crystal. T h e 6 - h r p h y s i c a l half-life as well as the lack of b e t a particles k e e p s the r a d i a t i o n dose low. T h i s r e v i e w will c o n c e n t r a t e p r i m a r i l y o n pediatric d i a g n o s t i c s t u d i e s w i t h 87mSr, b a s e d u p o n the a u t h o r ' s e x p e r i e n c e a n d the r a t h e r l i m i t e d literature. O t h e r r a d i o n u c l i d e s will also b e reviewed. It s h o u l d b e k e p t i n m i n d t h a t the d i a g n o s t i c i m p l i c a t i o n s of all b o n e tracers are similar. T h e p h y s i c a l p r o p e r t i e s a n d the associated r a d i a t i o n b u r d e n d a t a d e t e r m i n e the choice of r a d i o p h a r m a c e u t i c a l . MATERIALS AND METHODS Until 1970, onIy nonsterile 87mSr, available by elution from an 87y generator, was available in the United States. The sterile Stercow* 87mSr generator then became available by special arrangement with the European manufacturer. Shortly thereafter, a 87mSr generator from Englandt was marketed in the United States~ and was converted from a non sterile column to a sealed sterile generator similar to that available from the Netherlands. Fluorine-18 is not readily available except to institutions near production reactors or with cyclotron production facilities. It is not possible to keep 18F available at all times as can be done with 87y/87mSr generator. Either alpha particle bombardment of 160 producing the reactions: 160(a, pn)18F and 160(~, 2n) 18Ne B+ ._~ 18F or intense neutron bombardment of lithium carbonate, as in a production reactor, are used for 18F production. Technetium-99m polyphosphate kits are now available from several commercial sources where the pertechnetate eluted from a 99Mo--90mTc generator can be added easily. The 87raSr scans shown in this article were al] obtained with a commercially available dual headed, rectilinear scanner, using 5-in. crystals, 93-hole collimators of 31/z-in. focal depth and 1 cm resolution, and scanning speeds of 100--300 cm/min.w Electronic contrast enhancement of 10%-30% was frequently employed. Image minification, which allows a whole-body scan to be placed on one 14 X 17-in. film, is a useful accessory for this machine, especially for skeletal scanning. One essential step which is mandatory for skeletal scanning with 8?mSr is an adequate interval between the injection of radionuclide and the time of imaging. This time is essential for adequate clearance of radionuclide from the blood and its skeletal localization. Some reports in the literature4,5 have suggested that the best time for beginning scans with 8?mSr was 30--60 min after injection of the radionuclide. In adults and most children, especially adolescents, there is still a very high blood and soft-tissue background count at this time, and the scans obtained will have too little contrast. Even in young children, whose actively growing skeletons normally have a high affinity for 87mSr and a rapid blood clearance of the radionuclide,6 at least 2 hr waiting time between injection of 8"t'mSr and scanning is desirable. With electronic contrast enhancement adequate studies of the extremities usually are possible after 1 hr. In older children and in adults without skeletal disease, there is a relatively low skeletal affinity for 87mSr and, at least a 4--5 hr wait between injection and scanning is essential if meaningful studies are to be obtained. *Phillips-Duphar Co., Petten, Netherlands. ~'Radiochemical Center, Amersham, England. ~Amersham-Searle, Des Plaines, Ill. w Corp., Cleveland, Ohio, Model 54 or 84D.
SKELETAL SCINTIGRAPHY
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This means up to two half-lives of 87mSr will have elapsed before scanning begins. To compensate for this isotope, enough should be administered to ensure good counting statistics at the time of study: even a dose of 10 mCi of 87mSr has only one-half as much radiation dose to bone as 50/~Ci of 85Sr. The .usual dose range for 87mSr in pediatrics is from 0.25 to 2.5 mCi, with up to S mCi total dose given to older children with proven malignant disease. Using the collimators indicated above, this dose will produce a count rate of 15,000--25,000 cpm, which is enough to allow a reasonable scanning speed while retaining an information density of at least 300 ct/cm2. When using the 2 to I minifying accessory, it is acceptable to double the scanning speed, since the effective statistics are quadrupled on the film by reducing the image by one-half. In the latter case, a whole-body scan can be completed on a child 150 cm tall within 1 hr. A typical area scan, e.g., thorax or pelvis, should be completed easily within 30 min, even at full scale size. This compares favorably with gamma camera imaging time, and has the advantage of having the entire image unified on one film. In addition, the energies of 87mSr and 18F are handled more efficiently by the thicker crystal of the rectilinear scanner. As indicated previously, 09mTc gamma photons may be handled well with either instrument. With 18F the usual administered intravenous dose is from 0.5 to 2.0 mCi, with a subsequent wait before imaging of up to 5 hr. Since this "ideal" incubation time consumes nearly three half-lives of the radionuclide (Tp of 12F, 110 min), one usually settles for a wait of about 1 hr.4 Proper positioning of the patient is as important for good skeletal scanning as it is for roentgenography. With the patient lying supine, his arms usually should be elevated above the head to rotate the scapulae away from the lung fields, and the feet should be taped together to reduce involuntary motion artifact, even in the cooperative patient. It is essential to include normal skeletal structures superior and inferior to the area of interest and to always include the contralateral extremity in scans of long bones. Scans of the bones of the skull are usually best obtained by using the same positioning as for brain scanning, obtaining anterior, posterior, and both lateral views. For whole-body scans, only the anterior and posterior scans are needed usually, and if only a single-headed scanner is available it is possible to have useful information from the posterior scan alone. For the feet and ankles, lateral views are desired and may be obtained with the patient lying on his side with one foot in front of the other. (With this positioning the lateral view of one foot will be on the same film with the medial view of the other foot.) Immobilization is mandatory for interpretable skeletal scans. If the patient is cooperative, simple paper taping to the scanning table may suffice to minimize involuntary muscle twitches and jerks. If the patient is restless, only sedation will allow a satisfactory scan (see ConwayTa).
REVIEW OF REPORTED RESULTS
Historical T h e first r e p o r t e d use of s t r o n t i u m i s o t o p e s for the d i a g n o s i s of b o n e t u m o r s w a s i n 1942. T r e a d w e l l , Low-Beer, Friedell a n d L a w r e n c e 8 u s e d SOSr for this p i o n e e r i n g work. S u b s e q u e n t l y , M u l r y a n d D u d l e y ~ u s e d radiog a l l i u m for the d i a g n o s i s of b o n e t u m o r s , b u t f o u n d t h a t u p t a k e w a s n o t constant. Bauer a n d R a y 1~ s t u d i e d 85Sr m e t a b o l i s m a n d u p t a k e i n skeletal lesions, citing selective u p t a k e of the n u c l i d e i n P a g e t ' s disease, o s t e o m y e l i t i s , fracture, m e t a s t a t i c c a r c i n o m a , a n d b e n i g n b o n e t u m o r s (eosinophilic g r a n u l o m a a n d c h o n d r o m a ) . Lesions were d e m o n s t r a t e d o n l y b y e x t e r n a l c o u n t i n g since g a m m a - i m a g i n g e q u i p m e n t w a s n o t y e t available. 11 F l e m i n g , M c I l r a i t h , a n d K i n g is p u b l i s h e d the first p h o t o s c a n s s h o w i n g skeletal m e t a s t a s e s of cancer a n d fractures. By 1965, the use of 85Sr for i m a g i n g s t u d i e s of m a l i g n a n t b o n e l e s i o n s w a s c o n s i d e r e d r o u t i n e , lz H o w e v e r , u p to t h a t time t h e r e were
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only isolated pediatric cases, since the long 64-day physical half-life of ~Sr precluded its widespread use in children. In 1960, Myers 2 first proposed the use of 87mSr for skeletal scintigraphy, citing the advantages of low radiation dose and better imaging because of imuroved statistics and lower energy gamma emission (388 keV). The detection of pediatric bone tumors was included in the first clinical series of Charkes, Sklaroff, and Bierly, 13 but there were few pediatric cases reported during the next 5 yr. Samuels 14 has suggested the uptake of 87mSr by malignant bone tumors in children is somewhat more intense than in benign lesions. The author has also reported that 87mSr scans could be used for the detection and localization of nonossifying, soft-tissue malignant neoplasms as well as bone tumors. 1~ Briggs and Wegner 16 had reported previously the use of 85Sr in the detection of an ossifying soft tissue metastatic lesion. In 1962, Blau, Nagler, and Bender 17 proposed 18F for skeletal imaging but they apvarentlu studied very few children. During the next 5 yr there was little-published clinical material which used laF, especially in pediatrics. The University of Michigan laboratory was among those using 18F and first reported its uptake in extraosseous metastases of osteosarcoma. 18 As mentioned above, Briggs and Wegner 1~ had previously described the uptake of SSSr in calcifying soft-tissue metastases, while Samuels 1~ and Spencer et al. 2~ reported 87mSr visualization of pulmonary metastases of osteosarcoma in children. Subramanian, Bell, and their co-workers at the Upstate Medical Center in Syracuse, New York have shown very promising results with ~176 phosphate. CLINICAL STUDIES
Malignant Bone Disease There were only four children included in the first report by Charkes et al., 13 three of these with primary bone tumors and one teenage girl with a metastatic teratoma. One of the three primary bone tumors did not visualize with 87mSr. This tumor was a benign eosinophilic granuloma, of the type into which 85Sr uptake had been described by Bauer and Ray. 1~ The somewhat greater uptake of 8VmSr by malignant tumors as compared to benign tumors has been noted by the author. 14 Scheer et al. 21 scanned 125 patients with lSF and 87mSr. Of 39 patients with benign bone lesions, 34 had positive scans. Of these, 11 of 12 primary malignant bone tumors had positive scans, whereas only 46 of 70 secondary bone tumors apparently had increased radionuclide uptake. Of 58 patients with roentgenograms positive for malignant tumors, 49 also had positive scans. In this entire series, the youngest patient mentioned was a 16-yr old girl with metastatic Ewing's tumor. Spencer et al. ~~ reported a series of 50 cases, of which 22 were scanned with 87mSr. However, these was only one pediatric patient with a primary bone tumor scanned with 87mSr. Interestingly, one of two pediatric patients with pulmonary metastases from osteosarcoma showed increased uptake of
SKELETAL SCINTIGRAPHY
93
SSSr in the metastases. The author made a similar observation about the same time 19 and subsequently published a series of five such cases scanned with 87mSr in 1968. ~ Spencer et al. 2~ did notice an unusual uptake of 87mSr in a pediatric patient with a chromaffinoma, in that there appeared to be uptake of radiostr0ntium into the tumor itself. Kostamis et al. e3 analyzed 36 patients scanned with 87mSr. Included in this Series were five children, two of whom had primary bone tumors (both osteosarcomas with positive scans). In addition, one case of osteomyelitis, one of gout, and one metastatic carcinoma were found to have positive
87mSr scans. French and McCready9'4 have evaluated 57 18F scans and compared them with 100 85Sr scans and 8VmSr scans, but the ages of their patients are not stated. They found that 13 of 17 patients who had roentgenograms positive for tumors also had positive 18F bone scans, while 10 of 30 with negative X-rays had positive scans. Four scans were equivocal. A positive scan was seen with fibrous dysplasia, as Blau et al. iv had previously observed with 18F. Data on blood clearance of 18F indicate that only about 6% of the injected dose remains in the circulating blood by 1 hr after injection (see BlauZVa). These authors began their scans 1-11/2 hr after injection. Moon et al. 25 reported on patients scanned with 18F for tumor detection, of whom four were within the pediatric range of up to 20 yr. Two cases of Ewings" sarcoma had positive scans. An enchondroma and an osteochondroma with positive localization also were included in their series. Of special note is their assay of the amputation specimen of a 12-yr-old girl with Ewing's tumor, in which the 18F content of the osseous tumor was highest but the radioactivity present in the soft tissue component of the tumor was equal to that in nearby normal bone growth centers and 30 times that in muscle.. Detection of recurrent tumor was the prime value of lSF scans in the series of 150 cases reported by Harmer et al. ~6 Thirty-eight per cent of their
Fig. 1. Strontium-87m scintiscan of pelvis of 12-yr-old girl who had~pain in her left hip. Roentgenograms of pelvis and femurs were interpreted as within normal limits but on the scan there is a focus of intense abnormal Uptake extending superiorly from the left acetabulum toward the iliac crest. This was confirmed to be a reticulum cell sarcoma.
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LARRY D. SAMUELS
t !
t~
Fig. 2. Strontium 87m scintiscan (A) of both kness of a boy with pain in his right knee, whose X-ray (B) had revealed a radioTucent focus on the medial aspect of the femur just superior to the distal e p i p h y s i s . There is no increased radionuclide uptake associated with the roentgenographically abnormal focus. This is more typical of benign rather than malignant tumors. This was a benign bone cyst.
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patients with normal or equivocal roentgenograms had positive scans, but all positive scans did not indicate malignant tumors:fibrous dysplasia, hypertrophic pulmonary osteoarthropathy, fracture, and inflammatory disease also had positive scans. The number of pediatric patients in this series is not stated. Blau et alY reported on their studies with 18F and the early detection of bone neoplasms, but their experience appears to have been primarily in adults. The author has accumulated a series of 51 children and one 24-yr-old woman, who were scanned with 87mSr f o r suspected bone tumors. 14 By comparing the intensity of uptake of radiostrontium in the tumor with the intensity of t h e normal uptake in skeletal growth centers, 48 of
Fig. 3. Strontium-87m scintiscan of both knees of 16-yr-old boy who had pain in his left knee. There is normal, minimal epiphyseal uptake on the right side, typical of this age, but there is a prominent focus of abnormal uptake in the distal left femur, involving the ePiPhysis but notextending beyond it. There also is a t0ngue-shaped extension of the tumor superiorly up the shaft of the femur, not visible roentgeno~raphically. The author's experience indicates this pattern is mo~'e typ!ca! of'malignant tumors. This was confirmed to be an osteosarcoma.
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52 (92%) of the tumors were correctly assigned preoperatively to either benign or malignant categories. Those tumors whose intensity of 87mSr uptake equaled or surpassed the intensity of uptake in normal epiphyses and growth centers were considered malignant (Figs. 1-3). No primary malignant bone tumor was missed when this criterion was used, although one metastatic neuroblastoma in a child being treated with cyclophosphamide did not show 87mSr uptake. Although there were no false negative primary bone tumors, there were three false positive scans, one due to an unsuspected fracture through a benign bone cyst, one due to an unknown and atypical mycobacterium osteomyelitis (Fig. 6), and one due to a very vascular osteochondroma. A subseries of 34 patients had been specially studied with comparison of independent interpretations of 87mSr scans, roentgenograms, and microscopic diagnosis. 28 In this series, 32 of 34 scan diagnoses were correct as to malignancy or benignity. The two cases that were missed were the unsuspected fracture and the osteochondroma already mentioned. Following this study, the criteria used were tightened so that in the presence of roentgenographic evidence of fracture no guess as to malignancy or benignity is ventured. Furthermore, the time interval between administration of the s7mSr and the start of the study has been extended beyond the 2-hr limit previously employed. In this manner, highly vascular benign tumors no longer appear to have intense uptake of 87~Sr because of persisting high blood-borne activity (Fig. 4). Recently, Alexander and Gillespie~~ have confirmed that a longer injection to study time interval should be used for 87mSr scans, especially in adults.
Fig. 4. Anterior 87mSr scan of abdomen, performed 30-60 min after injection of radionuclide. There is activity in the bladder from urinary excretion, and prominent residual intravascular activitY within the liver, spleen and heart. Bone scans at this time are confusing because of such high vascular background as this; longer injection scan waiting times are mandatory.
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Fig. 5. Strontium-87m scintiscans of both femurs of 12-yr-old girl with recurrent fever and pain in her left thigh. There is increasing uptake along the shaft of the mid-left-femur. The author's experience has shown this pattern to be common in osteomyelitis, which was the case here.
It is necessary to offer a word of caution concerning the differentiation of osteomyelitis from malignant bone tumors. Although roentgenologically, osteomyelitis frequently involves larger areas (such as the entire shaft of a long bone as in Fig. 5 or both sides of a joint space as in Fig. 6), these factors cannot, at this time, be used as definitive criteria in radionuclide diagnosis. Although the author personally has had some success in differentiating malignant and benign tumors with radionuclide imaging techniques, corroboratory studies have not yet been forthcoming from others. More investigative work, obviously, is needed.
Extraosseous Malignant Tumors In the series just reviewed, there has been occasional mention of apparent uptake of bone-seeking nuclides into noncalcifying tumor tissue. ~L2~ Gallium isotopes have been investigated for their general tumor-localizing properties. Concerning 8~mSr, Papavasilou et al. ~~ in adults and myself 15 in children, have studied its potential use in nonosseous lesions. Uptake into such softtissue malignant processes as a subcutaneous leukemic infiltrate (Fig. 7), a noncalcifying fibrosarcoma (Fig. 8), and a alveolar soft-part" sarcoma led to a systematic study of the diagnosis of soft-tissue malignant tumors by 87mSr scanning, le At the present time, it is apparent that many thoracic tumors can be visualized well with s~mSr even if there is no involvement of bone (Fig. 9). A malignant pleural effusion, e.g., appears to show increased 87mSr uptake.
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Fig. 6. Strontium-87m scintiscans of both knees of a boy with pain in his right knee. There is an apparent increase in radionuclide uptake in the distal right femoral epiphysis, extending into the joint space. Such as extension across the epiphysis is more typical of osteomyelitis rather than tumor. The inflammatory etiology was confirmed in this case. (With permission. 14)
Fig. 7. Lateral 87mSr scintiscans of feet of a child who had a swelling on the dorsum of right foot. There is increased concentration of eTmSr in the area of swelling (arrow), suggesting a metabolically active and probably malignant focus in the soft tissue. This was a subcutaneous leukemic infiltrate.
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Abdominal tumors may likewise be imaged with 87mSr. One child who had no palpable tumor but an unusually prominent abdomen had an abdominal S7mSr scan performed (Fig. 10). The resulting pattern of increased 87mSr uptake throughout the abdomen, except for the areas of spleen and liver, led to the impression of diffuse tumor infiltration which was subsequently confirmed surgically. Except for localized Wilms" tumors, which may not have consistent 87mSr uptake, this technique has subsequently been successful in an on-going series of children with abdominal tumors. ~9b abdominal tumors. ~~
Nonmalignant Skeletal Disease Inflammatory bone and joint disease can be scanned with 87mSr,3~ lsF, or SSSr.31 Acute osteomyelitis is characteristically seen as a focus of intense 87mSr uptake throughout the entire medullary canal of the affected bone, frequently crossing the epiphysis into the joint space (Fig. 6) in contrast to malignant bone tumors (Fig. 3), which generally do not cross over epiphyseal lines. Subacute or chronic osteomyelitis typically has a relatively low intensity STmSr uptake so that exacerbations can frequently be detected if previous scans have shown quiescent disease. Inflammatory joint disease produces a localized increase in s7mSr uptake within the joint space itself (Fig. 14). This is quite intense with acute juvenile rheumatoid arthritis, but may decrease after therapy or remission so that the uptake in inactive juvenile rheumatoid arthritis is similar to the joint uptake seen when there is degenerative or traumatic arthritis, z~ Trauma that produces localized bleeding with formation of periosteal or intramuscular hematomas can lead to an abnormal 87mSr image (Fig. 12), either by direct irritation of the adjacent bone or by secondary calcification of the hematoma itself. 3~ Myositis ossificans that are secondary to previous often unrecognized trauma can be difficult to differentiate from malignant
Fig. 8. Posterior sT=Sr scintiscan of both thighs and lower pelvis of a 12-yr-old boy with a swollen left thigh. There is intense soft tissue uptake of 87=Sr in addition to increased uptake over the proximal femur, ex-
tending into the acetabulum. This was proven on biopsy to be a fibrosarcoma. (With permis-
sion. 14)
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tumors on 87=Sr scans, 3a but the location and configuration may provide important distinguishing information. Any active extraskeletal focus of calcification can be visualized by stronti/Im scanning. This includes a wicle variety of disorders such as calcifying tumors, :8"~2"zs'34 (Fig. 9), benign pulmonary disease, and nephrocalcinosis, zs As with skeletal scans, the intensity of 87mSr uptake is a useful measure of how active the ca]cificafion is at the time of scanning. :SF scintiphotos can also be used to visualize extraosseous tumors, ts'3e Fig. 9. (A) Chest X-ray of a 15-yr-old boy with shortness of breath. Diffuse nodular infiltration is present in both lungs. (B) Strontium-87m lung scintiscan shows diffuse uptake throughout both lungs. Diffuse, infiltrative calcifying metastatic osteosarcoma was subsequently confirmed. A possible metastatic lesion in the vicinity of the right humeral head is also visible on the study. (With permission. 14)
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Fig. 10. Strontium-87m scintiscan of abdomen of 6-yr-old girl who had a prominent abdomen but no palpable tumors. There is no significant isotope uptake in the regions of liver, spleen, or ifiac crests (outlined) but there is abnormal localization throughout the abdominal cavity. The author's experience suggests that such a pattern may be seen in patients with diffuse malignant disease, as was confirmed in this case a t laparotomy. Liver and spleen were not involved, just as is seen on the 87mSr scan.
Fig. 11. Strontium-87m scintiscans of knees, showing increased radioactivity in both joint spaces, compatible with bilateral inflammatory joint disease.
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Fig. 12. Strontium-87m scintiscan (L) and corresponding ro~htgenogram (R) of left femur, revealing minimal isotope uptake in a focus beside the femoral shaft, seen on X-ray as a calcifying mass, and suspected of being an osteosarcoma. The relatively low intensity of radionuclide uptake is more suggestive of a benign process; in this case a calcifying subperiosteal hematoma.
Strontium-87m scans have been used for evaluating growth abnormalities 37 that are clue to both metabolic disorders and to injury. Since the radionuclide uptake in the skeleton is directly proportional to the metabolic rate of the growth centers of the skeleton, the intensity of uptake provides a useful and semiquantitative index of growth rate while the scan image allows visualization of the approximate configuration and size of the maior epiphyses. Differences in growth rate across the epiphyses of a long bone, which can lead to significant bowing of the extremity, can thus be seen on the 87mSr scan. a7 Abnormal skeletal growth secondary to other disease, such as hypertrophic pulmonary osteoarthropathy s8 or acromegaly, can also produce abnormal skeletal scintigrams. There is increased affinity for 87mSr at the site of skeletal fractures, aa beginning within hours after the injury, z~ The rate of uptake has been quantitated with respect to the rate of healing in children. 6 Scan images of fractures are especially useful 4~ when there is uncertainty as to whether healing has occurred or whether there is nonunion, since nonunion produces a characteristic pattern on the 87mSr scan (Fig. 13). The presence of an unsuspected fracture through a benign bone cyst can result in the mistaken scan impression of a malignant tumor, for the increased uptake stimulated b y the fracture may simulate the very intense uptake seen in most malignant bone tumors. 15
THE CHOICE OF RADIONUCLIDE FOR BONE SCANNING
The relative advantages and disadvantages of different radionuclides available or potentially available for bone scanning have been considered by several groups 3'sI'41-47 but only with respect to their use in adults. In this context, SSSr is the usual standard by which other materials are judged. In pediatric use, where skeletal dynamics are so different because of the
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Fig. 13. Strontium-87m scintiscan of shoulders of a girl with history of a recent fracture through left clavicle. There is relatively poor uptake in the region of the distal fragment (arrow), suggesting nonunion and probable nonvascularity.
vastly increased affinity of the rapidly growing skeleton for calcium and calcium-mimetic nuclides, different criteria must be used and different conclusions may be expected. The most fundamental consideration for a bone-seeking nuclide for pediatric use in a variety of diseases is safety. Lack of any acute toxicity and minimal total radiation exposure must be considered first. On the other hand, a material must be adequate to produce satisfactory visualization of pathology or its clinical use for children, no matter how safe, is senseless. The most frequent objection to 8VmSr as it is used in adults is the persistantly high blood background activity. This can be responsible for false positive or false negative interpretations. 4a'49 The author feels that in studies with children, assuming a minimum injection to study time interval of 2-3 hr, this is very rarely a significant problem. The practical considerations of availability, cost, and ease of use also favor aVmSr over 18F in most centers. With a sterile yttrium generator now readily available in the United States, as had been the case in Europe for the past 2 yr, availability of 8VmSr is no longer a problem. As mentioned previously, 99mTc polyphosphate complex 3a and similar technitium-labeled phosphate compounds have gained considerable popularity in the past year. The increasing availability of commercial kits and increasingly favorable reports concerning its usage may help it supplant 87mSr or 18F as the agent of choice for imaging of pediatric skeletal disorders. Its use for imaging extraosseous lesions has yet to be shown. The author has had no experience with this radiopharmaceutical. OTHER BONE-SEEKING RADIONUCLIDES
Dysprosium-157 has been studied by the Berkeley group, 41 who found its cyclotron production similar in cost and difficulty to that of ISF, but its 8.1-hr half-life and 326 keV emission are obviously superior to those of 18F. Localization in tumors of bone approximated that with 18F when the two nuclides were compared at weekly intervals in the same patients. Dysprosium-157 did not have as fast a blood clearance as 18F, and the relative skeletal uptake was not as high, however.
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O'Mara et al.42 have studied the lanthanides 17emLutetium and 177Lu, 153Sm, and 171Er for their potential value in bone scanning. Their advantage is a relatively low-energy gamma emission but the total associated radiation exposure is near that from 85Sr and too excessive to seriously consider their use in pediatrics. The same objections must be raised for 131Ba and laSmBa, whose use was reported by Spencer et al. 43 The argument for their use is their superiority to 85Sr,44 but for pediatric use this is a specious argument. There is prominent gastrointestinal excretion, which interferes with visualization of abdominal and pelvic tumors. Thulium-16745 is similar to 131Ba in the radiation exposure associated with its use but its gamma emission, with major peak at 208 keV, allows better collimation and sharper imaging. In terms of relative radiation exposure, 167Tm has only one-third that of SSSr but this is not good enough to justify recommending its development for pediatric nuclear medicine. An 18F-albumin complex was recently proposed as being superior in animal studies of bone-seeking radionuclides 46 but no clinical data are yet available to support this. THE MECHANISM OF RADIONUCLIDE VISUALIZATION OF BONE LESIONS
The mechanism of uptake of bone-seeking radionuclides into malignant tumors remains unknown. This must be said despite several authors' attempts to explain localization of nuclides in focal skeletal lesions as a reaction of the bone to a focus of disease, 1~176 as a reflection of increased blood flow because of a disease focus, ~1 or as alterations in metabolism produced by the disease process. 15 Strontium isotopes are not calcium-mimetic in their kinetics of uptake and excretion but they do appear to be faithfully calcium-mimetic in their sites of active localization. 37 Fluorine-18 has been shown to be deposited directly on the crystalline lattice of bone mineral and probably would be incorporated directly into the lattice if it were stable, ng Undoubtedly, some form of ion exchange at the crystal surface is involved. Isolated cases of the accumulation of nuclide directly into soft-tissue tumor have been seen over the past decade, 2L~5'53 but not until very recently has this been studied systematically. 15"54 The author could find no data as to whether this has ever been observed with 4rCa or if it represents a unique function for Sr isotopes (and possibly also XSF).~n The similarity of this function to that seen with gallium isotopes, which are also bone seekers ~ but which have more recently won acclaim for their tumor-localizing properties 55"56 is probably no coincidence. Data are being accumulated that could answer this puzzle but a unified hypothesis is not yet possible. It does appear likely that the explanations usually given for localization of boneseeking isotopes into malignant bone tumors do not explain the entire mechanism. The author feels that affinity of the tumor tissue for the radionuclide also is an important possibility to be considered. 14 Data now accumulated appear to indicate that a roentgenographically visible or symptomatic bone lesions that have no significant radionuclide uptake is, in all
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likelihood, benign, and very possibly may be followed clinically without biopsy. Since the majority of bone lesions should fit into this category, a great deal of surgery is spared when this criterion is applied. Such an approach is now being evaluated. The exception to this, i.e., little or no radionuclide uptake into a primary malignant bone tumor (the false negative scan) is unknown in the author's experience, and no documented exceptions could be found in the literature as well. Up to 10% false positive scans may be seen because of increased radionuclide uptake into nonmalignant disease, 14 but requiring that these patients have biopsy is far less than demanding routine biopsy of all bone lesions in children. With improved technique for bone scanning, one may hope to reduce the number of false positive bone scans, and this should be the goal of any nuclear medicine laboratory. ACKNOWLEDGMENTS I am indebted to Dr. Edward Eyring and to other referring surgeons for the clinical cases included herein, to Mrs. Cornelia Stewart, Mrs. Mary O'Neil and Emil N e w m a n for technical assistance, to Miss G u n Tegstr6m for art work and to USPHS Institutional G r a n t FR05504 and the Brad Roquet Memorial Fund for financial support.
REFERENCES 1. Tefft, M.: More common radionuclide examinations in children: indications for use with a discussion of radiation dose received. Pediatrics 48:802, 1971. 2. Myers, W. G.: Radiostrontium-87m. J. Nucl. Med. 1:124, 1960. 3. Spencer, R., Herbert, R., Rish, M. W., and Little, W. A.: Bone scanning with Sr-85, Sr-87m and F-18. Br. J. Radiol. 44:984, 1971. 3a. Subramanian, G., and McAfee, J. G.: A new complex of 09mTc for skeletal imaging. Radiology 99, 1972. 4. Charkes, N. D.: In Blahd, W. H., ed. 2. (Ed.): Nuclear Medicine. New York, Blakiston, 1971, p. 453. 5. Bratherton, D. G., and Maysent, A. M.: The use of strontium-87m in bone scanning. In McCready, V. R. (Ed.): Radioactive Isotopes in the Localization of Tumors. London, Heinemann, 1969, p. 118. 6. Season, E. H., Eyring, E. J., and Samuels, L. D.: Uptake of Sr-87m in the knee region of children as a parameter of bone turnover, Clin. Orthoped. (In press). 7. Conway; J. J. : Scientific display, Society of N u c l e a r Medicine, Los Angeles, June 1971. 7a. - - : Considerations for the performance of radionuclide procedures in children. Semin. Nucl. Med. 2:305, 1972. 8. Treadwell, A. deG., Low-Beer, V. L., Friedell, H. L., and Lawrence, J. H.: Meta-
bolic studies on neoplasms of bone with the aid of radioactive strontium. Am. J. Med. Sci. 204:521, 1942. 9. Mulry, W. C., and Dudley, H. C.: Studies of radiogallium as a diagnostic agent in bone tumors. J. Lab. Clin. Med. 37:239, 1951. 10. Bauer, G. C. H., and Ray, R. D.: Kinetics of strontium metabolism in man. J. Bone Joint Surg. 40A:171, 1958. 11. - - , and Wendeberg, B.: External counting of Ca-47 and Sr-85 in studies of localized skeletal lesions in man. J. Bone Joint Surg. 41B:558, 1959. 12. Fleming, W. H., McIlraith, J. D., and King, E. R.: Photoscanning of bone lesions utilizing strontium-85. Radiology 77:635, 1961. 13. Charkes, N. D., Sklaroff, D. M., and Bierly, J.: Detection of metastatic cancer to bone by scintiscanning with strontium87m, Am. J. Roentgeno]. 91:1121, 1964. 14. Samuels, L. D.: Diagnosis of malign a n t bone disease with Sr-87m scans. Can. Med. Ass. J. 104:411, 1971. 15. - - , Detection a n d localization of extraskeletal malignant neoplasms of children with strontium-87m. Am. J. Roentgenol. 115:777, 1972. 16. Briggs, R. C., and Wegner, G. P., Osseous metaplasia in soft tissue, J.A.M.A. 195:185-188, 1966. 17. Blau, M., Nagler, W., and Bender,
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M. A.: F-18: a new isotope for bone scanning, J. Nucl. Med. 3:332-334, 1962. 17a. --:18F-Fluoride Imaging. Sem. Nucl. Med. 2:31, 1972. 18. Woodbury, D. H., and Brierwaltes, W. H.: Fluorine-18 uptake and localization in soft tissue deposits of osteogenic sarcoma in rat and man. J. Nucl. Med. 8:646, 1967. 19. Samuels, L. D.: Lung scanning with radiostrontium in metastatic osteosarcoma, Central Chapter, Society of Nuclear Medicine, 1967. 20. Spencer, R., Herbert, R., Rish, M. W., and Little, W. A.: Bone scanning with Sr-85, Sr-87m and F-18. Physical and radiopharmaceutical considerations and clinical experience in 50 cases. Br. J. Radiol. 40:641, 1967. 21. Scheer, K. E., Harbst, H., Kampmann, H., zum Winkel, K., Maier-Borst, W., Lorenz, W. J., and Bilaniuk, L.: Bone scintigraphy with F-18 and Sr-87m. In Medical Radioisotope Scintigraphy, Vol. II. Vienna, IAEA, 1969, p. 325. 22. Samuels, L. D.: Lung scanning with Sr-87m in metastatic osteosarcoma, Am. J. Roentgenol. 104:766, 1968. 23. Kostamis, P., Constantinides, C., Papavasiliou, C., Binopoulos, D., Sfontouris, J., and Malamos, B.: Early detection of bone lesions by photoscanning with radioactive strontium-87m. In Medical Radioisotope Scintigraphy, Vol. II. Vienna, IAEA, 1969, pp. 349-364. 24. French, R. J., and McCready, V. R.: The use of F-18 for bone scanning, Br. J. Radiol. 40:655, 1967. 25. Moon, N. F., Dworkin, H. J., and LaFluer, P. D.: The clinical use of sodium fluoride F-18 in bone photoscanning, JAMA 204:974, 1968. 26. Harmer, C. L., Burns, J. E., Sams, A., and Spittle, M.: The value of fluorine-18 for scanning bone tumors. Clin. Radiol. 20:204, 1969. 27. Blau, M., Laor, Y., and Bender, M. A.: Isotope scanning with F-18 for the early detection of bone tumors, in Medical Radioisotope Scintigraphy, Vol. II. Vienna, IAEA, 1969, p. 341. 28. Wankel, J., Eyring, E. J., and Samuels, L. D.: Diagnostic preoperative Sr-87m bone scans in malignant bone tumors. J. Nucl. Med. (In press). 29. Alexander, J. L., and Gillespie, P. J.:
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The optimum injection-to-scan interval for spinal scans using Sr-87m, Br. J. Radiol. 44:878, 1971. 29a. Papavasiliou, C., Kostamis, P., Constandinidis, C., GiamareIlou, H., Sfoundouris, J., Binopoulos, D., and Nicolaidis, C.: La valeur de la scintigraphie au Sr-87m dans la radioth6rapie palliative du cancer rectocolique r~cidivant. J. Radiol. Electrol. 52:497, 1971. 29b. Samuels, L. D. : Unpublished data. 30. Samuels, L. D.: Sr-87m bone scans in juvenile rheumatoid arthritis. Ann. AIlerg. 29:246, 1971. 31. Muheim, G., and Crutchlow, W. P.: F-18 and Sr-85 scintimetry in the study of primary arthropathies. Br. J. Radiol. 44:290, 1971. 32. Samuels, L. D.: Unpublished data. 33. Bateson, E. M.: Radiological observation on an alveolar soft-part sarcoma complicated by trauma and myositis ossificans. Clin. Radiol. 19:389, 1968. 34. Schall, G. L., Zeiger, L., Primrack, A., and DeLellis, R.: Uptake of Sr-85 by an osteosarcoma metastatic to lung. J. Nucl. Med. 12:131, 1971. 35. Samuels, L. D.: Nephrocalcinosis in children: diagnosis by Sr-87m scan. J. Urol. (In press). 36. O'Mara, R. E., Brettner, A., Danigelis, J., and Gould, H. W.: F-18 uptake within metastatic osteosarcoma of liver: case report. Radiology 100:113, 1971. 37. Samuels, L. D.: Sr-87m uptake and scans in growth disturbances of childhood. Ohio St. Med. J. (In press). 38. Ilingworth, G. I., and Schiess, F. A.: Sr-87m in the prognosis of fractures of the tibia. Proc. Roy. Soc. Med. 64:633, 1971. 39. Myers, W. G., and Olejar, M.: Radiostrontium-87m in studies of healing bone fracture, J. Nucl. Med. 4:202, 1963. 40. Fueger, G. F.: Private communication. 41. Yano, Y., Van Dyke, D. C., Verdon, T. A., Jr., and Anger, H. O.: Cyclotronproduced Dy-157 compared with F-18 for bone scanning using the whole-body scanner and scintillation camera. J. Nucl. Med. 12:815, 1971. 42. O'Mara, R. E., McAfee, J. G., and Subramanian, G.: Rare earth nuclides as potential agents for skeletal imaging. J. Nucl. Med. 10:49, 1969. 43. Spencer, R. P., Lange, R. C., and Treves, S.: Use of Ba-135m and Ba-131 as
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bone scanning agents, J. Nucl. Med. 12:216, 1971. 44. Hosain, F., Syed, I. B., Wagner, H. N~ Jr., and Poggenburg, J. K.: Ionic Ba-135m: a new agent for bone scanning. Radiology 98:684, 1971. 45. Chandra, g., Hernberg, J., Braunstein, P., and Rosenfeld, W.: Tm-167: a new bone scanning agent. Radiology 100:687, 1971. 46. Lorenz, W. J., Krauss, O., Maier Borst, W., et al., Knochenszintigraphie mit kurzlebigen Radionukliden und der positronen Kamera. Radiobiol. Radiother. (Berlin) 11: 171, 1970. 47. Weber, D. A., Greenberg, E. J., Dimich, A., Kenny, P. J., Rathschild, E. O., Myers, W. P. L., and Laughlin, J. S.: Kinetics of radionuclides used for bone studies. J. Nucl. Med. 10:8, 1969. 48. Charkes, N. D.: Some differences between bone scans made with Sr-87m and Sr-85. J. Nucl. Med. 10:491, 1969. 49. Galasko, C. S. B.: False positive and negatives with Sr-87m. J. Nucl. Med. 12:142, 1971.
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50. Charkes, N. D., Young, J., and Sklaroll, D. M.: The pathologic basis of the strontium bone scan. JAMA 206:2482, 1968. 51. Van Dyke, D., Anger, H. O., Yano, Y., and Bozzini, C.: Bone blood flow shown with F-18 and the positron camera. Am. J. Physiol. 209:65, 1965. 52. Posner, A. S., Eanes, E. D., Harper, R. A., and Zipkin, I.: X-ray diffraction analysis of the effect of fluorite on human bone apatite. Arch. Oral Biol. 8:549, 1963. 53. Papavasiliou, C., Kostamis, P., Angelaskis, P, and Constantinides, C.: Localization of Sr-87m in extraosseous tumors. J. Nucl. Med. 12:265, 1971. 54. Samuels, L. D.: Sr-87m scans in children with extraosseous pathology, Am. J. Roentgenol. 109:813, 1970. 55. Edwards, C. L., and Hayes, R. L.: Scannig malignant neoplasms with gallium67, JAMA 212:1182, 1970. 56. Langhammer, H., Glaubitt, G., Grebe, S. F., et al.: Ga-67 for tumor scanning. J. Nucl. Med. 13:25, 1972.