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Positron-Emission Computed Tomography of the Pancreas: A Preliminary Study 1 Edward Buonocore, M.D., and Karl F. Hubner, M.D. Twenty-seven patients with suspected pancreatic disease were examined with emission computed tomography (ECT) with 11C-labeled amino acids. Of 24 patients with known clinical outcome, there were 1 false positive and 2 false negative results. One finding of interest was the increased concentration of radiopharmaceutical that accurately delineated the presence and extent of 4 pancreatic carcinomas and 1 lymphoma. In the normal subjects, ECT reliably identified the pancreas. Disadvantages of ECT include the need for a cyclotron and high-quality hot chemistry laboratory, and the relatively long scanning time. The advantage of ECT is that it offers a unique opportunity to image biologic activity of the pancreas. INDEX TERMS: Emission computed tomography. Pancreas. neoplasms. Positron imaging. (Pancreas, radionuclidestudy. 77[ 1-31.1299) Radiology 133:195-201. October 1979 HE DEVELOPMENT of positron-emission computed tomography (ECT) and the substitution of carbon-11, a positron-emitting isotope, for carbon-12 in natural and synthetic amino acids, inspired hopes of a more physiological analysis and imaging of pancreatic function (1). The pancreatic concentration of "C-DL-valine, 1'C-DL-tryptophan, and l'C-aminocyclobutanecarboxylic acid (11C_ ACBC) after intravenous injection is readily visualized by a commercially available scanner." The purpose of this report is to present the initial results of ECT in patients with suspected pancreatic disease. Some of these patients also were examined by first-generation x-ray transmission CT and/or ultrasonography and thus allow a comparison of ECT with those modalities.

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Twenty-seven patients with suspected pancreatic disorders were examined with ECT and ltC-tagged amino acids. Eleven individuals were examined solely with ECT and represent the initial experience with this technique. Of the other 16, 12 also had ultrasound and 13 transmission CT studies. Two ECT studies were technically unsatisfactory, and a third patient was lost to follow-up. These 3 individuals were deleted from further evaluation. Radiopharmaceuticals. Carbon-11 was produced in the 218-cm (86-in.), 22-MeV proton cyclotron at the Oak Ridge National Laboratory (ORNL). The amino acid ra-

cemates DL-valine and DL-tryptophan, and the alicyclic amino acid aminocyclobutanecarboxylic acid were labeled in the carboxyl position with 1'C by using a modified Bucherer-Strecker technique (2). The radiopharmaceuticals were adjusted to isotonicity and tested for sterility and pyrogens after microfiltration (0.22 p). The dose range for "C-DL-valine was 13.4-45 mCi (496-1,665 MBq), for 11C-DL-tryptophan 6.0-35 mCi (222-1,295 MBq) and for llC-ACBC 10-45 mCi (3701,665 MBq). The estimated total body radiation doses were 0.009 rad/rnCi (2.4 X 10-6 Gy/MBq) for "C-DL-valine, and 0.011 rad/mCi (2.9 X 10-6 Gy/MBq) for '1C-DL-tryptophan and 11C-ACBC. The doses were 0.150-0.078 rad/mCi (4.05-2.1 X 10-5 Gy/MBq) for the pancreas, 0.027-0.015 rad/mCi (7.2-4.0 X 10- 6 Gy/MBq) for the liver, and 0.032-0.019 rad/mCi (8.6-5.1 X 10- 6 Gy/MBq) for the kidneys. Less than 20% of the "C-DL-valine and "CACBC, which are rapidly cleared after intravenous injection (3), was found in the blood after 10 minutes. This allowed scanning to be started promptly. In a few patients llC_ DL-tryptophan scans were followed by "C-ACBC scans to compare pancreas localization properties. Positron-Emission Computed Tomography. The ECT unit used was designed and developed according to the performance specifications of Phelps and Hoffman (4). The scanner consists of a hexagonal scanning unit equipped with 66 sodium iodide crystals measuring 3.8 X 7.5 cm arranged in three pairs of opposing detector banks (11

1 From the Department of Radiology, University of Tennessee Hospital, Knoxville (E.B.), and Oak Ridge Associated Universities, Oak Ridge (K.F.H.), TN. Presented at the Sixty-fourth Scientific Assembly and Annual Meeting of theRadiological Society of North America, Chicago, IL,Nov. 26-Dec. 1, 1978. Received Nov. 30, 1978; revision requested Jan. 30, 1979; received and accepted May 25. Oak Ridge Associated Universities operates under contract #DE-AC05-760R00033 with the U.S.D.O.E. Work supported by DBER and NCI, Grant #Ca 14669. This articlehasbeen authored bya contractor of theU.S. Government under contract #DE-AC05-760R00033. Accordingly. theU.S. Government retains a nonexclusive. royalty-free license to publish or reproduce thepublished formof this contribution, or allowothers to do so,for U.S. Government purposes. 2 EG & G ORTEC, Inc., Oak Ridge. TN. 3 Thisstudy wasapproved by the ORAU/ORNL Committee on Human Studies and under FDA INDs 12,457; 12,967; and 13,867. All patients participated with informed consent. jr

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Fig. 2. ECT scan at 24 minutes after administration of "C-DL-valine in a patient with a partial pancreatectomy for pancreatic carcinoma. The patient is asymptomatic 15 months after surgery. Note the isotope concentration in the residual body and tail. There is activity in the area of the remaining uncinate process (right arrow). The defects seen in the liver are due to quantummottle (see Methodand Materials). The left arrow indicates the pancreatic tail.

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Fig. 1. Normal ECT scans two minutes (a) and 24 minutes (b) after intravenous administration of "C-DL-tryptophan. At two minutes. note the high background, vascular, and renal activity. At 24 minutes. note the increased concentration in the normal pancreas (P). In sections 3 and 4. the liver (L) and stomach (Sf) are well defined. K kidney.

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detectors per bank) and a computer system for scanning, data collection, image reconstruction, and data storage. The images were computer-reconstructed tomographic views based on annihilation coincidence detection, with the coincidence time window set at 22 nsec. All ECT scans were corrected for decay and attenuation, the latter done by calculation according to the method of Phelps et al. (5, 6). In order to get correct ellipse parameters for the calculations, a transmission scan and outline of the upper abdomen were obtained, with a 0.5-mei (18.5MBq)68Ge/68Ga ring source providing the necessary

photons for transmission data which were collected over a 4-minute period per tomographic section. The resolution of the system in this study was 18 mm (full width at half maximum) using standard shadow shields and the high-resolution filter function. Scan time was 200 sec/plane for a total of 1,500,000 and 2,000,000 counts per section. Whenever four consecutive planes are presented in this report, one should be aware that the individual images are not normalized to each other with regard to intensity. Qualtitative conclusions cannot be drawn by comparing intensity displays in various regions in different image plans. Scanning of the pancreas was started within five minutes after intravenous injection of the radiopharmaceuticals. Thirty minutes prior to the injection of either 11C_ DL-valine or 11C-DL-tryptophan, each patient received a large milk shake. No dietary preparation was used prior to the 11C-ACBC studies. In all patients, at least 4 tomographic sections were scanned, starting approximately 2 cm below L1 and proceeding cephalad in 9-mm increments. Early and late scans over the liver frequently revealed nonuniform activity related to statistical noise (quantum mottle). Hence, liver defects were not considered significant unless they were identified in two separate studies with different radiopharmaceuticals (Fig. 7). CT Scanning and Ultrasonography. Transmission radiographic scans of the pancreas were made in the supine and right lateral decubitus positions. Scanning time was 2 1/2 minutes per section using a Oelta-50 4 unit. All patients drank 480 ml (16 fl. oz.) of 3% aqueous iodinated contrast media and received 1 mg of glucagon intramuscularly prior to scanning. The ultrasonograms were made on a Sonograf-1I1 unitS using a 3.5-mHz transducer focused 4 5

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at 7-11 cm (infinite gray scale). Full sweep and sector scans were made in multiple projections including supine, decubitus, and prone positions.

RESULTS Of the 24 patients who were successfully examined, 10 were found to be normal after clinical follow-up for at least one year. Of the other 14, 8 had carcinoma of the pancreas, 3 abdominal lymphoma without pancreatic involvement, and 3 relapsing pancreatitis. The findings in the 10 normal patients allowed a preliminary evaluation of the variation of pancreatic configurations on ECT. In each patient the image obtained was similar to that seen on radiographic transmission CT (Fig. 3). In normal subjects the concentration of isotope was uniform. On the early scans started two minutes after injection, there was high background activity with visualization of the aorta, kidneys, and liver as well as the pancreas. On the late examinations (24 minutes after injection), background activity cleared from the liver and kidneys, resulting in increased visualization of the pancreas (Fig. 1). In 1 patient with carcinoma of the head of the pancreas,

a Whipple procedure was performed, with resection of the head and a portion of the body of the pancreas. Postoperative ECT produced an image of the residual body and tail (Fig. 2), and an additional area of activity was identified to the right of the midline. This was thought to be the remaining uncinate process which is often not removed by our surgeons during resection of the pancreas because of its intimate association with the superior mesenteric artery and vein. For 18 months the patient has remained asymptomatic. In each of the 3 patients with pancreatitis there was diffuse enlargement of the gland. In 2 the isotope was nonuniformly distributed throughout the entire gland, while in the third, the nonuniformity was limited to the pancreatic head. In general, these findings were nonspecific. Although our experience with pancreatitis is limited, it was felt that ECT had little to offer in its diagnosis and differentiation from carcinoma. Of the 8 proved cases of pancreatic carcinoma, 2 were undetected by ECT. In 2 others there was loss of normal contour with nonvisualization of the portion of the pancreas involved by tumor (Fig. 4). This was the anticipated result, since these have been the characteristic findings in

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Fig. 4. Carcinoma of the head of the pancreas with metastasis to the liver. a. ECT llC-Dl-tryptophan scans at 24 minutes show absence of the pancreatic head and body. Visualization of the left kidney (K) in sections 1 and 2 and liver (L) in sections 3 and 4 indicate the correct scan levels. Note defects in the liver, which were histologically proved (arrow). Sf stomach; TP pancreatic tail. b. Comparison study in the same patient. A mass in the head of the pancreas was diagnosed on ultrasonic examination (arrows).

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75S e lenium-methionine nuclear scans. One unexpected finding was increased concentration of isotope visualized in the area of malignancy in the remaining 4 patients with pancreatic carcinoma. Three of these cases were correctly diagnosed by ultrasonography and radiographic CT. The areas of increased activity seen on ECT exceeded the size of the tumor imaged by the other modalities and more closely approximated the gross physical descriptions of the tumors found at surgery (Figs. 5 and 6). This increased concentration of isotope was found with both 11C-DLtryptophan and 11C-ACBC. In 1 patient who was examined

with both of these radiopharmaceuticals, the tumor took up more of the l1C-ACBC than of the llC-tryptophan, as based on the tumor-to-non-tumor ratios of isotope concentration. These ratios were determined from activity distribution profiles obtained with the PD 11/45 computer of the ECT. Horizontal histograms were derived for regions of interest selected to include tumor and non-tumor areas of the tomographic images. Liver metastases were identified by ECT in 3 patients with carcinoma of the pancreas. The findings were manifested by multiple defects throughout the liver in all 3

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Fig. 5. a. There is a high concentration of isotope in the carcinoma of the head and body of the pancreas. The apparent size of the tumor ( corresponded well with the surgical and physical findings. This scan was made four minutes after the administration of 9.7 mCi (359 MBq) of llC-DL-tryptophan. K = kidney. b. Corresponding CT scans show a large irregular head and body of the pancreas. The size of the lesion was underestimated on this examination.

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Fig. 6. a. Carcinoma of the head of the pancreas in a patient who presented with jaundice. Increased concentration of isotope was identified in the area of surgically proved carcinoma. These scans were made with llC-ACBC. K kidney; L liver; T tumor. b. Percutaneous cholangiogram in the same patient shows obstruction of the common bile duct by pancreatic carcinoma.

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patients, even though the primary tumor demonstrated increased isotopic activity in only 1 (Fig. 7). In 1 patient with lymphoma, the retroperitoneal tumor was extremely large, and encompassed and obscured the pancreas on radiographic CT. Arteriographic findings were inconclusive and suggested the possibility of pancreatic origin of the neoplasm. 11C-tryptophan studies demonstrated a normal pancreatic contour, while 11C-ACBC, more avidly taken up by the tumor, identified the extent of the mass. The histologic diagnosis by needle biopsy was well differenitated lymphocytic lymphosarcoma. In the 24 patients there were 1 false positive and 2 false negative ECT examinations. The false positive study was in a patient clinically suspected of having an insulinoma. The scan was erroneously interpreted as demonstrating increased activity in the pancreatic head, indicating a site of a metabolically active tumor (Fig. 8). Continued observation over a period of 18 months failed to confirm this diagnosis. Repeated glucose tolerance tests and serum insulin levels have been normal, and the patient was not SUbjected to surgical exploration. This case, encountered early in our experience with ECT, would most likely have been interpreted as normal with greater experience. An example of a false negative ECT examination was in a patient with carcinoma of the most distal portion of the tail of the pancreas. The mass, not identified with either 11C-DL-tryptophanor 11C-ACBC, was clearly delineated on radiographic transmission CT (Fig. 9). DISCUSSION

ECThas proved to be an accurate tool in measuring the in vivo concentration of a positron-emitting radionuclide within an organ. A direct linear relationship exists between the ECT number and the in vivo concentration of radio-

Fig. 7. ECT scans of the liver in a patient with metastatic pancreatic carcinoma. histologically verified. Defects (arrows) are identified on two separate studies using two different radiopharmaceuticals, COL-tryptophan in a and C-ACBC in b.

Fig. 8. Example of a false positive ECT study: a llG-DL-tryptophan scan in a patient with clinically suspected insulinoma. Note the activity in the head of the pancreas on sections 2-4. This scan was misinterpreted as showing increased activity in the head and nonvisualization of the body and tail. It is possible that the body and tail of the pancreas reside at a different level and were not included in the EeT study. The arrow in section 1 points to the right kidney (K).

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Fig. 9a. These selective ECT scans with llC-DL-tryptophan and llC-ACBC were interpreted as normal in a patient with known carcinoma of the tail of the pancreas (P). b. Radiographic CT scans identify a large mass in the most distal portion of the tail of the pancreas (arrow).

isotope (7-9). Although positron-emitting radiopharmaceuticals have not been organ specific, high quality images of the brain and heart have been obtained (10). The replacement of carbon-12 by carbon-11 in natural amino acids (valine and tryptophan) and synthetic amino acids (ACBC) provides a unique opportunity to trace amino acid metabolic turnover in the pancreas. In the early 1960's, alicyclic alpha-amino acids such as t-amlnocyclopentane-1-carboxylic acid were tested as chemotherapeutic agents for malignant tumors (11). These amino acids' presumed anti-tumor action was their inhibitory effect on valine utilization by tumor cells. Washburn et al. (12) speculated that the cyclobutane analogue would have even greater tumor affinity because of its smaller ring size, and they introduced it as a tumor imaging agent in 1978.

F. HOBNER

October 1979

The rapid blood clearance of 11C-aminoacids and the appearance of activity within the pancreas after one minute indicate an active trapping process. Prompt visualization of the normal pancreas most likely demonstrates rapid utilization. In this series, pancreatic activity was detected only up to 45 minutes after injection of radiopharmaceuticals, making longer scanning impractical. It was originally speculated that the prime value of ECT of the pancreas would be to visualize precisely the normally functioning portion of the gland. Pathological processes were expected to present as "cold" areas. The unexpected finding of high isotope activity within 4 pancreatic carcinomas and 1 lymphomatous tumor has altered our concept. The high metabolic activity of neoplasms may explain this enhanced uptake. The resolution and contrast of the pancreatic images from ECT are superior to those of rectilinear 75S e _ lenium-methionine scans but inferior to those of ultrasonography and transmission tomography. Other disadvantages include long scanning times (15-30 minutes), the need for readily available cyclotron-produced short-lived 11C radionuclides, and the need for a hot chemistry laboratory. These needs make the problems of ECl insurmountable for the usual medical facility. In the future, reasonably priced commercially available cyclotrons and simplified radiopharmaceutical production may make this procedure less formidable. The spatial-resolution characteristics of ECT may not be germane since the ECT examination, as used in this study, is a reflection of organ physiology as determined by the concentration and clearance of specific radiopharmaceuticals. Hence, comparison of spatial-resolution characteristics of ultrasonography and radiographic transmission CT with current state-of-the-art ECT would be of little interest other than their complementary value. Current diagnostic imaging techniques, including ECT, have made no impact on patient survival from pancreatic carcinoma, since the onset of symptoms usually occurs too late in the development of the disease for a cure to be possible. However, the differentiation of pancreatic neoplasms and lymphomas that show increased isotope activity may be a significant addition to oncologic diagnosis. Correlation with prognosis and changes after therapy may assist in medical management. Further refinements of ECT hold the promise of selective pancreatic function analysis, particularly as new radiopharmaceuticals become available. ACKNOWLEDGMENT: We thank L. C. Washburn, B. L. Byrd. and J. E. Carlton of ORAU, and T. A. Butler and A. P. Callahan of ORNL who were responsible for the preparation of the C-Iabeled amino acids. We also acknowledge the technical assistance of W. D. Gibbs and E. C. Holloway. Photographic and technical assistance was obtained from Ms. Linda Trusty, R.T.R. and Mr. Kenneth Short, R.T.R.

REFERENCES 1. Washburn LC, Wieland BW, Sun TT, et al: (1_11C) DL-valine, a potential pancreas-imaging agent. J Nucl Med 19:77-83, Jan 1978 2. Hayes RL, Washburn LC, et al: Synthesis and purification of

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11C-carboxyl-labeled amino acids. Int J Appl Radiat Isotop 29:186-187, 1978 3. Hubner KF, Andrews GA, Buonocore E, et al: Imaging the human pancreas with Carbon-11 labeled amino acids by rectilinear and positron tomographic scanning. J Nucl Med (in press) 4. Phelps ME, Hoffman EJ, Huang S-C, et al: ECAT: a new computerized tomographic imaging system for positron-emitting radiopharmaceuticals. J Nucl Me