Imaging studies of patients with malignant fibrous histiocytoma using C-11-alpha-aminoisobutyric acid (AIB).

Alpha-aminoisobutyric acid (AIB), a synthetic, nonmetabolized amino acid which is rapidly transported into viable cells by the A-type or alanine-preferring amino acid transport system, has been labeled with the short-lived, positron-emitting radionuclide carbon-11. Carbon-11 labeled AIB is currently being evaluated as a tumor imaging agent for in vivo amino acid transport studies in patients with cancer. In this study, C-11 AIB was used to image two patients with malignant fibrous histiocytoma (MFH), a pleomorphic sarcoma. Following intravenous administration of C-11 AIB, tumors in the distal femur of one patient and in the anterior chest wall of another patient were well visualized using high energy gamma scintigraphy. Since therapy may alter the accumulation of amino acids in tumor tissue, studies using C-11 AIB in patients with MFH before and after chemotherapy are in progress.

Imaging of human tumors and organs with N-13-labeled L-methionine.

The work described herein is the first reported use of nitrogen-13-labeled L-methionine in human subjects. Three volunteers and 14 patients with a variety of solid tumors were scanned after intravenous administration of L-(N-13) methionine. In both volunteers and cancer patients, uptake of label was seen in the liver and pancreas, with smaller amounts of label detected in the heart, urinary bladder, and salivary glands. Concentration of N-13 in tumor was seen in 12 of the 14 cancer patients. Five had repeat studies after chemotherapy; in each case, the change in tumor uptake of N-13 after N-13 methionine injection paralleled the clinical response to chemotherapy. Three patients had L-(N-13) glutamate scans the same day that they were studied with N-13 methionine. Concentration of the radiolabel in the tumor was very similar for the two compounds in each case. The systemic distribution of N-13 from methionine is similar to that from glutamate, except for a much smaller myocardial uptake and a prominent accumulation in the intestinal region. It is concluded that L-(N-13) methionine is potentially useful as a biologically significant agent for tumor visualization and assessment of therapeutic response.

Use of sodium chromate Cr51 in diagnosing childhood idiopathic pulmonary hemosiderosis.

The diagnosis of idiopathic pulmonary hemosiderosis (IPH) may be elusive. A 6-year-old boy had microcytic hypochromic anemia and a hemolytic component. Hemosiderin-laden macrophages were not found in the gastric aspirate. He had no pulmonary signs or symptoms. Extensive hematologic and roentgenologic investigations failed to reveal the cause of the anemia. Quantitative serial scintigraphic scanning showed significant (35%) pulmonary sequestration of autologous erythrocytes labeled with sodium chromate Cr51. The half-life of the RBCs was moderately decreased (half-life, 15 days; normal, 25 to 35 days). An open-lung biopsy specimen confirmed the diagnosis of IPH. A diagnosis of IPH should be considered when children have iron deficiency anemia and pulmonary signs or symptoms. Organ sequestration studies may be helpful in equivocal cases.

Intratumoral consumption of indium-111 labeled platelets in a patient with hemangiomatosis and intravascular coagulation (Kasabach-Merritt syndrome).

Previous studies regarding sites of platelet destruction in patients with the Kasabach-Merritt syndrome are conflicting. The authors recently studied an adult patient with multiple large hemangiomata, thrombocytopenia, and intravascular coagulation by external imaging following the injection of autologous Indium-111 labeled platelets. Sequential images showed prompt accumulation of platelet-associated radioactivity in areas within the right hemithorax which corresponded to certain tumors noted on the chest roentgenogram. Despite the presence of multiple other lesions in bone and soft tissues, platelet radioactivity was otherwise normally confined to liver and spleen. Using data obtained from serial images, it was shown that radioactivity within the thoracic masses actually increased over time. These data indicate that platelet consumption occurred as an active process and that localization was not a result of tumor vascularity. It is concluded that platelets are locally consumed within certain hemangiomata. However, within the same individual, there may exist considerable heterogeneity among these tumors with respect to platelet-trapping ability. In similar patients with multiple tumors, indium-platelet scanning might be used to direct local therapy to particular lesions in an effort to correct the thrombocytopenia.

Quantitative scanning of soft-tissue sarcomas with nitrogen-13-labeled L-glutamate.

Nitrogen-13-L-glutamate, a labeled amino acid enzymatically synthesized from cyclotron-produced N-13 ammonia and alpha-ketoglutaric acid, was used as an imaging agent in 14 patients with soft-tissue sarcomas. Concentration of nitrogen-13 label within the sarcoma was seen in 11 of the 14 patients; in some cases, clinically inapparent metastatic tumor lesions could also be detected. In eight patients, the tumor response to chemotherapy was evaluated by serial studies with this agent. In each case, the change in uptake of N-13 label by the sarcoma after therapy paralleled the clinical response to treatment. N-13-labeled L-glutamate may thus be of value as an imaging agent in the management of patients with soft-tissue sarcomas.

Imaging of brain tumors after administration of L-(N-13)glutamate: concise communication.

Cyclotron-produced L-(N-13)glutamate was used to visualize malignant intracranial tumors in 12 pediatric patients who had evidence of recurrent disease as documented by computed transaxial tomography (TCT). Imaging was performed using a rectilinear scanner, gamma camera, or a positron-emission tomograph (PET). The results indicate that N-13 is rapidly taken up by a majority of brain tumors following the administration of L-(N-13)glutamate, and that N-13 uptake is correlated with breakdown of the blood-brain barrier as demonstrated by contrast TCT or pertechnetate (Tc-99m) studies. The feasibility of using this agent in conjunction with PET is established.

Scanning with L-(13 N) glutamate: Assessment of the response to chemotherapy of a patient with embryonal rhabdomyosarcoma.

The use of (13) N-labeled L-glutamate as an imaging agent in a patient with embryonal rhabdomyosarcoma is described. Localization of (13)N in a large, poorly defined tumor of the left pectoral region was seen, and clinically occult right axilliary metastases were also detected. A marked reduction in uptake in these areas occurred after chemotherapy, paralleling the clinical disappearance of tumor. These changes were verified on gallium scan. (13)N-labeled glutamate may be useful as an imaging agent, especially in patients with soft-tissue sarcomas.

Imaging of primary Ewing sarcoma with 13N-L-glutamate.

Eleven patients with untreated primary Ewing sarcoma were studied with intravenously administered 13N-labeled L-glutamate. Seven were repeatedly scanned during chemotherapy using this agent and 99mTc-methylene diphosphonate (99mTc-MDP). The untreated primary tumor was distinctly visualized with 13N-L-glutamate in all cases; the distribution of 13N label in the tumor sometimes differed from that of 99mTc. A kinetic study showed rapid uptake of 13N by tumor tissue. Repeat scans following therapy indicated that 13N-L-glutamate and 99mTc-MDP uptake showed changes consistent with histological findings following subsequent surgery. 13N uptake often decreased more markedly than 99mTc uptake during chemotherapy, but metastatic lesions were not visualized with 13N-L-glutamate. Tumor imaging with this labeled amino acid may be of value in assessing the response of primary Ewing sarcoma to chemotherapy.

Quotient imaging with N-13 L-glutamate in osteogenic sarcoma: correlation with tumor viability.

An investigation was performed to correlate the regional uptake of N-13 L-glutamate with histologic changes in tumor tissue in patients undergoing adjuvant chemotherapy for osteogenic sarcoma. A parametric image was produced by calculating the ratio of N-13 uptake in the tumor in a pixel-by-pixel fashion, using the presurgical scan as the numerator and the pretherapy scan as the denominator. The change in N-13 uptake in 2 x 2-cm regions of the tumor was compared with residual cell viability as determined by microscopic examination of multiple thin sections obtained from the surgical specimens. Regions that showed decreases in N-13 uptake of more than 30% were frequently associated with areas of highly necrotic tumor, and regions that showed increasing uptake were associated with high residual cell viability and incomplete response to chemotherapy.

Tissue distribution studies of [18F]haloperidol, [18F]-beta-(4-fluorobenzoyl)propionic acid, and [82Br]bromperidol by external scintigraphy.

Tissue distribution studies of [18F]haloperidol and [82Br]bromperidol, two potent neuroleptic drugs, were performed in rats by serial sacrifice. The usefulness of external scintigraphy in obtaining tissue distribution data in large animals is demonstrated by the tissue distribution of [18F]haloperidol in rhesus monkeys. Both serial sacrifice and external scintigraphic studies demonstrated that uptake of the two drugs after intravenous administration into their target organ, the brain, was very fast and that the ratio of brain to blood levels was high throughout the 2-hr observation. Bromperidol appeared to reach peak brain levels faster than its chloro analog, haloperidol. Both bromperidol and haloperidol concentrated overwhelmingly in the rat lung. Haloperidol also showed a high affinity for the monkey lung. The disposition pattern in rats of [18F]-beta-(4-fluorobenzoyl)propionic acid, an apparent intermediate in butyrophenone metabolism, was entirely different from that of the parent drugs. This metabolite did not concentrate in the rat brain.

Imaging of the human heart after administration of L-(N-13)glutamate.

In normal volunteers and cancer patients, studies using L-(N-13)glutamate as an imaging agent showed localization of N-13 activity in the heart. Other organs that were well visualized include the liver, pancreas, and salivary glands. In ten subjects the average myocardial uptake after intravenous injection of labeled glutamate was (5.7 +/- 0.39)% (s.e.m.) of injected dose, as determined by a quantitative scanning system. The concentration of N-13 activity in the human heart could not be predicted from previous studies involving myocardial uptake in dogs and rodents after administration of L-(N-13)glutamate.

13N,15N isotope and kinetic evidence against hyponitrite as an intermediate in dentrification.

13N- and 15N-labeling experiments were carried out with Paracoccus denitrificans, grown anaerobically on nitrate, to determine whether hyponitrite might be an obligatory intermediate in denitrification and a precursor of nitrous oxide. From experiments designed to trap [13N]- or [15N,15N]hyponitrite by dilution into authentic hyponitrite it was calculated that the intracellular concentration of a presumptive hyponitrite pool must be less than 0.4 mM. In order for a pool of this size to turn over rapidly enough to handle the flux of nitrogen during dentrifucation, the spontaneous rate of hyponitrite dehydration must be enhanced by a factor of several thousand through enzyme catalysis. Cell extracts failed to catalyze this reaction under a variety of conditions. It is concluded that hyponitrite cannot be an intermediate in dentrification. In addition, the assimilation of inorganic nitrogen was studied in P. denitrificans using 13N as tracer. At low concentrations (less than 10(-8) M) of labeled nitrate and nitrite 5 to 10% of the label was assimilated into non-volatile metabolites and 90 to 95% was reduced to N2. Similarly, with 15 mM [13N]nitrate, 5% of the label went into metabolites and 95% to N2. High pressure liquid chromatography analysis of the labeled metabolites indicated that the major pathway for assimilation of inorganic nitrogen in P. denitrificans under these conditions is through ammonia incorporation via the aspartase reaction.

Quantitative scanning of osteogenic sarcoma with nitrogen-13-labeled L-glutamate.

N-13 L-glutamate was used to image an osteogenic sarcoma in a 9-year-old patient. Serial quantitative measurements of the amount of N-13 taken up by the primary tumor showed a decrease of 40% after 10 wk of chemotherapy. Blood-clearance data obtained from normal subjects indicate that more than 90% of the N-13 activity had left the blood before scanning of the tumor was begun. It appears that the N-13 label concentrated in the soft-tissue portion of this osteogenic sarcoma, whereas Tc-99m diphosphonate uptake was greatest in the regions where calcification was occurring.

The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia.

The cyclotron-produced radionuclide, 13N, was used to label ammonia and to study its metabolism in a group of 5 normal subjects and 17 patients with liver disease, including 5 with portacaval shunts and 11 with encephalopathy. Arterial ammonia levels were 52-264 micron. The rate of ammonia clearance from the vascular compartment (metabolism) was a linear function of its arterial concentration: mumol/min = 4.71 [NH3]a + 3.76, r = +0.85, P less than 0.005. Quantitative body scans showed that 7.4 +/- 0.3% of the isotope was metabolized by the brain. The brain ammonia utilization rate, calculated from brain and blood activities, was a function of the arterial ammonia concentration: mumol/min per whole brain = 0.375 [NH3]a - 3.6, r = +0.93, P less than 0.005. Assuming that cerebral blood flow and brain weights were normal, 47 +/- 3% of the ammonia was extracted from arterial blood during a single pass through the normal brains. Ammonia uptake was greatest in gray matter. The ammonia utilization reaction(s) appears to take place in a compartment, perhaps in astrocytes, that includes less than 20% of all brain ammonia. In the 11 nonencephalopathic subjects the [NH3]a was 100 +/- 8 micron and the brain ammonia utilization rate was 32 +/- 3 mumol/min per whole brain; in the 11 encephalopathic subjects these were respectively elevated to 149 +/- 18 micron (P less than 0.01), and 53 +/- 7 mumol/min per whole brain (P less than 0.01). In normal subjects, approximately equal to 50% of the arterial ammonia was metabolized by skeletal muscle. In patients with portal-systemic shunting, muscle may become the most important organ for ammonia detoxification. Muscle atrophy may thereby contribute to the development of hyperammonemic encephalopathy with an associated increase in the brain ammonia utilization rate.