Studies with positron emission tomography after systemic administration of fluorine-18-uracil in patients with liver metastases from colorectal carcinoma.

Fluorouracil (FU) is the most common cytostatic agent used for chemotherapy in patients with colorectal tumors. Fifty patients with 78 hepatic metastases from colorectal tumors were examined with positron emission tomography (PET) following intravenous infusion of 18F-FU. The uptake of the cytostatic agent was evaluated in normal liver parenchyma, liver metastases and the aorta. Tracer uptake was expressed with the standardized uptake value (SUV). The maximum liver activity was 11.3 SUV (mean value) with a standard deviation of 1.85 SUV. The highest activity concentrations were noted 30 min (mean value) postinjection. In comparison, the activity concentration of individual metastasis was low. Two hours after tracer injection, the mean activity in metastases was 1.3 SUV, but notable individual variation in uptake was seen. Fluorine-18 concentration values 2 hr after FU infusion were approximately 44% of the FU uptake 20 min postinfusion. Fifty-three metastases were also examined with 15O-labeled water. The examination was performed to compare the uptake of the nonmetabolized tracer with FU uptake. We noted a statistically significant correlation between 15O-water concentration, uptake of nonmetabolized FU 8 min after the end of the infusion and FU retention (120 min postinjection) in a subgroup of metastases. The results suggest that FU retention in different metastases is highly variable and mainly dependent on early FU uptake into tumor cells.

Fluorodeoxyglucose imaging of advanced head and neck cancer after chemotherapy.

Positron emission tomography (PET) was applied to evaluate therapeutic effects in patients with advanced head and neck cancer for use in monitoring therapy. In 18 patients with histologically proven head and neck cancer, PET studies with 330-440 MBq 18F-fluorodeoxyglucose (FDG) were performed prior to the first chemotherapeutic cycle with cisplatin and 5-FU. A second examination after the first chemotherapeutic cycle was performed in 11 patients. Tumor or lymph node volumes were determined from CT slices and the growth rate was calculated assuming an exponential function. Uptake in a region of interest was used for the quantitative evaluation of the PET images after standardization to injected dose and body weight. FDG data were available for 6 tumors and 10 metastases, volumetric data for 5 tumors and 7 metastases. One lesion showed an increase, seven a decrease in FDG uptake and eight lesions remained unchanged. Multiple lymph nodes in the same patient showed different baseline metabolisms and also different changes following therapy. Tumors were more sensitive to therapy than lymph node metastases. The growth rate and the change in FDG uptake were highly correlated with different regression functions for tumors and lymph node metastases. These data demonstrate that PET with FDG can be used to assess early chemotherapeutic effects. The information gained with PET can be included for treatment planning in patients undergoing systemic chemotherapy.

Increased thermal response to ultrasound in the Walker carcinosarcoma treated with vasoactive drugs.

In order to evaluate the potential of a highly selective Ca2+ entry blocker (nisoldipine) and of 5-hydroxytryptamine (5-HT) as adjuvant in hyperthermia treatment, we studied the differential flow response and time-course of tumor and normal tissue temperature following the administration of the two substances and during ultrasound heating. In 12 rats bearing Walker 256 carcinomas i.p. injection of 0.2-0.4 mg/kg nisoldipine caused a reduction in the tumor-to-muscle flow relationship of 4.4 +/- 1.9 (SD) to 1.74 +/- 0.86 as determined by intraarterial 133Xe injection; i.p. injection of 2-8 mg/kg 5-HT (N = 13) caused a respective reduction from 3.9 +/- 2.67 to 1.3 +/- 1.59. During a 20-min period of 41 degrees C normal tissue temperature-controlled ultrasound heating without drugs, tumor temperature attained 40.8 +/- 0.9 degrees C (N = 16). Nisoldipine or 5-HT injection at continuing 41 degrees C normal tissue temperature controlled energy delivery produced an instantaneous further increment of tumor temperature, eventually to 44.0 +/- 1.14 degrees C or 44.2 +/- 1.26 degrees C, respectively, after a period of 20 min. Injection of 0.9% NaCl (N = 4) solution caused only insignificant changes. Blood pressure and muscle perfusion were distinctly influenced by nisoldipine, but not by 5-HT. Since both drugs instantaneously increased the temperature differential between tumor and normal tissue, though by different vasoaction, they should be considered as adjuvants in hyperthermia.

Recurrence of colorectal tumors: PET evaluation.

Positron emission tomography (PET) was used in the follow-up of patients with colorectal malignancies to differentiate between recurrent colorectal tumor and scar. Patients were examined with oxygen-15-labeled water and with fluorine-18-labeled deoxyglucose (FDG). FDG was injected intravenously to assess tumor metabolism. The tracer concentration was quantitatively evaluated by means of a region-of-interest technique and standardized for both injected dose and body volume. Of 29 patients, 21 had recurrent colorectal malignancy, and eight had a nonmalignant mass. All malignancies were seen on the PET cross sections. Nonmalignant lesions had a low FDG accumulation on images obtained 60 minutes after injection. While the tumor-soft tissue ratio was highest shortly after the intravenous injection of FDG, the tumor-scar ratio was highest 60 minutes after injection. It was possible to differentiate tumor from non-malignant tissue with FDG with the use of standardized concentration values and tumor-soft tissue ratios. Imaging with O-15-labeled water gave no additional information.

Regional myocardial nitrogen-13 glutamate uptake in patients with coronary artery disease: inverse post-stress relation to thallium-201 uptake in ischemia.

The purpose of the present study was to evaluate the clinical significance of myocardial scintigraphy with nitrogen-13 (N-13) glutamate as a marker of myocardial metabolism. Within 2 weeks after cardiac catheterization, 25 patients with single vessel left anterior descending coronary artery disease underwent thallium-201 imaging (5 min and 3 h after injection) and N-13 glutamate scintigraphy (10 min after injection). Radionuclide studies were performed in the 30 degrees left anterior oblique projection after symptom-limited bicycle exercise, and regional tracer uptake was quantified by computer-assisted placement of regions of interest within the regions of myocardial activity. Poststenotic tracer uptake in the perfusion bed of the left anterior descending coronary artery (septum) was then normalized to the tracer uptake in the nondiseased left circumflex territory (posterolateral segments = 100%). In 14 patients with a history of previous myocardial infarction (Subgroup A), deficient poststenotic N-13 uptake correlated closely with thallium-201 uptake in both initial (r = 0.82, p less than 0.001) and redistribution (r = 0.74, p less than 0.01) scintigrams. By contrast, in 11 patients with no previous myocardial infarction and normal left ventricular function at rest (Subgroup B), initial uptake of both tracers was inverse: poststenotic N-13 glutamate uptake increased with decreasing thallium-201 uptake during exercise-induced ischemia (r = -0.64, p less than 0.05) and was closely correlated with the percent thallium-201 redistribution (r = 0.74, p less than 0.01). Thus, augmented accumulation of N-13 glutamate in reversibly ischemic (that is, viable) myocardium, and decreased uptake in myocardial scar tissue suggest the clinical usefulness of this metabolic tracer in the differentiation between viable (metabolically active) and irreversibly damaged myocardium.

Effect of methotrexate on perfusion and nitrogen-13 glutamate uptake in the Walker-256 carcinosarcoma.

The tissue uptake of [13N]glutamate (glu) was related to that of [11C]butanol (but), a highly diffusible perfusion tracer. In 25 rats bearing Walker-256 carcinomas tumor-to-muscle glu uptake averaged 6.34 +/- 2.84 (s.d.) prior to interventions and the respective uptake of but was 6.79 +/- 3.08 (y = 0.03 + 0.94x). One hour after selective intraarterial administration of methotrexate (mtx), glu uptake fell by 47%, whereas blood flow remained within the pretreatment range (N = 9). Four hours after mtx, perfusion was reduced by approximately 40%, and 2 days later both perfusion and glu uptake reached extremely low levels. No significant difference in the effect of 10 and 50 mg/kg mtx was observed. Regional tissue mtx uptake estimations using 77Br-labeled bromomethotrexate did not reveal any significant uptake in muscle. The relationship between tumor-to-muscle uptake of glu and but (13N/11C-index) was 0.94 +/- 0.015 (s.e.m., N = 25) before intervention. After methotrexate (1 hr, 4 hr, and 2 days) this index was 0.58 +/- 0.06 (N = 9), and 0.85 +/- 0.04 (N = 11) and 1.03 +/- 0.05 (N = 5), respectively. These values demonstrate an early mtx-induced uncoupling of glu uptake with respect to perfusion.

Nitrogen-13 glutamate uptake and perfusion in Walker 256 carcinosarcoma before and after single-dose irradiation.

Nitrogen-13 (13N) glutamate uptake was recorded in 18 anesthetized rats, both before and at least once after intervention. Each investigation was immediately followed by imaging of blood flow distribution using [11C]butanol. All animals had Walker 256 carcinosarcoma implants in one hind leg. Tumors were locally irradiated with a dose of 800 rad in 14 rats; in four rats, the vasoactive substance 5-hydroxytryptamine (5-HT) was administered. Prior to interventions, the [13N]glutamate tumor-to-muscle uptake showed a linear correlation with blood flow close to identity (y = 0.117 + 0.915x, r = 0.97). After irradiation, a discordant pattern was observed: blood flow tended to increase, while [13N]glutamate tumor-to-muscle uptake dropped from 4.30 +/- 0.66 (s.e.m.) to 3.06 +/- 0.36 (p less than 0.005) during 30 min and attained 4.04 +/- 0.67 2 days later. If [13N]glutamate tumor-to-muscle uptake was related to that of [11C] butanol in each individual animal, this index dropped from 0.93 +/- 0.03 (s.e.m.) to 0.62 +/- 0.04 (p less than 0.001) 30 min after irradiation and attained 0.90 +/- 0.09 after 2 days. In animals treated with 5-HT, [13N]glutamate and [11C]butanol showed a parallel drop from 6.60 +/- 0.84 to 2.10 +/- 0.60 (p less than 0.05) and from 6.8 +/- 0.78 to 2.08 +/- 0.74 (p less than 0.05), respectively. Thus, single-dose irradiation causes [13N]glutamate uptake to be uncoupled with respect to flow, while [13N]glutamate uptake in untreated tumors is flow-limited and responds together with flow on vasomotion.

Selective drug-induced reduction of blood flow in tumor transplants.

The effect of a calcium antagonist and a physiologic amine on tumor and muscle perfusion was investigated with the aim of improving the preconditions for external hyperthermia treatment of cancer. Nisoldipine (0.04-4.0 mg/kg) and 5-hydroxy tryptamine (5-HT) (0.2-8.0 mg/kg) were administered i.p. in Sprague-Dawley rats bearing Walker 256 carcinoma, Yoshida sarcoma, or a homologous tumor transplant derived from a spontaneous leiomyosarcoma of the uterus. At the maximum dosage used, nisoldipine injection caused a decrease of the regional washout rate of Xenon-133 of 63 +/- 8% (SEM) in the Walker carcinoma and an increase of 80 +/- 41% in the muscle of the hind leg. 5-HT (8 mg/kg) caused a drop of 79 +/- 29% in the Walker carcinoma and only a slight fall of the washout rate in muscle of 14 +/- 4.8%. Tumor-to-muscle uptake ratios of 11C-butanol fell from 5.63 +/- 1.98 to 3.32 +/- 1.21, and from 5.3 +/- 0.56 to 2.98 +/- 0.30, after injection of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT, respectively. Similar reaction patterns and percentage changes were observed in different tumor lines at constant doses of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT. Both drugs representing two different rationales of vasomotor action were able to reduce blood flow specifically in transplanted tumors; nisoldipine increased muscle blood flow and decreased arterial blood pressure, whereas 5-HT acted without substantial systemic effects.

Kinetics of 13N-ammonia uptake in myocardial single cells indicating potential limitations in its applicability as a marker of myocardial blood flow.

To study kinetics and principles of cellular uptake of 13N-ammonia, a marker of coronary perfusion in myocardial scintigraphy, heart muscle cells of adult rats were isolated by perfusion with collagenase and hyaluronidase. Net uptake of 13N, measured by flow dialysis, reached equilibrium within 20 sec in the presence of sodium bicarbonate and carbon dioxide (pH 7.4, 37 degrees C). Total extraction, 80 sec after the reaction start, was 786 +/- 159 mumol/ml cell volume. Cells destroyed by calcium overload were unable to extract 13N-ammonia. Omission of bicarbonate and carbon dioxide reduced total extraction to 36% of control. 13N-Ammonia uptake could also be reduced by 50 muM 4,4' diisothiocyanostilbene 2,2' disulfonic acid, by 100 micrograms/ml 1-methionine sulfoximine, and by preincubation with 5 muM free oleic acid. These results indicate that in addition to metabolic trapping by glutamine synthetase, the extraction of 13N-ammonia by myocardial cells is influenced by cell membrane integrity, intracellular-extracellular pH gradient, and possibly an anion exchange system for bicarbonate. For this reason, the uptake of 13N-ammonia may not always provide a valid measurement of myocardial perfusion.

11C-butanol for imaging of the blood-flow distribution in tumor-bearing animals.

1-11C-n-Butanol produced semiautomatically using a cyclotron was employed to investigate the whole-body distribution and kinetics of the label of this compound. Following the administration of 11C-butanol into the aorta of two dogs, more than 80% of the activity was cleared from the blood within 1 min. The activity distribution mirrored the cardiac output distribution as determined using 121I microspheres. Within 25 min p.i., a significant release of decay-corrected activity was only observed for the liver, spleen, and kidneys. Muscle and whole-body activity showed constant levels during this period. In 45 tumor transplants from rats, the dynamic behavior of the label was studied. The tissue retention of activity following injection into the a. femoralis was approximately 100% during the 1st 15 s for both tumor and muscle (n = 6). The activity release by tumors during the 1st 10 min after intra-aortic injection was 18% +/- 4.5% (n = 39; decay corrected). In five different tumor lines (n = 10), the initial 11C-butanol uptake was related to that of muscle, and the results were correlated with the tumor-to-muscle retention of 121I-microspheres (r = 0.89). In 17 tumors, the correlation between 11C-butanol uptake and the washout rate of 133Xe resulted in a correlation coefficient of 0.96. Tumor-to-muscle uptake ratios could be equally determined using intra-aortic and intravenous injection, as evaluated by intraindividual comparison in 12 rats (y = 0.01 + 0.98x; r = 0.98). 11C-Butanol appears to be an appropriate radiotracer for the assessment of blood supply to malignant tumors relative to muscle.

N-13 L-glutamate uptake in malignancy: its relationship to blood flow.

Studies on glutamate uptake, with special reference to perfusion, were carried out in 35 rats, each bearing one of five different tumor transplants; also in 15 rats after bone fracture, and in three rabbits. Single-pass extraction of N-13 glutamate was 85-93% in the VX2 tumor of the rabbit and in muscle. Bone fracture in rats caused a threefold increase of tracer uptake 2 days after the event. In tumor transplants, the tumor-to-muscle uptake ratio reached a maximum immediately following injection of the tracer. Comparing N-13 glutamate uptake with the retention of 1-121 microspheres, identical tumor-to-muscle ratios were found for three out of five tumor lines. Comparing the uptake with that of C-11 butanol (ten rats), a close correlation was observed throughout the range of tumor lines. The results suggested that glutamate uptake by malignant tumors is related to blood flow. In nine patients with malignant or benign lesions tumor-to-muscle uptake of N-13 glutamate and TI-201 showed a linear correlation close to identity.

Uptake and turnover of L-(13N)-glutamate in the normal human heart and in patients with coronary artery disease.

L-(13N)-glutamate (4-8 mCi) was administered IV to 27 patients with coronary artery disease and to 12 control subjects. Quantitative whole body imaging of the 13N label was performed in 31 individuals at different time intervals following the injection. Initial uptake of the total myocardium was estimated to be 5.0 +/- 0.88% of the dose. Standardized areas of reduced size on the projection plane contained 2.38 +2- 0.41% of the total dose in control subjects and 2.67 +/- 0.49% in coronary patients. Subsequent imaging exhibited significant differences in the dynamic behavior of both groups: 13N activity loss within 10 min was 3.2 +/- 4.2% of the initial value in control subjects and 16.0 +/- 9.8% in coronary patients. In individual cases a high myocardial accumulation of the 13N label was observed in regions of reduced 201Tl uptake. The findings are explained by an augmented extraction efficiency in cases of flow reduction. Glutamate utilization may be involved in metabolic adaptations of the myocardium to chronic or repetitive ischemia and may be worthy of further investigation by positron emission tomography.

Kr-81m for determination of right ventricular ejection fraction (RVEF).

A 10--12 mCi 81Rb leads to 81mKr generator was connected to a specially designed short-period infusion set, to produce an equilibrium activity distribution in the right heart. This procedure was tested in 25 individuals to calculate the right ventricular ejection fraction (RVEF). On average 30 heart cycles were analyzed per study. No background activity from the left heart was visualized because of the radionuclide exhalation. The background from the lungs could be neglected, which is partially due to the ultra-short half-life of the nuclide (t 1/2 = 13 S). Thus, an easy automatic procedure can be applied to delineate the ventricle and to calculate the RVEF. The data showed excellent reproducibility, when investigations were repeated. The method would benefit from use of higher activity generators.

Short-lived radionuclides for the assessment of rapid cardiovascular drug effects.

Continuous monitoring of cardiac output and sequential studies of right ventricular ejection fraction and of fractional myocardial uptake of substances with high cell affinity can be realized using 13N (t 1/2 = 9.6 min) and 81mKr (t 1/2 = 13 sec). Thus, it is possible to measure rapid changes of absolute myocardial blood flow and of the inotropic state of the right heart myocardium. This is shown in patients who underwent interventions with Dipyridamole and with Dobutamine which produce a marked increase in myocardial blood flow or cardiac dynamics, respectively.

Ventilation studies with krypton-81m.

Nuclear medicine offers well-established methods for regional lung function assessment in the preoperative evaluation of patients with lung disease. The perfusion study with Tc-99m macroaggregates is simple and can be performed without special precautions in radiation shielding. The ventilation study with Xe-133, however, requires more elaborate apparatus as well as special procedures to collect the exhaled radioactive rare gas. Nuclear medicine departments with access to short-lived radionuclides from a nearby cyclotron can use the krypton isotope Kr-81m. The physical half-life of Kr-81m is 13 s. Its gamma energy of 190 keV is optimal for gamma cameras. Kr-81m can be used as a medical isotope in spite of its short half-life. It can be eluted with a continuously flowing gas from the generator containing the mother nuclide Rb-81 which has half-life of 4.6 h. This short half-life not only simplifies radiation protection but allows repeated studies in different projections as well. Examples of comparative studies with Xe-133 and Kr-81m are presented. The importance of taking not only anterior and posterior pictures but also lateral oblique views is stressed.