Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease.

BACKGROUND: Positron emission tomographic (PET) scanning utilizing [18F]fluorodeoxyglucose (FDG) is a new method of tumor imaging based on the increased glucose metabolic activity of malignant tumors. In Hodgkin's disease (HD), PET has proven value for the evaluation of residual masses following treatment and for the early diagnosis of relapse. In the initial staging of HD, PET frequently shows a higher stage than conventional methods (upstaging by PET). In the present study, we evaluated the frequency of stage changes by PET in a multicenter setting and determined its prognostic relevance. PATIENTS AND METHODS: A total of 73 patients with newly diagnosed HD were staged with both conventional methods and whole-body PET scanning. All histological types and stages were represented. The median time of follow-up after the initial diagnosis was 25 months (range 1 month to 5 years). The response to treatment was determined by standard clinical and diagnostic criteria. For the purpose of this analysis, data from a PET center associated with a university medical center and a PET center associated with a group oncology practice were combined. RESULTS: A total of 21 patients (28.8%) were upstaged by PET compared with conventional methods. In two cases (2.7%), a lower stage was suggested by PET scanning. With one possible exception, the upstaging had no obvious clinical or biological correlate. Among 12 patients in stage I (A + B) by conventional methods, seven were upstaged by PET (58.3%), four to stage II, one to stage III and two to stage IV. Among 42 patients in stage II, eight were upstaged by PET (19.0%), six to stage III and two to stage IV. Among 12 patients in stage III, six (50%) were upstaged to stage IV by PET. If only early-stage patients and major changes are considered (stages IA-IIB to III or IV), among 49, 10 were upstaged to III or IV, whereas in 39 staging was unchanged following PET. In the former group, three relapsed or were refractory compared with none in the latter group (P<0.006). In advanced stage patients (IIIA or IIIB) a trend toward treatment failure was apparent in patients who were upstaged by PET. CONCLUSIONS: PET scanning is an interesting new modality for the accurate staging of patients with HD and frequently shows a higher stage than conventional methods. PET should be performed at initial diagnosis and should be included in prospective studies of patients with HD. Upstaging by PET may represent a risk factor for a more advanced stage or a biologically more aggressive tumor. Patients with early-stage disease as identified by conventional methods have a significant risk of treatment failure if a more advanced stage is indicated by PET. At present, major stage changes suggested by PET imaging should be confirmed by an independent diagnostic method.

Benign versus malignant intraosseous lesions: discrimination by means of PET with 2-[F-18]fluoro-2-deoxy-D-glucose.

PURPOSE: To assess the ability of positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) to allow differentiation of benign from malignant intraosseous lesions. MATERIALS AND METHODS: Twenty patients with strictly intraosseous lesions (five benign and 15 malignant [three primary and 12 metastatic]) were studied with FDG PET. The final diagnosis was confirmed with histopathologic examination in all patients. The uptake of FDG within each lesion was evaluated qualitatively as well as semiquantitatively by determination of the standardized uptake value (SUV). RESULTS: SUV assessment of FDG accumulation within osseous lesions was superior to subjective visual analysis for discriminating benign from malignant lesions. With use of a 2.0 cutoff value for SUV, 14 of 15 malignant lesions were categorized correctly versus 12 of 15 correctly categorized by means of subjective image evaluation; four of five benign lesions were categorized correctly with both techniques. CONCLUSION: FDG PET can aid in differentiating benign from malignant strictly intraosseous lesions.

FDG-PET evaluation of indeterminate pancreatic masses.

PURPOSE: The purpose of this study was to assess the ability of PET with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) to differentiate benign from malignant pancreatic masses in patients with indeterminate findings on CT. METHOD: We performed FDG-PET on 12 patients with indeterminate mass lesions and 2 patients with CT findings typical for malignancy. Eight were found to have pancreatic carcinoma and six had benign lesions. The final diagnosis was histopathologically confirmed in all patients but two with a presumed diagnosis of focal pancreatitis based on stable clinical follow-up for at least 12 months. Lesion uptake of FDG was evaluated qualitatively and semiquantitatively by determination of the standardized uptake value (SUV) RESULTS: With use of a 2.5 cutoff value for SUV, all eight malignant and four of six benign lesions were correctly categorized. Qualitative evaluation gave the same results. The two false-positive lesions had elevated SUV values of 3.4 and 3.8, respectively. CONCLUSION: Our results indicate that FDG-PET has potential value for assessing patients with CT findings that are indeterminate for pancreatic carcinoma. FDG-PET may obviate invasive diagnostic procedures in many patients with benign disease.

Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays.

UNLABELLED: The purpose of this study was to assess the results of PET with 16 alpha-[18F]fluoro-17 beta-estradiol (FES) and [18F]fluoro-2-deoxy-D-glucose (FDG) to validate the concordance between tumor estrogen-receptor (ER) status as determined by FES-PET and in vitro assays and to assess the relationship between tumor metabolic activity determined by FDG-PET and tumor ER status, both of which may provide information about tumor aggressiveness and prognosis. METHODS: We studied 32 patients with primary breast masses and 21 patients with clinical or radiological evidence of recurrent/metastatic breast carcinoma. A diagnosis of breast carcinoma was subsequently proven in 43 patients (24 primary, 15 metastatic and 4 recurrent tumors). In vitro assessment of ER status was available for 40 malignant lesions (23 primary and 17 metastatic/recurrent). The patients underwent PET with both FES and FDG, and the uptake of each tracer within each lesion was evaluated qualitatively as well as semiquantitatively using the standardized-uptake-value (SUV) method. RESULTS: We found good overall agreement (88%) between in vitro ER assays and FES-PET. This degree of agreement is similar to that observed between replicate in vitro assays (with discordances due to interlaboratory, interassay and specimen variability). We were, however, unable to demonstrate any significant relationship between tumor FDG uptake and ER status or between tumor FDG and tumor FES uptake in these patients. CONCLUSION: These results indicate that in vitro ER assays and/or FES-PET provide unique direct information about breast cancer ER status that cannot be obtained indirectly by FDG-PET.

Results of a clinical receiver operating characteristic study comparing filtered backprojection and maximum likelihood estimator images in FDG PET studies.

The results of a receiver operator characteristic (ROC) study comparing maximum likelihood estimator (MLE) reconstructions of human FDG PET brain scan data to filtered backprojection reconstructions of the same data are reported. The purpose of the study was to determine whether MLE reconstructions would result in higher detectability of small focal lesions introduced artificially into otherwise normal scan data. One physician assisted in defining the location and intensity of the lesions and five physicians read the final images. Data from 90 datasets were used for the study. Of those, 42 were left in their original "normal" condition and 48 were modified by added lesions. All datasets were reconstructed by the two methods and submitted to the five physicians for evaluation. The results show an increase in the area under the ROC curve from approximately 0.65 for filtered backprojection to approximately 0.71 for the maximum likelihood reconstructions for four of the five observers with good statistical significance.

Brain metastases from non-central nervous system tumors: evaluation with PET.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) was performed in 19 patients with brain metastases from non-central nervous system (CNS) neoplasms and one patient with a primary CNS lymphoma. Various histopathologic types were represented by the primary neoplasms in the patients with metastases. Only 21 of the 31 lesions (68%) were detected with FDG PET as discrete, metabolically active foci (relative to surrounding structures). Six of the nondetected lesions may have been nondiscernible owing to their small size and/or isointensity relative to closely apposed normal gray matter. However, four lesions of at least 1.2 cm in diameter showed frankly decreased FDG accumulation relative to normal brain. These findings suggest that studies of FDG accumulation by a variety of non-CNS neoplasms and their CNS metastases are in order and that extrapolation of the successes of FDG PET in imaging of primary glial tumors to imaging of brain metastases should proceed with caution.

Blinded clinical evaluation of positron emission tomography for diagnosis of probable Alzheimer's disease.

We evaluated the sensitivity and specificity of positron emission tomography for diagnosis of probable Alzheimer's disease under conditions similar to those encountered in the routine clinical practice of nuclear medicine. We obtained tomographic images of regional cerebral blood flow from three groups of subjects: (1) 13 subjects, ages 69 to 84, who had probable Alzheimer's disease diagnosed by validated clinical criteria; (2) 15 subjects, ages 57 to 77, who had Parkinson's disease without dementia; and (3) 11 subjects, ages 65 to 83, who were normal. Three blinded reviewers, who had not previously seen the images, categorized them as normal, bilateral temporoparietal flow defects typical of Alzheimer's disease, or other abnormality. Consensus interpretation demonstrated sensitivity of 0.38 (5/13) and specificity of 0.88 (23/26) for identifying patients with probable Alzheimer's disease. Thus, the criterion of bilateral temporoparietal reduction in cerebral blood flow used in this study did not have sufficient sensitivity to be of clinical value. While other criteria may be developed to improve diagnostic accuracy, clinical utility can be established only by testing for validity in patients with a full spectrum of complicating neurologic and psychiatric conditions for whom diagnosis is uncertain and who are then followed longitudinally to determine clinical outcome or pathologic findings.

Positron emission tomography in the study of acute radiation effects on renal blood flow in dogs.

Renal blood flow measurements have been carried out by means of positron emission tomography (PET) to facilitate the detection of radiation-induced injuries. The advantages of the method employed in animal experiments are described.

PET evaluation of soft-tissue masses with fluorine-18 fluoro-2-deoxy-D-glucose.

Positron emission tomography (PET) with fluorine-18 fluoro-2-deoxy-D-glucose (FDG) was performed in 19 patients referred for clinical evaluation of soft-tissue masses. These patients had 20 different lesions and had been evaluated previously with computed tomography (CT) and/or magnetic resonance (MR) imaging. The diagnoses were subsequently confirmed with open biopsy or excision (19 lesions) or by clinical and radiographic follow-up (one lesion). Semiquantitative assessment of FDG accumulation (differential uptake ratio) within the suspected tumor helped correctly separate the 10 malignant tumors from the 10 benign lesions. In contrast, a simple ratio of FDG uptake within the suspected tumor to that within comparable normal soft tissue was less successful in helping make this distinction, with overlap in 12 of the 20 cases. Careful comparison with findings from other available imaging studies is essential for accurate interpretation of PET studies of soft-tissue masses, but in many cases, PET may be a useful adjunct in the preoperative evaluation of suspected soft-tissue tumors, yielding valuable information that is not provided with CT or MR imaging.

Assessment of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas.

We have used 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP) for imaging progestin receptors by PET in patients with primary carcinoma of the breast. In vitro binding and in vivo tissue distribution studies in rats have shown that FENP has high specific activity, high affinity for progestin receptors, and receptor-mediated uptake in target tissues. Eight patients with primary breast carcinoma were studied. Breast carcinoma was identified correctly in 50% of the patients with progestin-receptor-positive tumors; however, the FENP uptake was not correlated with progestin-receptor levels. We noted a low target-to-background ratio in humans, with high relative activity in the spine, blood pool, and normal breast tissue. Our findings indicate that FENP is not a suitable agent for imaging progestin receptors in humans.

Cross-sectional imaging of the patellofemoral joint and surrounding structures.

Computed tomography (CT) and magnetic resonance (MR) imaging are extremely useful in the accurate diagnosis of anterior knee pain, a common complaint arising from numerous causes (including fracture, chondromalacia patellae, and alignment and tracking abnormalities). Plain CT is effective for evaluating intraosseous lesions of the knee. Although CT arthrography provides excellent visualization of the patellar articular cartilage, the technique is expensive and invasive. Cine CT is an excellent method for assessing patellofemoral tracking and alignment. Kinematic MR imaging can also perform this function. In addition, MR imaging can provide valuable information concerning the status of patellar cartilage. Although MR imaging can accurately show high-grade chondromalacia patellae, it is less accurate in the detection of low-grade disease. The authors believe that MR imaging and plain radiography offer radiologists the greatest latitude in making a specific diagnosis of the cause of anterior knee pain; however, CT is a useful alternative.

Sex-dependent differences in N-(3-[18F]fluoropropyl)-N-nordiprenorphine biodistribution and metabolism.

In our work with the new opioid receptor ligand, N-(3-[18F]fluoropropyl)-N-nordiprenorphine, ([18F]FPND), we have noted significant sex-dependent differences in metabolism and distribution. In female rats, metabolism of this ligand proceeds without significant P-450-mediated oxidation of the N-fluoroalkyl side chain, while in male rats, this is the dominant metabolic pathway. In biodistribution experiments, striatal uptake of this ligand is higher in female than in male rats, but no difference in cerebellar uptake is observed. In male rats, no metabolites of [18F]FPND are produced that cross the blood-brain barrier. In contrast, female rats produce a metabolite that both crosses the blood-brain barrier and exhibits opioid receptor-specific binding superior to that of the parent compound. These studies demonstrate that the possibility of sex-dependent metabolism must be considered when the rat is employed to screen new radiopharmaceuticals.

Effects of model traumatic injury on hepatic drug metabolism in the rat. VI. Major detoxification/toxification pathways.

A previously validated small mammal trauma model, hindlimb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on two of the major hepatic enzymes of detoxification, glutathione S-transferase and epoxide hydrolase. Hepatic cytosolic glutathione S-transferase activity toward a variety of substrates showed a 26-34% decrease at 24 hr after model injury. Hepatic microsomal epoxide hydrolase activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was diminished by 53% after model trauma. Both enzymatic activities toward styrene oxide were similarly depressed. The toxicological sequelae of these derangements were illustrated by administering a dose of styrene oxide (300 mg/kg, ip) which was below the threshold dose (350 mg/kg, ip) necessary to produce hepatotoxicity in control animals. Model trauma dramatically enhanced the hepatotoxic effects of the subthreshold dose, as well as the covalent binding of labeled styrene oxide to liver proteins. These findings indicate that traumatic injury renders the animal more susceptible to agents which are detoxified by glutathione S-transferase and epoxide hydrolase. Conversely, model trauma provided almost complete protection from the hepatotoxic effects of a standard dose (200 mg/kg, ip) of bromobenzene. This protection appeared to derive from a post-traumatic alteration of cytochrome P-450 subpopulations that decreased the formation of the potentially toxic 3,4-epoxide metabolite, despite an increase in the cytochrome P-448-mediated generation of the nontoxic 2,3-epoxide. For bromobenzene, the change in cytochrome P-450-mediated activation appeared quantitatively more significant in overall toxicity than the post-traumatic depression of detoxification pathways described above, leading to decreased toxicity in vivo. For other compounds, the combination of post-traumatic influences on cytochrome P-450/P-448 activity and epoxide hydrolase/glutathione S-transferase activities could lead to markedly enhanced toxicity.

Intrathecal administration of nitroxides as potential contrast agents for MR imaging.

The diagnosis of various disorders of the cerebrospinal fluid (CSF) with magnetic resonance (MR) imaging may require the intrathecal administration of a paramagnetic contrast agent. Furthermore, the CSF route provides direct access to the brain, circumventing the blood-brain barrier. Three nitroxides, two charged and one uncharged, were administered intrathecally to dogs to assess their potential as contrast agents for MR imaging of the CSF. Nitroxide concentrations and proton T1 values were measured in samples of CSF removed at various times after nitroxide administration, and pharmacokinetic curves were constructed. The charged nitroxides had considerably longer half-lives than the uncharged compound. On in vivo MR imaging of the CSF (surrounding the upper cervical cord and brain stem) in one dog, use of a charged nitroxide as contrast agent led to considerably higher CSF signal intensity than was observed in the nonenhanced, baseline T1-weighted images. This effect was achieved at low doses (20 mumol) and sustained for at least 90 minutes. The intrathecal use of nitroxides as contrast agents for MR imaging warrants continued investigation.

Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation.

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on hepatic glucuronidation activity. As was previously observed with hepatic oxidative drug metabolism, model trauma resulted in a significant decrease in the in vivo glucuronidation of chloramphenicol, with a 23% drop in clearance of this drug. The effect on in vivo pharmacokinetics appeared to result from a complex interaction between trauma's differential influences on conjugating enzyme(s), deconjugating enzyme(s), and hepatic UDP-glucuronic acid levels, as well as the relative physiological importance of these variables. Hepatic UDP-glucuronyltransferase activities towards both p-nitrophenol and chloramphenicol were elevated (44-54%) after model injury when measured in native hepatic microsomes. However, microsomes which had been "activated" by treatment with Triton X-100 showed no significant difference between control and traumatized animals. Serum beta-glucuronidase activities were elevated by 58%, while hepatic beta-glucuronidase rose by about 16%. Nevertheless, in vivo deconjugation showed no significant change. Model trauma also resulted in a 46% decrease in hepatic UDP-glucuronic acid content. Thus, the observed post-traumatic depression of in vivo chloramphenicol glucuronidation could be due either to a diminished availability of a necessary cofactor (UDP-glucuronic acid) or to an alteration in enzyme kinetics or function in vivo.

Effects of model traumatic injury on hepatic drug metabolism in the rat. V. Sulfation and acetylation.

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on sulfation and N-acetylation, two of the major phase II conjugative reactions of hepatic drug metabolism. Hepatic cytosolic sulfotransferase activity, as measured by several aryl and hydroxysteroid sulfation assays, was depressed by 20-29% after model injury. N-Acetyltransferase activity towards both isoniazid and p-aminobenzoic acid showed a similar 20-22% decrease. Moreover, as was previously observed with hepatic oxidative drug metabolism and with glucuronidation, the in vivo reactions of sulfation and acetylation were found to be significantly decreased by model trauma. In both cases, this effect on in vivo pharmacokinetics appeared to be correlated closely with trauma's influence on the conjugating enzymes, and relatively independent of the post-traumatic response of the necessary co-substrates. In vivo acetaminophen sulfation was depressed (24%) in parallel with hepatic sulfotransferase activity, despite an increased availability of sulfate for conjugation. Similarly, in vivo acetylation of isoniazid was diminished (23%) in conjunction with hepatic N-acetyltransferase activity, though hepatic acetyl-CoA content was elevated after model trauma. Thus, traumatic injury appears to have wide-ranging effects on a variety of determinants of hepatic drug metabolism.

Pharmacokinetics of nitroxide NMR contrast agents.

Pharmacokinetics of the nitroxide stable free radical functionality of compounds containing this moiety were evaluated in the rat. The agents were injected i.v. at either high (1.75 mmoles/kg) or low (10 mumoles/kg) dose, and timed blood samples were drawn and assayed for nitroxide concentration by EPR spectrometry. Similarly, various organs and tissues were removed at specified times after injection and homogenized for determination of nitroxide concentration. Urine was collected by catheter for estimation of urinary excretion of the intact nitroxide free radical. At high doses, the various nitroxides exhibited an initial rapid disposition phase, followed by a terminal disposition phase with disappearance from the blood showing apparent log-linear half-lives of about 5 to 30 minutes. Generally, 20 to 60% of the dose was recovered in the urine. At low doses, dissimilar results were obtained. Blood levels again showed biphasic decay; however, blood concentrations at all times were much lower than those predicted by the high dose kinetics, indicating probably nonlinear pharmacokinetic behavior. Tissue homogenate studies showed low or nondetectable levels of nitroxide signal, demonstrating that the low blood concentrations could not be accounted for by a rapid uptake into specific tissues. Moreover, only 2 to 6% of the nitroxide could be recovered in the urine. Additional studies demonstrated that at the low dose a rapid in vivo bioreduction occurred which appeared to be saturable at the higher dose.

Effects of model traumatic injury on hepatic drug metabolism in the rat. II. In vivo metabolism of hexobarbital and zoxazolamine.

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to further investigate the effects of traumatic injury on hepatic drug metabolism in vivo. The pharmacokinetic sequelae of the previously observed post-traumatic decrease in cytochrome P-450 content were demonstrated, using hexobarbital and zoxazolamine as model cytochrome P-450-oxidized drugs. Sleeping times after ip or iv administration of these drugs was prolonged by model injury. Longer sleeping times appeared to be caused by a slower elimination of the drugs from the bloodstream rather than to an increased sensitivity to their central nervous system effects or to an alteration in plasma protein-binding. Detailed pharmacokinetic analyses by the two-compartmental open system model revealed that the major alteration in post-traumatic drug metabolism was decreased in vivo elimination rather than a shift in distribution. These studies further confirm the pharmacokinetic utility of this convenient small mammal trauma model in the study of post-traumatic derangements in hepatic drug metabolism and emphasize the toxicologic importance of these derangements.

Effects of model traumatic injury on hepatic drug metabolism in the rat. III. Differential responses of cytochrome P-450 subpopulations.

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to further investigate the effects of traumatic injury on the hepatic cytochromes P-450. In vitro drug metabolism studies with hexobarbital and zoxazolamine as substrates confirmed the post-traumatic depression of the cytochrome P-450-catalyzed oxidation of these drugs which was suggested by previous in vivo pharmacokinetic studies. Enzyme kinetic studies revealed diminished Vmax values with no change in Km, a finding which would seem to concur with the previously demonstrated decrease in hepatic cytochrome P-450 content after model trauma. Moreover, a battery of in vitro microsomal monooxygenase assays demonstrated that model trauma exerted a differential effect on various hepatic cytochrome P-450 isoenzymes. This phenomenon was confirmed by anion-exchange HPLC of solubilized hepatic microsomal hemoproteins. One of the most interesting aspects of this selective effect on cytochrome P-450 subtypes was the relative induction of cytochrome P-448 content and activity, in contrast to the variable decrease seen with cytochrome P-450 activities. The potential in vivo sequelae of this differential influence were suggested by changes observed in the urinary metabolic profile of antipyrine after model trauma.