Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone.

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.

Leukotrienes as mediators in ischemia-reperfusion injury in a microcirculation model in the hamster.

Leukotriene (LT)B4 promotes leukocyte chemotaxis and adhesion to the endothelium of postcapillary venules. The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, elicit macromolecular leakage from this vessel segment. Both leukocyte adhesion to the endothelium and macromolecular leakage from postcapillary venules hallmark the microcirculatory failure after ischemia-reperfusion, suggesting a role of leukotrienes as mediators of ischemia-reperfusion injury. Using the dorsal skinfold chamber model for intravital fluorescence microscopy of the microcirculation in striated muscle in awake hamsters and sequential RP-HPLC and RIA for leukotrienes, we demonstrate in this study that (a) the leukotrienes (LT)B4 and LTD4 elicit leukocyte/endothelium interaction and macromolecular leakage from postcapillary venules, respectively, that (b) leukotrienes accumulate in the tissue after ischemia and reperfusion, and that (c) selective inhibition of leukotriene biosynthesis (by MK-886) prevents both postischemic leukotriene accumulation and the microcirculatory changes after ischemia-reperfusion, while blocking of LTD4/E4 receptors (by MK-571) inhibits postischemic macromolecular leakage. These results demonstrate a key role of leukotrienes in ischemia-reperfusion injury in striated muscle in vivo.

18-F-fluorodeoxyglucose-positron emission tomography as a new approach to detect lymphomatous bone marrow.

PURPOSE: Bone marrow involvement in patients with malignant lymphoma is considered a sign of generalized disease with less favorable prognosis. Bone marrow biopsy (BMB), which represents the standard diagnostic procedure, however, is associated with a high rate of false-negative findings, which may lead to errors in management. The present study was undertaken to investigate the efficacy of positron emission tomography (PET) with 18-F-fluorodeoxyglucose (FDG-PET) as a new method to evaluate bone marrow involvement in patients with malignant lymphoma. METHODS: Seventy-eight consecutive, untreated patients with either non-Hodgkin's lymphoma (NHL; n = 39) or Hodgkin's disease (HD; n = 39) were prospectively evaluated. Static FDG-PET imaging was performed following application of 270 MBq (F-18)-FDG. Attenuation correction was performed in 63 of 78 patients. Visual evaluation was performed by two examiners unaware of the clinical data. Material for BMB (70 bilateral, 8 unilateral) was obtained from the posterior iliac crest. Discordant results of PET and biopsy were settled, when possible, on the basis of further biopsy or magnetic resonance imaging (MRI). RESULTS: In addition to seven concordant positive and 57 concordant negative findings, biopsy revealed another four cases with bone marrow involvement not detectable by FDG-PET analysis (+5.1%). On the contrary, PET showed bone marrow areas of intensive FDG uptake that suggested bone marrow lymphoma in 10 patients with negative biopsies (+12.8%). In eight patients, FDG-PET findings were confirmed by either histologic verification (n = 4), MRI (n = 2), polymerase chain reaction (PCR) for rearranged immunoglobulin H sequences (n = 1), or clinical presentation (n = 1). Two cases remained unresolved. CONCLUSION: The results indicate that FDG-PET has a high potential to detect bone marrow involvement in malignant lymphoma. Besides confirming lesions found at BMB, FDG-PET provided additional information, which, in eight of 78 patients (10.3%), led to an upgrade of the tumor stage.

Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography.

PURPOSE: Previous studies have shown that bone metastases are revealed by magnetic resonance imaging (MRI) or bone marrow scintigraphy several months before they are visible by conventional bone scintigraphy (BS). We present a new approach for detecting bone metastases in patients with breast cancer. We compared findings obtained with fluoride ion (F-18) and positron emission tomography (PET) with those obtained with conventional BS. PATIENTS AND METHODS: Thirty-four breast cancer patients were prospectively examined using F-18-PET and conventional BS. F-18-PET and BS were performed within 3 weeks of each other. Metastatic bone disease was previously known to be present in six patients and was suspected (bone pain or increasing levels of tumor markers, Ca(2+), alkaline phosphatase) in 28 patients. Both imaging modalities were compared by patient-by-patient analysis and lesion-by-lesion analysis, using a five-point scale for receiver operating characteristic (ROC) curve analysis. A panel of reference methods was used, including MRI (28 patients), planar x-ray (17 patients), and spiral computed tomography (four patients). RESULTS: With F-18-PET, 64 bone metastases were detected in 17 patients. Only 29 metastases were detected in 11 patients with BS. As a result of F-18-PET imaging, clinical management was changed in four patients (11.7%). For F-18-PET, the area under the ROC curve was 0.99 on a lesion basis (for BS, it was 0.74; P <.05) and 1.00 on a patient basis (for BS, it was 0.82; P <.05). CONCLUSION: F-18-PET demonstrates a very early bone reaction when small bone marrow metastases are present, allowing accurate detection of breast cancer bone metastases. This accurate detection has a significant effect on clinical management, compared with the effect on management brought about by detection with conventional BS.

Fluorine-18-FDG PET and technetium-99m antigranulocyte antibody scintigraphy in chronic osteomyelitis.

UNLABELLED: The aim of this study was to assess the usefulness of PET with 2-18F-fluoro-2-deoxy-D-glucose (FDG), as compared to immunoscintigraphy (IS) with 99mTc-labeled monoclonal antigranulocyte antibodies (AGAbs), in the detection of chronic osteomyelitis. METHODS: Fifty-one patients suspected of having chronic osteomyelitis in the peripheral (n = 36) or central (n = 15) skeleton were evaluated prospectively with static FDG PET imaging and combined 99mTc-AGAb/99mTc-methylene diphosphonate (MDP) bone scanning within 5 days. FDG PET and IS were evaluated in a blinded and independent manner by visual interpretation, which was graded on a five-point scale of two observers' confident diagnosis of osteomyelitis. Receiver operating characteristic (ROC) curve analysis was performed for both imaging modalities. The final diagnosis was established by means of bacteriologic culture of surgical specimens and histopathologic analysis (n = 31) or by biopsy and clinical follow-up over 2 yr (n = 20). RESULTS: Of 51 patients, 28 had osteomyelitis and 23 did not. According to the unanimous evaluation of both readers, FDG PET correctly identified 27 of the 28 positives and 22 of the 23 negatives (IS identified 15 of 28 positives and 17 of 23 negatives, respectively). The area under the ROC curve was 0.97/0.97 (reader 1/reader 2) for FDG PET and 0.87/0.90 for IS, with a high degree of interobserver concordance (K-values were 0.96 for FDG PET and 0.91 for IS). In the central skeleton, the ROC curve area was 0.98/1.00 for FDG PET and 0.71/0.77 for IS (p<0.05). On the basis of ROC analysis, the overall accuracies of FDG PET and IS in the detection of chronic osteomyelitis were 96%/96% and 82%/ 88%, respectively. With regard to the optimal threshold values, sensitivity and specificity were 100%/97% and 95%/95% with FDG PET, compared to 86%/92% and 77%/82% with IS, respectively. CONCLUSION: In the peripheral skeleton, both FDG PET and combined 99mTc-AGAb/99mTc-MDP scanning are appropriate imaging modalities to diagnose chronic osteomyelitis. FDG PET additionally allows reliable differentiation between osteomyelitis and infection of the surrounding soft tissue. In the central skeleton within active bone marrow, FDG PET is highly accurate and superior to AGAb imaging in the diagnosis of chronic osteomyelitis, which frequently presents as a nonspecific photopenic lesion at scintigraphy with labeled white blood cells.

Grading of tumors and tumorlike lesions of bone: evaluation by FDG PET.

UNLABELLED: Clinical diagnosis of skeletal tumors can be difficult, because such lesions compose a large, heterogeneous group of entities with different biologic behaviors. The aim of this prospective study was to assess the value of PET in grading tumors and tumorlike lesions of bone. METHODS: Two hundred two patients with suspected primary bone tumors were investigated using FDG PET. Uptake of FDG was evaluated semiquantitatively by determining the tumor-to-background ratio (T/B). All patients underwent biopsy, resulting in the histologic detection of 70 high-grade sarcomas, 21 low-grade sarcomas, 40 benign tumors, 47 tumorlike lesions, 6 osseous lymphomas, 6 plasmacytomas, and 12 metastases of an unknown primary tumor. RESULTS: All lesions, with the exception of 3 benign tumors, were detected by increased FDG uptake. Although sarcomas showed significantly higher T/Bs than did latent or active benign lesions (P < 0.001), aggressive benign lesions could not be distinguished from sarcomas. Using a T/B cutoff level for malignancy of 3.0, the sensitivity of FDG PET was 93.0%, the specificity was 66.7%, and the accuracy was 81.7%. CONCLUSION: FDG PET provides a promising tool for estimating the biologic activity of skeletal lesions, implicating consequences for the choice of surgical strategy.

Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET.

UNLABELLED: Radionuclide bone scanning (RNB) is considered to be the most practical screening technique for assessing the entire skeleton for skeletal metastases. However, RNB has been shown to be of lower sensitivity than MRI and CT in detecting osteolytic metastases. A prospective study was designed to evaluate the accuracy of planar RNB versus tomographic bone imaging with 18F-labeled NaF and PET (18F PET) in detecting osteolytic and osteoblastic metastases and its dependency on their anatomic localization. METHODS: Forty-four patients with known prostate, lung or thyroid carcinoma were examined with both planar RNB and 18F PET. A panel of reference methods including MRI of the spine, 1311 scintigraphy, conventional radiography and spiral CT was used as the gold standard. RNB and 18F PET were compared by a lesion-by-lesion analysis using a five-point score for receiver operating characteristic (ROC) curve analysis. RESULTS: 18F PET showed 96 metastases (67 of prostate carcinoma and 29 of lung or thyroid cancer), whereas RNB revealed 46 metastases (33 of prostate carcinoma and 13 of lung or thyroid cancer). All lesions found with RNB were also detected with 18F PET. Compared with 18F PET and the reference methods, RNB had a sensitivity of 82.8% in detecting malignant and benign osseous lesions in the skull, thorax and extremities and a sensitivity of 40% in the spine and pelvis. The area under the ROC curve was 0.99 for 18F PET and 0.64 for RNB. CONCLUSION: 18F PET is more sensitive than RNB in detecting osseous lesions. With RNB, sensitivity in detecting osseous metastases is highly dependent on anatomic localization of these lesions, whereas detection rates of osteoblastic and osteolytic metastases are similar. Higher detection rates and more accurate differentiation between benign and malignant lesions with 18F PET suggest the use of 18F PET when possible.

Evaluation of neoadjuvant therapy response of osteogenic sarcoma using FDG PET.

UNLABELLED: According to the current treatment protocol of the Cooperative Osteosarcoma Study (COSS), monitoring preoperative chemotherapy response and estimating grade of tumor regression in patients with osteosarcoma is mandatory before surgical removal of the tumor, particularly if a limb salvage procedure is intended. In addition, response to neoadjuvant chemotherapy is considered as an important prognostic indicator. The aim of this prospective study was to assess the usefulness of 2-(18F) fluoro-2-deoxy-D-glucose (FDG) PET in the noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. METHODS: In 27 patients with osteosarcoma, we determined tumor-to-background ratios (TBRs) of FDG uptake with PET, before and after neoadjuvant chemotherapy according to COSS 86c or COSS 96 protocols, respectively. We compared changes in glucose metabolism of osteosarcomas with the histologic grade of regression in the resected specimen, according to Salzer-Kuntschik, discriminating responders (grades I-III; n = 17) and nonresponders (grades IV-VI; n = 10). RESULTS: The decrease of FDG uptake in osteosarcomas expressed as a ratio of posttherapeutic and pretherapeutic TBRs showed a close correlation to the amount of tumor necrosis induced by polychemotherapy (P < 0.001; Spearman). With a TBR ratio cutoff level of 0.6, all responders and 8 of 10 nonresponders could be identified by PET. In addition, lung metastases of osteosarcoma were detected with FDG PET in 4 patients. CONCLUSION: FDG PET provides a promising tool for noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. This could imply consequences for the choice of surgical strategy, because a limb salvage procedure cannot be recommended in patients nonresponsive to preoperative chemotherapy unless wide surgical margins can safely be achieved.

Metabolic inactivation of leukotrienes.

The metabolic inactivation of the cysteinyl leukotrienes LTC4 and LTD4 and of the chemotactic LTB4 was studied in the rat in vivo and in hepatocyte suspensions, respectively. 1. Deactivation of LTC4 via LTD4 to LTE4 was a most active process in the blood circulation, catalyzed mainly by ectoenzymes located on the internal wall of blood vessels. Uptake of cysteinyl leukotrienes by hepatocytes and kidney cells contributed to the rapid elimination of these potent mediators whenever they were released into the blood circulation. The initial half-life of LTC4 in vivo was 12 seconds. 2. omega-Oxidation leads to the formation of omega-hydroxylated and omega-carboxylated cysteinyl leukotrienes which were detected in bile and urine. Biliary metabolites included those formed by stepwise beta-oxidative degradation of omega-carboxy-N-acetyl-LTE4, yielding the dinor, tetranor, and hexanor derivative. 3. The peroxisome proliferator clofibrate strongly increased the degradation of LTE4 by omega-oxidation and subsequent beta-oxidation in vivo. The generation of new polar metabolites was detected by HPLC methods and by the use of 3H8-labeled cysteinyl leukotrienes in comparison with the 3H2-labeled precursor. 4. The metabolic degradation and inactivation of cysteinyl leukotrienes in vivo and of LTB4 in isolated hepatocytes was potently inhibited by ethanol. The site of inhibition was the oxidation of omega-hydroxy-N-acetyl-LTE4 and of omega-hydroxy-LTB4 to the respective omega-carboxylated metabolite. This inhibition led to an accumulation of the biologically active LTB4 and of N-acetyl-LTE4. The interference of leukotriene inactivation in the liver may provide a novel explanation for the ethanol-induced inflammatory reaction in acute alcoholic liver disease.

Leukotriene C4 metabolism by hepatoma cells and liver.

The metabolism of the glutathionyl leukotriene LTC4 in the mercapturic acid pathway was studied in suspensions of AS-30D hepatoma cells and hepatocytes, as well as in vivo in the bile duct-cannulated rat and in primates. 1. Isolated hepatocytes actively took up cysteinyl leukotrienes and metabolized LTC4 not only to LTD4 and LTE4 but also to N-acetyl-LTE4 and to metabolites more polar than LTC4. 2. AS-30D hepatoma cells are deficient in the transport system for the uptake of cysteinyl leukotrienes. Peptide cleavage of LTC4 to LTD4 and LTE4 was catalyzed by ectoenzymes of these cells. Inactivation of gamma-glutamyltransferase by acivicin and inhibition of LTD4 dipeptidase by penicillamine largely prevented further catabolism of LTC4 and LTD4, respectively. 3. [3H]LTC4 injected i.v. into rats was rapidly eliminated from the circulating blood, taken up by the liver, and excreted into bile where 77% of the administered radioactivity was recovered within 1 hr. The biliary LTC4 metabolites included LTD4, N-acetyl-LTE4, and metabolites more polar than LTC4. 4. Inhibition of [3H]LTC4 metabolism in vivo by i.v. penicillamine shifted the pattern of biliary cysteinyl leukotrienes; an extended half-life of [3H]LTD4 was associated with a retarded formation of N-acetyl-LTE4 and of polar metabolites. 5. Endogenous cysteinyl leukotrienes elicited by trauma were measured after HPLC separation by radioimmunologic analysis in plasma and bile of rats. The biliary concentration of these leukotrienes was up to 100 times as great as in plasma. N-Acetyl-LTE4 was the predominant endogenous metabolite in rat bile. 6. In the monkey Macaca fascicularis, cysteinyl leukotrienes were predominantly eliminated from blood via the liver into bile; renal excretion amounted to about 50% of the hepatobiliary elimination. Absorption of cysteinyl leukotrienes from the intestine resulted in enterohepatic circulation of these mediators. 7. Metabolites of [3H]LTC4 injected i.v. in the monkey were analyzed in bile and urine. In addition to polar metabolites and a small percentage of [3H]LTD4, [3H]LTE4 was a predominant metabolite particularly in bile. LTE4 was also the major endogenous cysteinyl leukotriene detected by radioimmunologic analysis in monkey bile. 8. LTE4 was the predominant endogenous cysteinyl leukotriene measured in human bile in patients suffering from acute pancreatitis. The detected amounts of LTE4 may be sufficient to induce known phenomena associated with acute pancreatitis including the shock-like reaction.

Transport and in vivo elimination of cysteinyl leukotrienes.

Transport processes control not only synthesis and release of LTC4 but also the elimination and excretion of LTC4 and its metabolites. (i) A primary-active ATP-dependent export carrier mediates the release of LTC4 from a leukotriene-generating cell, as exemplified by mastocytoma cells, and as measured in mastocytoma plasma membrane vesicles (2). (ii) Release of cysteinyl leukotrienes into the blood circulation is followed by a rapid elimination with an initial half-life of 38 sec in rats and 4.0 min in man, as measured with the labeled, representative LTC4 catabolite, N-acetyl-LTE4. (iii) 11C-labeled N-acetyl-LTE4 can serve for non-invasive studies on cysteinyl leukotriene elimination and excretion by the liver and kidney in the intact organism using positron emission tomography. An impairment of leukotriene transport from the liver across the canalicular membrane into bile, studied in mutant rats and in extrahepatic cholestasis, leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney. N-Acetyl-LTE4 labeled with a short-lived positron-emitting isotope provides quantitative insight into the pathways of cysteinyl leukotriene elimination in vivo. (iv) Cysteinyl leukotriene export from the liver into bile is mediated by an ATP-dependent primary-active export carrier. This decisive step in cysteinyl leukotriene elimination has been characterized in hepatocyte canalicular membrane vesicles (3). The leukotriene exporter is deficient in transport mutant rats. The leukotriene carrier is distinct from other ATP-dependent export carriers identified in this membrane domain, such as the ATP-dependent bile salt export carrier (25) and the multidrug export carrier (27).

Anatomical distribution and sclerotic activity of bone metastases from thyroid cancer assessed with F-18 sodium fluoride positron emission tomography.

Currently, bone scintigraphy (BS) is considered to lack sensitivity in detecting bone metastases (BM) from thyroid cancer. We evaluated the anatomical distribution and metabolic behavior of BM as well as the accuracy of BS with and without combination of whole-body iodine scintigraphy (WBI) in detecting metastatic bone disease in thyroid carcinoma. F-18 positron emission tomography (PET), x-ray, BS, and WBI were performed in 35 patients with known or suspected bone metastases from papillary (9 patients) or follicular (26 patients) thyroid carcinoma. Twenty-two metastases were previously known in 14 patients. The indication was staging in 21 patients with high risk for BM, elevated thyroglobulin (Tg)-levels or evaluation of exact extent of BM (14 patients). In addition, results of WBI (35 patients), X-ray (35 patients) F-18 PET (35 patients), MRI of the spine (13 patients), and FDG-PET (15 patients) as well as the clinical course (1.5-4 years) were correlated. BM were detected in 18 patients. Solitary, bifocal, or multiple lesions were present in 9, 2, and 7 patients, respectively. The anatomical distribution of BM (n = 43) was as follows: spine, 42%; skull, 2%; thorax, 16%; femur, 9%; pelvis, 26%; humerus and clavicle, 5%. Sensitivity of BS in interpreting patients as positive or negative for having BM was 64%-85% (specificity, 95%-81%). The combination of BS and WBI was 100% sensitive in detecting metastatic bone disease. One patient had a single BM that was positive at BS but negative on WBI. All metastases were osteolytic on x-ray and two-thirds presented a missing or very limited osteosclerotic bone reaction on F-18 PET. Our data confirm the limited sensitivity of planar BS in detecting BM from thyroid cancer. The combination of BS and WBI, however, was highly accurate. Compared to other malignancies, the distribution pattern of BM presented a lower percentage of vertebral metastases and more patients with single metastases. Those findings in combination with a missing or only slight osteosclerotic bone reaction explain the limited sensitivity of planar BS alone.

[Clinical value of positron emission tomography (PET) in oncologic questions: results of an interdisciplinary consensus conference. Schirmerreschaft der Deutschen Gesellschaft for Nuklearmedizin]. / Klinische Wertigkeit der Positronen-Emissions-Tomographie (PET) bei onkologischen Fragestellungen: Ergebnisse einer interdisziplinären Konsensuskonferenz.

AIM: The purpose of the present paper is to assess clinical value of PET in oncology on the basis of published studies. METHODS: Clinical value of PET in oncology was evaluated by a panel of recognized experts in the framework of an interdisciplinary consensus conference. On the basis of PET studies, well documented in the international literature, the value of PET for solving clinical questions was classified according to the following categories (classes 1a, 1b, 2a, 2b, 3): "appropriate" (1a), "mostly acceptable" (1b), "helpful" (2a), "value as yet unknown" (2b), "useless" (3). RESULTS: 2-fluorodeoxyglucose (FDG) acts as the radiopharmaceutical of choice for PET in clinical oncology. PET is indicated (1a) for diagnosing relapse in high grade glioma (FDG) or low grade glioma (C-11 methionine or F-18 fluorotyrosine), differential diagnosis of solitary peripheral pulmonary nodules in high risk patients and for diagnosis of pancreatic carcinoma. PET may be clinically used (1b): In "low-grade" glioma, search for unknown primary in head and neck tumors, suspicion of relapse in non-small cell bronchial carcinoma (NSCBC) and colorectal carcinoma, lymphnode staging in NSCBC, pancreatic carcinoma, muscle invasive bladder carcinoma and testicular cancer. Staging of Hodgkin's disease (HD, stage I/II vs III), early therapy control in patients with a residual mass or suspicion of relapse in HD and in high grade NHL, lymph node staging and search for distant metastases in malignant melanoma (Breslow > 1.5 mm), search for lymph node or distant metastases in differentiated thyroid cancer with elevated hTG and a negative radioiodide whole body scan. Many further indications are emerging, but are not yet sufficiently well documented in the literature. For most indications beside scientific studies, an individual cost benefit utility evaluation by the responsible physician is recommended. CONCLUSION: Metabolic imaging of PET provides for many principle advantages compared to conventional anatomically based cross sectional imaging. For routine use in oncology a detailed assessment of specific efficiency of PET is indicated.

Pharmacokinetics of 99Tcm-pertechnetate and 188Re-perrhenate after oral administration of perchlorate: option for subsequent care after the use of liquid 188Re in a balloon catheter.

Radioactive wires and other linear sources are currently being used in clinical trials as endovascular brachytherapy to prevent restenosis after percutaneous transluminal coronary angioplasty. A new concept is the use of a liquid-filled balloon containing a beta-emitting radioisotope. A major advantage is optimal delivery of the radioactivity to the vessel wall. Rhenium-188 (188Re) is a high-energy beta-emitter that is routinely available from a 188W/188Re generator in liquid form. Since 188Re-perrhenate could be released in the unlikely event of balloon rupture, we investigated whether, in analogy to pertechnetate, subsequent use of perchlorate can reduce the uptake of perrhenate in the thyroid. We performed static (n = 9) and dynamic (n = 11) thyroid scintigraphy with 99Tcm-pertechnetate to estimate the overall reduction in activity within 30 min and the washout from the thyroid after oral administration of 600 mg perchlorate (T1/2). In two patients, 188Re was injected to estimate the whole-body distribution and the discharge of thyroid activity after perchlorate use. Based on MIRD Dose Estimate Report No. 8 (valid for 99Tcm-pertechnetate), the radiation burden was calculated for intravenous administration of 188Re and competitive blocking with perchlorate. In 20 patients, 99Tcm uptake by the thyroid was reduced by 85% within 30 min by perchlorate. The mean (+/- S.D.) washout rate (T1/2) was 8 +/- 2 min in 11 patients. Perrhenate showed a whole-body distribution similar to that of pertechnetate and the thyroid activity could be displaced (T1/2 = 6.3 and 9.3 min, respectively) by oral administration of perchlorate, with reductions in uptake of 83% and 75% within 30 min, respectively. Whole-body scanning demonstrated no regional accumulation of 188Re-perrhenate with excretion by urine. Dose estimates gave an effective dose equivalent of 0.42 mSv MBq-1, which decreased to 0.16 mSv MBq-1 after perchlorate blocking. 188Re has favourable properties for endovascular brachytherapy via a balloon catheter and, in the unlikely event of balloon rupture, whole-body radiation can be reduced to 38% by subsequent oral administration of perchlorate.

Enterohepatic circulation of N-acetyl-leukotriene E4.

N-Acetyl-leukotriene E4, the end product of leukotriene C4 metabolism in the mercapturic acid pathway, was rapidly eliminated from the blood circulation into the bile of rats. Part of the N-acetyl-leukotriene E4 secreted from bile into the intestine underwent enterohepatic circulation. Leukotriene absorption occurred from the small intestine and from the colon. Biliary and urinary excretion within 5.5 h amounted to 15 and 2%, respectively, of the intraduodenally administered N-acetyl- 3H leukotriene E4 in animals anesthetized with ketamine. HPLC analyses indicated that 35% of the biliary radioactivity corresponded to unchanged N-acetyl-3H leukotriene E4, while 65% in bile and 100% in urine were polar metabolites. Enterohepatic circulation extends the biological half-life of N-acetyl-leukotriene E4.

[Positron-emission tomography in the diagnosis of abdominal tumors]. / Positronen-Emissions-Tomographie in der Diagnostik abdomineller Tumore.

PET is recognized as a powerful imaging research tool. Its clinical application has been increasing significantly in recent years. Based on pathophysiological and biochemical principles, functional PET imaging makes it possible to assess parameters of tumor biology not easily accessible to conventional imaging, such as metabolic activity, proliferation, adrenergic transmitter uptake or accumulation of cytostatics in individual tumor manifestations. For clinical application, PET imaging with 2-[F-18]fluorodeoxyglucose (FDG) is of paramount importance. This article reviews recent developments in the use of PET in the diagnosis of abdominal malignant tumors. Diagnosis of pancreatic carcinoma and related liver metastases, locoregional and distant recurrence, as well as therapy control of colorectal cancer, nodal and extranodal staging and therapy monitoring of malignant lymphoma, can be reliably performed with PET. Several appropriately labeled adrenergic transmitters are currently being developed for specific imaging of neuroendocrine tumors. Radiolabeled cytostatics such as F-18 5-FU will shortly be available for clinical use as probes for primary or secondary cytostatic resistance. Encouraging clinical results and attractive new imaging concepts promise increasing use and importance for PET for imaging of abdominal malignancies.

Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion.

Hepatobiliary and renal elimination of cysteinyl leukotrienes were investigated in a mutant rat strain with a hereditary defect in the hepatobiliary excretion of conjugated bilirubin, dibromosulfophthalein and ouabain. After intravenous injection of [3H]leukotriene C4, the initial half-life of radioactivity circulating in blood was 79 +/- 15 sec (S.D.) in transport mutant rats as compared to 31 +/- 6 sec (S.D.) in normal Wistar rats. The intrahepatic leukotriene radioactivity was increased 5-fold after 1 hr in mutant rats, while the biliary elimination of [3H]leukotrienes was reduced to 1.8% of control. In normal rats, 77 +/- 7% (S.D.) of the administered leukotriene radioactivity were recovered in bile within 1 hr. The total recovery of radioactivity from bile, urine, liver, intestine, stomach, kidneys, muscular system and blood 1 hr after intravenous [3H]leukotriene C4 was 89 +/- 6% (S.D.) in normal rats and 46 +/- 4% (S.D.) in transport mutants. Enterohepatic circulation was studied after intraduodenal administration of N-acetyl-[3H]leukotriene E4, a major cysteinyl leukotriene metabolite in rat bile. In transport mutants, hepatobiliary elimination of the intestinally absorbed [3H]leukotriene was reduced to 5%, whereas urinary excretion was not significantly affected. [3H]Leukotriene metabolites in bile, liver and urine were separated by reversed-phase high-performance liquid chromatography. The proportion of N-acetyl-[3H]leukotriene E4 relative to polar leukotriene metabolites was higher in the bile of transport mutants as compared to control Wistar rats when analyzed within 30 to 60 min after intravenous injection of [3H]leukotriene C4.(ABSTRACT TRUNCATED AT 250 WORDS)