[Fluorine-18 in radiopharmacy]. / Le fluor 18 en radiopharmacie.

Positron emission tomography (PET) is a recent and expanding functional nuclear imaging technique. Its extensive development is related to the radiophysical properties fluorine 18 (18F) (weak energy of positron, sufficiently long physical half-life) and to the simple production and labeling procedures for 18F. [18F]fluorodesoxyglucose was the first licensed radiopharmaceutical in France in 1998. [18F]fluoroDOPA was registered in 2006. Introduction of automated chemistry modules enable development of new fluorinated tracers.

[Value of [18F]-fluorodeoxyglucose (FDG) positron emission tomography in digestive cancerology]. / Apport de la tomographie par émission de positons au [18F]-fluorodésoxyglucose (FDG) en cancérologie digestive.

COLORECTAL CANCERS: FDG-PET is a very effective tool in the follow-up of colorectal cancer for the early detection of recurrences, the search for other localisations in case of resectable lesions and for the evaluation of therapies. For the other digestive cancers, the data in the literature are less abundant and they do not yet have Marketing Authorization in France. OESOPHAGEAL CANCER: FDG-PET appears very promising for staging and detection of recurrences of oesophageal carcinomas. Pancreatic cancer Although the indication is difficult, FDG-PET appears superior to morphological techniques for the characterization and the locoregional staging of pancreatic tumours. BILARY AND GASTRIC CARCINOMAS: FDG-PET is promising but its role has to be confirmed in larger series for the detection of biliary and gastric carcinomas. OTHER DIGESTIVE TUMOURS: In cases of hepatocarcinoma, FDG-PET appears efficient only in cases of undifferentiated tumours, and in cases of malignant neuroendocrine digestive tumours, is useful in combination with somatostatin receptor imaging.

[(18F)-fluoro-2-deoxyglucose PET in imaging of gynecologic cancers]. / La TEP au [18F]-fluoro-2-désoxyglucose dans l'imagerie des cancers gynécologiques.

Although gynaecological cancers are not currently part of the clinical indications in the French registration for [18F]-fluoro-2-deoxyglucose (FDG), various studies indicate in this context a potential clinical benefit of imaging with this radiopharmaceutical and PET, a new imaging modality that can be performed either with a dedicated machine or with a "hybrid" gamma-camera (CDET). The potential indications of FDG-PET in mammary, ovarian or cervical cancers are reviewed according to the diagnostic phase: screening, tumour characterisation, staging, therapeutic follow-up and search for recurrence. By pooling the published results, the accuracy of FDG-PET could be estimated with a reasonable precision in various clinical settings: characterisation of a breast tumour (598/696 = 86%), lymph node invasion in breast cancer (525/602 = 87%), recurrence of breast cancer (114/127 = 90%), characterisation of adnexal masses (130/176 = 78%), recurrence of ovarian cancer (152/172 = 88%), lymph node invasion in cervical cancer (98/103 = 95%). Authors also present original data concerning their experience of recurrence detection with CDET in breast or ovarian cancers. In 44 patients suspicious of recurrence of breast cancer, FDG-CDET sensitivity was 94%, specificity 82% and accuracy 91%; in 18 patients suspicious of recurrence of ovarian cancer, specificity, sensitivity and accuracy were 100%. The impact of dedicated PET and CDET examinations performed by our team during year 2000, led, according to 63 forms returned to us, to a modification of stage in 48% of breast cancers, 36% of ovarian cancers, 43% of cervical cancers and above all induced a modification in patients' management in respectively 69%, 64% and 60% of cases, more than the average rate in cancer patients which was 50%. No significant difference was observed between clinical impact of dedicated PET and CDET examinations.

Assessment of malignancy in pulmonary lesions: FDG dual-head coincidence gamma camera imaging in association with serum tumor marker measurement.

UNLABELLED: The purpose of the study was to evaluate the performance of dual-head coincidence gamma camera imaging using FDG in association with serum marker assays in identifying lung carcinoma in patients with abnormal findings on chest radiography. METHODS: A prospective evaluation of FDG imaging with coincidence detection emission tomography (CDET) using a dual-head gamma camera combined with the assessment of 3 sensitive serum markers of lung cancer (carcinoembryonic antigen, neuron specific enolase, and CYFRA 21-1) was performed on the same day on 58 consecutive patients with known or suspected lung malignancy. RESULTS: Fifty-three patients were proven to have lung cancer, and 5 patients had benign lung disease. Coincidence imaging showed significantly increased FDG uptake in 49 of 53 patients with proven malignancy (sensitivity, 92.5%) and in 3 patients with benign disease. FDG imaging had negative findings in 4 patients with proven malignancy and 2 patients with benign disease. Serum tumor marker levels were elevated in 42 of 53 cancer patients (sensitivity, 79.2%) and normal in 11 patients with proven malignancy. Nine patients with proven malignancy had positive findings on FDG images and negative marker assays. Two patients with proven malignancy had negative findings on FDG images and positive marker assays. The positive predictive value for lung cancer was 94.2% for FDG alone and 97.6% for FDG in association with serum markers. CONCLUSION: In this study, FDG CDET imaging was a powerful tool for evaluating patients with lung lesions suggestive of malignancy. Although the determination of serum marker levels was less accurate than FDG imaging, positive FDG results found in association with positive markers significantly increased the likelihood of lung malignancy.

Effect of cyclodextrin complexation on the in vivo disposition of the brain imaging radiopharmaceutical 99mTechnetium ethyl cysteinate dimer (99mTc-ECD).

The brain imaging radiopharmaceutical, 99mTechnetium ethyl cysteinate dimer (99mTc-ECD, 99mTc-bicisate) is the most recent addition to the available set of radiopharmaceuticals for measuring cerebral blood flow. Ideally radiotracers should be trapped in the brain long enough so that their distribution can be quantitated and should demonstrate good spatial resolution. Furthermore, the stability (chemical and metabolic) and bioavailability of radiopharmaceuticals have in general proved to be a challenge during development and clinical administration. In view of these challenges and background, this study with 99mTc-ECD is presented. The aims of this research program were to develop novel approaches to improve the chemical and metabolic stability and the bioavailability of 99mTc-ECD across the blood brain barrier for cerebral blood flow determinations, using the well known non-human primate in vivo baboon model. These aims were addressed by investigating the influence of cyclodextrin--99mTc-ECD complexation on normal cerebral blood flow patterns, using two different cyclodextrins, i.e., gamma-cyclodextrin (CAS 17465-86-0) and beta-trimethylcyclodextrin (CAS 55216-11-0). The effect of incubation of 99mTc-ECD (with or without cyclodextrin complexation) in plasma, on metabolic esterase action, was also investigated. Possible protection against plasma esterase by acetylcholine (CAS 51-84-3) of 99mTc-ECD was further determined. The current study has shown that cyclodextrin complexation of 99mTc-ECD indeed offers a useful approach to improve the stability of the radiopharmaceutical against peripheral metabolism. The acetylcholine shows also potential to protect 99mTc-ECD. However, it is clear from the current data that the choice of cyclodextrin is of utmost importance, as has been observed from significantly reduced the bioavailability of 99mTc-ECD when complexed with beta-trimethylcyclodextrin. The plasma incubation procedures showed that gamma-cyclodextrin offers protection with only slightly reduced bioavailability. This study has indicated that novel approaches, such as cyclodextrin technologies, indeed show potential to modify the performance in its currently available 99mTc-ECD form.

14. FDG CDET (2D Dual-Head Coincidence Gamma Camera) in the Primary Staging of Oesophageal Cancer. Histopathological Correlation.

Purpose: The aim of this study was to evaluate the role of FDG-CDET for the detection of primary oesophageal tumour, lymph node involvement and distant extension before surgery.Methods and patients: In patients fasting for 6h or more, 150-250 MBq of 18F-FDG were injected i.v. and 2D imaging (whole-body scan and at least a tomoscintigram) was started 45 min. later, using a PICKER gamma camera. We studied 14 patients (pts). All of them were operated on (mean time between FDG and surgery: 5.4 +/- 3.8 days) and staging results were correlated with post surgical histology.Results: The primary lesion took up FDG in all cases but one (FN in a 5 mm lesion). The primary NM staging of these 14 pts was negative with FDG-CDET in 7 cases (4 TN and 3 FN corresponding to an invasion of satellite lymph nodes in 2 cases and to a metastatic infracentimetric subdiaphragmatic lymph node in one case) and positive in 7 cases (7 TP corresponding to 10 foci), revealing in 4 cases a sub-diaphragmatic lymph node extension unknown prior to FDG-CDET. One pt referred for characterisation of an oesophageal lesion (failure of multiple biopsies) had an intense focus of FDG uptake in this area (TP confirmed by surgery). The overall sensitivity was 13/14 = 93% on a per patient basis and 21/25 = 84% on a per lesion basis. Specificity on a per lesion basis was 5/5 = 100%.Conclusion: These first results, obtained in an indication of FDG not frequently evaluated even with dedicated PET systems, seem very promising, the oesophageal neoplastic lesions appearing to take up FDG with a high intensity.

15. Sensitivity of FDG CDET (2D Dual-Head Coincidence Gamma Camera) for the Detection of Occult or Doubtful Recurrences of Colorectal Cancer. Histopathological Correlation.

Purpose: The aim of this study was to evaluate the efficacy of FDG-CDET for the detection of recurrences of colorectal cancer, in occult disease or in doubtful cases at conventional imaging (CI). In all the evaluated cases, the result of FDG-CDET was compared with post surgical histology both on patient and on site bases.Methods and patients: After fasting for 6h or more, 150-250 MBq of 18F-FDG were injected i.v. and 2D imaging (whole-body scan and at least a tomoscintigram) was started 45 min. later, using a PICKER CDET gamma camera. Among the 214 examinations (ex) performed for detection of recurrences of colorectal cancer between Jul 1997 and Feb 2000, we only considered the 58 cases with negative or questionable CI and a post surgical histologic proof.Results: Patients were referred in three different contexts:

32. Detection of Recurrence of Ovarian Cancer using

Purpose: The aim of this preliminary study was to evaluate the role of FDG-CDET in detection of recurrence of ovarian cancer.Methods and patients: After a fast of 6 hours, the patient (pt) was injected I. V. with 150-250 MBq of [F-18]-FDG and imaging (whole-body scan and at least a tomoscintigram) was started 45 min. later, using a PICKER Prism XP 2000 CDET gamma camera. Between July 1997 and December 1999, 40 patients were studied for ovarian carcinoma. To date, the results of 23 patients are evaluable with reference to histology after surgery or long-term follow-up. From these 23 patients, 18 pts were referred for suspected recurrence of ovarian carcinoma: occult recurrence (OR) defined by an increase in serum CA-125 levels with negative conventional imaging (13 pts) or equivocal aspect at conventional imaging (5 pts).Results: In 13 pts referred for suspicion of OR, FDG-CDET was true positive (TP) in 11 cases all confirmed by histology after surgery and was true negative (TN) in the remaining 2 cases as confirmed by spontaneous normalization of CA-125 levels and no events during a 20-month follow-up. In the 5 pts with equivocal aspect on CT, 4 were (TP) with recurrent foci at FDG-CDET in 1 case and 1 was (TN) corresponding to a leïomyoma on histology after surgery. In summary, the overall sensitivity and accuracy on a per patient basis were 18/18 for FDG-CDET while sensitivity and accuracy of conventional imaging was only 6/18.Conclusion: These preliminary results in a clinical setting, which is not frequently evaluated on CDET gamma cameras, seem very promising.

Uptake of liposome-encapsulated 99Tcm-MIBI by sensitive and multidrug-resistant tumour cell lines.

It is well established that accumulation of 99Tcm-sestamibi (99Tcm-MIBI) is much higher in sensitive than multidrug-resistant tumour cells expressing the permeability glycoprotein 170 (Pgp 170) as well as a multidrug-resistance related protein (MRP). Thus 99Tcm-MIBI is a good candidate for diagnosing the multidrug-resistance phenotype by in vivo imaging. However, the blood clearance of 99Tcm-MIBI is too rapid to achieve optimal accumulation in tumours and uptake in the liver, spleen, heart and muscle is too high for it to be an excellent in vivo tumour tracer. One way of prolonging the bioavailability of 99Tcm-MIBI is to use liposomes which do not affect its accumulation in tumour cells. We explored this possibility in vitro using two sensitive and five resistant cell lines, two of them expressing Pgp 170 and three others over-expressing MRP. 99Tcm-MIBI was incorporated into liposomes prepared by thin film hydration with phosphate-buffered saline using distearoyl phosphatidyl choline, distearoyl phosphatidyl ethanolamine and cholesterol in a ratio of 1.85:0.15:1.00. Liposome diameter was 97.9 +/- 4.5 nm as determined by dynamic light scattering. 99Tcm-MIBI uptake was quantified by measuring radioactivity retained in the cells incubated at 37 degrees C with liposome-encapsulated 99Tcm-MIBI or with free radiotracer in the presence of empty liposomes. In both experimental cases, 99Tcm-MIBI accumulation was similar to that obtained in the presence of free 99Tcm-MIBI only: it was much higher in sensitive than in resistant Pgp 170-positive and MRP-positive cells. Encapsulation in liposomes does not alter the potency of 99Tcm-MIBI to distinguish the sensitive and resistant tumour cells. Our results suggest that future studies should assess the usefulness of the encapsulated form of 99Tcm-MIBI for in vivo imaging of tumours.

Involvement of glutathione in loss of technetium-99m-MIBI accumulation related to membrane MDR protein expression in tumor cells.

UNLABELLED: It was reported recently that 99mTc-hexakis-2-methoxyisobutyl isonitrile (MIBI) uptake is drastically reduced in cancer cells that express the multidrug resistance (MDR) product, Pgp 170 kDa (Pgp), suggesting that 99mTc-MIBI is a transport substrate for this transmembrane glycoprotein. In our study, we explored if another pump, a multidrug resistance-associated protein (MRP), could affect 99mTc-MIBI uptake. In addition, we studied the involvement of intracellular glutathione (GSH) as a modulator of 99mTc-MIBI uptake by both Pgp and MRP proteins. METHODS: MDR1 and MRP gene expression in seven human tumor cell lines was determined on a transcriptional level by reverse transcriptase polymerase chain reaction and on a protein level using immunocytochemistry. Technetium-99m-MIBI uptake was quantified by measuring radioactivity retained in the cells incubated at 37 degrees C in the presence or absence of buthionine sulfoximine (BSO), which depletes cellular GSH. The cellular GSH content was determined with Ellman's reagent. RESULTS: Cell lines were classified according to their phenotypic characteristics: 1/MRP-/Pgp-: breast cancer cells (MCF7), lung carcinoma cells (H69S) and mouth epidermoid tumor cells (KB 3.1), 2/MRP-/Pgp+: MCF7 mdr+, KBA.1; and 3/MRP+/Pgp-: small-cell lung carcinoma (H69 AR and A 549). Technetium-99m-MIBI uptake was significantly lower in cells expressing MRP as well as Pgp compared to MRP/Pgp cells. Depletion of GSH by BSO resulted in an increase of 99mTc-MIBI uptake in multidrug resistant cells overexpressing MRP but not expressing Pgp. CONCLUSION: Technetium-99m-MIBI is extruded by both Pgp and MRP efflux pumps. However, MRP action is indirect and involves intracellular GSH for a presumed interaction with the 99mTc-MIBI before its effLux. Technetium-99m-MIBI seems to be a good candidate for a noninvasive marker to diagnose MDR1 related to Pgp and MRP expression in tumors of different origin.

Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes.

BACKGROUND & AIMS: 4,4'-Diethylaminoethoxyhexestrol (DEAEH), amiodarone, and perhexiline cause steatohepatitis in humans. The mechanisms of these effects are unknown for DEAEH and have not been completely elucidated for amiodarone and perhexiline. The aim of this study was to determine these mechanisms. METHODS: Rat liver mitochondria, cultured rat hepatocytes, or rats were treated with these drugs, and the effects on mitochondrial respiration, beta-oxidation, reactive oxygen species formation, and lipid peroxidation were determined. RESULTS: DEAEH accumulated in mitochondria and inhibited carnitine palmitoyl transferase I and acyl-coenzyme A dehydrogenases; it decreased beta-oxidation and caused lipid deposits in hepatocytes. DEAEH also inhibited mitochondrial respiration and decreased adenosine triphosphate (ATP) levels in hepatocytes. DEAEH, amiodarone, and perhexiline augmented the mitochondrial formation of reactive oxygen species and caused lipid peroxidation in rats. CONCLUSIONS: Like amiodarone and perhexiline, DEAEH accumulates in mitochondria, where it inhibits both beta-oxidation (causing steatosis) and respiration. Inhibition of respiration decreases ATP and also increases the mitochondrial formation of reactive oxygen species. The latter oxidize fat deposits, causing lipid peroxidation. We suggest that ATP depletion and lipid peroxidation may cause cell death and that lipid peroxidation products may account, in part, for other steatohepatitis lesions.

Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients.

Vancomycin penetration into the fluid lining the epithelial surface of the lower respiratory tract was studied by performing fiberoptic bronchoscopy with bronchoalveolar lavage on 14 critically ill, ventilated patients who had received the drug for at least 5 days. The apparent volume of epithelial lining fluid (ELF) recovered by bronchoalveolar lavage was determined by using urea as an endogenous marker. Vancomycin levels in ELF ranged from 0.4 to 8.1 micrograms/ml (mean, 4.5 micrograms/ml), while the mean simultaneous level of the drug in plasma was 24 micrograms/ml (range, 9 to 37.4 micrograms/ml). There was a significant relationship (r = 0.64, P < 0.02) between vancomycin levels in plasma and those in ELF, with a correlation whose slope (0.15) indicated that the blood-to-ELF ratio of drug penetration was 6:1. Using the albumin concentration in ELF as a marker of lung inflammation, we found that vancomycin penetration was higher in patients with ELF albumin values of > or = 3.4 mg/ml than in patients with normal values (< 3.4 mg/ml) (P < 0.02). These results suggest that the vancomycin distribution includes the ELF of the lower respiratory tract at a concentration that is dependent upon the levels in blood and the alveolar capillary membrane protein permeability. These concentrations were well above the MICs for most staphylococci and enterococci.