Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma

Summary A total of 42 patients with cerebral metastases of malignant melanoma were included in this study of the nitrosourea fotemustine. The treatment plan consisted of a 1-h i. v. infusion of 100 mg/m² fotemustine every week for 3–4 weeks, followed by a 4- to 5-week rest period. Responding or stabilised patients then received 100 mg/m² fotemustine every 3 weeks. Among the 39 evaluable patients, 2 complete responses and 9 partial responses were documented, leading to an overall response rate of 28.2%. Most of the responses were obtained in previously untreated patients and/or those presenting with a single cerebral metastasis. Toxicity was mild and mainly hematological, especially in patients previously treated by polychemotherapeutic regimen. Our study confirms the activity of fotemustine in cerebral metastases of disseminated malignant melanoma.Others institutions involved in this trial: A. Bernadou, Hôtel Dieu, Paris; J. Clavier, CHR de Brest; M. Delaunay, Hôpital Pellegrin Tripode, Bordeaux; J. P. Escande, Hôpital Tarnier, Paris; P. Fargeot, Centre George François Leclerc, Dijon; P. Lauret, Hôpital Charles Nicolle, Rouen; R. Leblay, Hôpital Sud, Rennes; P. Litoux, CHR de Nantes; G. Lorette, Hôpital Trousseau, Tours; R. Metz, Centre Alexis Vautrin, Nancy; A. Monnier, CHR Boulloche, Montbelliard; M. Mousseau, CHR de la Tronche, Grenoble; J. P. Olivier, Hôpital Dupuytren, Limoges; R. Touraine, Hôpital Henri Mondor, Créteil; F. Truchetet, Hôpital de Thionville, France     

One‐step radiosynthesis of [18F]LBT‐999: a selective radioligand for the visualization of the dopamine transporter with PET

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3‐beta‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2‐beta‐carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (K_D : 9 nM for the DAT and IC₅₀ > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine‐18‐labelling of LBT‐999 was based on the robust and reliable two‐step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)‐1‐[¹⁸F]fluoro‐4‐tosyloxybut‐2‐ene followed by a N‐alkylation reaction with the appropriate nor‐tropane moiety. In the present work, a simple one‐step fluorine‐18‐labelling of LBT‐999 is reported, based on a chlorine‐for‐fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high‐performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[¹⁸F]F–Kryptofix^®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C‐18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative HPLC purification on a Waters Symmetry^® C‐18. Typically, 3.70–5.92 GBq of [¹⁸F]LBT‐999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep‐Pak‐based formulation included), starting from a 37.0 GBq [¹⁸F]fluoride batch (overall radiochemical yields: 10–16%, non‐decay‐corrected). Copyright © 2007 John Wiley & Sons, Ltd.     

A new set of electronic modules (NIM standard) for a coincidence system using the pulse mixing method.

The three electronic modules presented here, connected to two MTR2 modules of extended dead-time discriminators, allow setting-up a complete coincidence system according to the principle of the pulse-mixing method. Results produced by such a system including these modules were compared with those of an older system working in a completely different mode (IMPECC).     

The response to long-term overfeeding in identical twins

We undertook this study to determine whether there are differences in the responses of different persons to long-term overfeeding and to assess the possibility that genotypes are involved in such differences. After a two-week base-line period, 12 pairs of young adult male monozygotic twins were overfed by 4.2 MJ (1000 kcal) per day, 6 days a week, for a total of 84 days during a 100-day period. The total excess amount each man consumed was 353 MJ (84,000 kcal). During overfeeding, individual changes in body composition and topography of fat deposition varied considerably. The mean weight gain was 8.1 kg, but the range was 4.3 to 13.3 kg. The similarity within each pair in the response to overfeeding was significant (P less than 0.05) with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about three times more variance among pairs than within pairs (r approximately 0.5). After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat (P less than 0.01), with about six times as much variance among pairs as within pairs (r approximately 0.7). We conclude that the most likely explanation for the intrapair similarity in the adaptation to long-term overfeeding and for the variations in weight gain and fat distribution among the pairs of twins is that genetic factors are involved. These may govern the tendency to store energy as either fat or lean tissue and the various determinants of the resting expenditure of energy.     

Protective effect of anethol dithiolthione against acetaminophen hepatotoxicity in mice

Anethol dithiolthione (ADT), usually prescribed as a choleretic drug, when given orally 1 hour prior to acetaminophen (AAP) (450 mg/kg intraperitoneally) in Swiss female mice, exhibited an hepatoprotective potency at doses as low as 10 mg/kg relative to serum aminotransferase activities and hepatic glutathione related enzyme system (glutathione reductase, peroxidase, transferase). These preliminary results are relevant with the use of pharmacologic dosage of ADT in hepatotoxicity prevention.     

Radiolabelled monoclonal antibodies against alpha-fetoprotein for in vivo localization of human hepatocellular carcinoma by immunotomoscintigraphy

Two high affinity monoclonal antibodies, designated AF01 and AF04, directed against distinct epitopes of human alpha-fetoprotein (AFP) and the Fab fragments of one of them, were labelled with ¹³¹I and injected into 18 patients with AFP producing hepatocellular carcinoma (HCC) in order to carry out imaging studies by tomoscintigraphy. Twelve patients were injected with whole antibody, only three of seven patients injected with AF01 and two of five patients injected with AF04 had a positive scan. In contrast, five out of six patients injected with labelled Fab fragments of AF04 had positive imaging. These results confirm that tumour imaging of HCC using ¹³¹I labelled monoclonal antibody against AFP is feasible. Moreover, utilization of tomoscintigraphy in place of linear scintigraphy and Fab fragments instead of whole immunoglobulin may improve the sensitivity of radioimmunolocalization. This technique provides useful information on the in vivo distribution of monoclonal antibodies directed against AFP and on the practicability of the eventual therapeutic use of anti-AFP antibodies in HCC.This work was supported by Grant number 84D16 from the Institut Gustave-Roussy     

Lateral ankle fracture with missed proximal tibiofibular joint instability (Maisonneuve injury)

We present a case of a soccer player who sustained a lateral ankle fracture and the associated proximal anterolateral tibiofibular joint instability (Maisonneuve injury) was overlooked. After a non-contact injury the (incomplete) diagnosis of a lateral malleolar fracture (type Weber B, AO 44-B1) was made and the patient was surgically treated with open reduction and internal fixation including a distal syndesmosis screw. After removal of the syndesmosis screw (six weeks after surgery) the patient suffered from activity-related pain around the fibular head. After thorough clinical and radiologic examination, temporary screw transfixation of the fibular head and capsular repair under meticulous fluoroscopic control of fibular rotation helped to restore patient’s sport activity level. This case report emphasizes the importance of precise clinical examination for detection of a proximal tibiofibular joint instability. Restoration of a well functioning and stable proximal tibiofibular joint may be difficult to achieve in previously operated and missed instabilities. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Thermodynamic and kinetic basicities of the carbon and oxygen ends of enolates. Their role in the reductive cleavage electrochemistry of α-substituted acetophenones

The electrochemical reductive cleavage of α-substituted acetophenones may follow a mechanism in which electron transfer and bond breaking are concerted, as with α-chloro-acetophenone, or a mechanism where the two steps are successive, as with, e.g. α-benzoyloxy–acetophenone. In both cases, the resulting phenacyl radical is immediately reduced, giving rise to the phenacyl enolate, the protonation of which is expected eventually to yield acetophenone. However, in cyclic voltammetry, the acetophenone wave, present at low scan rates, vanishes upon raising the scan rate. The disappearance of the wave is observed at lower scan rates when an acid, such as phenol, is added to the solution. This surprising behavior is the result of the oxygen end of the enolate being a thermodynamically weaker but kinetically faster base than its carbon end.