Lack of antitumour activity of human recombinant tumour necrosis factor-alpha, alone or in combination with melphalan in a nude mouse human melanoma xenograft system.

The most promising developments in the field of isolated limb perfusion have centred around the use of the recombinant cytokine tumour necrosis factor-alpha (rTNF-alpha) in combination with melphalan. While the results of clinical trials are impressive, the exact antitumour mechanisms of rTNF-alpha and its role in combination with melphalan remain unclear. Our aim was to study the antitumour activity of human rTNF-alpha with or without the combination of melphalan in a nude mouse human melanoma xenograft system. In a first attempt to define the maximal tolerated single dose of rTNF-alpha in this setting, 15 animals were exposed to increasing doses of rTNF-alpha (60-2500 microg/kg intraperitoneally). All but one animal survived and tumour growth was not influenced by these single dose applications of rTNF-alpha even at the very high doses. Anti-tumour activity of repeated application of melphalan (three times 9 mg/kg in group 2 and three times 6 mg/kg in group 3), of rTNF-alpha alone (nine doses of 50 microg/kg in group 4), and of rTNF-alpha in combination with melphalan (nine doses of 50 microg/kg rTNF-alpha and three times 6 mg/kg melphalan in group 5) was further compared with non-treated animals (group 1). Tumour growth was significantly inhibited in all animals treated with melphalan (group 2, 3 and 5), but was not decreased in animals treated with rTNF-alpha alone (group 4). Mean final tumour volumes and mean tumour weight were not different in group 2 (789 +/- 836 mm3, 0.38 +/- 0.20 g), group 3 (1173 +/- 591 mm3, 0.55 +/- 0.29 g) and group 5 (230 +/- 632 mm3, 0.37 +/- 0.29 g), but significant lower than group 1 (3156 +/- 1512 mm3, 2.35 +/- 0.90 g) and group 4 (3228 +/- 1990 mm3, 2.00 +/- 1.16 g). There were no significant differences between high and low dose melphalan treatment and between melphalan treatment in combination with rTNF-alpha. Histological examination did not show differences between treated and non-treated animals besides slightly inhibited mitotic activities of tumour cells in melphalan-treated animals. While tumour growth of human xenotransplanted melanoma in nude mice could be inhibited by melphalan, we failed to demonstrate any antitumour effect of rTNF-alpha. The combination of melphalan and rTNF-alpha did not enhance the antiproliferative effect of melphalan alone. Human xenotransplanted tumours on nude mice might not be the ideal experimental setting for studies of potential direct antineoplastic activity of rTNF-alpha, and these results support the concept that TNF-alpha exerts its antitumour activity indirectly, possibly by impairing the tumour vasculature and by activating the immune system.

Validation française de l'échelle d'expérience temporelle du plaisir [Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment.]

INTRODUCTION: Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. OBJECTIVE: The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. METHODS: A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. RESULTS: Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. CONCLUSION: The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample.

Demographic and geographic vascular risk factor differences in European young adults with ischemic stroke: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: We compared among young patients with ischemic stroke the distribution of vascular risk factors among sex, age groups, and 3 distinct geographic regions in Europe. METHODS: We included patients with first-ever ischemic stroke aged 15 to 49 years from existing hospital- or population-based prospective or consecutive young stroke registries involving 15 cities in 12 countries. Geographic regions were defined as northern (Finland, Norway), central (Austria, Belgium, France, Germany, Hungary, The Netherlands, Switzerland), and southern (Greece, Italy, Turkey) Europe. Hierarchical regression models were used for comparisons. RESULTS: In the study cohort (n=3944), the 3 most frequent risk factors were current smoking (48.7%), dyslipidemia (45.8%), and hypertension (35.9%). Compared with central (n=1868; median age, 43 years) and northern (n=1330; median age, 44 years) European patients, southern Europeans (n=746; median age, 41 years) were younger. No sex difference emerged between the regions, male:female ratio being 0.7 in those aged <34 years and reaching 1.7 in those aged 45 to 49 years. After accounting for confounders, no risk-factor differences emerged at the region level. Compared with females, males were older and they more frequently had dyslipidemia or coronary heart disease, or were smokers, irrespective of region. In both sexes, prevalence of family history of stroke, dyslipidemia, smoking, hypertension, diabetes mellitus, coronary heart disease, peripheral arterial disease, and atrial fibrillation positively correlated with age across all regions. CONCLUSIONS: Primary preventive strategies for ischemic stroke in young adults-having high rate of modifiable risk factors-should be targeted according to sex and age at continental level.