The decreased metastatic potential of rhabdomyosarcoma cells obtained through MET receptor downregulation and the induction of differentiation.

Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. The MET receptor has an important role in the biology of RMS, and its overexpression and hyperactivation correlate with the metastatic ability of RMS. Consequently, interfering with MET expression or functionality may constitute a sound strategy for reducing the progression and metastatic potential of RMS. Our study reveals that downregulation of the MET receptor leads to changes in the morphology of ARMS cell in vivo. Tumors acquire a spindle shape that is characteristic of muscle fibers. Inhibition of MET expression or function leads to (i) a decreased expression of the early myogenic marker MyoD, (ii) a decreased ability of ARMS cells to metastasize to bone marrow cavities, (iii) downregulation of CXCR4 receptor expression and (iv) a decreased migration of MET-depleted cells towards gradients of HGF and SDF-1. Finally, we demonstrate that in vitro differentiation of alveolar RMS cells decreases their metastatic behavior by reducing both the expression of the MET and CXCR4 receptors and their migratory response to HGF and SDF-1. These findings suggest that blockers of MET receptor function and inducers of RMS cells differentiation may be clinically useful for reducing the aggressiveness and metastatic potential of RMS and may have significant implications for its treatment.

Prediction of nonSVR to therapy with pegylated interferon-alpha2a and ribavirin in chronic hepatitis C genotype 1 patients after 4, 8 and 12 weeks of treatment.

In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction.

High anti tumor activity against rhabdomyosarcoma cells and low normal cells cytotoxicity of heat shock protein 90 inhibitors, with special emphasis on 17-[2-(pyrrolidin-1-yl)ethyl]-aminno-17-demethoxygeldanamycin.

Rhabdomyosarcoma is a highly metastatic tumor, mostly observed in children and adolescence. When diagnosed at early stages it is mostly curable. However, in advanced or metastatic stages the 5-years survival rate is below 20%. Thus, new treatment strategies for this tumor are needed. In this paper we showed that HSP90 inhibitors, geldanamycin and its analogs, can profoundly affect proliferation of rhabdomyosarcoma cells. We also showed that blocking of HSP90 function induces apoptosis of tumor cells and downregulates expression of anti apoptotic protein AKT. Cells exposed to geldanamycin and its analogs exhibit strong reduction of MET receptor expression and subsequent inhibition of HGF-dependent tumor cells migration and invasion. Interestingly, at concentrations sufficient to block tumor cells growth and motility, the 17AEP-GA, 17AAG and 17DMAP-GA were not toxic or only slightly toxic toward normal hematopoietic, mesenchymal and endothelial cells. This could be due to low HSP90 expression both at mRNA and protein level in these cells. Collectively, our findings suggest that blocking HSP90 action through geldanmycins could be in the future a part of new therapeutic strategies in rhabdomyosarcoma treatment.

Prevalence, risk factors and outcome of hyperlactataemia in HIV-infected patients.

OBJECTIVE: We describe the prevalence, risk factors and outcome of hyperlactataemia (HL) in a cohort of 140 HIV-infected patients. PATIENTS AND METHODS: Patients were enrolled consecutively within a 3-month period (July to September 1999) and followed until 31 October 2000. One hundred and forty HIV-infected patients had venous plasma lactate levels measured. HL was defined at baseline by two consecutive lactate levels > 2.1 mmol/L (upper limit of normal). We compared baseline demographic characteristics, immuno-virological parameters, antiretroviral therapy and outcome between patients with HL (cases) or without HL (controls). We described the clinical features of patients with HL. RESULTS: Among 129 patients included in the analysis, HL was found in 11 patients (8.5%), all of whom were receiving nucleoside reverse transcriptase inhibitors (NRTIs). Cases were more likely than controls to receive didanosine or stavudine (82% vs. 19%, P= 2.7 x 10(-6) and 82% vs. 48%, P= 0.03, respectively). Only 4/11 cases (36%) had symptoms consistent with HL. After a median follow-up of 15 months, lactate level returned to normal in all three patients who discontinued NRTIs, but in only 2/8 patients who did not (P = 0.06). Only one case experienced lactic acidosis and died during follow-up. Mortality rate was similar in cases and controls. CONCLUSION: HL is associated with NRTI use, in particular didanosine and stavudine, and discontinuation of NRTIs seems to be associated with rapid resolution of HL. Lactic acidosis remains rare and the long-term outcome of patients with HL does not seem to be poorer than controls.

[Incidence and management of condylomata acuminata by French general physicians]. / Incidence et prise en charge des condylomes acuminés externes en médecine générale.

OBJECTIVES: Condylomata acuminata (or genital warts) are sexually transmitted diseases caused by human papillomavirus. Until now, there has been no available epidemiologic data about this disease in France. We conducted a prospective study among French general practitioners (GPs) to estimate the incidence of consultations for external condylomata acuminata in general practice. We also assessed the management of patients with external condylomata acuminata by French GP's. DESIGN: A panel of French general practitioners, members of the Sentinel network, had to fill-in prospectively a questionnaire for each patient with condylomata acuminata diagnosed between July and November 2000. RESULTS: The annual number of consultations for external condylomata acuminata with French GP's was estimated at 23,000 (CI (95 p. 100) 21,000-25,000) including 15,000 new cases (CI (95 p. 100) 13,000-17,000). Taking into account the estimations we made at the same time in office-based private dermatologists, we estimated the annual incidence of external condylomata acuminata in France at 107/100 000 inhabitants. The management of patients with external condylomata acuminata by French GP's was in accordance with the European guidelines in 54 to 78 p. 100 of cases. French GP's mostly prescribed chemical treatment. DISCUSSION: A proportion of cases of condylomata acuminata may have not been diagnosed. Similarly, some lesions may have been wrongly diagnosed as condylomata acuminata, but these proportions of false positive and false negative remain unknown. The incidence of external condylomata acuminata in France is similar to those estimated in others developed countries.

[Dermatology in private practice in France in 2000]. / La dermatologie libérale en France métropolitaine en 2000.

OBJECTIVES: Data regarding French dermatological practice are scarce. Our objective was to identify the skin disorders most commonly diagnosed by office-based dermatologists. We also documented the severity of these skin disorders, as reflected by the repercussions on patient's everyday life, and the way physicians managed patients. DESIGN: We carried out a one-day survey of visits to a randomly selected sample of 900 French office-based dermatologists. The randomization was stratified according to the five French different dialing area codes. RESULTS: Office-based dermatologists saw 6411 patients with 7839 skin disorders during the survey. The daily number of visits to French dermatologists was estimated at 47 000 and the annual number between 12 and 14 millions. Office-based dermatologists mostly managed warts, acne, nevus, dermatitis, malignancies and pre-malignancies, fungal infection and psoriasis. Repercussions on patients'everyday life were assessed by physicians as important or very important in 28 p. 100 of cases. Half of the patients received topical treatment, 20.5 p. 100 a systemic drug and 40 p. 100 a minor surgical procedure (including cryotherapy). CONCLUSION: Although dermatologists frequently see benign skin disorders such as warts or nevus, more severe diseases represent an important part of their activity.

[Comparison of three scales to assess health risk perception]. / Comparaison de trois échelles d'évaluation de la perception des risques sanitaires.

BACKGROUND: Health risks management consists of quantitative and qualitative assessment of risks including risk perception among different samples of the population. Little work has been done to develop and validate scales to measure risk perception. METHODS: We conducted, in December, 1999, a study among 1358 French GPs, members of the Sentinels network, in order to compare three scales: a visual analog scale, a verbal scale and a numerical scale. GPs were asked about their own perception of two risks: the Creutzfeldt-Jakob disease new variant (vMCJ) and the bug. RESULTS: The response rate was 55%, with no difference between the three groups (p=0.85). No statistically significant difference was observed between the distributions of the visual analog scale and the numerical scale (p=0.11 for the question about the vMCJ and p=0.98 for the question about the bug). Conversely, distributions of the verbal scale were significantly different from those of the visual analog scale (p<0.0001 for both of the questions) and from those of the numerical scale (p<0.0001 for both of the questions). Separation between worried and non worried people didn't occur in the middle of the visual analog scale but at 33 millimeters from the left extremity for the question about the vMCJ and at 41 millimeters from the same extremity for the question about the bug. CONCLUSION: We recommend the use of verbal scales to measure instantaneous perception of a given risk. Visual analog scales and numerical scales are known to be the best scales to detect minimum changes in the perception of functional signs such as pain. On this purpose, their superiority with regard to verbal scales has to be confirmed in the field of risk perception.