Urolithiasis in HIV-positive patients treated with atazanavir.

Among protease inhibitors, atazanavir has not been associated with urolithiasis in clinical studies. We describe 11 cases of atazanavir-associated urolithiasis in patients with human immunodeficiency virus (HIV) infection. Patients with low water intake, high urinary pH, and a prior history of urinary stones may have a higher risk of atazanavir-associated urine crystallization.     

Response of a multidrug-resistant human small-cell lung cancer xenograft to chemotherapy

Small-cell lung carcinomas (SCLC) are highly responsive to various chemotherapies. However only a minority of patients benefit from long survival. SCLC patients treated at the Institut Gustave Roussy received a combined chemotherapy (CCAV) including cisplatin, cyclophosphamide (Cpa), Adriamycin (doxorubicin; Adm) and vepeside (VP16). We report here the intrinsic sensitivity of a small-cell lung carcinoma, designated SCLC-6, grafted in nude mice. This xenografted tumour was derived from an untreated patient. The CCAV regimen given to the patient donor of the tumour sample resulted in a complete response followed by recurrence and death, 8 months after the initial cure. The expression of P-glycoprotein encoded by theMDR1 gene was detected with the C219 antibody on the membrane of SCLC-6 tumour cells. When given to SCLC-6-tumour-bearing nude mice, CCAV induced a strong inhibition of tumour growth (84% of growth inhibition, 20 days after start of the treatment), but no cure. Intensification of CCAV doses did not improve the response. The efficacy of individual agents of the CCAV, given at maximal tolerated doses was analysed. Only cisplatin (10 mg/kg) and Cpa (3×50 mg/kg) inhibited SCLC-6 growth (79% and 100% inhibition respectively), VP16 (3×24 mg/kg) was poorly efficient (42%) and Adm (10 mg/kg) not at all. Two-drug combinations such as cisplatin plus VP16 or cisplatin plus Cpa inhibited tumour growth (81% and 70%, respectively). Curiously, the efficacy of Cpa, given in combination with cisplatin was less than that of Cpa alone. Repeated treatments with CCAV administered to mice at each in vivo passage of the tumour induced a loss of chemosensitivity, which was observed until the ninth passage. An improvement of the therapeutic response was obtained by adding a headline reverser of multidrug resistance, verapamil (25 mg/kg), to CCAV (81% versus 63% inhibition). MDR1-related resistance appeared to play a role in the failure of SCLC-6 chemotherapy; frequent recurrences after treatment with cisplatin and Cpa, two drugs that are not recognized by the P-glycoprotein, indicated that other modes of resistance were simultaneously active.Abbreviations SCLC small-cell lung cancer - CCAV cyclophosphamiede (CPA)/cisplatin/Adriamycin (Adm)/vepeside (V)16)     

Constitutional thinness: unusual human phenotype of low bone quality

CONTEXT: Low fat mass and hormonal or nutritional deficiencies are often incriminated in bone loss related to thinness. Constitutional thinness has been described in young women with low body mass index (BMI) but close-to-normal body composition, physiological menstruation, no hormonal abnormalities, and no anorexia nervosa (AN) psychological profile. OBJECTIVE: Our objective was to determine whether constitutional thinness is associated with impaired bone quality. DESIGN, SETTING, AND PARTICIPANTS: This was an observational, cross-sectional study on 25 constitutionally thin and 44 AN young women with similar low BMI (<16.5 kg/m2) and 28 age-matched controls. MAIN OUTCOME MEASURES: Femoral and lumbar spine bone mineral density by dual-energy x-ray absorptiometry, distal tibia and radius bone architecture and breaking strength by three-dimensional peripheral quantitative computed tomography, and bone turnover markers were determined. RESULTS: Constitutionally thin subjects displayed a higher percentage of fat mass than AN subjects but had similar lumbar and femoral bone mineral density, which were significantly lower than in controls (P < 0.001). Constitutionally thin subjects displayed more markedly impaired trabecular and cortical bone parameters in the distal tibia than in the radius. AN bone structure was impaired only in subjects with a long history of disease. Calculated breaking strength was decreased in constitutional thinness and long-standing AN in both the radius and the tibia. Bone markers in constitutionally thin subjects were similar to those of controls. Osteoprotegerin to receptor activator of nuclear factor kappa B ligand ratio was higher in constitutionally thin subjects than in controls or AN women. CONCLUSIONS: Young women with constitutional thinness present an unexpectedly high prevalence of low bone mass (44%) associated with small bone size, overall diminished breaking strength, but normal bone turnover. Mechanisms related to insufficient skeletal load and/or genetics are proposed to explain this new phenotype of impaired bone quality.