Clinical significance of increased serum levels of FGF-23 in fibrous dysplasia. / Significado clínico del aumento de los valores séricos de FGF-23 en la displasia fibrosa.

INTRODUCTION AND OBJECTIVE: Fibrous dysplasia (FD) can be associated with the development of hypophosphatemic osteomalacia, caused by the production of FGF-23 by dysplastic bone tissue. This study analysed FGF-23 levels in patients with FD, and their association with disease activity and serum phosphate values. PATIENTS AND METHODS: Twelve adult patients with FD were included in the study. Clinical history, disease extension and activity and treatments received were reviewed, and the relationship of those values with FGF-23 and serum P levels was analysed. RESULTS: FGF-23 was elevated in 6/12 patients (50%). Patients with high FGF-23 levels had similar age and disease activity and extension than those who did not. No differences were observed in serum phosphate values between both groups (increased FGF-23: 3.9±0.9 mg/dl vs. decreased FGF-23: 3.5±0.6 mg/dl). In fact, none of the patients with increased FGF-23 had low serum phosphate values. CONCLUSION: Adult FD patients frequently present elevated FGF-23 values with no serum phosphate level repercussion, suggesting an alteration in the processing of this protein in the dysplastic bone tissue for this pathology.

Prospective study of individualized or high fixed doses of vitamin D supplementation after bariatric surgery.

BACKGROUND: The degree of bariatric surgery (BS) induced vitamin D (VD) malabsorption is not well established. OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of achieving 25-hydroxy VD (25(OH)D) levels ≥75 nmol/L with two regimens of VD supplementation after BS. METHODS: We performed two open-label, prospective studies in patients undergoing BS from 2009 to 2011. Postoperatively, all patients received Ca citrate 1,000 mg and 800 IU of VD3/day. In the first study, additional VD3 was prescribed according to preoperative 25(OH)D levels- < 25 nmol/L:2,800 IU/day; 26-50 nmol/L:2,000-1,200 IU/day, 51-62 nmol/L:1,000 IU; >63 nmol/L:0 IU/day-and we evaluated the patients at baseline and at 4 months. In the second study, an additional fixed high dose of 2,000 IU/day of VD3 was administered, and we evaluated patients at baseline and at 4 and 12 months after BS. RESULTS: The first study included 176 patients [mean age 44 (11)]; 140 were females. Before BS, 171 subjects (98 %) presented 25(OH)D levels <75 nmol/L. Postoperatively, the mean 25(OH)D levels increased from 40 (17) to 77 nmol/L (29) (p < 0.001) with no differences in parathormone (PTH) or 25(OH)D levels between dose groups. In the second study, we enrolled 52 patients [mean age 45 (10)]; 32 were females. Postoperatively, the mean 25(OH)D levels increased from 32 (12) to 80 (22) and to 75 nmol/L (15) (p < 0.001) at 4 and 12 months, respectively. In both studies, a high percentage of patients achieved 25(OH)D ≥75 nmol/L levels and no subject reported any serious adverse event. CONCLUSIONS: Both schedules of daily VD3 supplementation were effective and safe under conditions of clinical practice.

Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity.

PURPOSE: To investigate whether nuclear factor kappaB (NF-kappaB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-kappaB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-kappaB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients. EXPERIMENTAL DESIGN: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-kappaB inhibitor PS-1145 (an inhibitor of IkappaB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-kappaB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter. RESULTS: PC-3 and DU-145 cells had higher NF-kappaB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-kappaB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-kappaB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8+/-9.5 pg/mL in PSA responders versus 36.7+/-20.8 pg/mL (P=0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P=0.0007). On multivariate analysis, pretreatment IL-6 (P=0.05) was an independent prognostic factor for time to disease progression and survival. CONCLUSIONS: Inhibition of NF-kappaB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.