Using a large series of myeloma patients, we could show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, indicating that DKK-1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

OBJECTIVE: To assess evidence from randomized controlled trials (RCTs) on the safety of isotonic versus hypotonic intravenous (IV) maintenance fluids in hospitalized children. METHODS:We searched PubMed, Embase, Cochrane Library, and clinicaltrials.gov (up to April 11, 2013) for RCTs that compared isotonic to hypotonic maintenance IV fluid therapy in hospitalized children. Relative risk (RR), weighted mean differences, and 95% confidence intervals (CIs) were calculated based on the effects on plasma sodium (pNa). The risk of developing hyponatremia (pNa ,136 mmol/L), severe hyponatremia (pNa ,130 mmol/L), and hypernatremia (pNa .145 mmol/L) was evaluated. We adopted a random-effects model in all meta-analyses. Sensitivity analyses by missing data were also performed.RESULTS: Ten RCTs were included in this review. The meta-analysis showed significantly higher risk of hypotonic IV fluids for developing hyponatremia (RR 2.24, 95% CI 1.52 to 3.31) and severe hyponatremia (RR 5.29, 95% CI 1.74 to 16.06). There was a significantly greater fall in pNa in children who received hypotonic IV fluids (-3.49 mmol/L versus isotonic IV fluids, 95% CI -5.63 to -1.35). No significant difference was found between the 2 interventions in the risk of hypernatremia (RR 0.73, 95% CI 0.22 to 2.48). None of the findings was sensitive to imputation of missing data.CONCLUSIONS: Isotonic fluids are safer than hypotonic fluids in hospitalized children requiring maintenance IV fluid therapy in terms of pNa. Pediatrics 2014;133:105-113

Lytic bone disease is one of the major clinical problems in multiple myeloma (MM) patients and has negative impact both on overall survival and quality of life (1, 2). Myeloma bone disease is characterized by a dysbalance in bone remodeling, caused by enhanced osteoclast activity and decreased bone formation (3,4). In animal models a mutual stimulation has been found between myeloma bone disease and tumor progression (5, 6). Furthermore, the bone marker carboxy-terminal telopeptide of type I-collagen (ICTP) recently proved to be a powerful prognostic marker in MM (1).An increase in receptor activator of nuclear factor kappa B ligand (RANKL) and decrease of osteoprotegerin (OPG) in the bone marrow microenvironment stimulates osteoclast formation and activity in MM (7-9). Additionally, macrophage inflammatory protein-1 alpha (10) is another factor important in attraction of osteoclast precursors. On the other hand, osteoblast activity is strongly reduced in patients with MM (3). Bone formation is impaired through reduced mesenchymal stem cell proliferation and differentiation and inhibition of osteoblast function (11). AbstractLytic bone destruction is a hallmark of multiple myeloma (MM) and is because of an uncoupling of bone remodeling. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. In this study, the effect of different treatment regimens for MM on serum DKK-1 was evaluated and correlated with the response to treatment in 101 myeloma patients receiving bortezomib, thalidomide, lenalidomide, adriamycin and dexamethasone (AD) or high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT). At baseline, myeloma patients had increased serum DKK-1 as compared with patients with MGUS (mean 3786 pg ⁄ mL vs. 1993 pg ⁄ mL). There was no difference between previously untreated MM patients and patients at relapse. A significant decrease of DKK-1 after therapy was seen in the following groups: Bortezomib (4059 pg ⁄ mL vs. 1862 pg ⁄ mL, P = 0.016), lenalidomide (11837 pg ⁄ mL vs. 4374 pg ⁄ mL, P = 0.039), AD (1668 pg ⁄ mL vs. 1241 pg ⁄ mL, P = 0.016), and AD + HDCT + ASCT (2446 pg ⁄ mL vs. 1082 pg ⁄ mL, P = 0.001). Thalidomide led to a nonsignificant decrease in DKK-1 (1705 pg ⁄ mL vs. 1269 pg ⁄ mL, P = 0.081). Within all groups, a significant decrease of DKK-1 was only seen in responders (i.e. patients achieving complete remission or partial remission), but not in non-responders. We show for the first time that serum DKK-1 levels decrease in myeloma patients responding to treatment, irrespective of the regimen chosen. These data suggest that myeloma cells are the main source of circulating DKK-1 protein and provide a framework for clinical trials on anti-DKK-1 treatment in MM.

OBJECTIVETo assess the extent and mechanism of renal reabsorption and excretion in patients with an ileal neobladder, as mild metabolic acidosis cause by proton reabsorption is common after such surgery, and long-term pharmacological correction is often necessary. PATIENTS AND METHODSThe study comprised 30 patients (29 men and one woman) with ileal neobladders after oncological surgery; before surgery all had normal retention values. Before and after withdrawing the transurethral catheter, serum creatinine and urea were analysed and used to assess the effect of the neobladder on retention values, expressed as the percentage change from baseline ( D creatinine and urea). RESULTSThere was a significant correlation between the D-creatinine and D-urea values ( P < 0.001; r = 0.66); 15 patients (50%) showed resorption of creatinine and urea, eight (27%) excreted creatinine into the neobladder and resorbed urea from it at the same time, and three (10%) showed the reverse response, i.e. creatinine resorption and urea excretion. Interestingly, four patients (13%) excreted both creatinine and urea into the neobladder. CONCLUSIONSWe assume that there was both a resorptive and excretory function. Probably the metabolic state (resorption or secretion) of the neobladder depends on its mucus production and on the internal surface, or on diuresis. Further investigation is required to characterize these different influences.

10591 Background: Macrophage colony stimulating factor (M-CSF) and its receptor (CSF-1R, the c-fms oncogene protein product) have been reported to be expressed in a variety of cancers, including breast cancer. The M-CSF produced by breast cancer cells and surrounding stromal cells increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation. In this study we evaluated the predictive and prognostic potential of circulating M-CSF in metastatic breast cancer patients treated with hormone therapy. Methods: Using an M-CSF ELISA (R&D Systems, Minneapolis, MN), M-CSF concentration was determined in pretreatment sera from 204 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial of fadrozole vs. megace, and also in sera from 25 post-menopausal control female subjects. Results: The serum M-CSF level from the 25 healthy post-menopausal female control subjects had a mean ± SD of 835.6 ± 276.1 pg/ml (range 319.0 - 1,465.8 pg/ml). The upper limit of normal was defined as the 95th percentile of the serum M-CSF level from the female control group (1277 pg/ml). Pretreatment serum M-CSF levels from the metastatic breast cancer patients ranged from 82.2 - 3,019.8 pg/ml, and were found elevated above the upper limit of normal in 15 of 204 patients (7.35 %). Patients with elevated pretreatment serum M- CSF did not have a significantly different objective response rate, clinical benefit rate, or time to progression to hormone therapy; but these patients did have significantly reduced overall survival (median survival 10.0 months) compared to patients with normal serum M-CSF levels (median survival 24.3 months)(p = 0.007). In multivariate analysis with serum HER-2/neu included as a covariate, elevated serum M-CSF level remained a significant independent variable for reduced survival (p= 0.032). Conclusions: Pretreatment serum M-CSF levels were elevated in 7 % of metastatic breast cancer patients compared to healthy female control subjects, and these patients had significantly reduced overall survival. Serum M-CSF deserves further study to determine its predictive and prognostic biomarker potential in breast cancer patients. No significant financial relationships to disclose.