Coamplification of DDX1 correlates with an improved survival probability in children with MYCN-amplified human neuroblastoma.

PURPOSE: Amplification of the MYCN oncogene at chromosome 2p24-25 identifies an aggressive subtype of human neuroblastoma with a poor clinical outcome. Differences in amplicon structure and coamplification of genes telomeric and centromeric to the MYCN oncogene have previously been described. A relevant role of gene coamplification for neuroblastoma pathogenesis remains elusive. PATIENTS AND METHODS: We analyzed 98 primary neuroblastoma tumors with MYCN amplification for coamplification of seven additional genes at chromosome 2p24-25 (DDX1, NAG, NSE1, LPIN1, EST-AA581763, SMC6, and SDC1). Two semiquantitative multiplex polymerase chain reactions were used to obtain the amplification status of the target genes in relation to a reference gene on chromosome 2q (Inhibin-beta-b). Furthermore, mRNA expression pattern of coamplified genes in a subset of tumors was analyzed. RESULTS: Our results show that the frequency of gene coamplification on 2p24-25 in neuroblastoma is correlated directly to the physical distance to MYCN. Coamplification is correlated to an upregulated gene expression for DDX1 and NAG. Coamplification of the DDX1 gene within 400kb telomeric to MYCN identifies a subgroup of advanced stage neuroblastoma tumors with a more favorable outcome (P =.027, log-rank test). A high expression level of DDX1 is associated with a trend towards a better survival probability (P =.058, log-rank test). CONCLUSION: Our results indicate that DDX1 coamplification correlates with a better prognosis and improved patient survival in MYCN-amplified neurobastoma.     

Safety and efficacy of drospirenone used in a continuous combination with 17beta-estradiol for prevention of postmenopausal osteoporosis.

OBJECTIVE: To evaluate the combination of 17beta-estradiol and continuous drospirenone for the prevention of postmenopausal osteoporosis. METHODS: A total of 180 (75%) healthy postmenopausal women aged 45-65 years completed a 2-year prospective study. Bone mineral density (BMD) at lumbar spine, hip and total body as well as endometrial thickness, markers of bone turnover and serum lipids were measured regularly. Treatment groups were given placebo or 1 mg 17beta-estradiol combined with 1, 2 or 3 mg drospirenone daily. RESULTS: BMD at the lumbar spine, hip and total body increased by 7, 4 and 3%, respectively, in all hormone groups versus placebo (all p < 0.001). Bone markers all decreased accordingly (serum osteocalcin 52%, serum bone specific alkaline phosphatase 36%, serum CrossLaps 67% and urinary CrossLaps 75% from baseline; all p < 0.001). Total cholesterol and low-density lipoprotein cholesterol decreased by 8% and 13%, respectively (both p < 0.001). High-density lipoprotein cholesterol and triglycerides remained unchanged. No significant dose-related effects were found. Endometrial thickness increased by 1.2 mm only in the 1-mg drospirenone group (p < 0.01 versus placebo). CONCLUSION: The combination of 17beta-estradiol and drospirenone has a positive effect on BMD and a potentially beneficial effect on lipids. Although endometrial thickness increased slightly, the safety of the endometrium was assured, as no cases of hyperplasia or cancer occurred.     

The long-term impact of 2-3 years of hormone replacement therapy on cardiovascular mortality and atherosclerosis in healthy women.

OBJECTIVE: The effect of hormone replacement therapy (HRT) on cardiovascular risk is intensely debated. The aim of this study was to investigate the long-term effects of HRT given for a few years on all-cause and cardiovascular mortality and the severity of atherosclerosis. METHODS: This analysis was based on a cohort of 1,458 postmenopausal women (55.8 +/- 6.1 years old) who previously participated in a number of randomized, placebo-controlled, clinical trials assessing the efficacy of 2-3 years of therapy with various estrogen plus progestin combinations for preventing bone loss. Women were followed on average for 9.8 years and came for a follow-up visit. Outcome variables were all-cause and cardiovascular mortality and the severity of atherosclerosis, as estimated by semi-quantitative scoring of vascular calcification in the lumbar aorta on lateral radiographs. RESULTS: A total of 174 women died during the observation period. All-cause mortality was decreased by 30% in the HRT+ group compared with the HRT- group (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.50-0.97) after adjusting for age, body mass index and smoking. Under the same conditions, similar results characterized mortality from cardiovascular disease (n = 61 deaths; 35.1% of all deaths) and coronary heart disease (n = 39 deaths; 22.4% of all deaths), which were decreased by 46% (HR 0.54, 95% CI 0.29-0.98, p = 0.045) and 53% (HR 0.47, 95% CI 0.21-1.03, p = 0.062), respectively. Furthermore, the mean severity score of aortic calcification at follow-up was significantly lower in hormone-treated compared to non-treated women (p < 0.0001). CONCLUSION: Women who receive 2-3 years of HRT after menopause do not have increased all-cause mortality, and results of the present study suggest relative cardiovascular benefits compared to those who had not used hormones.     

Serum leptin in first-trimester Down syndrome pregnancies

BACKGROUND: Leptin is a key regulator of satiety; and the serum concentration is considered to reflect nutritional status. Expressed predominantly by the adipocytes, leptin is also expressed in placenta, which is a major source of both leptin and the leptin receptor in pregnancy serum. As a placenta protein, leptin serum concentrations may be perturbed in Down syndrome (DS) pregnancies as seen for pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin-beta (hCGbeta). We examined whether leptin is a maternal serum marker for foetal DS in the first trimester. MATERIALS AND METHODS: Serum samples from 44 pregnant women with a DS foetus, and 135 control pregnant women in week 8 to 14 had the leptin concentration determined by immunoassay and the concentrations were converted into multiples of the median (MoM) of controls based on log-regression analysis. The distributions of log10 MoM leptin was compared in DS and control pregnancies. RESULTS: Serum leptin increased significantly with gestational age in controls (p = 0.02). The mean log10 MoM in controls was - 0.0486, with a median empirical MoM of 0.89, and - 0.0618, with a median empirical MoM of 0.80, in DS pregnancies. This difference was not significant. The log10 MoM leptin values in DS pregnancies did not change with gestational age (p = 0.32). CONCLUSION: Leptin is not a first-trimester marker for foetal DS.     

First-trimester combined screening for Down syndrome: prediction of low birth weight, small for gestational age and pre-term delivery in a cohort of non-selected women

OBJECTIVE: To establish the relationship between the first-trimester screening markers [pregnancy-associated plasma protein A (PAPP-A), free human chorionic gonadotrophin-beta (beta-hCG), nuchal translucency (NT)], the Down syndrome (DS) risk estimate, and the adverse outcomes such as low birth weight, small for gestational age (SGA) and pre-term delivery. METHODS: A retrospective cohort study including 1,734 non-selected singleton pregnancies consecutively enrolled into the programme of first-trimester combined screening for DS in a 12-month period at a single centre. Data from the Prenatal Patient Registry in ASTRAIA were combined with the Danish National Newborn Screening Registry and Danish Birth Registry. RESULTS: There was a significant relation between low PAPP-A MoM, low beta-hCG MoM, increased risk estimate for DS and low birth weight and SGA. Low PAPP-A MoM and increased NT showed a significant relation to pre-term and spontaneous pre-term delivery. Low PAPP-A MoM showed a significant relation to early pre-term delivery. CONCLUSION: First-trimester screening markers exhibited a significant relation to low birth weight, SGA and to some extent, to pre-term and early pre-term delivery. The screening performance of individual markers was poor.     

First-trimester maternal serum progesterone in aneuploid pregnancies

BACKGROUND: First-trimester maternal serum screening for Down syndrome (DS) can be improved by the use of additional serum markers. We examined whether progesterone (P), synthesized by placenta, might be a first-trimester maternal serum marker for fetal DS. MATERIALS AND METHODS: P was quantified in first-trimester maternal serum from 42 DS, six trisomy 18 and two trisomy 13 pregnancies and 115 controls. Log-regression of P versus gestational age in days was used to convert P concentrations into multiples of the median (MoM). RESULTS: The P concentrations in controls increased with gestational age (p = 9.5 x 10(-7)). The log10MoM P distribution in DS pregnancies was not significantly different from that in controls. However, from day 58-67, the log10MoM P was elevated in DS pregnancies (n = 10) with a mean (SD) of 0.1040 (0.0956), compared to a mean (SD) of - 0.0109 (0.1661) in controls (n = 24) (p = 0.05). Five out of six trisomy 18 and both trisomy 13 pregnancies had a P MoM < 1. CONCLUSION: P is not a useful marker for DS in first trimester, except perhaps in a narrow gestational age window from day 58 to 67. P is a trisomy 18/13 marker.