A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Elucidating the risk factors for chronic obstructive pulmonary disease: an umbrella review of meta-analyses.

Chronic obstructive pulmonary disease (COPD) is commonly attributed to smoking, and other potential risk factors are ignored. We aimed to critically appraise the epidemiological credibility of the risk factors for COPD that have been examined in published meta-analyses. We performed a systematic search to capture systematic reviews and meta-analyses of observational studies on environmental factors and biomarkers for risk of COPD. We applied a set of standardised methodological criteria based on the level of statistical significance, sample size, between-study heterogeneity and statistical biases. Our search yielded 11 eligible papers, including 18 meta-analyses on environmental factors or biomarkers for COPD risk, and eight eligible papers with systematic reviews only. Eleven associations achieved statistical significance at P < 0.001 and six associations at P < 1 × 10-6. Thirteen associations presented an I²  50%, while six associations had evidence of small-study effects and/or excess significance bias. History of tuberculosis or rheumatoid arthritis, exposure to biomass fuels, tobacco smoking and second hand smoking were supported by high epidemiological credibility for an increased risk of COPD. Furthermore, highly suggestive evidence was found for increased levels of serum C-reactive protein, and serum fibrinogen in COPD patients compared with healthy controls. To summarise, our approach suggests that, while a proportion of COPD patients are non-smokers, only a narrow range of risk factors not related to smoking have been studied for an association with COPD. There is also a need to decipher possible protective factors in COPD pathogenesis given that more than a half of ever-smokers do not develop COPD.

Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies.

OBJECTIVE: To summarize evidence from the literature on genetic and non-genetic risk factors associated with pre-eclampsia (PE), assess the presence of statistical bias in the studies and identify risk factors for which there is robust evidence supporting their association with PE. METHODS: PubMed and ISI Web of Science were searched from inception to October 2016, to identify systematic reviews and meta-analyses of observational studies examining associations between genetic or non-genetic risk factors and PE. For each meta-analysis, the summary-effect size was estimated using random-effects and fixed-effects models, along with 95% CIs and the 95% prediction interval. Between-study heterogeneity was expressed using the I2 statistic, and evidence of small-study effects (large studies had significantly more conservative results than smaller studies) and evidence of excess significance bias (too many studies with statistically significant results) were estimated. RESULTS: Fifty-eight eligible meta-analyses were identified, which included 1466 primary studies and provided data on 130 comparisons of risk factors associated with PE, covering a wide range of comorbid diseases, genetic factors, exposure to environmental agents and biomarkers. Sixty-five (50%) associations had nominally statistically significant findings at P < 0.05, while 16 (12%) were significant at P < 10-6 . Sixty-five (50%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 10 (8%) and 26 (20%) associations, respectively. The only non-genetic risk factor with convincing evidence for an association with PE was oocyte donation vs spontaneous conception, which had a summary odds ratio of 4.33 (95% CI, 3.11-6.03), was supported by 2712 cases with small heterogeneity (I2 = 26%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10) or excess of significance (P > 0.05). Of the statistically significant (P < 0.05) genetic risk factors for PE, only PAI-1 4G/5G (recessive model) polymorphism was supported by strong evidence for a contribution to the pathogenesis of PE. Eleven factors (serum iron level, pregnancy-associated plasma protein-A, chronic kidney disease, polycystic ovary syndrome, mental stress, bacterial and viral infections, cigarette smoking, oocyte donation vs assisted reproductive technology, obesity vs normal weight, severe obesity vs normal weight and primiparity) presented highly suggestive evidence for an association with PE. CONCLUSIONS: A large proportion of meta-analyses of genetic and non-genetic risk factors for PE have caveats that threaten their validity. Oocyte donation vs spontaneous conception and PAI-1 4G/5G polymorphism (recessive model) showed the strongest consistent evidence for an association with risk for PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

CRD-BP: a c-Myc mRNA stabilizing protein with an oncofetal pattern of expression.

The Coding Region Determinant-Binding Protein (CRD-BP) is an RRM and KH-domain-containing protein that recognizes specifically at least three RNAs. It binds to one of the two c-myc mRNA instability elements, to the 5'Un Translated Region (UTR) of the leader 3 IGF-II mRNA and to the oncofetal H19 RNA. CRD-BP has been assigned a role in stabilizing c-myc mRNA by preventing its endonucleolytic cleavage and in repressing the translation of the leader 3 IGF-II mRNA, the major embryonic species of this message. CRD-BP is normally expressed only in fetal tissues. However, its expression is detected in primary tumors and transformed cell lines of different origins. The vast majority of colon (80%) and breast (60%) tumors and sarcomas (73%) express CRD-BP whereas in other tumor types, for example prostate carcinomas, its expression is rare. CRD-BP expression has also been detected in benign tumors such as breast fibroadenomas, meningiomas and other benign mesenchymal tumors, implying a role for this gene in abnormal cell proliferation. In breast carcinomas, CRD-BP expression and or gene copy number gains in the region encompassing the c-myc locus were detected in approximately 75% of tumors, implying that the deregulated expression of c-myc may be more widespread than previously believed. Infiltrated lymph nodes, corresponding to CRD-BP-positive primary tumors, were also found positive indicating that monitoring for CRD-BP could prove useful for the detection and monitoring of disseminated disease.

The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches.

OBJECTIVE: The osteoporosis seen in thalassaemia major is of multifactorial origin. The aim of the study was to evaluate the contribution of hypogonadism to the development of this osteoporosis and to assess the efficacy of new sex hormone replacement therapy regimens. DESIGN AND PATIENTS: Sixty-seven patients were studied: 12 were hypogonadal, 32 had been on previous hormone replacement therapy (conjugated oestrogens plus medroxyprogesterone for females, depot testosterone esters for males); 10 had received continuous courses of treatment and 22 3-monthly on/off courses, and 22 were eugonadal without previous replacement therapy. Twenty-seven of the above patients were evaluated prospectively at 16 and 32 months during different therapeutic approaches (12 without treatment, 7 on continuous replacement and 8 on/off schemes followed by continuous therapy during the second observation period). The continuous schemes comprised either transdermal oestradiol (100 micrograms) plus medroxyprogesterone for females or hCG to produce serum testosterone concentrations within normal range, for males. MEASUREMENTS: Bone mineral density (BMD) and bone mineral content (BMC) of lumbar spine and distal end of radius were measured by dual-energy X-ray absorptiometry. RESULTS: Spinal BMD was found to be more than 30% lower than that of controls matched for sex and age with no difference between sexes. Radial BMD was less impaired and showed significantly (P < 0.01) higher levels in males (decrease of 5.8% +/- 2.3, mean +/- SD) than in females (-14.5 +/- 3.4%, mean +/- SD). In the retrospective evaluation it was found that the hypogonadal group had the lowest (P < 0.0001) BMD levels (0.62 +/- 0.01, mean +/- SE) and the highest were observed on the continuous replacement group (0.83 +/- 0.04), whereas the values of the other groups were similar. In a multiple regression analysis model it was found that only sex steroid levels were related to the BMD measurements (for oestradiol t = 2.6, P = 0.01 and for testosterone t = 6.5, P = 0.0001), whereas parameters related to haemolytic anaemia and desferrioxamine treatment were not. In the prospective study the continuous replacement group increased BMD and BMC values more than the on/off treatment courses (P = 0.01). CONCLUSIONS: Hypogonadism seems to play an important role in the development of osteopenia-osteoporosis in thalassaemia major; continuous hormone replacement therapy with transdermal oestrogen for females or hCG for responding males best improves the bone density parameters.

Neurotransmitter parameters in plasma and urine of affective patients in depression and in normothymia after drug treatment.

Several neurochemical parameters were estimated in plasma and urine of patients with affective disorders in the depressive phase and later in normothymia, after successful drug treatment. Significant increases were found for the activity of the enzyme dopamine-beta-hydroxylase in plasma and the concentrations of cyclic AMP in plasma and urine. No consistent changes were found for prolactin or cyclic GMP in plasma, and for methoxyhydroxyphenylgkyglycol, homovanillic acid, 5-hydroxyindoleacetic acid and cyclic GMP in urine. The major change we observed in the clinical state of the patients is thus not reflected in change in the urinary biogenic amine metabolites. Their changes were found to correlate inversely to their pretreatment values. In normothymia, high values decrease and low values increase for all three amine metabolites, indicating that antidepressives act towards a normalization of the amine turnover mechanisms.