Citations

Background Turner syndrome ( TS ) is the most common sex chromosome abnormality in women and is associated with increased morbidity and mortality. We describe long‐term outcomes in a large cohort of patients with TS . Methods and Results Retrospective review of patients with TS followed at Mayo Clinic Rochester from 1950 to 2017 was performed. Clinical, imaging, surgical, and genetic data were analyzed. Survival analysis was performed with the Kaplan–Meier method using age‐ and sex‐matched Olmsted County residents as the reference group. The study cohort comprised 317 patients with TS . Average age at diagnosis was 9 (range, 2–12) years, genetic testing was performed in 202 (64%), and pure monosomy X was present in 75 (37%). Congenital heart disease occurred in 131 (41%), with the most frequent lesions being bicuspid aortic valve (n=102, 32%) and coarctation of the aorta (n=43, 14%). Ascending aortic dilation was common, with mean aortic root size index 2 cm/m 2 , and aortic dissection occurred in 6 (2%) patients. The average follow‐up was 11 (range, 2–26) years, yielding 3898 patient‐years, and during this period 46 (14%) patients died; mean age at the time of death was 53±17 years. Patients with TS had reduced survival compared with the control group (82% versus 94% at 30 years; P <0.001), and the leading causes of death were cardiovascular disease, liver disease, and malignancy. Conclusions Patients with TS have reduced survival compared with age‐matched controls, and cardiovascular disease is the major cause of death. Further studies are required to determine if targeted cardiovascular risk factor modification will result in improved survival in this population.

Abstractβ‐Blockers’ heart rate (HR)‐lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β‐blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β‐blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single‐nucleotide polymorphisms (SNPs) previously associated with the HR response to β‐blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β‐blocker used in the PEAR (n = 757), PEAR‐2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR‐2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β‐blockers in whites (rs1042714 C‐allele carriers, meta‐analysis β = –0.95 beats per minute [bpm], meta‐analysis P = 3×10–4; rs1042713 A‐allele carriers, meta‐analysis β = –1.15 bpm, meta‐analysis P = 2×10–3). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β‐blockade in hypertensive patient cohorts.

Abstract Objective: The established link between estrogen and breast cancer occurs via both estrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including estrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. Recent data showed that childhood obesity is associated with significantly higher levels of genotoxic estrogens in the blood compared with lean children, raising the possibility of a potential pathogenic roles of these metabolites in breast cancer starting even prior to the onset of puberty (Mauras et al: J Clin Endocrinol Metab. 100:2322, 2015). A finding of higher levels of genotoxic estrogens associated with oral estradiol may have breast cancer prevention implications.We hence aimed to assess if the route of administration of 17β estradiol (E2) affects the accumulation of genotoxic estrogen metabolites in a model of ovarian failure in young girls with Turner Syndrome. Methods: Stored plasma were used from 40 adolescents with Turner's who participated in a previous 12 months randomized controlled trial of the metabolic impact of E2 orally (2mg/d) vs. transdermally (100μg/d). The doses of oral and transdermal E2 were determined to result in similar plasma levels of unconjugated E2. Previously we had reported that despite the similar plasma levels of unconjugated E2, the oral E2 administration route was associated with higher levels of biologically active estrogen activity than the transdermal route (Torres-Santiago L et al:J Clin Endocrinol Metab. 98:2716, 2013). In this study, we measured 12 estrogen metabolites (conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. Results: After treatment, least square mean (SE) total (conjugated plus unconjugated) E2 and estrone (E1) concentrations were higher in the oral vs. transdermal group (p&lt;0·0001), as were catechol-estrogens 4-OH-E2 (149 vs. 28 (49) pmol/L), 2-OH-E2 (300 vs 76 (52)), 4-OH-E1 (450 vs 105 (113)), 2-OH-E1 (304 vs 740 (684)) and 16α-OH-E1 (3007 vs 157 (534)) (&lt;0·001 between groups). Levels were much closer to controls in the transdermal group. Conclusions: Common feminizing doses of oral estradiol for 12 months result in greater accumulation of unphysiologic, genotoxic estrogens than transdermal estradiol, expanding concerns about oral estrogens' first hepatic passage contributing to the accumulation of these metabolites. These metabolites have the potential for inducing breast cancer in post-menopausal women. These results suggest the potential benefit of preferential use of transdermal versus oral estrogens as replacement and possibly contraceptive options, in the prevention of breast cancer. Further studies to assess long-term risks of these metabolites in women taking different forms of estrogen replacement are needed. Citation Format: Colon-Otero G, Torres-Santiago L, Santen R, Mericq V, Ross J, Damaso L, Hossain J, Wang Q, Mesaros C, Blair IA, Mauras N. Impact of route of administration of estradiol (oral vs. transdermal) on genotoxic estrogens concentrations in girls with ovarian failure due to Turner syndrome: Potential implications for breast cancer prevention [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-14.

European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.

Introduction The optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children. Methods A writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of >80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of >80% on all statements. Comments from the members were incorporated in the text. Results The commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text. Conclusion The viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic.

Abstract Background Radiographic leptomeningeal disease (LMD) develops in up to 30% of patients following postoperative stereotactic radiosurgery (SRS) for brain metastases. However, the clinical relevancy of this finding and outcomes after various salvage treatments are not known. Methods Patients with brain metastases, of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. LMD pattern was categorized as nodular (nLMD) or classical (“sugarcoating,” cLMD). Results The study cohort was 147 patients. Most patients (60%) were symptomatic at LMD presentation, with cLMD more likely to be symptomatic than nLMD (71% vs. 51%, P = 0.01). Salvage therapy was whole brain radiotherapy (WBRT) alone (47%), SRS (27%), craniospinal radiotherapy (RT) (10%), and other (16%), with 58% receiving a WBRT-containing regimen. WBRT was associated with lower second LMD recurrence compared with focal RT (40% vs 68%, P = 0.02). Patients with nLMD had longer median overall survival (OS) than those with cLMD (8.2 vs 3.3 mo, P < 0.001). On multivariable analysis for OS, pattern of initial LMD (nodular vs classical) was significant, but type of salvage RT (WBRT vs focal) was not. Conclusions Nodular LMD is a distinct pattern of LMD associated with postoperative SRS that is less likely to be symptomatic and has better OS outcomes than classical “sugarcoating” LMD. Although focal RT demonstrated increased second LMD recurrence compared with WBRT, there was no associated OS detriment. Focal cranial RT for nLMD recurrence after surgery and SRS for brain metastases may be a reasonable alternative to WBRT.