Citations

It has been postulated that catheter-based renal denervation (RDN) may lower blood pressure (BP) and improve severity of obstructive sleep apnea (OSA) in resistant hypertensive patients. The aim of our study (NCT01366625) was to investigate in a prospective randomized trial the effect of RDN on BP and clinical course of OSA. Sixty patients with true resistant hypertension coexisting with moderate-to-severe OSA (apnea/hypopnea index, ≥15) were randomly allocated to RDN group (30 patients) and to control group (30 patients). The primary end point was reduction in office systolic BP at 3 months. Secondary end points included reduction in diastolic office and ambulatory BP, change in apnea/hypopnea index and biochemical measurements at 3 months, and change in echocardiographic measurements at 6 months. There were no differences in clinical characteristics between the groups. At 3 months in the RDN group, both office and ambulatory BP were significantly reduced, and a significant decrease in OSA severity (apnea/hypopnea index, 39.4 versus 31.2 events per hour; P =0.015) was observed. Between-group difference in apnea/hypopnea index change was significant at 0.05. At 6 months in the RDN group, reductions in office and ambulatory BP were sustained and were accompanied by significant improvement in echocardiographic measures of global longitudinal strain. There were no differences in metabolic variables in follow-up in both groups. In a randomized controlled trial, RDN lowered both office and ambulatory BP in patients with resistant hypertension and OSA. This was accompanied by improvement of the clinical severity of OSA. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01366625.

Objectives To define the elementary ultrasound (US) lesions in giant cell arteritis (GCA) and to evaluate the reliability of the assessment of US lesions according to these definitions in a web-based reliability exercise. Methods Potential definitions of normal and abnormal US findings of temporal and extracranial large arteries were retrieved by a systematic literature review. As a subsequent step, a structured Delphi exercise was conducted involving an expert panel of the Outcome Measures in Rheumatology (OMERACT) US Large Vessel Vasculitis Group to agree definitions of normal US appearance and key elementary US lesions of vasculitis of temporal and extracranial large arteries. The reliability of these definitions on normal and abnormal blood vessels was tested on 150 still images and videos in a web-based reliability exercise. Results Twenty-four experts participated in both Delphi rounds. From originally 25 statements, nine definitions were obtained for normal appearance, vasculitis and arteriosclerosis of cranial and extracranial vessels. The ‘halo’ and ‘compression’ signs were the key US lesions in GCA. The reliability of the definitions for normal temporal and axillary arteries, the ‘halo’ sign and the ‘compression’ sign was excellent with inter-rater agreements of 91–99% and mean kappa values of 0.83–0.98 for both inter-rater and intra-rater reliabilities of all 25 experts. Conclusions The ‘halo’ and the ‘compression’ signs are regarded as the most important US abnormalities for GCA. The inter-rater and intra-rater agreement of the new OMERACT definitions for US lesions in GCA was excellent.

AbstractBackgroundBlepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole‐exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation.MethodsWe performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis.ResultsCosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio‐cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia.ConclusionsOur WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p‐values for case–case and case–control comparisons for risk factors in relation to levels of grade and quartiles (Q1–Q4) of KI67 were estimated using polytomous logistic regression models. Case–case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1 = 1.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 (0.16, 0.44)] tumors. In case–control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors.

Abstract Introduction. Male breast cancer (male BC) is a rare disease for which disease management is extrapolated from females. IMBC, an international consortium, which previously reported on clinico-pathological aspects, now reports on molecular subgroups revealed by RNA sequencing and their relation to patient outcome. Methods. Tumor samples from the retrospective MALE BC registry diagnosed between 1990-2010 and with pathology and outcome data (relapse-free- (RFS) and overall survival (OS)) were included (n=699). To allow the discovery of prognostic features, we selected, stratified for known risk factors (TN stage, grade, age at diagnose and adjuvant endocrine treatment), from the cohort 152 cases with poor (RFS <= 4 yrs) and good outcome (RFS > 7yrs) evenly distributed. Here, we report RNA sequencing results of the first 73 cases, 38 with poor and 35 with good outcome. RNA sequencing reads were used to generate gene expression values and to report transcripts carrying driver mutations. Unsupervised clustering identified subgroups and within subgroups differentially expressed genes were identified. The reported prognostic male BC subgroups M1 and M2 (Johansson BCR 2012(14):R31) were also annotated. All identified subgroups were related to outcome using logistic regression (p-value using Wald test). Results. Unsupervised clustering revealed 2 main subgroups of which group 1 was enriched for expression of ER target genes, WNT3 and genes from amplicons known for female BC, e.g. 19p13 (CCNE1), 8q24 (MYC), and 11q13 (CCND1). The biology of the smaller group 2 was less defined but TGFβ2 expression was high as were various kallikreins (KLK) including interestingly KLK3 (prostate specific antigen). Other known amplified regions [(8p11 (FGFR1), 20q13 (ZNF217) and 12q15 (MDM2)] and mutated transcripts [PIK3CA (H1047R/L/Q; E542K, E545K, N345K; 16% of cases), TP53 and SF3B1 (K700E) (2% of cases)] were identified. Profound tumor infiltrate gene expression was present in 5% of cases and one third of cases expressed proliferation markers. Except for TP53, none of these latter characteristics were unevenly distributed among the 2 main subgroups. ER and AR were highly correlated, particularly in group 1. The two main groups could be further subdivided. Group 1 comprised 3 subgroups of which subgroup 1a expressed TFF1/3 and NAT1, well-known ER targets, while subgroups 1b and 1c expressed other ER targets,respectively BEX1 and PITX1. HOXC cluster expression differentiated subgroup 1b from 1a and 1c. None of these intrinsic subgroups were, however, related to RFS. The previously reported M2 subgroup, which largely segregated with subclusters 1a and 1b, was associated with a better RFS than the M1 subgroup (OR=2.9; 95%CI 1.1-7.5; p-value=0.03). Conclusions. 1) Intrinsic subtypes of male BC were revealed and their subgrouping is defined by ER associated subsets of genes. 2) The association of the reported M2 subgroup of male BC with longer RFS was validated; 3) Currently identified biological characteristics of male BC may improve future treatments. The full report on 152 cases including a comparison to female BC will be presented at the conference. This research was funded by Breast Cancer Research Foundation Citation Format: Martens JWM, Sieuwerts A, Ponchet C, Smid M, de Weerd V, Slaets L, Piper T, van Deurzen CHM, Schroder CP, Stangle C, Kloosterman W, van Leeuwen-Stok E, Nilsson C, Vermeij J, Peeters S, Goulioti T, Nowaczyk M, Aebi S, Rubio IT, Kelly C, Bayani J, Porter P, Murray M, Hudis C, Middleton L, Korde L, Ruddy K, Winer E, Bogler O, van den Weyngaert D, dal Lago L, Fraser J, Benstead K, van Asperen C, Linderholm B, Hedenfalk I, Tryfonidis K, Giordano S, Bartlett J, Cardoso F. Molecular subtyping of male breast cancer by the International male breast cancer program (IMBC): EORTC 10085/TBCRC 0-29/BIG 2-07/NABCG/BOOG 2009-04 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-12.