Citations

Objective To better characterize the genomics of patients with biochemical recurrence ( BCR ) who have metastatic disease progression in order to improve treatment decisions for prostate cancer. Methods The expression profiles of three clinical outcome groups after radical prostatectomy ( RP ) were compared: those with no evidence of disease ( NED ; n = 108); those with BCR (rise in prostate‐specific antigen [ PSA ] level without metastasis; n = 163); and those with metastasis ( n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow‐up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology. Results Minimal gene expression differences were observed between adjuvant treatment‐naïve patients in the NED group and patients without metastasis in the BCR group. More than 95% of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin‐mediated proteolysis, DNA repair, androgen, G‐protein coupled and NOTCH signal transduction pathways. Conclusion This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision‐making.

Background— The goal of this study was to identify genetic determinants of plasma N-terminal proatrial natriuretic peptide (NT-proANP) in the general community by performing a large-scale genetic association study and to assess its functional significance in in vitro cell studies and on disease susceptibility. Methods and Results— Genotyping was performed across 16 000 genes in 893 randomly selected individuals, with replication in 891 subjects from the community. Plasma NT-proANP 1–98 concentrations were determined using a radioimmunoassay. Thirty-three genome-wide significant single-nucleotide polymorphisms were identified in the MTHFR-CLCN6-NPPA-NPPB locus and were all replicated. To assess the significance, in vitro functional genomic studies and clinical outcomes for carriers of a single-nucleotide polymorphism rs5063 (V32M) located in NPPA that represented the most significant variation in this genetic locus were assessed. The rs5063 variant allozyme in transfected HEK293 cells was decreased to 55±8% of wild-type protein ( P =0.01) as assessed by quantitative western blots. Carriers of rs5063 had lower NT-proANP levels (1427 versus 2291 pmol/L; P <0.001) and higher diastolic blood pressures (75 versus 73 mm Hg; P =0.009) and were at an increased risk of stroke when compared with wild-type subjects independent of age, sex, diabetes mellitus, hypertension, atrial fibrillation, and cholesterol levels (hazard ratio, 1.6; P =0.004). Conclusions— This is the first large-scale genetic association study of circulating NT-proANP levels performed with replication and functional assessment that identified genetic variants in the MTHFR-CLCN6-NPPA-NPPB cluster to be significantly associated with NT-proANP levels. The clinical significance of this variation is related to lower NT-proANP levels, higher blood pressures, and an increased risk of stroke in the general community.

AbstractBackgroundRib fracture stabilization has become a more accepted practice although stabilization of the most cephalad ribs presents a unique challenge. We present our experience with use of a 90° drill and screwdriver to bridge these difficult rib fractures.MethodsThis retrospective review included patients who underwent rib fracture stabilization from August 1, 2009, through September 30, 2012. Patients were divided into two groups: those whose procedure used the 90° device and those that did not. Data were compared using standard statistical analysis and reported as percentages and medians [interquartile ranges]. P values <0.05 were considered significant.ResultsWe identified 89 patients: 29 (33 %) had 90° devices used and 60 (67 %) did not. There were no differences between groups in age, sex, Trauma‐Related Injury Severity Score, the presence of flail chest, occurrence of pneumonia, and intensive care unit or hospital length of stay. The Injury Severity Score was higher in the 90° group (22 vs. 16; P = 0.03). The highest rib stabilized was different between the 2 groups (3 [2–5] vs. 5 [2–9]; P = 0.001), with more third rib stabilizations in the 90° group (38 vs. 20 %; P = 0.04) as well as more total number of ribs fixed (5 vs. 4; P = 0.001). There was no difference in operative time between the 2 groups.ConclusionsThe surgical reach for rib fracture stabilization has been extended with use of a 90° drill and screwdriver. High fractures under the scapula where access is technically challenging can be stabilized without prolonging operative times.

In this report, sex/gender research relevant to reproduction on Earth, in conjunction with the extant human and animal observations in space, was used to identify knowledge gaps and prioritize recommendations for future sex- and gender-specific surveillance and monitoring of male and female astronauts. With overall increased durations of contemporary space missions, a deeper understanding of sex/gender effects on reproduction-related responses and adaptations to the space environment is warranted to minimize risks and insure healthy aging of the men and women who travel into space.

AbstractPrognostic significance of histological anaplasia and BRAF V600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma (PXA). Median age at diagnosis was 21.5 years (31 pediatric, 43 adult) and median follow‐up 7.6 years. Anaplasia (PXA‐AF), defined as mitotic index ≥ 5/10HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 (R132H). Mitotic index ≥ 5/10HPF and necrosis were associated with decreased overall survival (OS; P = 0.0005 and P = 0.0002, respectively). In all cases except two, necrosis was associated with mitotic index ≥ 5/10HPF. Patients with BRAF V600E mutant tumors had significantly longer OS compared with those without BRAF V600E mutation (P = 0.02). PXA‐AF patients, regardless of age, had significantly shorter OS compared with those without (P = 0.0003). Recurrence‐free survival was significantly shorter for adult PXA‐AF patients (P = 0.047) only. Patients who either recurred or died ≤3 years from diagnosis were more likely to have had either PXA‐AF at first diagnosis (P = 0.008) or undergone a non‐gross total resection procedure (P = 0.004) as compared with patients who did not. This study provides further evidence that PXA‐AF behaves more aggressively than PXA and may qualify for WHO grade III “anaplastic” designation.

Background: We examined patient interest in a telehealth model in which the patient supplies the hardware and Internet connectivity to meet with a healthcare provider from his or her home via video call (video appointment). We hoped to understand prospectively the desirability, feasibility, and viability from the patient perspective. Materials and Methods: A phone survey was conducted of a random sample of patients who had been seen in the outpatient setting at a single institution. The sample was stratified by proximity to the local institution with oversampling for patients living outside a 120-mile radius. Results: Out of 500 total patients, 301 patients responded, and 263 met the inclusion criteria. Of those 263 respondents, 38% indicated “very likely” to accept an invitation to see their provider via video, 28.1% “somewhat likely,” and 33.8% “not at all likely.” Of respondents, 75% have broadband, although only 36% reported having a Web camera. The primary factors affecting willingness to participate in a video appointment include comfort in setting up a video call, age, and distance participants would have traveled for an in-clinic appointment. Conclusions: Patient survey data indicate that most patients are likely to be accepting of telehealth care to the home using video call and that most have the required technology. Nevertheless, there are still significant hurdles to effectively implement this adaptation of telehealth care as part of mainstream practice.