ERG Protein Expression in Diagnostic Specimens Is Associated with Increased Risk of Progression During Active Surveillance for Prostate Cancer

Background

Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed.

Objective

To examine the association between ERG expression at diagnosis and the risk of progression during AS.

Design, setting, and participants

This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10–12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression.

Outcome measurements and statistical analysis

Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events.

Results and limitations

A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p < 0.0001) and of the subgroups PSA progression (p < 0.0001) and histopathologic progression (p < 0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3–29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7–68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62–3.72; p < 0.0001). The main limitation of this study is its observational nature.

Conclusions

In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes.

Patient summary

The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.     

Increased Trabecular Volumetric Bone Mass Density in Familial Hypocalciuric Hypercalcemia (FHH) Type 1: A Cross-Sectional Study

Familial Hypocalciuric Hypercalcaemia (FHH) Type 1 is caused by an inactivating mutation in the calcium-sensing receptor (CASR) gene resulting in elevated plasma calcium levels. We investigated whether FHH is associated with change in bone density and structure. We compared 50 FHH patients with age- and gender-matched population-based controls (mean age 56 years, 69 % females). We assessed areal BMD (aBMD) by DXA-scans and total, cortical, and trabecular volumetric BMD (vBMD) as well as bone geometry by quantitative computed tomography (QCT) and High-Resolution peripheral-QCT (HR-pQCT). Compared with controls, FHH females had a higher total and trabecular hip vBMD and a lower cortical vBMD and hip bone volume. Areal BMD and HRpQCT indices did not differ except an increased trabecular thickness and an increased vBMD at the transition zone between cancellous and cortical bone in of the tibia in FHH. Finite element analyses showed no differences in bone strength. Multiple regression analyses revealed correlations between vBMD and P-Ca²⁺ levels but not with P-PTH. Overall, bone health does not seem to be impaired in patients with FHH. In FHH females, bone volume is decreased, with a lower trabecular volume but a higher vBMD, whereas cortical vBMD is decreased in the hip. This may be due to either an impaired endosteal resorption or corticalization of trabecular bone. The smaller total bone volume suggests an impaired periosteal accrual, but bone strength is not impaired. The findings of more pronounced changes in females may suggest an interaction between sex hormones and the activity of the CaSR on bone.     

Radiographic evaluation of ventral instability in lumbar spondylolisthesis: do we need extension radiographs in routine exams?

Purpose

To determine the usefulness of acquiring extension radiographs for the evaluation of the degree of spondylolisthesis.

Methods

Routine radiographs of the lumbar spine were retrospectively evaluated in 87 patients (mean-age 63, range 32–86) by two independent radiologists. All patients received radiographs in standing neutral, flexion and extension position. Vertebral body depth, sagittal translational displacement and lordosis angle were measured and slip percentage (SP) was calculated on standing neutral, flexion and extension radiographs. Statistical analysis was performed with a two-sided t test. Inter- and intraobserver reliability was assessed using the kappa-coefficient.

Results

There was no statistically significant SP-difference between neutral standing and extension images. Ventral instability was diagnosed in 25–34 % (cut-off >8 % SP-difference) for neutral versus flexion comparison. The detection rate of flexion–extension radiographs representing the extremes of motion was lower with 15–22 %. Inter- and intraobserver reliability was good to excellent.

Conclusion

Slip percentage in routine standing extension radiography ultimately does not differ from that obtained in a static neutral standing view. Extension radiography may therefore be omitted in a routine work-up of ventral instability in lumbar spondylolisthesis.     

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea

BackgroundIron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear.Methods and ResultsConsecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO₂), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO₂ (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV–pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm² vs 2.58 ± 1.14 mm Hg/cm²; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO₂/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.ConclusionsIn patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.     

The origin of secondary microseism Love waves

The interaction of ocean surface waves produces pressure fluctuations at the seafloor capable of generating seismic waves in the solid Earth. The accepted mechanism satisfactorily explains secondary microseisms of the Rayleigh type, but it does not justify the presence of transversely polarized Love waves, nevertheless widely observed. An explanation for two-thirds of the worldwide ambient wave field has been wanting for over a century. Using numerical simulations of global-scale seismic wave propagation at unprecedented high frequency, here we explain the origin of secondary microseism Love waves. A small fraction of those is generated by boundary force-splitting at bathymetric inclines, but the majority is generated by the interaction of the seismic wave field with three-dimensional heterogeneity within the Earth. We present evidence for an ergodic model that explains observed seismic wave partitioning, a requirement for full-wave field ambient-noise tomography to account for realistic source distributions.

The surface of the Earth is continuously subjected to perturbing forces that generate seismic waves. Given that 70% of the surface of our planet is covered by oceans, seismic signals due to ocean storms represent the vast majority of seismic data recorded by seismometers on Earth (1). Such data carry information about the energy exchange between different Earth systems, allowing for probing our changing climate (2–4) as well as imaging the internal structure of the Earth (5). The strongest vibrations are called secondary microseisms, excited in the 0.1 to 0.3 Hz frequency range by nonlinear ocean wave–wave interaction (6, 7). They are predominantly composed of seismic surface waves, and Rayleigh waves dominate the vertical component of microseism records (8).The generation mechanism currently accepted for secondary microseisms explains the Rayleigh wave content of vertical-component noise records (9). Secondary microseisms are produced by pressure-like sources at the surface of the ocean. Rayleigh waves are excited below the seafloor due to constructive interference of P and SV body waves. At the ocean–crust interface, they are called Scholte waves when their phase velocity becomes smaller than the minimum phase velocity of the system (10). While at longer periods, ocean waves can directly couple with the seafloor and generate Love waves (11, 12), the generation mechanism of secondary microseisms cannot explain the presence of Love waves on the horizontal components of microseismic records. Observations of secondary microseism Love waves date back to the early (13) and middle (14) 20th century. A few recent studies based on high-quality digital data focused on quantifying the Love-to-Rayleigh ratio in the secondary microseism frequency range (SI Appendix, Table S1). They found that Love-to-Rayleigh ratios are frequency dependent (15) and show a predominance of Rayleigh waves (16, 17), with few exceptions (18).Hypotheses for the generation of secondary microseism Love waves envisage that they can be generated either in the region where the pressure power spectral density (PSD) is strong or along distinct propagation paths within the Earth. The first hypothesis is supported by the presence of bathymetric inclines in the source regions. Such bathymetry may lead to splitting of the vertical second-order pressure force in a component perpendicular to inclines—responsible for Rayleigh waves—and a component tangent to inclines—responsible for Love waves. The second hypothesis is supported by the presence of lateral heterogeneities within the Earth, which can lead to the generation of Love waves due to scattering and focusing/defocusing effects. Ref. 8 observed Love and Rayleigh waves coming from the same direction, concluding that Love waves do originate in the source region. On the other hand, ref. 19 noted that the greater the distance of propagation of Rayleigh waves, the larger the Love wave energy. In addition to these hypotheses, Love waves may originate from Rayleigh-to-Love wave conversion at the ocean–continent boundary, although early numerical simulations suggest that only a few percent of incident Rayleigh wave energy can be converted to Love wave energy (20). To date, no comprehensive theoretical investigations as to which mechanisms can lead to the observed secondary microseism Love waves have been conducted.