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.     

Impact of Availability of Immediate Breast Reconstruction on Bilateral Mastectomy Rates for Breast Cancer across the United States: Data from the Nationwide Inpatient Sample

Background

Availability of immediate breast reconstruction (IBR) varies among institutions, yet the impact of IBR availability on the rates of bilateral mastectomy (BM) versus unilateral mastectomy (UM) for breast cancer is unknown.

Methods

From the 2002 to 2010 Nationwide Inpatient Sample, we identified women with breast cancer undergoing UM or BM with and without IBR using ICD-9 codes. Hospitals were classified as performing IBR if at least one hospitalization included both mastectomy and reconstruction and then by IBR volume. Statistical comparisons utilized Chi square tests, tests for trend, and multivariable logistic regression.

Results

We identified 130,420 women undergoing UM (76.9 %) or BM (23.1 %) for breast cancer. Of 6,579 hospitals, 3,358 (51.0 %) performed no IBRs, while in the remaining 3,221 hospitals, 1 to 638 IBRs were performed per year. Large, teaching, urban, and Northeastern hospitals were more likely to have higher IBR volumes. BM rates were significantly higher in patients treated at those hospitals with higher IBR volumes, from 33.1 % at hospitals performing ≥24 IBRs per year to 9.0 % at hospitals without IBR (p < 0.001). Upon adjusted analysis, patients who elected BM were more likely to be seen at hospitals performing ≥24 IBRs per year (odds ratio 1.69 vs. UM, p < 0.001).

Conclusions

In this analysis of national data, BM rates were higher in hospitals where IBR was available, suggesting a significant influence of institutional factors on treatment options for breast cancer patients. Efforts are needed to ensure patients have access to IBR when desired and to better understand the reasons for hospital variation in BM rates.     

Estimation of absolute left ventricular volume from gated radionuclide ventriculograms. A method using phase image assisted automated edge detection and two-dimensional echocardiography

Twenty-four patients underwent gated cardiac blood pool (GBP) imaging, two-dimensional echocardiography (2-D echo), and single-plane contrast ventriculography (within 24 hours). Variable left ventricular (LV) regions of interest on GBP images were identified by an automated threshold radial search. To avoid excluding LV counts we indexed the search threshold to the threshold identified by a phase image generated by Fourier analysis. LV depth calculated by 2-D echo was used for attenuation correction of LV counts. LV end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated by dividing attenuation, background and deadtime corrected LV count rates by the background corrected count rate/ml of venous blood drawn during the study. Correlations between radionuclide and contrast volumes were good (EDV + ESV r = 0.97, EDV r = 0.94, ESV r = 0.95). Regression lines were close to the lines of identity. This method, in which GBP imaging and automated LV edge finding are complemented by 2-D echo for count attenuation correction, demonstrated reliable and reproducible noninvasive estimates of absolute LV volume.     

Native associations of early hematopoietic stem cells and stromal cells isolated in bone marrow cell aggregates

In suspensions of murine bone marrow, many stromal cells are tightly entwined with hematopoietic cells. These cellular aggregations appear to exist normally within the marrow. Previous studies showed that lymphocytes and stem cells adhered to stromal cells via vascular cell adhesion molecule 1 (VCAM1). Injection of anti-VCAM1 antibody into mice disrupts the aggregates, showing the importance of VCAM1 in the adhesion between stromal cells and hematopoietic cells in vivo. Early hematopoietic stem cells were shown to be enriched in aggregates by using a limiting-dilution culture assay. Myeloid progenitors responsive to WEHI-3CM in combination with stem cell factor (c-kit ligand) and B220- B-cell progenitors responsive to insulin-like growth factor-1 in combination with interleukin-7 are not enriched. We propose a scheme of stromal cell-hematopoietic cell interactions based on the cell types selectively retained within the aggregates. The existence of these aggregates as native elements of bone marrow organization presents a novel means to study in vivo stem cell-stromal cell interaction.     

Primary structure of the (1-->3,1-->4)-beta-D-glucan 4-glucohydrolase from barley aleurone

During germination of barley grains, the cell walls of the starchy endosperm are degraded by (1→3,1→4)-β-glucanases (EC 3.2.1.73) secreted from the aleurone and scutellar tissues. The complete sequence of the aleurone (1→3,1→4)-β-glucanase isoenzyme II comprises 306 amino acids and was determined by sequencing nine tryptic peptides (110 residues) and aligning them with the amino acid sequence deduced from a cDNA clone encoding the 291 NH₂-terminal residues. Although no amino acid sequence homology with a bacterial (1→3)(1→4)-β-glucanase is apparent, close to 50% homology is found with two large regions of a (1→3)-β-glucanase from tobacco pith tissue. The gene for barley (1→3,1→4)-β-glucanase isoenzyme II shares with that for the α-amylase isoenzyme 1 a strongly preferred use of codons with G and C in the wobble position (94% and 90%, respectively). Both enzymes are secreted from the aleurone cells during germination. Such one-sided codon usage is not characteristic for the gene encoding the (1→3)-β-glucanase of tobacco pith tissue or the hor2-4 gene encoding the B₁ hordein storage protein in the endosperm.