PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with prostate cancer

Background

Conventional systematic prostate biopsies (SBx) have multiple limitations, and magnetic resonance imaging (MRI)-ultrasound fusion targeting is increasingly applied (fusion biopsies [FBx]). In our previous studies, we have shown that loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in radical prostatectomy (RP) specimens predicts poor disease-specific survival, and in active surveillance (AS), PTEN loss in SBx predicts an adverse AS outcome, although SBx PTEN status does not correlate well with the corresponding RP status. Here, we have hypothesized that PTEN and erythroblast transformation-specific related gene (ERG) status in FBx correlate better with RP than they would in SBx.

Methods

A total of 106 men, who had undergone FBx and subsequent RP in a single center between June 2015 and May 2017 were included. Fifty-three of the men had concomitant or previous SBx's. All biopsy and RP specimens were collected, and tissue microarrays (TMA) were constructed from RP specimens. Immunohistochemical stainings for PTEN and ERG expression were conducted on biopsies and RP TMAs and results were compared by using Fisher's exact test.

Results

The immunohistochemical predictive power of FBx, determined by the concordance of biopsy PTEN and ERG status with RP, is superior to SBx (77.6% vs 66.7% in PTEN, 92.4% vs 66.6% in ERG). FBx was superior to SBx in correlation with RP Gleason Grade Groups and MRI prostate imaging reporting and data system scores.

Conclusion

FBx grading correlates with RP histology and MRI findings and predicts the biomarker status in the RP specimens more accurately than SBx. A longer follow-up is needed to evaluate if this translates to better prediction of disease outcomes, especially in AS and radiation therapy where prostatectomy specimens are not available for prognostication.

     

Relationship Between Certain Radiographic and Biologic Characteristics in Breast Cancer

The relationship between mammographic appearance of micro-calcifications and tumor stage, malignancy grade, estrogen receptor (ER) content and nuclear DNA pattern was studied in 92 mammary carcinomas. The results indicate that no complementary prognostic guidance can be obtained from the radiographic appearance of a tumor apart from a high probability of a spiculated cancer being ER-rich. The finding of a relatively high proportion of aneuploid and ER-poor carcinomas among tumors with microcalcifications indicates that this radiographic characteristic might be associated with increased growth potential.     

Altered synaptic dynamics and hippocampal excitability but normal long-term plasticity in mice lacking hyperpolarizing GABA A receptor-mediated inhibition in CA1 pyramidal neurons

GABA(A) receptor (GABA-AR)-mediated inhibition is critical for proper operation of neuronal networks. Synaptic inhibition either shifts the membrane potential farther away from the action potential firing threshold (hyperpolarizing inhibition) or via increase in the membrane conductance shunts the excitatory currents. However, the relative importance of these different forms of inhibition on the hippocampal function is unclear. To study the functional consequences of the absence of hyperpolarizing inhibition, we have used KCC2-deficient mice (KCC2hy/null) maintaining only 15-20% of the neuron-specific K-Cl-cotransporter. Gramicidin-perforated patch-clamp recordings in hippocampal CA1 pyramidal cells revealed that the reversal potential of the GABA-AR-mediated postsynaptic currents (E(GABA-A)) was approximately 20 mV more positive in KCC2hy/null mice than in wild-type (WT) animals. The basic glutamatergic transmission appeared unaltered in the KCC2hy/null mice, yet they displayed lowered threshold for stimulation-induced synchronous afterdischarges in the CA1 area. Also fatigue of field excitatory postsynaptic potentials/excitatory postsynaptic currents in response to repetitious stimulation was smaller in KCC2hy/null mice, indicating altered synaptic dynamics. Interestingly, this effect was present also under blockade of GABA-ARs and was dependent on the extracellular K+ concentration. Moreover, there were no differences in the levels of either long-term potentiation or long-term depression between the genotypes. The local hippocampal CA1 network can in several aspects maintain its functional viability even in the absence of hyperpolarizing inhibition in pyramidal cells. Our results underscore the central role of shunting type of inhibition in controlling the neuronal excitation/inhibition balance. Moreover, our data demonstrate a novel, unexpected role for the KCC2, namely the modulation of properties of glutamatergic transmission during repetitious afferent activity.     

Evaluating the health benefits and cost-effectiveness of the radon remediation programme in domestic properties in Northamptonshire, UK

Although previous analysis of health benefits and cost-effectiveness of radon remediation in a series of houses in Northamptonshire suggested that testing and remediation was justified, recent results indicate fewer predicted affected houses than previously assumed. Despite numerous awareness campaigns, limited numbers of householders have tested their homes, only a minority of affected householders have remediated, and those most at risk generally fail to remediate. Moreover, a recent survey shows a wide range of public perception of radon risk, not significantly influenced by public health campaigns. These observations impact our previous analysis, which has been reviewed in the light of these observations. Following the declaration of Northamptonshire, UK, as a radon Affected Area in 1992, a series of public awareness campaigns encouraged householders to assess domestic radon levels and, if appropriate, to take action to reduce them. Despite these awareness campaigns, however, only moderate numbers of householders have taken remediatory action. The costs of such remedial work in a series of domestic properties in Northamptonshire, the radon level reduction achieved, and the resultant heath benefit to the residents, have been the subject of study by our group for some years. Previous analysis, based on estimates of the total number of affected houses derived from the National Radiological Protection Board (NRPB) test data for the area, suggested that a programme of testing and remediation in Northamptonshire could be justified. The NRPB has continued to initiate and to collate radon testing, and published further results in 2003. These results include revised predictions of the numbers of affected houses, now considered to be less than the numbers previously assumed. More recently, the availability of the European Community Radon Software (ECRS) has permitted calculation of individual, rather than population-average, risk, demonstrating that those most at risk are generally those who do not take action. In addition, a recent survey of risk perception shows an extremely wide range of public perception of radon risk, a perception that has not been significantly altered by public health campaigns. These predictions have profound effects, both on our previous analysis, particularly since only limited numbers of householders test their homes and even fewer remediate if they discover raised levels, and also on the public health strategies for this risk.     

KCC2-deficient mice show reduced sensitivity to diazepam, but normal alcohol-induced motor impairment, gaboxadol-induced sedation, and neurosteroid-induced hypnosis.

GABA(A) receptors mediate both fast phasic inhibitory postsynaptic potentials and slower tonic extrasynaptic inhibition. Hyperpolarizing phasic GABAergic inhibition requires the activity of neuron-specific chloride-extruding potassium-chloride cotransporter KCC2 in adult CNS. However, the possible role of KCC2 in tonic GABAergic inhibition and the associated behaviors is unknown. Here, we have examined the role of KCC2 in phasic vs tonic GABA inhibition by measuring the behavioral effects of pharmacological agents that presumably enhance phasic vs tonic inhibition in mice that retain 15-20% of normal KCC2 protein levels. These KCC2-deficient mice show decreased sensitivity to diazepam-induced sedation and motor impairment consistent with the reported role for KCC2 in fast hyperpolarizing inhibition. In contrast, the mice exhibit normal responses to low-dose alcohol-induced motor impairment, gaboxadol-induced sedation, and neurosteroid-induced hypnosis; behaviors thought to be associated with tonic GABAergic inhibition. Electrophysiological recordings show that the tonic conductance is not affected. The results suggest that KCC2 activity is more critical for behaviors dependent on phasic than tonic GABAergic inhibition.     

The cost-effectiveness of radon-proof membranes in new homes: a case study from Brixworth, Northamptonshire, UK

Installing radon-proof membranes in new homes can reduce the exposure of those living in the properties to the radiation caused by a build up of radon gas. This paper considers whether doing so is cost-effective for a group of new houses constructed in the village of Brixworth, Northamptonshire, UK. The measure of cost-effectiveness used is cost per quality-adjusted life-year gained. Brixworth is situated in a high-radon area of the UK. As a result, all properties built there must comply with building regulations that require installation of membranes. When compared with a number of medical interventions and a well-established threshold value for cost-effectiveness, the use of membranes in new properties in the village is shown to be cost-effective. This result also pertains when adjustment is made for a number of assumptions adopted in estimating the cost per quality-adjusted life-year gained. The paper concludes with suggestions for future research to establish whether or not the use of membranes in new properties in other areas would be cost-effective.