Androgen Receptor Drives Cellular Senescence

The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor

Baseline renal function, ischaemia time and blood loss predict the rate of renal failure after partial nephrectomy

To identify independent predictors of renal failure after partial nephrectomy (PN) in patients with renal cell carcinoma (RCC). Data were available for 166 patients with pathological T1-3 N0M0 RCC treated with PN. Renal failure after PN was defined as a decrease in glomerular filtration rate (GFR) of > 25% (RIFLE criteria). The GFR before and after PN was estimated using the Modification of Diet in Renal Disease study group equation. Univariable and multivariable logistic regression models were used to assess a decrease of > 25% in GFR from the preoperative level. Candidate predictor variables were age, gender, PN indication (absolute vs relative), preoperative GFR, tumour size, perioperative blood loss, surgery duration and clamping time. After PN, 22 (13.3%) patients had a decrease in GFR of > 25%. The perioperative blood loss (P = 0.02), clamping time (P = 0.04) and preoperative GFR (P = 0.002) were independent predictors of a decrease in GFR of > 25%. We identified two important potentially modifiable variables that should be considered in the planning of PN, i.e. the clamping time and blood loss. It is possible that selective referral to experienced surgeons who can perform PN within short surgical and clamping times, and with minimal blood loss, could minimize the rate of renal failure, especially in patients with an underlying renal function impairment

Patients with renal cell carcinoma nodal metastases can be accurately identified: External validation of a new nomogram

Outcome of patients with renal cell carcinoma nodal metastases (NM) is substantially worse than that of patients with localized disease. This justifies more thorough staging and possibly more aggressive treatment in those at risk of or with established NM. We developed and externally validated a nomogram capable of highly accurately predicting renal cell carcinoma NM in patients without radiographic evidence of distant metastases. Age, symptom classification, tumour size and the pathological nodal stage were available for 4,658 individuals. The data of 2,522 (54.1%) individuals from 7 centers were used to develop a multivariable logistic regression model-based nomogram predicting the individual probability of NM. The remaining data from 2,136 (45.9%) patients from 5 institutions were used for external validation. In the development cohort, 107/2,522 (4.2%) had lymph node metastases vs. 100/2,136 (4.7%) in the external validation cohort. Symptom classification and tumour size were independent predictors of NM in the development cohort. Age failed to reach independent predictor status, but added to discriminant properties of the model. A nomogram based on age, symptom classification and tumour size was 78.4% accurate in predicting the individual probability of NM in the external validation cohort. Our nomogram can contribute to the identification of patients at low risk of NM. This tool can help to risk adjust the need and the extent of nodal staging in patients without known distant metastases. More thorough staging can hopefully better select those in whom adjuvant treatment is necessary