Niall M. Corcoran

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model.

Neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein are a hallmark of Alzheimers disease (AD) and related tauopathies. Tau hyperphosphorylation is thought to promote aggregation with subsequent tangle formation. Reducing tau phosphorylation by boosting the activity of the key phosphatase/s that mediate dephosphorylation of tau could be a viable clinical strategy in AD. One of the key phosphatases implicated in regulating tau protein phosphorylation is the serine-threonine phosphatase PP2A. We have determined that sodium selenate can act as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of either neuroblastoma cells or normal aged mice with sodium selenate rapidly reduced tau protein phosphorylation. Sodium selenate-treated transgenic TAU441 mice had significantly lower levels of phospho- and total tau levels in the hippocampus and amygdala compared with controls and exhibited significantly improved spatial learning and memory on the Morris Water Maze task. Sodium selenate is a specific activator of PP2A with excellent oral bioavailability, and favourable central nervous system penetrating properties. Clinical studies in patients with AD are envisaged in the near future.

Upgrade in Gleason score between prostate biopsies and pathology following radical prostatectomy significantly impacts upon the risk of biochemical recurrence

Study Type – Prognosis (retrospective cohort)

A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma

Study Type – Therapy (systematic review)

Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array

BackgroundThe Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues.ResultsWe comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation.ConclusionsOur method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer.

The impact of multidisciplinary team meetings on patient assessment, management and outcomes in oncology settings: A systematic review of the literature.

BACKGROUND Conducting regular multidisciplinary team (MDT) meetings requires significant investment of time and finances. It is thus important to assess the empirical benefits of such practice. A systematic review was conducted to evaluate the literature regarding the impact of MDT meetings on patient assessment, management and outcomes in oncology settings. METHODS Relevant studies were identified by searching OVID MEDLINE, PsycINFO, and EMBASE databases from 1995 to April 2015, using the keywords: multidisciplinary team meeting* OR multidisciplinary discussion* OR multidisciplinary conference* OR case review meeting* OR multidisciplinary care forum* OR multidisciplinary tumour board* OR case conference* OR case discussion* AND oncology OR cancer. Studies were included if they assessed measurable outcomes, and used a comparison group and/or a pre- and post-test design. RESULTS Twenty-seven articles met inclusion criteria. There was limited evidence for improved survival outcomes of patients discussed at MDT meetings. Between 4% and 45% of patients discussed at MDT meetings experienced changes in diagnostic reports following the meeting. Patients discussed at MDT meetings were more likely to receive more accurate and complete pre-operative staging, and neo-adjuvant/adjuvant treatment. Quality of studies was affected by selection bias and the use of historical cohorts impacted study quality. CONCLUSIONS MDT meetings impact upon patient assessment and management practices. However, there was little evidence indicating that MDT meetings resulted in improvements in clinical outcomes. Future research should assess the impact of MDT meetings on patient satisfaction and quality of life, as well as, rates of cross-referral between disciplines.

Preservation of the Neurovascular Bundles Is Associated with Improved Time to Continence After Radical Prostatectomy But Not Long-term Continence Rates: Results of a Systematic Review and Meta-analysis

CONTEXT The aetiology of urinary incontinence following radical prostatectomy (RP) is incompletely understood. In particular, it is unclear whether there is a relationship between neurovascular bundle (NVB) sparing and post-RP urinary continence. OBJECTIVE To review systematically the association of NVB sparing in RP with postoperative urinary continence outcomes and synthesise the results in a meta-analysis. EVIDENCE ACQUISITION This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. PubMed, Medline, and Cochrane Central Register of Controlled Trials were searched (December 2013), yielding 3413 unique records. A total of 27 longitudinal cohort studies were selected for inclusion. Studies were evaluated using a predefined criteria adapted from the Cochrane Tool to Assess Risk of Bias in Cohort Studies. EVIDENCE SYNTHESIS Data from 13 749 participants in 27 studies were synthesised in a meta-analysis. An assessment of the study methodology revealed a high risk of bias due to differences in baseline characteristics, outcome assessment, and the likely presence of unreported confounding factors such as meticulous apical dissection. Meta-analysis demonstrated that nerve sparing (NS) compared with non-nerve sparing (NNS) resulted in improved early urinary continence rates up to 6 mo postoperatively. Beyond this time, no significant difference was observed. This effect was seen most clearly for bilateral NS compared with NNS. A sensitivity analysis of prospective cohort studies revealed consistent results. CONCLUSIONS This analysis demonstrates an association between NS and improved urinary continence outcomes up to 6 mo postoperatively. NS in men with poor preoperative erectile function should be considered in the context of oncologic risk stratification because it may improve time to continence recovery. The underlying cause of the relationship between NS and continence is unknown. It may represent preservation of the intrapelvic somatic nerves supplying the rhabdosphincter or the influence of other confounding factors. Future research should be directed towards improving understanding of the anatomy of urinary continence and the pathophysiology of post-RP incontinence. PATIENT SUMMARY We found that avoiding damage to the nerves around the prostate improves urinary continence in the first 6 mo after surgery. After this time, there is no difference in continence between men who had these nerves removed and those who had them saved. This finding could be due to a true effect of saving these nerves or to a number of other factors affecting the research.

Adverse effects of androgen-deprivation therapy in prostate cancer and their management

To provide an up‐to‐date summary of current literature on the management of adverse effects of androgen‐deprivation therapy (ADT).

Interleukin‐6: minor player or starring role in the development of hormone‐refractory prostate cancer?

Rational therapeutic design and the clinical evaluation of novel interventions requires a thorough knowledge of the pathogenetic mechanisms underlying the emergence of hormone-refractory disease. At its most basic level, carcinogenesis can be viewed as an imbalance between cell proliferation and cell death. Since the contribution of Huggins and Hodges in 1941 [1], androgens, especially dihydrotestosterone, have been considered the primary mitogenic influence promoting the uncontrolled proliferation of transformed prostatic epithelial cells. In line with this premise, the initial treatment of disseminated disease has been based upon androgen ablation, in the form of either medical or surgical castration. However, after a median of 12–18 months, hormone resistance develops, as detected by biochemical or clinical progression [2]. While quantitative or qualitative changes in the androgen receptor protein which allow signal transduction in the absence of significant levels of circulating androgens have been identified in hormonerefractory prostate cancer, in up to 40% of cases no such changes are identified [3]. This suggests the involvement of other mitogenic signalling pathways in the emergence of androgen independence.

Snail expression is an independent predictor of tumor recurrence in superficial bladder cancers

BACKGROUND Epithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin. OBJECTIVES Our aim was to investigate the role of Snail transcription repressor family members in human bladder pathogenesis. MATERIAL AND METHODS We evaluated levels of Snail and Slug in 87 patients who received transurethral resection of a transitional cell carcinoma at our institution during the period from June 1999 until November 2003. Immunohistochemistry was performed on tissue microarrays, and expression correlated with pathological variables and clinical outcomes. Degree and intensity of Snail and Slug staining was quantified by immunohistochemistry. RESULTS There was no apparent enrichment in strong vs. weak staining for either Snail (43.7% vs. 56.3%) or Slug (46% vs. 54%) in the superficial bladder tumors. Univariate analysis determined that tumor focality and Snail expression were significantly associated with tumor recurrence (P < 0.05). Only for tumor focality did such a relationship exist when assessing tumor progression. Multivariate analysis using the Coxs proportional hazards model revealed similar results to that of the univariate analysis. Snail expression (P = 0.038) and tumor focality (P = 0.011) were independent and significant prognostic factors for tumor recurrence in all patients. However, only tumor focality was an independent predictor of tumor progression (P = 0.034). CONCLUSIONS High expression of Snail in superficial bladder tumors is a strong predictor of tumor recurrence enhancing risk stratification and prognostication.