Delayed blood transfusion is associated with mortality following radical cystectomy

Objectives: To examine the temporal association between blood transfusion and 90-day mortality in patients with bladder cancer treated with radical cystectomy. / Methods: This represents a retrospective cohort study of patients treated with radical cystectomy within the Premier Hospital network between 2003 and 2015. Patients outcomes were stratified those who received early blood transfusion (day of surgery) vs delayed blood transfusion (postoperative day ≥1) during the index admission. Primary end point was 90-day mortality following surgery. / Results: The median age of 12,056 patients identified was 70 years. A total of 7,201 (59.7%) patients received blood transfusion. Within 90 days following surgery, 57 (2.2%), 162 (5.9%) and 123 (6.7%) patients in the early, delayed and both early and delayed transfused patients died respectively. Following multivariate logistic regression to account for patient (age and Charlson Comorbidity Index [CCI]) and hospital (surgeon volume, surgical approach and academic status) factors, delayed blood transfusion was independently associated with 90-day mortality (Odds ratio [OR], 2.64; 95% Confidence Interval [CI], 1.98–3.53; p < 0.001). A sensitivity analysis defining early blood transfusion as <2 days postoperatively, increased 90-day mortality persisted in patients receiving delayed transfusion (OR, 2.20; 95% CI, 1.63-3.00; p < 0.001). Older patients (≥77 years) with the highest CCI (≥2) had a 7% absolute increase in the predicted probability of 90-day mortality if they were transfused late compared to patients transfused early. / Conclusion: Patient undergoing cystectomy may benefit from expedited transfusion to prevent subsequent clinical deterioration which may lead to patient mortality. Future work is needed to elucidate the optimal timing of blood transfusion

Delayed nephrectomy has comparable long-term overall survival to immediate nephrectomy for cT1a renal cell carcinoma: A population-based analysis

Objectives: Early surgical resection remains the recommended treatment option for most small renal mass (≤4 cm). We examined the long-term overall survival (OS) of patients managed with delayed and immediate nephrectomy of cT1a renal cancer. / Patient and methods: We utilized the National Cancer Database (2005–2010) to identify 14,677 patients (immediate nephrectomy: 14,050 patients vs. late nephrectomy: 627 patients) aged 180 days from diagnosis, respectively. Inverse probability of treatment weighting–adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the 2 treatment arms. Influence of patient age and Charlson Comorbidity Index on treatment effect was tested by interactions. Sensitivity analysis was performed to explore the outcome of delaying nephrectomy for >12 months. / Results: Median patient age was 55 years with a median follow-up of 82.5 months. Inverse probability of treatment weighting-adjusted Kaplan-Meier curves suggest no significant difference between treatment arms (immediate nephrectomy [180 days]) (Hazard ratio 0.96; 95% confidence interval 0.73–1.26; P = 0.77). This outcome was consistent between all patients regardless of age (P = 0.48). Sensitivity analysis reports no difference in OS even if nephrectomy was delayed by >12 months (P = 0.60). / Conclusions: We report that delayed and immediate nephrectomy for cT1a renal cell carcinoma confers comparable long-term OS. These findings suggest that a period of observation of between 6 and 12 months is safe to allow identification of renal masses, which will benefit from surgical resection

Ablative therapy for people with localised prostate cancer : a systematic review and economic evaluation

The research reported in this issue of the journal was funded by the HTA programme as project number 10/136/01. The contractual start date was in April 2012. The draft report began editorial review in October 2013 and was accepted for publication in April 2014. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. Acknowledgements We thank l the people recruited from the local UCAN for providing valuable consumer insight and advice through their participation as members of the project focus group: - Mark Emberton (Professor of Interventional Oncology), Damian Greene (consultant urologist), Axel Heidenreich (Professor and Director of Department of Urology), Christoph von Klot (specialist in brachytherapy), Roger Kockelbergh (BAUS chairman and Clinical Director of Urology) and Axel Merserburger (Deputy Clinical Director of Urology and Urologic Oncology) for providing their clinical expertise as members of the project advisory group - Edgar Paez (consultant urologist) and Gill Lawrence (Head of Radiotherapy Physics) for providing a list of staff time by grade and specialty involved in EBRT - Debbie Bennett (Radiotherapy Service Manager) for providing estimates for the expected number of uses for EBRT - Ian Pedley (clinical director/clinical oncologist) and Gill Lawrence for providing a list of all resource inputs relevant to brachytherapy - Steve Locks (Consultant Clinical Scientist in Radiotherapy) for providing a list of reusable equipment and consumables used during brachytherapy, along with their unit costs - Sue Asterling (urology research nurse) and Mark Kelly (Acting Divisional General Manager – Theatres) for providing a list of all resource inputs relevant to cryotherapy - Lara Kemp for providing secretarial support. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health Directorates.Peer reviewedPublisher PD

Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed  = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed  = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression

Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort

BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease

Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort

Background: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach.Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample.Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high-vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade.Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease

Blood lipids and prostate cancer: a Mendelian randomization analysis

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy

Clinical relevance of genetic instability in prostatic cells obtained by prostatic massage in early prostate cancer

We investigated whether genetic lesions such as loss of heterozygosity (LOH) are detected in prostatic cells obtained by prostatic massage during early diagnosis of prostate cancer (CaP) and discussed their clinical relevance. Blood and first urine voided after prostatic massage were collected in 99 patients with total prostate-specific antigen (PSA) between 4 and 10 ng ml−1, prior to prostate biopsies. Presence of prostatic cells was confirmed by quantitative RT–PCR analysis of PSA mRNA. Genomic DNA was analysed for LOH on six chromosomal regions. One or more allelic deletions were found in prostatic fluid from 57 patients analysed, of whom 33 (58%) had CaP. Sensitivity and specificity of LOH detection and PSA free to total ratio <15% for positive biopsy were respectively 86.7 and 44% (P=0.002) for LOH, and 55 and 74% (P=0.006) for PSA ratio <15%. Analysis of LOH obtained from prostatic tumours revealed similar patterns compared to prostatic fluid cells in 86% of cases, confirming its accuracy. The presence of LOH of urinary prostatic cells obtained after prostatic massage is significantly associated with CaP on biopsy and may potentially help to identify a set of patients who are candidates for further prostate biopsies

Positive and Negative Regulation of Prostate Stem Cell Antigen Expression by Yin Yang 1 in Prostate Epithelial Cell Lines

Prostate cancer is influenced by epigenetic modification of genes involved in cancer development and progression. Increased expression of Prostate Stem Cell Antigen (PSCA) is correlated with development of malignant human prostate cancer, while studies in mouse models suggest that decreased PSCA levels promote prostate cancer metastasis. These studies suggest that PSCA has context-dependent functions, and could be differentially regulated during tumor progression. In the present study, we identified the multi-functional transcription factor Yin Yang 1 (YY1) as a modulator of PSCA expression in prostate epithelial cell lines. Increased YY1 levels are observed in prostatic intraepithelial neoplasia (PIN) and advanced disease. We show that androgen-mediated up-regulation of PSCA in prostate epithelial cell lines is dependent on YY1. We identified two direct YY1 binding sites within the PSCA promoter, and showed that the upstream site inhibited, while the downstream site, proximal to the androgen-responsive element, stimulated PSCA promoter activity. Thus, changes in PSCA expression levels in prostate cancer may at least partly be affected by cellular levels of YY1. Our results also suggest multiple roles for YY1 in prostate cancer which may contribute to disease progression by modulation of genes such as PSCA

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10-9) and 3145 (P < 1 × 10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness