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Differences between clinical (cT) and pathological tumor (pT) stage occur often after radical cystectomy (RC) for muscle-invasive bladder cancer. In order to evaluate the impact of downstaging on recurrence and survival, we selected patients from a large, contemporary, population-based series of 1,409 patients with MIBC. We included all patients who underwent RC (N = 643) and excluded patients who received (neo)adjuvant therapy, those with known metastasis at time of diagnosis, and those with nonurothelial cell tumors. Disease outcomes were defined as recurrence-free survival (RFS) and relative survival (RS), as a good approximation of bladder cancer-specific survival. After applying the exclusion criteria, 375 patients were eligible for analysis. Tumor downstaging was found to be common after RC; in 99 patients (26.4%), tumor downstaging to non-muscle-invasive stages at RC occurred. Hydronephrosis at baseline and positive lymph nodes at RC occurred significantly less often in these patients. In 62 patients, no tumor was left in the cystectomy specimen. pT stage was pT1 in 20 patients and pTis in 17 patients. Patients with tumor downstaging have about a 30% higher RFS and RS compared to those without. Consequently, tumor downstaging is a favorable marker for prognosis after RC. [ABSTRACT FROM AUTHOR]

Background: The health-related quality of life (HRQoL) of patients with non-muscle-invasive bladder cancer (NMIBC) may be impaired due to the chronic and burdensome disease course, but longitudinal data are limited., Objective: To evaluate HRQoL outcomes during the first 4 yr after NMIBC diagnosis, and to compare HRQoL across patient characteristics and with a normative population., Design, Setting, and Participants: Patients with NMIBC (n = 1019) were included from the multicentre prospective cohort UroLife. Data were collected at 6 wk (baseline), and 3, 15, and 51 mo after diagnosis. Longitudinal reference data were obtained from an age- and sex-matched normative population (n = 490)., Outcome Measurements and Statistical Analysis: Cancer- and NMIBC-specific HRQoL outcomes (range 0-100) were evaluated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-NMIBC24 questionnaires, respectively. Linear mixed modelling was used to analyse within-group changes and between-group differences., Results and Limitations: The majority of HRQoL outcomes remained stable over time. Observed changes were only of small clinical relevance. Improvements were noted in insomnia, social functioning, and three NMIBC-specific symptoms, while minor deteriorations in appetite and diarrhoea lasted until 51 mo. HRQoL in some domains was worse for high-grade NMIBC, high European Association of Urology (EAU) risk group, initial Bacillus Calmette-Guérin (BCG) treatment, being female, and being younger (<65 yr); yet differences were few, small, and temporary. No differences were observed across recurrence status. Compared with a normative population, clinically relevant worse scores were observed for six of 15 outcomes, which mostly recovered at 51 mo, except for minor symptoms of appetite loss and diarrhoea., Conclusions: No remarkable changes in HRQoL were observed during the first 4 yr after NMIBC diagnosis. Grade, EAU risk group, initial treatment, recurrence, sex, and age did not importantly affect HRQoL. HRQoL was largely comparable with that of the general population, especially after 4 yr., Patient Summary: Quality of life is not largely affected during the first 4 yr after non-muscle-invasive bladder cancer diagnosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs)., Methods: PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a 'Trial within cohorts' studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician., Trial Registration: Ethical board approval has been obtained (2021&#95;218) and the study has been registered at ClinicalTrials.gov (NCT05326620)., Discussion: PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization., (© 2023. The Author(s).)

Background: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology., Objective: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data., Design, Setting, and Participants: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis., Outcome Measurements and Statistical Analyses: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking., Results and Limitations: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10 -8 ) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [p M-I ] = 0.004), 8q21.13 (PAG1; p M-I  = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-I  = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers., Conclusions: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer., Patient Summary: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer., (Published by Elsevier B.V.)

Background: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa)., Methods: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT., Results: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints., Conclusion: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Although the role of lifestyle in health-related quality of life (HRQoL) outcomes has been increasingly recognized for various types of cancer, evidence in patients with non-muscle invasive bladder cancer (NMIBC) is very limited. We aimed to evaluate the longitudinal association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations and HRQoL in patients with NMIBC. This study included 1029 patients with NMIBC recruited between May 2014 and April 2017 from the Dutch multi-centre prospective cohort study UroLife. Lifestyle and HRQoL data were collected at 6 weeks (baseline), 3 months and 15 months after diagnosis. Information on body mass index (BMI), physical activity, diet and alcohol was used to compute the standardized WCRF/AICR adherence score (0-7). HRQoL outcomes were evaluated by the EORTC QLQ-C30. Linear mixed models were used to assess longitudinal confounder-adjusted associations between the WCRF/AICR adherence score and HRQoL outcomes. Adherence to each additional WCRF/AICR recommendation was associated with better global quality of life, physical, role and social functioning, and less fatigue. We found stronger inter-individual than intra-individual associations, suggesting that associations were mainly driven by between-subject differences. Higher adherence to the BMI, physical activity and dietary recommendations was associated with better scores for most HRQoL outcomes, while adherence to the alcohol recommendation (ie, non-consumption) was associated with worse HRQoL. Following the WCRF/AICR lifestyle recommendations may improve HRQoL in patients with NMIBC. Intervention studies are needed to establish whether the association between lifestyle and HRQoL is causal., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Patients with non-muscle invasive bladder cancer (NMIBC) are at a high risk of tumor recurrence. It has not been previously investigated if adherence to cancer prevention recommendations lowers the risk of recurrence., Objectives: We examined whether the standardized lifestyle score measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations was associated with the risk of recurrence and progression among patients with NMIBC., Methods: The study population included patients diagnosed with primary NMIBC between 2014 and 2017 from the prospective cohort UroLife. Lifestyle was assessed at baseline (n = 979; reflecting the prediagnosis period) and 3-mo postdiagnosis (n = 885). The standardized 2018 WCRF/AICR score was constructed based on recommendations for body weight, physical activity, diet, and alcohol intake. We computed multivariable-adjusted HRs and 95% CIs using Cox proportional hazard regression models., Results: During a median follow-up time of 3.7 y, 320 patients developed ≥1 recurrence(s) and 49 experienced progression. Patients in the highest compared with the lowest tertile of postdiagnosis WCRF/AICR scores had a lower risk of first bladder cancer recurrence (HR: 0.74; 95% CI: 0.56, 0.98). No associations were observed for multiple recurrences (HR: 0.90; 95% CI: 0.70, 1.15) or for the baseline score with either first (HR: 1.07; 95% CI: 0.82, 1.40) or multiple recurrences (HR: 1.04; 95% CI: 0.82, 1.31). Improving lifestyle after diagnosis (per 1-point increase) was not significantly associated with the risk of first or multiple recurrence(s) (HR: 0.87; 95% CI: 0.74, 1.02; HR: 0.93; 95% CI: 0.80, 1.08, respectively). No associations were observed for bladder cancer progression, but the power was limited., Conclusions: Better adherence to the WCRF/AICR cancer prevention recommendations 3 mo after NMIBC diagnosis, but not before diagnosis, is associated with a decreased risk of first bladder cancer recurrence. More studies evaluating postdiagnosis lifestyles are needed to provide solid support for lifestyle recommendations for cancer survivors., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed., Objective: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC., Design, Setting, and Participants: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation., Outcome Measurements and Statistical Analysis: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort., Results and Limitations: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10 -8 ), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, p FDR = 0.003). Twelve other loci were suggestively associated with RFS (p < 10 -5 ), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature., Conclusions: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression., Patient Summary: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: A better understanding of the molecular profile of bladder tumours, the identification of novel therapeutic targets, and introduction of new drugs and has renewed research interest in the field of bladder cancer. We describe the design and setup of a Dutch Prospective Bladder Cancer Infrastructure (ProBCI) as a means to stimulate and accelerate clinically meaningful experimental and observational research., Methods and Analysis: ProBCI entails an open cohort of patients with bladder cancer in which the trials within cohorts (TwiCs) design can be embedded. Physicians in participating hospitals prospectively recruit invasive (≥T1) patients with bladder cancer on primary diagnosis for inclusion into the study. Extensive clinical data are collected and updated every 4 months, along with patient-reported outcomes and biomaterials. Informed consent includes participation in TwiCs studies and renewed contact for future studies. Consent for participation in questionnaires and molecular analyses that may yield incidental findings is optional., Ethics and Dissemination: The Dutch ProBCI is a unique effort to construct a nation-wide cohort of patients with bladder cancer including clinical data, patient-reported outcomes and biomaterial, to facilitate observational and experimental research. Data and materials are available for other research groups on request through www.probci.nl. Ethics approval was obtained from METC Utrecht (reference: NL70207.041.19)., Trial Registration Number: NCT04503577., Competing Interests: Competing interests: NM reports grants and personal fees from Merck Sharp & Dohme, Roche, Janssen, AstraZeneca, grants from Sanofi and Pfizer, and personal fees from Astellas Pharma, Bristol-Myers Squibb, and Bayer outside the submitted work. JLB reports personal fees from Merck Sharp & Dohme, Roche and Janssen outside the submitted work. AGvdH reports personal fees from Merck Sharp & Dohme, Roche, Janssen, Sanofi, Ipsen Farmacuetica, Astellas Pharma and MML outside the submitted work. MSvdH reports grants and personal fees from Roche, Bristol-Myers Squibb and AstraZeneca, and personal fees from Merck Sharp & Dohme, Janssen, Astellas Pharma and Seattle Genetics outside the submitted work. AR, KKA, RPM and LAK have nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Timing of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to alternative options and short window of opportunity. Methods : Ra-223 treated patients in the CAPRI-registry were included. Outcomes were evaluated based on treatment line of Ra-223. Results: Out of 285 patients, 49% received Ra-223 in line ≥3. 51% completed six Ra-223 injections and 34% had a symptomatic skeletal event after first Ra-223 without differences between subgroups. After correction of known prognostic factors Ra-223 in line ≥3 (HR: 3.267; 95% CI: 1.689-6.317; p < 0.01) remained associated with worse OS. Conclusion : In the Netherlands, Ra-223 was mainly started as second or third mCRPC-treatment in 2014-2018. Later timing of Ra-223 did affect OS, but not treatment completion and occurrence of symptomatic skeletal events.

Background: Prostate cancer is a common cancer but is oftentimes slow growing. When confined to the prostate, radical prostatectomy (RP), which involves removal of the prostate, offers potential cure that may come at the price of adverse events. Deferred treatment, involving observation and palliative treatment only (watchful waiting (WW)) or close monitoring and delayed local treatment with curative intent as needed in the setting of disease progression (active monitoring (AM)/surveillance (AS)) might be an alternative. This is an update of a Cochrane Review previously published in 2010., Objectives: To assess effects of RP compared with deferred treatment for clinically localised prostate cancer., Search Methods: We searched the Cochrane Library (including CDSR, CENTRAL, DARE, and HTA), MEDLINE, Embase, AMED, Web of Science, LILACS, Scopus, and OpenGrey. Additionally, we searched two trial registries and conference abstracts of three conferences (EAU, AUA, and ASCO) until 3 March 2020., Selection Criteria: We included all randomised controlled trials (RCTs) that compared RP versus deferred treatment in patients with localised prostate cancer, defined as T1-2, N0, M0 prostate cancer., Data Collection and Analysis: Two review authors independently assessed the eligibility of references and extracted data from included studies. The primary outcome was time to death from any cause; secondary outcomes were: time to death from prostate cancer; time to disease progression; time to metastatic disease; quality of life, including urinary and sexual function; and adverse events. We assessed the certainty of evidence per outcome using the GRADE approach.  MAIN RESULTS: We included four studies with 2635 participants (average age between 60 to 70 years). Three multicentre RCTs, from Europe and USA, compared RP with WW (n = 1537), and one compared RP with AM (n = 1098). Radical prostatectomy versus watchful waiting RP probably reduces the risk of death from any cause (hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.70-0.90; 3 studies with 1537 participants; moderate-certainty evidence). Based on overall mortality at 29 years, this corresponds to 764 deaths per 1000 men in the RP group compared to 839 deaths per 1000 men in the WW group. RP probably also lowers the risk of death from prostate cancer (HR 0.57, 95% CI 0.44-0.73; 2 studies with 1426 participants; moderate-certainty evidence). Based on prostate cancer-specific mortality at 29 years, this corresponds to 195 deaths from prostate cancer per 1000 men in the RP group compared with 316 deaths from prostate cancer per 1000 men in the WW group. RP may reduce the risk of progression (HR 0.43, 95% CI 0.35-0.54; 2 studies with 1426 participants; I² = 54%; low-certainty evidence); at 19.5 years, this corresponds to 391 progressions per 1000 men for the RP group compared with 684 progressions per 1000 men for the WW group) and probably reduces the risk of developing metastatic disease (HR 0.56, 95% CI 0.46-0.70; 2 studies with 1426 participants; I² = 0%; moderate-certainty evidence); at 29 years, this corresponds to 271 metastatic diseases per 1000 men for RP compared with 431 metastatic diseases per 1000 men for WW. General quality of life at 12 years' follow-up is probably similar for both groups (risk ratio (RR) 1.0, 95% CI 0.85-1.16; low-certainty evidence), corresponding to 344  patients with high quality of life per 1000 men for the RP group compared with 344 patients with high quality of life per 1000 men for the WW group. Rates of urinary incontinence may be considerably higher (RR 3.97, 95% CI 2.34-6.74; low-certainty evidence), corresponding to 173 incontinent men per 1000 in the RP group compared with 44 incontinent men per 1000 in the WW group, as are rates of erectile dysfunction (RR 2.67, 95% CI 1.63-4.38; low-certainty evidence), corresponding to 389 erectile dysfunction events per 1000 for the RP group compared with 146 erectile dysfunction events per 1000 for the WW group, both at 10 years' follow-up. Radical prostatectomy versus active monitoring Based on one study including 1098 participants with 10 years' follow-up, there are probably no differences between RP and AM in time to death from any cause (HR 0.93, 95% CI 0.65-1.33; moderate-certainty evidence). Based on overall mortality at 10 years, this corresponds to 101 deaths per 1000 men in the RP group compared with 108 deaths per 1000 men in the AM group. Similarly, risk of death from prostate cancer probably is not different between the two groups (HR 0.63, 95% CI 0.21-1.89; moderate-certainty evidence). Based on prostate cancer-specific mortality at 10 years, this corresponds to nine prostate cancer deaths per 1000 men in the RP group compared with 15 prostate cancer deaths per 1000 men in the AM group. RP probably reduces the risk of progression (HR 0.39, 95% CI 0.27-0.56; moderate-certainty evidence; at 10 years, this corresponds to 86 progressions per 1000 men for RP compared with 206 progressions per 1000 men for AM) and the risk of developing metastatic disease (RR 0.39, 95% CI 0.21-0.73; moderate-certainty evidence; at 10 years, this corresponds to 24 metastatic diseases per 1000 men for the RP group compared with 61 metastatic diseases per 1000 men for the AM group).The general quality of life during follow-up was not different between the treatment groups. However, urinary function (mean difference (MD) 8.60 points lower, 95% CI 11.2-6.0 lower) and sexual function (MD 14.9 points lower, 95% CI 18.5-11.3 lower) on the Expanded Prostate Cancer Index Composite-26 (EPIC-26) instrument, were worse in the RP group., Authors' Conclusions: Based on long-term follow-up, RP compared with WW probably results in substantially improved oncological outcomes in men with localised prostate cancer but also markedly increases rates of urinary incontinence and erectile dysfunction. These findings are largely based on men diagnosed before widespread PSA screening, thereby limiting generalisability. Compared to AM, based on follow-up to 10 years, RP probably has similar outcomes with regard to overall and disease-specific survival yet probably reduces the risks of disease progression and metastatic disease. Urinary function and sexual function are probably decreased for the patients treated with RP., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: With the introduction of new therapeutic options, the landscape of metastatic bladder cancer (mBC) management is shifting. We describe current clinical practice and outcomes of mBC patients as a benchmark for translation of developments into clinical practice in the near future., Patients and Methods: Nation-wide population-based cohort study including all patients diagnosed with synchronous metastatic bladder cancer in the Netherlands in 2016-2017, identified through the Netherlands Cancer Registry (NCR). Clinical data on patient and disease characteristics, treatments and survival from the NCR were supplemented with specific information from electronic health records and descriptively analyzed. This study was part of the Prospective Bladder Cancer Infrastructure., Results: Synchronous metastatic bladder cancer was diagnosed in 636 patients in the Netherlands in 2016 and 2017. 35% (221 patients) received systemic treatment, of whom 88 received multiple treatment lines. Most common first-line regimen was carboplatin-based chemotherapy (49%), followed by cisplatin-based chemotherapy (41%) and immunotherapy (8%). Factors associated with systemic treatment were: young age, <2 comorbidities, adequate renal function and performance-status (WHO-0-1/Karnofsky-80-100), urothelial carcinoma and lymph node only metastases. Median overall survival was 4.4 months for the total cohort, and 12.3, 12.9 and 11.1 months for patients treated with first-line immunotherapy, cisplatin-based and carboplatin-based chemotherapy, respectively., Conclusions: Many mBC patients received no systemic treatment or received carboplatin-based chemotherapy, partly because of cisplatin-ineligibility. Observed survival corresponded relatively well with rates reported from trials among chemotherapy-treated patients. These data can serve as a benchmark for future studies evaluating the application of immunotherapy outside a trial setting., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Patients with non-muscle-invasive bladder cancer (NMIBC) have a good survival but are at high risk for tumour recurrence and disease progression. It is important to identify lifestyle habits that may reduce the risk of recurrence and progression and improve health-related quality of life (HRQOL). This paper describes the rationale and design of the UroLife study. The main aim of this study is to evaluate whether lifestyle habits are related to prognosis and HRQOL in patients with NMIBC., Methods and Analysis: The UroLife study is a multicentre prospective cohort study among more than 1100 newly diagnosed patients with NMIBC recruited from 22 hospitals in the Netherlands. At 6 weeks and 3, 15 and 51 months after diagnosis, participants fill out a general questionnaire, and questionnaires about their lifestyle habits and HRQOL. At 3, 15 and 51 months after diagnosis, information about fluid intake and micturition is collected with a 4-day diary. At 3 and 15 months after diagnosis, patients donate blood samples for DNA extraction and (dietary) biomarker analysis. Tumour samples are collected from all patients with T1 disease to assess molecular subtypes. Information about disease characteristics and therapy for the primary tumour and subsequent recurrences is collected from the medical records by the Netherlands Cancer Registry. Statistical analyses will be adjusted for age, gender, tumour characteristics and other known confounders., Ethics and Dissemination: The study protocol has been approved by the Committee for Human Research region Arnhem-Nijmegen (CMO 2013-494). Patients who agree to participate in the study provide written informed consent. The findings from our study will be disseminated through peer-reviewed scientific journals and presentations at (inter)national scientific meetings. Patients will be informed about the progress and results of this study through biannual newsletters and through the website of the study and of the bladder cancer patient association., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A healthy lifestyle may reduce the risk of non-muscle-invasive bladder cancer (NMIBC) recurrence. The objective of this study was to obtain insight in whether NMIBC patients are aware of possible risk factors for (bladder) cancer, adhere to lifestyle recommendations for cancer prevention, received lifestyle advice from their physician, and what their attitudes are towards physicians giving lifestyle advice., Methods: Patients with newly diagnosed NMIBC between 2014 and 2017 participating in the UroLife cohort study completed questionnaires at 6 weeks and 3 months after diagnosis about awareness of (bladder) cancer risk factors, adherence to lifestyle recommendations, reception of lifestyle advice, and attitudes towards physicians giving lifestyle advice., Results: A total of 969 NMIBC patients were included (response rate 46%). Most patients (89%) were aware that smoking is a risk factor for cancer, and knowledge of other risk factors for cancer varied between 29% (low fruit and vegetable consumption) and 67% (overweight). Adherence to cancer prevention recommendations varied between 34% (body weight) and 85% (smoking). Of the smokers, 70% reported they were advised to quit, and 36% quit smoking in the three months before or after diagnosis. Only 21% of all patients indicated they received other lifestyle advice. More than 80% of patients had a positive attitude towards receiving lifestyle advice from their physician., Conclusions: These findings show that awareness of (bladder) cancer risk factors and adherence to cancer prevention lifestyle recommendations among NMIBC patients is low and that physicians' information provision should be improved., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3-4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo- (NAC) or radiotherapy (NAR). A population-based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2-4aN0M0 UC between 1995-2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD-rates were compared using Chi-square tests and OS was estimated by Kaplan-Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD-status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3-4a UC. Median follow-up was 9.2 years. In cT2 UC, pCD-rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3-4a UC, pCD-rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5-year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3-4a UC, 5-year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3-4a UC (HR: 0.67, 95%CI 0.51-0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72-1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3-4a disease., (© 2018 UICC.)

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.

Objective: To explore the relation between cigarette smoking intensity and bladder cancer aggressiveness at first diagnosis., Methods: Patients diagnosed with urinary bladder cancer (BC) between 1995-2011 under the age of 75 years were retrospectively identified from the Netherlands Cancer Registry and invited for a study on genetic and lifestyle risk factors for BC. Information on patients' self-reported smoking history was retrieved by means of a postal questionnaire. Tumors were stratified regarding the risk of progression defined by tumor stage and grade. Multinomial logistic regression was used to analyze the relation between smoking intensity and aggressiveness of the tumor., Results: The UBC study population comprised 323 (17.4%) never smokers, 870 (46.8%) former cigarette smokers, and 630 (33.9%) current cigarette smokers. A higher smoking amount was a risk factor of getting high-risk non-muscle invasive bladder cancer (NMIBC) compared with low-risk NMIBC in ever and former cigarette smokers (OR: 1.02 per cigarette smoked, 95% CI: 1.00-1.03 and OR: 1.03, 95% CI: 1.01-1.05, respectively). A statistically significant dose-response increase in the risk of a more aggressive cancer type (high-risk NMIBC and MIBC) was observed with increasing smoking duration among former smokers (p for trend 0.035 and 0.008, respectively). No significant association of the evaluated smoking intensity variables was observed in current smokers. A longer time of smoking cessation correlated with a lower odds of a more aggressive cancer., Conclusion: We observed a weak increase in the risk of a more aggressive tumor type with increasing smoking intensity in former smokers, but this association was absent in current smokers. This conflicting result may suggest that there is no strong relation between smoking intensity and bladder cancer aggressiveness. Analyses of prospective studies with longitudinal smoking assessment may provide a more definitive answer to the research question.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10 -11 ). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation., Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases., Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015., Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available., Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population., Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation., Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15])., Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Importance: The number of very elderly (≥80 years) is rapidly growing worldwide. Basal cell carcinoma (BCC) are common in this age group and treatment is often challenging in this population., Objective: Obtaining an overview of the epidemiology and clinicopathological features of BCC in the very elderly to guide clinicians and policy makers., Evidence Review: A systematic review of literature was performed using PubMed, Excerpta Medica Database (EMBASE), and the Cochrane Library. Study selection, quality assessment, and data extraction was performed by 2 independent reviewers. For quality assessment (including the risk of bias) the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist was used, combined with the Quality Rating Scheme for Studies and Other Evidence. Data were described though a narrative synthesis and tabulation., Findings: Of 13 628 studies identified, 83 studies were included and quality assesment was performed for 76 studies; 27 studies (representing >350 000 patients) were found that included age-specific incidence rates of BCC in the very elderly. High and increasing incidence rates of BCC in the very elderly were found ranging from 13 to 12 112 per 100 000 person-years, strongly depending on factors like study population and clinical setting. Basal cell carcinoma in the very elderly were more common in men, mostly of the nodular subtype, and located in the head and neck region. Interpretation and generalization of the data was limited by the heterogeneity of study populations, methods, and outcomes. Data concerning impact on health-related quality of life (HRQoL) and prognostication were scarce., Conclusions and Relevance: The incidence of BCC among the very elderly is high and increasing. Epidemiologic and clinicopathological data from current literature provide only limited guidance in clinical decision making owing to heterogeneity and scarcity. Future research should focus more specifically on BCC in the very elderly, together with prognostication and their relation with HRQoL in both the short and longer term.

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study., Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant., Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10 -5 ), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10 -8 ) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants., Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Induction chemotherapy (IC) for clinically node-positive bladder cancer is applied without clinical evidence of improved outcome. Our objective was to compare complete pathological downstaging (pCD) and overall survival (OS) for IC versus upfront radical cystectomy (RC) in cT1-4aN1-3M0 urothelial carcinoma (UC)., Methods: This population-based study included 659 cN+ patients treated with RC between 1995 and 2013. IC was applied in 212 (32%) patients. We defined pCD as ≤(y)pT1N0 at RC. Multivariable analyses were preformed to identify independent predictors of pCD and OS., Results: In cN1 and cN2-3 patients, 31% and 19% of patients proved to be pN0 at upfront RC. In cN1, pCD was achieved in 39% following IC versus 5% for upfront RC (P < 0.001). In cN2-3 UC, rates were 27% versus 3% (P < 0.001). Three-year OS for pCD and ypCD were 81% and 84%, respectively. Three-year OS rates were 66% versus 37% (cN1) and 43% versus 22% (cN2-3), again in favour of IC (P < 0.001). In multivariable analyses, IC was associated with pCD (Odds ratio, 14; 95% confidence interval [CI], 7.4-25) and a 53% decreased risk of death (Hazard ratio [HR], 0.47; 95% CI, 0.36-0.61). Indication bias and unequal distributions of factors associated with OS (e.g. patients proceeding to RC) limit interpretation of our results., Conclusions: Patients with clinical nodal involvement should not be neglected. Up to 1/4 of patients with cN+ disease had pN0 at upfront RC. Moreover, IC followed by RC for clinically node-positive UC was associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial., Take Home Message: IC followed by RC for clinically node-positive UC is associated with improved pathological downstaging compared with RC alone. A potential OS benefit for IC needs to be validated in a randomised trial., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer., Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients., Results: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively)., Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Background: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer., Methods: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases)., Results: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01)., Conclusions: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not., Methods: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium., Results: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10 -10 ). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype., Conclusion: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., (Copyright © 2016 Forschungsgesellschaft für Arbeitsphysiologie und Arbeitschutz e.V. Published by Elsevier B.V. All rights reserved.)

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.)

Purpose: For decades, small renal cancers are treated by radical nephrectomy (RN). Current guidelines recommend partial nephrectomy (PN) to preserve renal function and minimize cardiovascular comorbidity. As adherence to guidelines is largely unknown and international comparison to evaluate quality of health care is lacking, an pre-specified guideline evaluation of quality indicators concerning management of cT1 renal cancers was performed., Methods: We performed a cohort study including patients with cT1 renal cancer between 2010 and 2014, identified through the Netherlands Cancer Registry. Time trends and variation in treatment were described. Factors associated with PN in cT1a and laparoscopic RN in cT1b were evaluated with logistic regression analyses., Results: An increase in nephron-sparing treatment strategies (NSS) of cT1a patients (N total = 2436) was observed; in 2014, 67 % underwent NSS (62 % PN and 5 % thermal ablation). Age, a non-central tumor localization and being treated in a high-volume hospital were associated with PN. Although NSS were applied more frequently over time, the majority (70 %) of cT1b patients (N total = 2205) underwent RN in 2014, mainly performed laparoscopically. Increasing tumor size, tumor localization in the right kidney and being treated in a university hospital were associated with a lower probability of a laparoscopic RN versus open. Treatment in a high-volume hospital was associated with a higher probability of laparoscopic RN., Conclusions: Dutch patients with cT1 renal cancer are predominantly treated according to current guidelines. Data of this pre-specified quality indicator analysis of a urological national guideline may serve as a model for international comparison of treatment of cT1 renal cancers.

Background: The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form of prostate cancer (SPC)., Methods: HPC patients were identified through a national registry of HPC families in the Netherlands, selecting patients diagnosed from the year 2000 onward (n = 324). SPC patients were identified from the Netherlands Cancer Registry (NCR) between 2003 and 2006 for a population-based study into the genetic susceptibility of PC (n = 1,664). Detailed clinical data were collected by NCR-registrars, using a standardized registration form. Follow-up extended up to the end of 2013. Differences between the groups were evaluated by cross-tabulations and tested for statistical significance while accounting for familial dependency of observations by GEE. Differences in progression-free and overall survival were evaluated using χ(2) testing with GEE in a proportional-hazards model., Results: HPC patients were on average 3 years younger at diagnosis, had lower PSA values, lower Gleason scores, and more often locally confined disease. Of the HPC patients, 35% had high-risk disease (NICE-criteria) versus 51% of the SPC patients. HPC patients were less often treated with active surveillance. Kaplan-Meier 5-year progression-free survival after radical prostatectomy was comparable for HPC (78%) and SPC (74%; P = 0.30). The 5-year overall survival was 85% (95%CI 81-89%) for HPC versus 80% (95%CI 78-82%) for SPC (P = 0.03)., Conclusions: HPC has a favorable clinical phenotype but patients more often underwent radical treatment. The major limitation of HPC is the absence of a genetics-based definition of HPC, which may lead to over-diagnosis of PC in men with a family history of prostate cancer. The HPC definition should, therefore, be re-evaluated, aiming at a reduction of over-diagnosis and overtreatment among men with multiple relatives diagnosed with PC. Prostate 76:897-904, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc., (© 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.)

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Background: Data on urinary bladder cancer (UBC) patients' perceptions about causes of bladder cancer is limited, while this may be important knowledge for health prevention and education. We evaluated self-reported perceptions and beliefs about the causes of bladder cancer among UBC survivors in the Netherlands., Methods: UBC survivors identified through the Netherlands Cancer Registry from 2007 to 2012 were invited to participate. Patients who consented were asked to fill out a questionnaire, including questions on lifestyle characteristics, occupational and medical history, and family history of cancer. The final question was 'You have been diagnosed with bladder cancer. Do you have any idea what may have been the cause of your cancer?'., Results: Of the 1793 UBC survivors included, 366 (20%) reported a possible cause for their bladder cancer. The most frequently reported suspected causes were smoking (10%), occupational exposure (5%), and heredity (2%). Smoking, occupational exposure and heredity were mentioned only slightly more frequently by participants with these risk factors (11%, 8%, and 5%, respectively) compared to the total population., Conclusions: Most UBC survivors did not suspect any cause that might have contributed to the development of their cancer. Even among participants with established risk factors for bladder cancer, these risk factors were not commonly perceived. This finding probably reflects the superficial knowledge of risk factors for bladder cancer in the population and highlights the importance of effective education on cancer prevention., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)